HK1196132B - Method for preparing 1-(4-(4-(3,4-dichloro-2-fluorophenylamino)-7-methoxyquinazolin-6-yloxy)piperidin-1-yl)-prop-2-en-1-one hydrochloride and intermediates used therein - Google Patents

Description

Method for preparing 1-(4-(4-(3,4-dichloro-2-fluorophenylamino)-7-methoxyquinazolin-6-yloxy)piperidin-1-yl)-prop-2-en-1-one hydrochloride and intermediates used therein

Technical Field

The present invention relates to an improved process for preparing 1-(4-(4-(3,4-dichloro-2-fluorophenylamino)-7-methoxyquinazolin-6-yloxy)piperidin-1-yl)-prop-2-en-1-one hydrochloride, which selectively and effectively inhibits the growth of cancer cells induced by epidermal growth factor receptor and prevents the development of drug resistance caused by tyrosine kinase mutation, and intermediates used therein.

Background Art

1-(4-(4-(3,4-dichloro-2-fluoroanilino)-7-methoxyquinazolin-6-yloxy)piperidin-1-yl)-prop-2-en-1-one hydrochloride of the following formula (I) is an important drug having anti-malignant cell proliferative activity (e.g., anti-tumor activity) and can be used to selectively and effectively treat drug resistance caused by tyrosine kinase mutations. Its free base form, i.e., 1-(4-(4-(3,4-dichloro-2-fluoroanilino)-7-methoxyquinazolin-6-yloxy)piperidin-1-yl)-prop-2-en-1-one having the following formula (II), is identified as CAS Registry No. 1092364-38-9.

For example, the compound of formula (II) is prepared by the method disclosed in Korean Patent No. 1013319, and its reaction mechanism is shown in the following Reaction Scheme 1. Then, the compound of formula (II) prepared according to Reaction Scheme 1 can be reacted with hydrochloric acid to produce the compound of formula (I).

<Reaction Scheme 1>

wherein R is a halogen.

In Reaction Scheme 1, the compound of Formula 10 is subjected to a condensation reaction with formamidine hydrochloride at an elevated temperature (e.g., 210° C.) to produce a compound of Formula 9, which is then reacted with L-methionine in an organic acid (e.g., methanesulfonic acid) to remove the methyl group at the C-6 position of the compound of Formula 9 to produce a compound of Formula 8.

Subsequently, the compound of Formula 8 is subjected to a protection reaction in a base (e.g., piperidine) and anhydrous acetic acid to produce a compound of Formula 7, and then reacted with an inorganic acid (e.g., thionyl chloride or phosphorus oxychloride) in the presence of a catalytic amount of N,N-dimethylformamide under reflux conditions to produce a compound of Formula 6 in the form of a hydrochloride salt.

Under stirring, the compound of formula 6 is added to an ammoniacal alcohol solution (e.g., 7N ammoniacal methanol solution) to remove the acetyl group to produce a compound of formula 5. The compound of formula 5 is subjected to a Mitsunobu reaction with tert-butyl 4-hydroxypiperidine-1-carboxylate to produce a compound of formula 4, and then, in an organic solvent (e.g., 2-propanol or acetonitrile), it is subjected to a substitution reaction with aniline to produce a compound of formula 3. Diisopropyl azodicarboxylate, diethyl azodicarboxylate or di-tert-butyl azodicarboxylate and triphenylphosphine can be used for the Mitsunobu reaction. In an organic solvent (e.g., dichloromethane), the compound of formula 3 is reacted with an organic or inorganic acid (e.g., trifluoroacetic acid or heavy hydrochloric acid) to remove the tert-butyl carbonyl group to produce a compound of formula 2.

Subsequently, to produce the compound of Formula 1 (i.e., the compound of Formula (II) of the present invention), the compound of Formula 2 is subjected to an acylation reaction with acryloyl chloride in the presence of an inorganic or organic base (e.g., sodium bicarbonate, pyridine, or triethylamine) in a mixture of an organic solvent (e.g., tetrahydrofuran) and water, or in dichloromethane. Alternatively, the compound of Formula 2 is subjected to a condensation reaction with acrylic acid in the presence of a coupling agent (e.g., 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) or 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU)).

However, according to the above method, the step for preparing the compound of Formula 9 is dangerous because it is carried out at high temperature without a solvent, and the reaction does not occur uniformly. Furthermore, excessive thionyl chloride is used in the step for preparing the compound of Formula 5, causing difficulties in the subsequent steps. Therefore, this method is not feasible for commercialization.

The main drawbacks of the above-described method for preparing the compound of formula (I) are that the yield of the final product in the acrylic acid reaction is very low (i.e., 13%), and the reaction is accompanied by numerous side reactions, which require a purification step by column chromatography. Similarly, when the compound of formula 3 is prepared by the Mitsunobu reaction, a variety of side products are formed, which require a purification step by column chromatography. Because of the expensive silica gel and excessive mobile phase solvent required in such cases, the above-described method is not feasible for commercialization.

Therefore, the inventors have endeavored to develop a novel process for preparing the compound of formula (I) in high purity and high yield, which process is economical and suitable for commercialization.

Summary of the Invention

Therefore, it is an object of the present invention to provide a process for preparing 1-(4-(4-(3,4-dichloro-2-fluoroanilino)-7-methoxyquinazolin-6-yloxy)piperidin-1-yl)-prop-2-en-1-one hydrochloride.

Another object of the present invention is to provide an intermediate used in the preparation of 1-(4-(4-(3,4-dichloro-2-fluorophenylamino)-7-methoxyquinazolin-6-yloxy)piperidin-1-yl)-prop-2-en-1-one hydrochloride.

According to one aspect of the present invention, there is provided a method for preparing 1-(4-(4-(3,4-dichloro-2-fluorophenylamino)-7-methoxyquinazolin-6-yloxy)piperidin-1-yl)-prop-2-en-1-one hydrochloride of formula (I), comprising the following steps:

(1) reacting a compound of formula (VIII) with a halogenating agent in the presence of an organic base, and then reacting with a compound of formula (X) to produce a compound of formula (VI);

(2) reacting the compound of formula (VI) with an ammonia solution in a polar protic solvent to produce a compound of formula (V);

(3) reacting a compound of formula (V) with a compound of formula (IX) in an inert polar protic solvent in the presence of a base to produce a compound of formula (IV);

(4) reacting the compound of formula (IV) with hydrochloric acid in an inert solvent to produce the compound of formula (III);

(5) subjecting the compound of formula (III) to an acrylation reaction with (wherein X is a halogen) in the presence of a base to produce a compound of formula (II); and

(6) reacting the compound of formula (II) with hydrochloric acid to produce the compound of formula (I):

According to another aspect of the present invention, provided are N-(3,4-dichloro-2-fluorophenyl)-7-methoxy-6-(piperidin-4-yloxy)quinazolin-4-amine dihydrochloride of formula (III), tert-butyl 4-(4-(3,4-dichloro-2-fluorophenylamino)-7-methoxyquinazolin-6-yloxy)piperidine-1-carboxylate of formula (IV) and 4-(3,4-dichloro-2-fluorophenylamino)-7-methoxyquinazolin-6-ol of formula (V), which can be used as intermediates for preparing compounds of formula (I).

DETAILED DESCRIPTION

The present method can be carried out as shown in the following reaction schemes 2 to 6. Steps (1) and (2) of the present method can be carried out according to reaction scheme 2:

<Reaction Scheme 2>

In step (1), a compound of formula (VIII) as a starting material is reacted with a halogenating agent in the presence of an organic base in a solvent such as toluene or benzene, and then reacted with a compound of formula (X) to produce 4-(3,4-dichloro-2-fluorophenylamino)-7-methoxyquinazolin-6-yl acetate of formula (VI).

The compound of formula (VIII) can be prepared by the method disclosed in Korean Patent No. 1013319.

The organic base used in step (1) of the present method can be selected from the group consisting of diisopropylamine, triethylamine, diisopropylethylamine, diethylamine, pyridine, morpholine and mixtures thereof; and the halogenating agent can be selected from the group consisting of thionyl chloride, phosphorusoxy chloride and mixtures thereof.

The reaction can be carried out at a temperature of 50°C to 150°C, preferably 60°C to 90°C, and more preferably about 75°C. Due to the reaction with the halogenating agent, the compound of formula (VII) may be prepared as being contained in an organic solvent and cannot be easily isolated. Subsequently, the compound of formula (VII) contained in the organic solvent is reacted with the compound of formula (X) to produce 4-(3,4-dichloro-2-fluorophenylamino)-7-methoxyquinazolin-6-yl acetate of formula (VI).

In step (2), the compound of formula (VI) prepared in step (1) is reacted with ammonia solution or ammonia gas at a temperature of 0°C to 40°C, preferably 10°C to 30°C, more preferably about 25°C in a polar protic solvent (e.g., methanol, ethanol and propanol) to produce 4-(3,4-dichloro-2-fluorophenylamino)-7-methoxyquinazolin-6-ol of formula (V).

In step (3), as illustrated in Reaction Scheme 3, a compound of formula (V) is reacted with tert-butyl 4-(tosyloxy)piperidine-1-carboxylate of formula (IX) in the presence of a base in an inert polar protic solvent to produce tert-butyl 4-(4-(3,4-dichloro-2-fluoroanilino)-7-methoxyquinazolin-6-yloxy)piperidine-1-carboxylate of formula (IV).

<Reaction Scheme 3>

The inert polar protic solvent used in step (3) of the present method can be selected from the group consisting of N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidin-2-one, dimethyl sulfoxide and mixtures thereof. The base can be an alkali metal carbonate selected from the group consisting of sodium bicarbonate, potassium carbonate, cesium carbonate and mixtures thereof. The base is used in an amount of 1 to 5 molar equivalents based on 1 molar equivalent of the compound of formula (V). The reaction can be carried out at a temperature of 60°C to 100°C, preferably 70°C to 90°C, and more preferably about 80°C.

According to one embodiment of the present invention, the compound of formula (IV) can be prepared in high purity and high yield by simple recrystallization _{from K₂CO₃} in step (3) of the present method. In contrast, the conventional method disclosed in Korean Patent No. 1013319 requires the use of expensive diisopropyl azodicarboxylate (DIAD) as a primary reagent and requires column chromatography to purify the product. Therefore, compared to the present method, the conventional method is not only uneconomical but also inefficient in terms of yield and purity (see Table 1).

<Table 1>

*Prices are based on Aldrich brochures (2009-2010)

In step (4), the compound of formula (IV) is reacted with hydrochloric acid in an inert solvent as described in Reaction Scheme 4 to produce N-(3,4-dichloro-2-fluorophenyl)-7-methoxy-6-(piperidin-4-yloxy)quinazolin-4-amine dihydrochloride of formula (III).

<Reaction Scheme 4>

The inert solvent used in step (4) of the present method can be selected from the group consisting of methanol, ethanol, propanol, ethyl acetate, methyl acetate, acetone, and mixtures thereof. Hydrochloric acid can be used in an amount of 3 to 10 molar equivalents based on 1 molar equivalent of the compound of formula (IV). The reaction can be carried out at a temperature of 0°C to 60°C, preferably 10°C to 40°C, and more preferably about 25°C, with stirring for 1 to 24 hours.

In step 5, as shown in Reaction Scheme 5, the compound of formula (III) is subjected to an acylation reaction with (wherein X is a halogen), for example, acryloyl chloride, in the presence of a base to produce 1-(4-(4-(3,4-dichloro-2-fluorophenylamino)-7-methoxyquinazolin-6-yloxy)piperidin-1-yl)prop-2-en-1-one of formula (II).

<Reaction Scheme 5>

Step (5) of the present method can be carried out in an organic solvent such as tetrahydrofuran, ethyl acetate, acetone, 1,4-dioxane, acetonitrile, dichloromethane, carbon tetrachloride, chloroform, N,N-dimethylformamide or dimethyl sulfoxide, or a mixture of the organic solvent and water. Preferably, the step (5) is carried out in a mixture of an organic solvent selected from the group consisting of tetrahydrofuran, ethyl acetate, acetone, 1,4-dioxane and acetonitrile and water.

The base used in step (5) can be selected from the group consisting of an inorganic base such as sodium carbonate, calcium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide or cesium carbonate, or an organic base such as diisopropylamine, triethylamine, diisopropylethylamine or diethylamine. In this reaction, the base can be used in an amount of 3 to 5 molar equivalents based on 1 molar equivalent of the compound of formula (III). The reaction can be carried out at a temperature of -30°C to 20°C, preferably about 0°C, with stirring for 20 minutes to 3 hours.

When the reaction is completed, the resulting mixture is recrystallized with an acetone aqueous solution in an amount of 15 to 30 (w/v) times based on the amount of the compound of formula (III).

According to one embodiment of the present invention, the compound of formula (II) can be prepared with high purity and yield by simple recrystallization in step (5) of the present method. Meanwhile, according to the conventional method disclosed in Korean Patent No. 1013319, it requires purification of the product by column chromatography. Therefore, in terms of yield and purity, the conventional method is ineffective compared to the present method (see Table 2).

<Table 2>

In step (6), as shown in Reaction Scheme 6, the compound of formula (II) is reacted with hydrochloric acid in an organic solvent to produce 1-(4-(4-(3,4-dichloro-2-fluorophenylamino)-7-methoxyquinazolin-6-yloxy)piperidin-1-yl)prop-2-en-1-one hydrochloride of formula (I).

<Reaction Scheme 6>

The organic solvent used in step (6) of the present method can be selected from the group consisting of methanol, ethanol, propanol, isopropanol, butanol, ethyl acetate, acetone, tetrahydrofuran, acetonitrile, 1,4-dioxane, and mixtures thereof. The reaction can be carried out at a temperature of 0°C to 60°C, preferably 10°C to 40°C, and more preferably about 25°C.

According to the present invention, there are provided novel compounds such as N-(3,4-dichloro-2-fluorophenyl)-7-methoxy-6-(piperidin-4-yloxy)quinazolin-4-amine dihydrochloride of formula (III), tert-butyl 4-(4-(3,4-dichloro-2-fluorophenylamino)-7-methoxyquinazolin-6-yloxy)piperidine-1-carboxylate of formula (IV) and 4-(3,4-dichloro-2-fluorophenylamino)-7-methoxyquinazolin-6-ol of formula (V), which are key intermediates used in the present method. These compounds can be used to prepare 1-(4-(4-(3,4-dichloro-2-fluorophenylamino)-7-methoxyquinazolin-6-yloxy)piperidin-1-yl)prop-2-en-1-one hydrochloride of formula (I), which selectively and effectively inhibits the growth of cancer cells induced by epidermal growth factor receptor and prevents the development of drug resistance caused by tyrosine kinase mutations.

According to the present invention, compounds of formula (I) and (II) can be prepared in high yields by a simple and low-cost method. According to this method, the compound of formula (VIII) can be simply converted into the compound of formula (VI) in situ, and the compound of formula (V) can be produced without any special purification steps. Similarly, the traditional method for preparing the compound of formula (II), (III) and (IV) requires additional purification or extraction steps by column chromatography, which makes its commercialization less feasible. However, the present method makes it possible to produce a high-purity and high-yield final product by adding a solvent to the reaction mixture to produce a solid phase product and recrystallizing and filtering the product.

The following examples are intended to further illustrate the present invention without limiting its scope.

Example 1: Preparation of 4-(3,4-dichloro-2-fluorophenylamino)-7-methoxyquinazolin-6-yl acetate (compound of formula (VI))

7-Methoxy-4-oxo-3,4-dihydroquinazolin-yl acetate (100 g) was added to toluene (850 ml) and N,N-diisopropylethylamine (82.5 ml). Phosphorus oxychloride (100 ml) was added thereto at 75° C. over 20 minutes, followed by stirring for 3 hours. Toluene (450 ml) and 3,4-dichloro-2-fluoroaniline (84.6 g) were added to the resulting mixture, followed by stirring for 2 hours. When the reaction was complete, the resulting mixture was cooled to 25° C. The solid thus obtained was filtered under reduced pressure and washed with toluene (400 ml). Isopropyl alcohol (1000 ml) was added to the solid, which was then stirred for 2 hours. The resulting solid was filtered and washed with isopropyl alcohol (400 ml). The solid was dried in an oven at 40° C. to produce a compound of formula (VI) (143 g, yield: 83%).

¹ H-NMR (DMSO-d6, 300MHz, ppm) δ8.92 (s, 1H), 8.76 (s, 1H), 7.69-7.57 (m, 3H), 4.01 (s, 3H), 2.38 (s, 3H).

Example 2: Preparation of 4-(3,4-dichloro-2-fluorophenylamino)-7-methoxyquinazolin-6-ol (compound of formula (V))

4-(3,4-Dichloro-2-fluorophenylamino)-7-methoxyquinazolin-6-yl acetate (100 g) was mixed with methanol (1000 ml). The mixture was cooled to 10 to 15°C, and aqueous ammonia solution (460 g) was added and stirred at 25°C for 3 hours. The resulting solid was filtered and washed with a mixed solvent of methanol (200 ml) and water (200 ml). The resulting solid was dried in an oven at 40°C to produce the compound of formula (V) (74 g, yield: 83%).

¹ H-NMR (DMSO-d6, 300MHz, ppm) δ9.57 (br, 2H), 8.35 (s, 1H), 7.68 (s, 1H), 7.61-7.52 (m, 2H), 7.21 (s, 1H), 3.97 (s, 3H).

Example 3: Preparation of tert-butyl-4-(4-(3,4-dichloro-2-fluorophenylamino)-7-methoxyquinazolin-6-yloxy)piperidine-1-carboxylate (compound of formula (IV))

Under stirring, 4-(3,4-dichloro-2-fluorophenylamino)-7-methoxyquinazoline-6-ol (60g) is mixed with N-dimethylformamide (360ml), and then tert-butyl 4-(tosyloxy) piperidine-1-carboxylate (120g) and potassium carbonate (72g) are added to the mixture. The reaction temperature is raised to 70°C, and the mixture is stirred for 14 hours. The temperature of the solution obtained is cooled to 25°C, and water (480ml) is slowly added thereto. The solid thus obtained is filtered and dried. The solid is dissolved in a mixed solvent of dichloromethane and methanol (600ml). Then, activated carbon (6g) is added thereto, and then stirred for 30 minutes. The mixture obtained is filtered through a diatomaceous earth plate (Celite pad), distilled under reduced pressure, acetone (300ml) is added, and stirred for 2 hours. The solid obtained is filtered and washed with acetone (100ml). The solid was dried in an oven at 40°C to produce the compound of formula (IV) (75 g, yield: 83%).

¹ H-NMR(DMSO-d6,300MHz,ppm)δ8.69(s,1H),8.47(t,1H), 7.34-7.29(m,2H),7.20(s,1H),4.63-4.60(m,1H),3.82(s,3H),3.83-3.76(m, 2H),3.37-3.29(m,2H),1.99-1.96(m,2H),1.90-1.84(m,2H),1.48(s,9H).

Example 4: Preparation of N-(3,4-dichloro-2-fluorophenyl)-7-methoxy-6-(piperidin-4-yloxy)quinazolin-4-amine dihydrochloride (compound of formula (III))

Acetone (740 ml) was added to tert-butyl 4-(4-(3,4-dichloro-2-fluorophenylamino)-7-methoxyquinazolin-6-yloxy)piperidine-1-carboxylate (75 g), which was then stirred. Hydrochloric acid (145 ml) was added to the mixture over 10 minutes, and the mixture was stirred for 5 hours. When the reaction was complete, the resulting mixture was filtered, and the solid obtained was washed with acetone (73 ml). The solid was dried in an oven at 30°C to produce the compound of formula (III) (71 g, yield: 99%).

¹ H-NMR(DMSO-d ₆ ,300MHz,ppm)δ12.95(bs,1H),9.42(bs,1H), 9.18(bs,1H),9.01(s,1H),8.86(s,1H),7.69-7.56(m,2H),7.45(s,1H), 5.11-5.08(m,1H),4.03(s,3H),3.29-3.20(m,4H),2.33-2.30(m,2H), 1.96-1.93(m,2H).

Example 5: Preparation of 1-(4-(4-(3,4-dichloro-2-fluorophenylamino)-7-methoxyquinazolin-6-yloxy)piperidin-1-yl)prop-2-en-1-one (compound of formula (II))

N-(3,4-dichloro-2-fluorophenyl)-7-methoxy-6-(piperidin-4-oxy)quinazolin-4-amine dihydrochloride (100 g) and sodium bicarbonate (66 g) were added to a mixed solvent of tetrahydrofuran (630 ml) and water (1 L), and the temperature of the reaction mixture was cooled to 0°C with ice water. Acryloyl chloride (24 ml) diluted with tetrahydrofuran (370 ml) was slowly added to the reaction mixture over 30 minutes, followed by stirring at 0°C for 30 minutes. When the reaction was complete, aqueous acetone (2.0 L) was added to the resulting mixture, which was stirred for 12 hours and filtered to produce 1-(4-(4-(3,4-dichloro-2-fluorophenylamino)-7-methoxyquinazolin-6-yloxy)piperidin-1-yl)prop-2-en-1-one (72 g, yield: 75%). The solid thus obtained was dissolved in a mixed solvent of dichloromethane (200 ml) and methanol (100 ml), ethyl acetate (1.2 L) was added, and the mixture was stirred for 12 hours. The resulting solid was filtered and washed with ethyl acetate (100 ml). The solid was dried in an oven at 40°C to produce the compound of formula (II) (55 g, yield: 76%, total yield = 57%).

¹ H-NMR(CDCl3,300MHz,ppm)δ8.68(s,1H),8.39(t,3H),7.31(m,3H),6.61(m,1H),6.29(m,1H),5.72(m,1H),4.75(m,1H),4.02(s,3H),3.89(m, 2H),3.60(m,2H),1.86(m,4H).

Example 6: Preparation of 1-(4-(4-(3,4-dichloro-2-fluorophenylamino)-7-methoxyquinazolin-6-yloxy)piperidin-1-yl)prop-2-en-1-one hydrochloride (compound of formula (I))

1-(4-(4-(3,4-dichloro-2-fluorophenylamino)-7-methoxyquinazolin-6-yloxy)piperidin-1-yl)prop-2-en-1-one (150 g) was added to methanol (700 ml). Hydrochloric acid (38.2 ml) diluted with methanol (300 ml) was added thereto, followed by stirring for 24 hours. The solid thus obtained was filtered and washed with acetone (100 ml). The resulting solid was dried in an oven at 40°C for 24 hours to produce the compound of formula (I) (131 g, yield: 81%).

¹ H-NMR(DMSO-d6,300MHz,ppm)δ12.31(bs,1H),8.83(s,1H),8.67(s,1H),7.64-7.55(m,2H),7.39(s,1H),6.87-6.78(m,1H),6.12-6.06(m,1H), 5.68-5.64(m,1H),5.07-5.01(m,1H),4.06-3.88(m,5H),3.51(t,1H),3.32(t,1H),2.10(t,1H),1.60(t,1H).

Although the present invention has been described with respect to the above specific embodiments, it will be appreciated that numerous modifications and variations may be made by those skilled in the art which fall within the scope of the present invention as defined by the appended claims.

Claims (7)

1. A method for preparing 1-(4-(4-(3,4-dichloro-2-fluorophenylamino)-7-methoxyquinazoline-6-yloxy)piperidin-1-yl)-prop-2-en-1-one hydrochloride of formula (I), the method comprising the following steps: (1) The compound of formula (VIII) is reacted with phosphorus oxychloride in the presence of an organic base to produce the compound of formula (VII), and then reacted in situ with the compound of formula (X) without separating the compound of formula (VII) to produce the compound of formula (VI). (2) React the compound of formula (VI) with an ammonia solution in a polar protic solvent to produce the compound of formula (V); (3) In the presence of a base, the compound of formula (V) is reacted with the compound of formula (IX) in a polar aprotic solvent to produce the compound of formula (Ⅳ); (4) React the compound of formula (Ⅳ) with hydrochloric acid in an inert solvent to produce the compound of formula (Ⅲ); (5) In the presence of a base, the compound of formula (III) is subjected to an acrylation reaction to produce the compound of formula (II), wherein X is a halogen; and (6) React the compound of formula (II) with hydrochloric acid to produce the compound of formula (I): The polar aprotic solvent in step (3) is selected from the group consisting of N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone-2-one, dimethyl sulfoxide and mixtures thereof; Wherein, the alkali in step (3) is an alkali metal carbonate selected from the group consisting of sodium bicarbonate, potassium carbonate, cesium carbonate and mixtures thereof; Wherein, the base in step (3) is used in an amount of 1 to 5 molar equivalents based on the compound of formula (V); Step (3) further includes recrystallizing the compound of formula (Ⅳ) with acetone; Step (5) is carried out in an organic solvent selected from the group consisting of tetrahydrofuran, ethyl acetate, acetone, 1,4-dioxane, acetonitrile, dichloromethane, carbon tetrachloride, chloroform, N,N-dimethylformamide and dimethyl sulfoxide, or in a mixture of the organic solvent and water. In step (5), the alkali is selected from the group consisting of sodium carbonate, calcium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, cesium carbonate, diisopropylamine, triethylamine, diisopropylethylamine and diethylamine; The base described in step (5) is used in an amount of 3 to 5 molar equivalents based on the compound of formula (III) in 1 molar equivalent. Step (5) further includes crystallizing the compound of formula (II) with an aqueous solution of acetone in an amount of 15 to 30 (ml/g) times the amount of the compound of formula (III). 2. The method according to claim 1, wherein step (1) is carried out in a solvent selected from the group consisting of toluene, benzene and mixtures thereof. 3. The method according to claim 1, wherein the organic base in step (1) is selected from the group consisting of diisopropylamine, triethylamine, diisopropylethylamine, diethylamine, pyridine, morpholine and mixtures thereof. 4. The method according to claim 1, wherein the polar protic solvent in step (2) is selected from the group consisting of methanol, ethanol, propanol and mixtures thereof. 5. The method according to claim 1, wherein the inert solvent in step (4) is selected from the group consisting of methanol, ethanol, propanol, ethyl acetate, methyl acetate, acetone and mixtures thereof. 6. The method according to claim 1, wherein the hydrochloric acid in step (4) is used in an amount of 3 to 10 molar equivalents based on 1 molar equivalent of the compound of formula (IV). 7. The method according to claim 1, wherein step (6) is carried out in an organic solvent comprising the group consisting of methanol, ethanol, propanol, isopropanol, butanol, ethyl acetate, acetone, tetrahydrofuran, acetonitrile, 1,4-dioxane and mixtures thereof.