CN107325078B - Preparation method of cilostazol - Google Patents

Preparation method of cilostazol Download PDF

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CN107325078B
CN107325078B CN201710581321.9A CN201710581321A CN107325078B CN 107325078 B CN107325078 B CN 107325078B CN 201710581321 A CN201710581321 A CN 201710581321A CN 107325078 B CN107325078 B CN 107325078B
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cilostazol
hydroxy
dihydroquinolin
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CN107325078A (en
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马振堂
乔磊
马志珂
陈龙
孙秋霞
夏晓丽
孙宝佳
易朝辉
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YANTAI WANRUN PHARMACEUTICAL Co Ltd
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    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Abstract

The invention discloses a preparation method of cilostazol, belonging to the technical field of medicines. Which comprises the following steps: step 1: in the presence or absence of a solvent, 4-methoxyaniline reacts with 3-chloropropionyl chloride, after TLC detection reaction is finished, aluminum trichloride is added into the system, and the temperature is raised for reaction for 1-16h to obtain 6-hydroxy-3, 4-dihydroquinolin-2-one; step 2: and (2) in the presence of alkali, heating the 6-hydroxy-3, 4-dihydroquinoline-2-ketone obtained in the step (1) and 5- (4-chlorobutyl) -1-cyclohexyltetrazole in n-propanol for reaction to obtain the cilostazol. The method can obtain high-purity cilostazol, and the whole synthesis route has the advantages of few steps, high yield, low cost and less waste water, and is suitable for industrial production.

Description

Preparation method of cilostazol
Technical Field
The invention relates to a preparation method of cilostazol, belonging to the technical field of medicines.
Background
Cilostazol (Cilostazol) having the following structure:
Figure BDA0001352365100000011
cilostazol is a quinoline derivative, is a novel antiplatelet drug, and is mainly used for treating thrombotic diseases by inhibiting phosphodiesterase activity. Cilostazol tablets are a drug developed by large tsukau corporation of japan, and are approved by tsukau pharmaceutical companies in tianjin in 1996 to be imported from tsukau pharmaceutical companies in china. Cilostazol has attracted more and more attention in the fields of prevention of recurrent stroke, prevention and treatment of restenosis after angioplasty, treatment of diabetes complicated with arterial occlusion of the lower extremities, and treatment of diabetic neuropathy.
Currently, cilostazol is prepared by etherification of 6-hydroxy-3, 4-dihydroquinoline-2-ketone and 5- (4-chlorobutyl) -1-cyclohexyltetrazole, and the difference lies in the difference between the reaction system and (or) the preparation method of the raw materials, and the reaction formula is as follows:
Figure BDA0001352365100000012
the existing process for preparing cilostazol is stated as follows:
1. in the US patent No. 6630590, a mixed solvent of toluene and water is used as a reaction solvent, potassium carbonate is used as alkali for reaction, and because the toluene and water phases have poor mutual solubility and slow reaction, more phase transfer catalysts are required to be added, and the cost is increased.
2. The U.S. Pat. No. 8, 20040024017 uses water as reaction solvent, potassium carbonate as base and tetrabutylammonium chloride as catalyst, but requires a special circulating disperser, which is not suitable for large-scale production.
3. Chinese patent CN101434598 uses ethanol or isopropanol as solvent, but the reaction is slow (>24 h).
The existing method for synthesizing the intermediate 6-hydroxy-3, 4-dihydroquinolin-2-one is stated as follows:
1. the synthesis research of new medicine cilostazol published in the Tang Dynasty, the synthesis of new medicine cilostazol published in the Liuliyan, and the Chinese patent CN105111190 all adopt two-step method to prepare 6-hydroxy-3, 4-dihydroquinoline-2-ketone: p-aminophenol (or p-aminobenzene/diethyl ether) and 3-chloropropionyl chloride are adopted as raw materials to react in acetone to prepare N-substituted-3-chloropropionamide, and after post-treatment, filtration and drying, 6-hydroxy-3, 4-dihydroquinoline-2-ketone is obtained by ring closure under the catalysis of aluminum trichloride. The reaction is as follows:
Figure BDA0001352365100000021
2. chinese patent CN102850270 adopts ionic liquid as solvent and solid acid as catalyst to prepare 6-hydroxy-3, 4-dihydroquinolin-2-one by one-pot method, and has the disadvantages of large dosage of ionic liquid, high price compared with the product, and unsuitability for industrialized production.
3. The Chinese patent CN102816115 adopts gemini surfactant as a catalyst to prepare 6-hydroxy-3, 4-dihydroquinolin-2-one by a one-pot method, and has the defects that the surfactant is self-made by the applicant, the using amount is large, the preparation process is complicated, and the industrial production is not suitable.
In summary, the preparation method of cilostazol in the prior art has the following disadvantages: the industrial production method of the intermediate 6-hydroxy-3, 4-dihydroquinoline-2-ketone mostly adopts a two-step method, the steps are complicated, the yield is low, the synthesis reaction of cilostazol is slow, a phase transfer catalyst is needed, and the production cost is high.
In view of this, there is a need for a novel process for preparing cilostazol.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a preparation method of cilostazol, which has the advantages of cheap and easily available raw materials, simple process and low production cost. The method can obtain high-purity cilostazol, and the whole synthesis route has the advantages of few steps, high yield, low cost and less waste water, and is suitable for industrial production.
The technical scheme for solving the technical problems is as follows: a preparation method of cilostazol comprises the following steps:
step 1: in the presence or absence of a solvent, 4-methoxyaniline and 3-chloropropionyl chloride react, after TLC detection reaction is finished, aluminum trichloride is added into the system, and the temperature is raised for reaction for 1-16h to obtain 6-hydroxy-3, 4-dihydroquinolin-2-one, wherein the molar ratio of the 4-methoxyaniline, the 3-chloropropionyl chloride, the aluminum trichloride and the solvent is 1 (0.9-1.2) to (3-5) to (0-5);
step 2: heating 6-hydroxy-3, 4-dihydroquinolin-2-one obtained in the step (1) and 5- (4-chlorobutyl) -1-cyclohexyltetrazole in n-propanol in the presence of alkali for reaction, wherein the molar ratio of the 6-hydroxy-3, 4-dihydroquinolin-2-one, the 5- (4-chlorobutyl) -1-cyclohexyltetrazole, the alkali and the n-propanol is 1 (0.8-1.2) to (1-1.5): (10-30) to obtain the cilostazol.
The invention takes 4-methoxyaniline and 3-chloropropionyl chloride as raw materials, adopts a one-pot method to synthesize 6-hydroxy-3, 4-dihydroquinolin-2-one, and etherifies the 6-hydroxy-3, 4-dihydroquinolin-2-one and 5- (4-chlorobutyl) -1-cyclohexyltetrazole in the presence of alkali to generate cilostazol.
Among them, TLC (Thin Layer Chromatography) in step 1 is one of Chromatography, which is an experimental technique for rapid separation and qualitative analysis of a small amount of substances, and belongs to solid-liquid adsorption Chromatography.
The reaction formula of the invention is as follows:
Figure BDA0001352365100000041
on the basis of the technical scheme, the invention can be further improved as follows.
Further, in the step 1, the solvent is one of N, N-dimethylformamide, N-dimethylacetamide and dimethylsulfoxide.
The adoption of the further beneficial effects is as follows: the solvent is N, N-dimethylformamide, N-dimethylacetamide or dimethyl sulfoxide, which are dipolar solvents with high boiling points and can promote the reaction.
Further, in the step 1, the temperature of the temperature-raising reaction is 100-250 ℃.
Further, in the step 2, the alkali is one or a mixture of several of sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate.
Further, the alkali is a mixture of sodium hydroxide/potassium hydroxide and sodium carbonate/potassium carbonate according to a molar ratio of 1 (0-0.5).
Further, in the step 2, the temperature of the heating reaction is 50-120 ℃.
The invention has the beneficial effects that:
(1) in the step 1 of the invention, the 6-hydroxy-3, 4-dihydroquinoline-2-ketone is synthesized by adopting a one-pot method, and compared with the prior art, the method has the following advantages: firstly, acylation and ring closure demethylation are combined into one step, so that compared with the prior art, one step of procedure is saved, and the production operation is greatly simplified; secondly, the consumption of solvent and materials is reduced, and the generation and the discharge of three wastes are correspondingly reduced; and thirdly, all the generated intermediates are reacted with aluminum trichloride, and the total yield is improved by about 10 percent (based on the raw material substituted for aniline) compared with other two-step methods in the prior art.
(2) In the step 2 of the invention, n-propanol which is a solvent with low toxicity and three types of solvents with boiling point higher than ethanol and isopropanol by more than 15 ℃ is adopted, so that the reaction speed is higher, and the reaction system is homogeneous without adding a phase transfer catalyst.
(3) The method can obtain high-purity cilostazol, and has the advantages of less steps of the whole synthesis route, high yield, low cost, simple method, wide market prospect and suitability for industrial production.
Drawings
FIG. 1 is an IR spectrum of cilostazol obtained in example 1.
Detailed Description
The principles and features of this invention are described below in conjunction with the following detailed drawings, which are given by way of illustration only and are not intended to limit the scope of the invention.
Example 1
Step 1: adding 61.6g (0.5mol) of 4-methoxyaniline into a 2L three-necked bottle, starting stirring, beginning to dropwise add 63.5g (0.5mol) of 3-chloropropionyl chloride, generating heat along with the reaction, enabling the product to be in a molten state, continuing to stir for 0.5h after the dropwise adding is completed, detecting by TLC (thin layer chromatography), completely converting the raw materials, adding 200.0g (1.5mol) of aluminum trichloride into the system, heating to 150 ℃ after the addition is completed, keeping the temperature for reaction for 2h, completing the TLC detection reaction, stirring and cooling to 60 ℃, slowly adding 1500g of ice water into the system for quenching, separating out the product, filtering, recrystallizing the obtained crude product by 1000mL of ethanol to obtain 69.4g of similar white solid, namely 6-hydroxy-3, 4-dihydroquinolin-2-one, wherein the yield is 85.05%, and the purity is 99.22%.
Step 2: a 1L three-neck flask, which is provided with a mechanical stirrer, a thermometer, an n-propanol liquid seal and a nitrogen protection (15-25mL/min), 32.6g (0.2mol) of 6-hydroxy-3, 4-dihydroquinoline-2-ketone, 46.8g (0.2mol) of 5- (4-chlorobutyl) -1-cyclohexyltetrazole, 12.3g (0.22mol) of potassium hydroxide and 326g of n-propanol (5.42mol) are sequentially added into the three-neck flask, the temperature is raised to 90 ℃, reflux reaction and TLC detection reaction are carried out, and the TLC shows that the reaction is finished after 6 hours, and the reaction is stopped. Cooling to 0 ℃, keeping the temperature for 0.5h, carrying out suction filtration to obtain light yellow solid, wherein the yield is 96.8%, the HPLC purity of the product is 99.3%, adding the crude product into a 2L three-necked bottle, adding 1200mL of methanol, heating for dissolution, carrying out hot filtration, cooling to-10 ℃, crystallizing, filtering, and drying to obtain 66.4g of white crystal, namely cilostazol, and the infrared spectrogram of the cilostazol is shown in figure 1. Yield 90%, purity 99.87%, m.p. 158-.
The above m.p. is a short hand for melting point, i.e. the temperature at which the pure substance is in an equilibrium state between solid and liquid states under a certain pressure.
Example 2
Step 1: adding 61.6g (0.5mol) of 4-methoxyaniline and 175g (2.0mol) of N, N-dimethylacetamide into a 2L three-necked flask, stirring for dissolving, then beginning to dropwise add 63.5g (0.5mol) of 3-chloropropionyl chloride, continuing to stir for 0.5h after dropwise adding is completed, detecting by TLC (thin layer chromatography), completely converting raw materials, adding 333.4g (2.5mol) of aluminum trichloride into the system, heating to 100 ℃, carrying out heat preservation reaction for 1h after the completion of the addition, stirring and cooling to 60 ℃, slowly adding 1500g of ice water into the system for quenching, separating out a product, filtering, and recrystallizing the obtained crude product by 1000mL of ethanol to obtain 69.8g of similar white solid, namely 6-hydroxy-3, 4-dihydroquinoline-2-one, wherein the yield is 85.5%, and the purity is 99.34%.
Step 2: A1L three-neck flask is provided with a mechanical stirrer, a thermometer, an n-propanol liquid seal and a nitrogen protection (15-25mL/min), 32.6g (0.2mol) of 6-hydroxy-3, 4-dihydroquinolin-2-one, 46.8g (0.2mol) of 5- (4-chlorobutyl) -1-cyclohexyltetrazole, 11.2g (0.2mol) of potassium hydroxide, 2.7g of potassium carbonate (0.02mol) and 289g (4.81mol) of n-propanol are sequentially added into the three-neck flask, the temperature is increased to 50 ℃, reflux reaction and TLC detection reaction are carried out, and the TLC shows that the reaction is finished after 8 hours and the reaction is stopped. Cooling to 2 ℃, keeping the temperature for 0.5h, performing suction filtration to obtain light yellow solid, wherein the yield is 95.0%, the HPLC purity of the product is 99.3%, adding the crude product into a 2L three-necked bottle, adding 1200mL of methanol, heating for dissolution, performing heat filtration, cooling to-10 ℃, crystallizing, filtering, and drying to obtain 63.1g of white crystal, namely cilostazol, wherein the yield is 85.5%, the purity is 99.90%, and the m.p. is 158 and 159 ℃.
Example 3
Step 1: adding 61.6g (0.5mol) of 4-methoxyaniline and 150g (2.05mol) of N, N-dimethylformamide into a 2L three-necked bottle, stirring for dissolving, then beginning to dropwise add 63.5g (0.5mol) of 3-chloropropionyl chloride, continuing to stir for 0.5h after dropwise adding is completed, detecting by TLC (thin layer chromatography), completely converting raw materials, adding 333.4g (2.5mol) of aluminum trichloride into the system, heating to 250 ℃, carrying out heat preservation reaction for 1h after the completion of the addition, stirring and cooling to 60 ℃, slowly adding 1500g of ice water into the system for quenching, separating out a product, filtering, recrystallizing the obtained crude product by 1000mL of ethanol to obtain 69.9g of similar white solid, namely 6-hydroxy-3, 4-dihydroquinoline-2-ketone, wherein the yield is 85.7%, and the purity is 99.17%.
Step 2: a 1L three-neck flask, which is provided with a mechanical stirrer, a thermometer, an n-propanol liquid seal and a nitrogen protection (15-25mL/min), 32.6g (0.2mol) of 6-hydroxy-3, 4-dihydroquinolin-2-one, 46.8g (0.2mol) of 5- (4-chlorobutyl) -1-cyclohexyltetrazole, 8.0g (0.2mol) of sodium hydroxide, 2.7g of potassium carbonate (0.02mol) and 360g of n-propanol (6.0mol) are sequentially added into the three-neck flask, the temperature is increased to 120 ℃, reflux reaction and TLC detection reaction are carried out, and the TLC shows that the reaction is finished after 8 hours and stops the reaction. Cooling to 5 ℃, keeping the temperature for 0.5h, performing suction filtration to obtain light yellow solid, wherein the yield is 95.0%, the HPLC purity of the product is 99.3%, adding the crude product into a 2L three-necked bottle, adding 1200mL of methanol, heating for dissolution, performing heat filtration, cooling to-10 ℃, crystallizing, filtering, and drying to obtain 63.1g of white crystal, namely cilostazol, wherein the yield is 85.5%, the purity is 99.87%, and the m.p. is 158 and 159 ℃.
Example 4
Step 1: adding 61.6g (0.5mol) of 4-methoxyaniline and 150g (1.92mol) of dimethyl sulfoxide into a 2L three-necked bottle, stirring for dissolving, then beginning to dropwise add 63.5g (0.5mol) of 3-chloropropionyl chloride, continuing to stir for 0.5h after dropwise adding is completed, detecting by TLC (thin layer chromatography), completely converting raw materials, adding 333.4g (2.5mol) of aluminum trichloride into the system, heating to 150 ℃, keeping the temperature for reaction for 1h, detecting by TLC to be completed, stirring and cooling to 60 ℃, slowly adding 1500g of ice water into the system for quenching, precipitating a product, filtering, recrystallizing the obtained crude product by 1000mL of ethanol to obtain 68.9g of similar white solid, namely 6-hydroxy-3, 4-dihydroquinolin-2-one, wherein the yield is 84.4%, and the purity is 99.17%.
Step 2: a 1L three-neck flask, which is provided with a mechanical stirrer, a thermometer, an n-propanol liquid seal and a nitrogen protection (15-25mL/min), 32.6g (0.2mol) of 6-hydroxy-3, 4-dihydroquinolin-2-one, 46.8g (0.2mol) of 5- (4-chlorobutyl) -1-cyclohexyltetrazole, 11.2g (0.2mol) of potassium hydroxide, 10.6g (0.1mol) of sodium carbonate and 120g (2.0mol) of n-propanol are sequentially added into the three-neck flask, the temperature is increased to 100 ℃, reflux reaction and TLC detection reaction are carried out, and the TLC shows that the reaction is finished after 8 hours and stops the reaction. Cooling to 3 ℃, keeping the temperature for 0.5h, performing suction filtration to obtain light yellow solid, wherein the yield is 95.0%, the HPLC purity of the product is 99.3%, adding the crude product into a 2L three-necked bottle, adding 1200mL of methanol, heating for dissolution, performing heat filtration, cooling to-10 ℃, crystallizing, filtering, and drying to obtain 64.3g of white crystal, namely cilostazol, wherein the yield is 87.1%, the purity is 99.85%, and the m.p. is 158 and 159 ℃.
Comparative experiment 1: synthesis of 6-hydroxy-3, 4-dihydroquinolin-2-one
Step 1: adding 61.6g (0.5mol) of 4-methoxyaniline, 150g (2.58mol) of acetone and 76g (0.55mol) of potassium carbonate into a 1L three-necked bottle, stirring and dissolving, then beginning to dropwise add 63.5g (0.5mol) of 3-chloropropionyl chloride, continuing to stir for 0.5h after dropwise adding is completed, detecting by TLC (thin layer chromatography), completely converting the raw materials, slowly dropwise adding 400mL of 5% hydrochloric acid into the system, cooling to 0 ℃, keeping the temperature and stirring for 1h, filtering, drying a filter cake, and obtaining 95.1g of white-like solid, namely N- (4' -methoxyphenyl) -3-chloropropionamide, wherein the yield is 89.0%.
Step 2: adding 96.1g (0.45mol) of N- (4' -methoxyphenyl) -3-chloropropamide into a 2L three-necked bottle, starting stirring, adding 200.0g (1.5mol) of aluminum trichloride into the system, heating to 150 ℃, carrying out heat preservation reaction for 2h, completing TLC detection reaction, stirring and cooling to 60 ℃, slowly adding 1500g of ice water into the system for quenching, separating out a product, filtering, recrystallizing the obtained crude product with 1000mL of ethanol to obtain 62.4g of white-like solid, namely 6-hydroxy-3, 4-dihydroquinolin-2-one, wherein the yield is 85.0 percent, (the yield is 75.6 percent in terms of 4-methoxyaniline) and the purity is 99.17 percent.
Comparative experiment 2: synthesis of 6-hydroxy-3, 4-dihydroquinolin-2-one
Step 1: adding 61.6g (0.5mol) of 4-methoxyaniline, 150g of toluene and 76g (0.55mol) of potassium carbonate into a 1L three-necked bottle, stirring for dissolving, then beginning to dropwise add 63.5g (0.5mol) of 3-chloropropionyl chloride, continuing to stir for 0.5h after dropwise adding is completed, detecting by TLC (thin layer chromatography), completely converting the raw materials, slowly dropwise adding 400mL of 5% hydrochloric acid into the system, cooling to 0 ℃, keeping the temperature and stirring for 1h, filtering, drying a filter cake, and obtaining 94.3g of white-like solid, namely N- (4' -methoxyphenyl) -3-chloropropionamide with the yield of 88.4%.
Step 2: adding 96.1g (0.45mol) of N- (4' -methoxyphenyl) -3-chloropropionamide and 150g (2.05mol) of N, N-dimethylacetamide into a 2L three-necked bottle, starting stirring, adding 240.0g (1.8mol) of aluminum trichloride into the system, heating to 150 ℃, carrying out heat preservation reaction for 2h after the addition is finished, carrying out TLC detection reaction, stirring and cooling to 60 ℃, slowly adding 1500g of ice water into the system for quenching, separating out a product, filtering, recrystallizing the obtained crude product with 1000mL of ethanol to obtain 63.5g of a white-like solid, namely 6-hydroxy-3, 4-dihydroquinolin-2-one, wherein the yield is 86.5% (the yield is 76.5% by 4-methoxyaniline), and the purity is 99.20%.
Comparative experiment 3: synthesis of cilostazol
A 1L three-neck flask, which is provided with a mechanical stirrer, a thermometer, an ethanol liquid seal and a nitrogen protection (15-25mL/min), 32.6g (0.2mol) of 6-hydroxy-3, 4-dihydroquinolin-2-one, 46.8g (0.2mol) of 5- (4-chlorobutyl) -1-cyclohexyltetrazole, 12.3g (0.22mol) of potassium hydroxide and 326g of ethanol are sequentially added into the three-neck flask, the temperature is raised to 80 ℃, reflux reaction and TLC detection reaction are carried out, and the reaction is stopped after TLC shows that the reaction is finished after 12 h. Cooling to 0 ℃, preserving heat for 0.5h, performing suction filtration to obtain light yellow solid, wherein the yield is 96.8%, the HPLC purity of the product is 99.3%, adding the crude product into a 2L three-necked bottle, adding 1200mL of methanol, heating for dissolution, performing heat filtration, cooling to-10 ℃, crystallizing, filtering, and drying to obtain 66.4g of white crystal, namely cilostazol, wherein the yield is 90% and the purity is 99.88%.
Comparative experiment 4: synthesis of cilostazol
A 1L three-neck flask, which is provided with a mechanical stirrer, a thermometer, an isopropanol liquid seal and a nitrogen protection (15-25mL/min), 32.6g (0.2mol) of 6-hydroxy-3, 4-dihydroquinolin-2-one, 46.8g (0.2mol) of 5- (4-chlorobutyl) -1-cyclohexyltetrazole, 12.3g (0.22mol) of potassium hydroxide and 326g of isopropanol are sequentially added into the three-neck flask, the temperature is raised to 70 ℃, reflux reaction is carried out, TLC detection reaction is carried out, TLC shows that the reaction is finished after 18h, and the reaction is stopped. Cooling to 0 ℃, preserving heat for 0.5h, performing suction filtration to obtain light yellow solid, wherein the yield is 96.8%, the product HPLC purity is 99.3%, adding the crude product into a 2L three-necked bottle, adding 1200mL of methanol, heating for dissolution, performing hot filtration, cooling to-10 ℃, crystallizing, filtering, and drying to obtain 66.0g of white crystal, namely cilostazol, wherein the yield is 89.5%, and the purity is 99.89%.
Conclusion
As can be seen from the above examples 1-4 and comparative experiments 1-4, in terms of the synthesis method of 6-hydroxy-3, 4-dihydroquinolin-2-one, the 6-hydroxy-3, 4-dihydroquinolin-2-one is synthesized by a one-pot method in the examples 1-4 of the present invention, and the acylation and the ring closure demethylation are combined into one step, so that one step is saved. Whereas comparative experiments 1-2 all required two steps. Therefore, the method greatly enlarges the production operation, reduces the consumption of the solvent and the materials, and correspondingly reduces the generation and the discharge of three wastes.
With respect to the yield of 6-hydroxy-3, 4-dihydroquinolin-2-one, the yield of 6-hydroxy-3, 4-dihydroquinolin-2-one obtained in examples 1-4 according to the present invention, based on the starting material substituted aniline, was 84.4% to 85.7%, and the yield of 6-hydroxy-3, 4-dihydroquinolin-2-one obtained in comparative experiment 1-2 was 75.6% to 76.5%. Thus, the yield of the process of the invention is improved by about 10% relative to the control.
For the synthesis of cilostazol, in step 2 of the embodiments 1-3 of the present invention, n-propanol is used for the synthesis of cilostazol, the reaction speed is faster, the reaction system is homogeneous, and no phase transfer catalyst is required. While comparative runs 3-4 used ethanol or isopropanol, the reaction time was relatively long due to the low boiling point of the solvent.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like that fall within the spirit and principle of the present invention are intended to be included therein.

Claims (3)

1. A preparation method of cilostazol is characterized by comprising the following steps:
step 1: in the presence or absence of a solvent, 4-methoxyaniline and 3-chloropropionyl chloride react, after TLC detection reaction is finished, aluminum trichloride is added into the system, and the temperature is raised for reaction for 1-16h to obtain 6-hydroxy-3, 4-dihydroquinolin-2-one, wherein the molar ratio of the 4-methoxyaniline, the 3-chloropropionyl chloride, the aluminum trichloride and the solvent is 1 (0.9-1.2) to (3-5) to (0-5); wherein the solvent is one of N, N-dimethylformamide, N-dimethylacetamide and dimethyl sulfoxide; the temperature of the temperature rise reaction is 100-250 ℃;
step 2: heating 6-hydroxy-3, 4-dihydroquinolin-2-one obtained in the step (1) and 5- (4-chlorobutyl) -1-cyclohexyltetrazole in n-propanol in the presence of alkali for reaction, wherein the molar ratio of the 6-hydroxy-3, 4-dihydroquinolin-2-one, the 5- (4-chlorobutyl) -1-cyclohexyltetrazole, the alkali and the n-propanol is 1 (0.8-1.2) to (1-1.5): (10-30) to obtain the cilostazol.
2. The method for preparing cilostazol as claimed in claim 1, wherein in the step 2, the alkali is one or a mixture of several of sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate.
3. The method for preparing cilostazol as claimed in claim 1, wherein the temperature of said heating reaction in step 2 is 50-120 ℃.
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