KR100665794B1 - A novel process for preparing 4-4-fluorophenyl-2-isobutiryl-3-phenyl-4-oxo-n-phenyl-butylamide - Google Patents

Abstract

The present invention relates to a method for preparing 4- (4-fluorophenyl) -2-isobutyryl-3-phenyl-4-oxo-N-phenyl-butylamide useful as an intermediate for preparing atorvastatin having blood cholesterol inhibitory activity. The present invention relates to a 4- (4-fluorophenyl) -2-iso which is an atorvastatin intermediate by reacting an alphasulfonyloxycarbonyl compound with a 4-methyl-3-oxo-N-phenylpentaamide compound according to the preparation method of the present invention. Butyryl-3-phenyl-4-oxo-N-phenyl-butylamide can be prepared under mild conditions as well as easy for industrial mass production.

Cholesterol, Atorvastatin, Atorvastatin, Alphasulfonyloxycarbonyl

Description

A novel method for preparing 4- (4-fluorophenyl) -2-isobutyryl-3-phenyl-4-oxo-N-phenyl-butylamide {A NOVEL PROCESS FOR PREPARING 4- (4-FLUOROPHENYL-2-ISOBUTIRYL) -3-PHENYL-4-OXO-N-PHENYL-BUTYLAMIDE}

The present invention relates to 4- (4-fluorophenyl) -2-isobutyryl-3-phenyl-4-oxo-N-phenyl-butylamide of formula 1, which is useful as an intermediate for preparing atorvastatin having cholesterol inhibitory activity. It relates to a manufacturing method.

The compound of Formula 1 is a compound useful as an intermediate for the preparation of atorvastatin (trade name: Lipitor, Pfizer Co., Ltd.), a hyperlipidemic agent having a cholesterol inhibitory activity, and as a conventional manufacturing method, US Pat. , WO 03/004457 and Korean Patent Publication No. 2004-0001435 are known.

The methods disclosed in US Pat. Nos. 5,124,482, 5,216,174 and 5,245,047 are shown in Scheme 1 below.

However, the preparation method according to Scheme 1 is not only takes a long time to the reaction of step 1, the yield is low, there are a lot of by-products, the process is difficult and complicated because the reaction of step 3 must be performed under a high anhydrous condition. In addition, since expensive catalysts must be used, it is difficult to industrialize.

The preparation method disclosed in WO 03/004457 is shown in Scheme 2 below.

However, the preparation method of Scheme 2 not only generates excess hydrochloric acid gas in the process of preparing 2-bromo-1- (4-fluorophenyl) -2-phenylethan-1-one as a reactant, but also poisonous bromine. Should be used and the reaction is violently difficult to industrialize.

The manufacturing method disclosed in Korean Patent Publication No. 2004-0001435 is shown in Scheme 3 below.

However, the preparation method according to Scheme 3 may also be 2-bromo-1- (4-fluorophenyl) -2-phenylethan-1-one or 2,2-dibromo-1- (4-fluorophenyl) as a reactant. Since -2-phenylethan-1-one is used, not only toxic bromine is used, but also industrialization is difficult because the reaction must be carried out under vigorous reaction conditions for a long time.

Therefore, the present inventors have conducted a study to overcome the problems of the prior art, as a result of reacting the alphasulfonyloxycarbonyl compound with 4-methyl-3-oxo-N-phenylpentaamide without using toxic bromine. The present invention was completed by developing a method for preparing an atorvastatin intermediate under mild reaction conditions.

It is therefore an object of the present invention to provide a more improved process for the preparation of 4- (4-fluorophenyl) -2-isobutyryl-3-phenyl-4-oxo-N-phenyl-butylamide of formula (I).

The present invention relates to 4- (4) of (1) comprising nucleophilic substitution of an alphasulfonyloxycarbonyl compound of formula (2) and 4-methyl-3-oxo-N-phenylpentaamide compound of formula (3) in the presence of a base. Provided are methods for the preparation of -fluorophenyl) -2-isobutyryl-3-phenyl-4-oxo-N-phenyl-butylamide:

[Formula 1]

In which R represents C _1-3 alkyl, phenyl, kempo or phenyl substituted with R '. R 'here represents C _1-3 alkyl, nitro, cyano or halogen.

Hereinafter, the present invention will be described in more detail.

Representative method for preparing a compound of Formula 1 according to the present invention is shown in Scheme 4:

In Scheme 4, R is the same as described above.

In Scheme 4, the compound of Formula 2 used as a starting material may be prepared by applying a known method (J. Org. Chem. 1982, 47, 2487-2489 and Aldrichinica Acta. 2001, 34, 89-102). ).

More preferably, the compound of Chemical Formula 2 may be prepared by reacting the compound of Chemical Formula 4 with the ultravalent iodine compound in an organic solvent.

In the above, the compound of formula 4 can be easily prepared according to known methods (Tetrahedron, 2003, 8199-8202).

In the above, the term hypervalent self-iodine compound is hydroxy (methanesulfonyloxy iodine) benzene, hydroxy (paratoluenesulfonyloxy iodine) benzene, hydroxy (paranitrobenzenesulfonyloxy iodine) benzene, or hydroxy (Camphorsulfonyloxyiodine) benzene. The amount of the ultraviolet iodine compound is preferably 1 to 5 equivalents based on the compound of the formula (4). As the organic solvent, acetonitrile, dichloromethane, tetrahydrofuran, diethyl ether, acetone, dimethylformamide, dimethyl sulfoxide and the like may be used, and the reaction temperature is preferably 0 ° C to 100 ° C.

 In addition, the compound of Chemical Formula 2 may be prepared by reacting the compound of Chemical Formula 4 with a non-VGA compound in a mixed solvent of dimethyl sulfoxide and distilled water to prepare a compound of Chemical Formula 5, followed by sulfonation of the compound of Chemical Formula 5 .

In the above, the term “VGA” compound refers to hydroxy (methanesulfonyloxy iodine) benzene, hydroxy (paratoluenesulfonyloxy iodine) benzene, hydroxy (paranitrobenzenesulfonyloxy iodine) benzene, or hydroxy. (Camphorsulfonyloxyiodine) benzene. It is preferable that the usage-amount of a ultraviolet iodine compound is 1-5 equivalents. In addition, the mixed solvent volume ratio of dimethyl sulfoxide: distilled water is preferably 2: 1 to 20: 1, and the reaction temperature is preferably 20 ° C to 60 ° C.

The compound of Formula 5 may be sulfonated with methanesulfonyl chloride or paratoluenesulfonyl chloride compound in the presence of a base such as triethylamine, diisopropylethylamine, or pyridine to prepare a compound of Formula 2. Can be.

In Scheme 4 of the present invention, the compound of formula 3 to be used as a starting material can be easily prepared according to known methods (J. Org. Chem., 1978, 2087-2088, US Patent No. 5,124,482).

In the scheme 4 of the present invention, usable bases include inorganic bases such as potassium carbonate, calcium carbonate, sodium hydroxide, sodium carbonate, potassium tert-butoxide and potassium methoxylate, triethylamine, diisopropylethylamine, 1, Organic bases such as 8-diazabicyclo [5.4.0] -7-undecene can be used. The base may be used in an amount of 1 to 10 equivalents based on Formula 3, and more preferably 1 to 3 equivalents.

The reaction of Scheme 4 may be carried out in the presence of a polar or nonpolar solvent. Preferable solvents include acetonitrile, dichloromethane, tetrahydrofuran, diethyl ether, acetone, dimethylformamide, ethyl acetate, chloroform and the like. At this time, it is preferable that reaction temperature is 0 degreeC-100 degreeC.

According to the preparation method of the present invention as described above, 4- (4-fluorine which is an atorvastatin intermediate by reacting an alphasulfonyloxycarbonyl compound of formula 2 with a 4-methyl-3-oxo-N-phenylpentaamide compound of formula 3 Phenyl) -2-isobutyryl-3-phenyl-4-oxo-N-phenyl-butylamide can be prepared under mild conditions as well as easy for industrial mass production.

Hereinafter, it will be described in detail in the embodiment of the present invention. However, the following examples are illustrative of the invention and do not limit the scope of the invention.

Example

Preparation Example 1 Preparation of 1- (4-fluorophenyl) -2-phenylethan-1-one

In acetonitrile (150 ml) cobalt bromide (6.0 g, 27.4 mmol), zinc bromide (6.1 g, 27.4 mmol), bromobenzene (2.9 g, 7.4 mmol), zinc (53.6 g, 819.8 mmol) and trifluoride Acetic acid (0.6 ml) was added and stirred at room temperature for 20 minutes. 1-bromo-4-fluorobenzene (30 ml, 273.0 mmol) was added to the reaction solution, and stirred for 40 minutes at room temperature, followed by dropwise addition of phenylacetyl chloride (43.3 ml, 327.4 mmol) at 0 ° C to 10 ° C. After the reaction was completed, 2N hydrochloric acid aqueous solution (50 ml) was added dropwise, and the organic layer was extracted and concentrated under reduced pressure. Dichloromethane (150 ml) and distilled water (150 ml) were added to the concentrated residue, and the organic layer was extracted. 2 N The organic layer was washed with aqueous hydrochloric acid and aqueous sodium bicarbonate solution and concentrated under reduced pressure to give the title compound (64.3 g, 92%) as a brown solid.

1 H NMR (CDCl 3): 4.2 ppm (s, 2H), 7.1 ppm (t, 2H), 7.2 ppm (m, 3H) 7.3 ppm (m, 2H), 8.0 ppm (m, 2H)

Example 1.Preparation of 2-tosyloxy-1- (4-fluorophenyl) -2-phenylethan-1-one

1- (4-fluorophenyl) -2-phenylethan-1-one (4.0 g, 18.7 mmol) obtained in Preparation Example 1 was dissolved in dichloromethane (20 ml), and hydroxy (paratoluenesulfonyloxyiodine ) Benzene (8.8 g, 22.4 mmol) was added and stirred under reflux for 15 hours. After the reaction was completed, the reaction solution was washed with distilled water (20 ml), the organic layer was separated and concentrated under reduced pressure to give the title compound (6.6g, 92%) as a white solid.

1 H NMR (CDCl 3): 2.4 ppm (s, 3H), 6.6 ppm (s, 1H), 7.0 ppm (t, 2H), 7.2-7.3 ppm (m, 7H), 7.7 ppm (d, 2H), 7.9 ppm (m, 2H)

Example 2. Preparation of 2-tosyloxy-1- (4-fluorophenyl) -2-phenylethan-1-one

1- (4-fluorophenyl) -2-phenylethan-1-one (1.0 g, 5.0 mmol) obtained in Preparation Example 1 was dissolved in acetonitrile (5 ml), and hydroxy (paratoluenesulfonyloxy Iodine) benzene (2.3 g, 6.0 mmol) was added and stirred under reflux for 15 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, dichloromethane (5 mL) and distilled water (5 ml) were added, and the organic layer was separated and concentrated under reduced pressure. The brown crude compound obtained was subjected to silica gel column chromatography to obtain the title compound (1.5 g, 80%) as a white solid.

Example 3. Preparation of 2-tosyloxy-1- (4-fluorophenyl) -2-phenylethan-1-one

1- (4-fluorophenyl) -2-phenylethan-1-one (1.0 g, 5.0 mmol) obtained in Preparation Example 1 was dissolved in tetrahydrofuran (5 ml), and hydroxy (paratoluenesulfonyloxy Iodine) benzene (2.3 g, 6.0 mmol) was added and stirred under reflux for 15 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, dichloromethane (5 mL) and distilled water (5 ml) were added, and the organic layer was separated and concentrated under reduced pressure. The brown crude compound obtained was subjected to silica gel column chromatography to obtain the title compound (1.4 g, 74%) as a white solid.

Example 4. Preparation of 2-tosyloxy-1- (4-fluorophenyl) -2-phenylethan-1-one

1- (4-fluorophenyl) -2-phenylethan-1-one (1.0 g, 5.0 mmol) obtained in Preparation Example 1 was dissolved in dimethylformamide (5 ml), and hydroxy (paratoluenesulfonyloxy Iodine) benzene (2.3 g, 6.0 mmol) was added and stirred at 80 ° C. for 15 hours. After the reaction was completed, toluene (5 mL) and distilled water (5 ml) were added to the reaction solution, and the organic layer was separated and concentrated under reduced pressure. The brown crude compound obtained was subjected to silica gel column chromatography to obtain the title compound (1.3 g, 67%) as a white solid.

Example 5. Preparation of 2-hydroxy-1- (4-fluorophenyl) -2-phenylethan-1-one

1- (4-fluorophenyl) -2-phenylethan-1-one (5 g, 23.3 mmol) obtained in Preparation Example 1 was dissolved in a mixed solvent of dimethyl sulfoxide and distilled water (10: 1), and hydroxy (para). Toluenesulfonyloxyiodine) benzene (27.4 g, 70 mmol) was added and stirred at 80 ° C. for 17 hours. After the reaction was completed, distilled water (30 ml) and ethyl acetate (30 ml) were added to the reaction solution, and the organic layer was separated and concentrated under reduced pressure. The obtained crude crude compound was subjected to silica gel column chromatography to obtain the title compound (4.5 g, 84%) as a white solid.

1 H NMR (CDCl 3): 4.5 ppm (d, 1H), 5.9 ppm (d, 1H), 7.2 ppm (t, 2H), 7.3 ppm (m, 5H) 7.9 ppm (m, 2H)

Example 6. Preparation of 2-hydroxy-1- (4-fluorophenyl) -2-phenylethan-1-one

1- (4-fluorophenyl) -2-phenylethan-1-one (5 g, 23.3 mmol) obtained in Preparation Example 1 was dissolved in a mixed solvent of dimethyl sulfoxide and distilled water (20: 1), and hydroxy (para). Toluenesulfonyloxyiod) benzene (27.4 g, 70 mmol) was added and stirred at 80 ° C. for 16 hours. After the reaction was completed, distilled water (30 ml) and ethyl acetate (30 ml) were added to the reaction solution, and the organic layer was separated and concentrated under reduced pressure. The obtained crude crude compound was subjected to silica gel column chromatography to obtain the title compound (3.6 g, 67%) as a white solid.

Example 7. Preparation of 2-hydroxy-1- (4-fluorophenyl) -2-phenylethan-1-one

1- (4-fluorophenyl) -2-phenylethan-1-one (5 g, 23.3 mmol) obtained in Preparation Example 1 was dissolved in a mixed solvent of dimethyl sulfoxide and distilled water (6: 1), and hydroxy (para). Toluenesulfonyloxyiod) benzene (27.4 g, 70 mmol) was added and stirred at 80 ° C. for 16 hours. After the reaction was completed, distilled water (30 ml) and ethyl acetate (30 ml) were added to the reaction solution, and the organic layer was separated and concentrated under reduced pressure. The obtained crude crude compound was subjected to silica gel column chromatography to obtain the title compound (3.5 g, 65%) as a white solid.

Example 8. Preparation of 2-Mesyloxy-1- (4-fluorophenyl) -2-phenylethan-1-one

2-hydroxy-1- (4-fluorophenyl) -2-phenylethan-1-one (1 g, 4.3 mmol) prepared in Example 5 was dissolved in dichloromethane (5 ml), and the temperature was 0 ° C. or lower. Triethylamine (0.82 ml, 5.2 mmol) and methanesulfonylchloride (0.37 ml, 4.7 mmol) were added dropwise and stirred for 10 minutes. After the reaction was completed, distilled water (5 ml) was added dropwise, and the organic layer was separated and concentrated to obtain the title compound (1.24 g, 94%) as a yellow solid.

1 H NMR (CDCl 3): 3.0 ppm (s, 3H), 6.8 ppm (s, 1H), 7.1 ppm (t, 2H), 7.2 ppm (m, 3H) 7.3 ppm (m, 2H), 8.0 ppm (m, 2H)

Example 9 Preparation of 4- (4-Fluorophenyl) -2-isobutyryl-3-phenyl-4-oxo-N-phenyl-butylamide

4-Methyl-3-oxo-N-phenyl-pentanamide (1.1 g, 5.2 mmol) was dissolved in dimethylformamide (10 ml) and then 2-tosyloxy-1- (4-fluorine prepared in Example 1 was prepared. Phenyl) -2-phenylethan-1-one (2.0 g, 5.2 mmol) and potassium carbonate (1.05 g, 7.8 mmol) were added and stirred at room temperature for 16 hours. After the reaction was completed, dichloromethane (20ml) and distilled water (20ml) were added to the reaction solution, and the organic layer was separated and concentrated under reduced pressure to obtain the title compound (1.9g, 89%) as a white solid.

1 H NMR (CDCl 3): 1.1 ppm (d, 3H), 1.2 ppm (d, 3H), 2.9 ppm (m, 1H), 4.5 ppm (d, 1H), 4.5 ppm (d, 1H), 7.0 ppm-7.3 (m, 12H), 7.9 ppm (m, 2H)

Example 10 Preparation of 4- (4-fluorophenyl) -2-isobutyryl-3-phenyl-4-oxo-N-phenyl-butylamide

4-Methyl-3-oxo-N-phenyl-pentanamide (0.11 g, 0.52 mmol) was dissolved in dichloromethane (2 ml) and then 2-tosyloxy-1- (4-fluorophenyl) prepared in Example 1 ) -2-phenylethan-1-one (0.2 g, 0.52 mmol) was added thereto and triethylamine (0.11 ml, 0.78 mmol) was added thereto and stirred for 15 hours. After the reaction was completed after stirring was added a 2 N aqueous solution of hydrochloric acid (2ml) to the reaction solution and the organic layer was separated and concentrated under reduced pressure. The brown crude compound obtained was subjected to silica gel column chromatography to obtain the title compound (0.15 g, 68%) as a white solid.

Example 11 Preparation of 4- (4-Fluorophenyl) -2-isobutyryl-3-phenyl-4-oxo-N-phenyl-butylamide

4-Methyl-3-oxo-N-phenyl-pentanamide (0.11 g, 0.52 mmol) was dissolved in dichloromethane (2 ml) and then 2-tosyloxy-1- (4-fluorophenyl) prepared in Example 1 ) -2-phenylethan-1-one (0.2 g, 0.52 mmol) and 1,8-diazabicyclo [5.4.0] -7-undecene (0.09ml, 0.62 mmol) were added and stirred for 15 hours. After the reaction was completed after stirring was added a 2 N aqueous solution of hydrochloric acid (2ml) to the reaction solution and the organic layer was separated and concentrated under reduced pressure. The brown crude compound obtained was subjected to silica gel column chromatography to obtain the title compound (0.13 g, 62%) as a white solid.

Example 12 Preparation of 4- (4-fluorophenyl) -2-isobutyryl-3-phenyl-4-oxo-N-phenyl-butylamide

4-Methyl-3-oxo-N-phenyl-pentanamide (0.11 g, 0.52 mmol) was dissolved in tetrahydrofuran (2 ml) and then 2-tosyloxy-1- (4-fluorine prepared in Example 1 was prepared. Phenyl) -2-phenylethan-1-one (0.2 g, 0.52 mmol) and tertiary potassium butoxide (0.07 ml, 0.62 mmol) were added and stirred for 15 hours. After the reaction was completed, the reaction solvent was concentrated under reduced pressure, dichloromethane (2 ml) and 2 N aqueous hydrochloric acid solution (2 ml) were added thereto, and the mixture was stirred. The crude compound obtained by separating the organic layer and concentrated under reduced pressure was subjected to silica gel column chromatography to obtain the title compound (0.11 g, 51%) as a white solid.

Example 13. Preparation of 4- (4-fluorophenyl) -2-isobutyryl-3-phenyl-4-oxo-N-phenyl-butylamide

2-tosyloxy-1- (4-fluorophenyl) prepared in Example 1 after dissolving 4-methyl-3-oxo-N-phenyl-pentanamide (0.11 g, 0.52 mmol) in dimethylformamide (2 ml). ) -2-phenylethan-1-one (0.2 g, 0.52 mmol) and sodium hydroxide (0.03 g, 0.78 mmol) were added and stirred at room temperature for 15 hours. After the reaction was completed, dichloromethane (2ml) and distilled water (2ml) were added to the reaction solution, and the organic layer was separated after stirring. The organic layer was washed with distilled water (2 ml) and concentrated under reduced pressure. The crude brown compound was purified by silica gel column chromatography to obtain the title compound (0.17 g, 78%) as a white solid.

Example 14 Preparation of 4- (4-Fluorophenyl) -2-isobutyryl-3-phenyl-4-oxo-N-phenyl-butylamide

4-Methyl-3-oxo-N-phenyl-pentanamide (0.11 g, 0.52 mmol) was dissolved in dimethylformamide (1.6 ml) and then 2-mesyloxy-1- (4-fluorine prepared in Example 8 was prepared. Phenyl) -2-phenylethan-1-one (0.16 g, 0.52 mmol) and potassium carbonate (0.11 g, 0.78 mmol) were added and stirred at room temperature for 15 hours. After the reaction was completed, dichloromethane (1.6ml) and distilled water (1.6ml) were added to the reaction solution, and the organic layer was separated after stirring. The organic layer was washed with distilled water (1.6 ml) and concentrated under reduced pressure to obtain the title compound (0.18 g, 81%) as a white solid.

As described above, atorvastatin intermediate 4- (4-fluorophenyl) -2-isobutyryl-3-phenyl under mild reaction conditions without the use of toxic bromine by using a new reactant according to the process of the present invention Not only can -4-oxo-N-phenyl-butylamide be prepared, but industrial mass production is easy.

Claims (12)

To prepare a compound of formula 1 by reacting a compound of formula 2 with a compound of formula 3 in the presence of a base:

In the above, R represents phenyl substituted with C _1-3 alkyl, phenyl, kempo or R '. Where R 'represents methyl, nitro, cyano or fluorine. The method of claim 1, wherein the bases used are potassium carbonate, calcium carbonate, sodium hydroxide, sodium carbonate, potassium tert-butoxide, potassium methoxylated, triethylamine, diisopropylethylamine and 1,8-diazabicyclo [5.4 .0] -7-undecene. The method of claim 1, wherein the base is used in an amount of 1 to 10 equivalents based on the formula (3). The process according to claim 1, wherein the reaction is carried out in the presence of a solvent selected from the group consisting of acetonitrile, dichloromethane, tetrahydrofuran, diethyl ether, acetone, dimethylformamide, ethyl acetate and chloroform. . The process according to claim 1, wherein the reaction is carried out at 0 ° C to 100 ° C. According to claim 1, wherein the compound of formula (2) is a compound of formula (4) hydroxy (methanesulfonyloxy iodine) benzene, hydroxy (paratoluenesulfonyloxy iodine) benzene, hydroxy (paranitrobenzene A process characterized in that it is prepared by reacting with an ultraviolet iodine compound selected from the group consisting of sulfonyloxyiodine) benzene and hydroxy (camphorsulfonyloxyiodine) benzene.

delete 7. The process according to claim 6, wherein the organic solvent is selected from the group consisting of acetonitrile, dichloromethane, tetrahydrofuran, diethyl ether, acetone, dimethylformamide and dimethyl sulfoxide. According to claim 1, wherein the compound of formula 2 is a compound of formula (4) hydroxy (methanesulfonyloxy iodine) benzene, hydroxy (paratoluenesulfonyloxy iodine) benzene, hydride in a mixed solvent of dimethyl sulfoxide and distilled water The compound of formula 5 is prepared by reacting with a non-valent self-iodine compound selected from the group consisting of oxy (paranitrobenzenesulfonyloxyiodine) benzene and hydroxy (camphorsulfonyloxyiodine) benzene. A method characterized in that it is prepared by the phonation reaction.

delete 10. The method according to claim 9, wherein the volume ratio of the mixed solvent of dimethyl sulfoxide and distilled water is 2: 1 to 20: 1. 10. The method according to claim 6 or 9, wherein the amount of the ultraviolet iodine compound is 1 to 5 equivalents based on the compound of the formula (4).