WO2008103016A1

WO2008103016A1 - Atorvastatin intermediates and method for producing the same

Info

Publication number: WO2008103016A1
Application number: PCT/KR2008/001069
Authority: WO
Inventors: In Hwa Chung
Original assignee: SUNGWUN PHARMACOPIA Corp
Current assignee: SUNGWUN PHARMACOPIA Corp
Priority date: 2007-02-22
Filing date: 2008-02-22
Publication date: 2008-08-28
Anticipated expiration: 2009-08-22
Also published as: KR20080078127A; KR100881617B1

Abstract

The present invention provides a novel boronate ether of Formula 1 useful for the synthesis of atorvastatin, and a preparation method thereof.

Description

[DESCRIPTION] [Invention Title]

ATORVASTATIN INTERMEDIATES AND METHOD FOR PRODUCING THE SAME

[Technical Field]

<i> The present invention relates to a compound of Formula 1(FIG. 1, where R is an alkyl having three or more carbon atoms, phenylethyl or a substituted phenylethyl) that can be used as a key intermediate to get atorvastatin of Formula 3, and a novel preparation method for producing a high purity atorvastatin intermediate at a high efficiency.

<2>

[Background Art] o> [R-(R' ,R" )]-2-(4-fluorophenyl)-3,5-dihydroxy-5-(l-methylethyl)-3- phynel]-4-[(phenylamino) carbonyl]-lH-pyrrole-l-heptanoic acid hemi- potassium(hereinafter atorvastatin) of Formula 3(FIG. 3) in U.S. Pat. No. 4,681,893 and U.S. Pat. No. 5,273,995 is known as a pharmaceutical composition useful as hyperlipidemic and hypocholesterolemic agents by inhibiting HMG-CoA reductase.

<4> U.S. Pat. No. 5,003,080 as a cited reference of the patents discloses a synthetic process for the preparation of atorvastatin by reacting (4R)^~6-(2- aminoethyl )2,2-dimethyl-l,3-dioxane~4-acetate and 4-fluoro-alpha-[2-methyl-l- oxopropyl]-gamma-oxo-N-beta-diphenylbenzenebutaneamide to produce a lactone compound followed by deprotection and hydrolysis to give the product. U.S. Pat. No. 5,216,174 describes a process for the preparation of atorvastatin by reacting hydroxyphenylamino-2-isopropylcarbonyl-3-phenyl-4-(4- fluorophenyl)l,4-dioxobutane with R,R-6-(2-aminoethyl)2,2-dimethyl-l,3- dioxane-4-acetic acid.

<5> A number of experiments have been carried out to produce high-purity atorvastatin at a high efficiency. Particularly, there are many ongoing studies to produce (4R)-6-(2-aminoethyl)-2,2-dimethyl-l,3-dioxane-4-acetate effectively. U.S. Pat. No. 5,155,251 provides a process for the synthesis of (3R)-4-cyano-3-hydroxybutyric acid from (S)-3-hydroxy butyrolactone. In addition, Korean Pat. No. 10-0308524 discloses a preparation method of (S)-3- hydroxy butyrolactone by reacting amylopectin with an enzyme, followed by oxidation, esterification, and cyclization. Japanese Patent Application Nos. 6-65,226 and 4-69,355 describe a process for the preparation of 3,5,6- trihydroxy hexanoic acid ester derivatives from 4-chloroacetic acid ester and from maleic acid, respectively. U.S. Pat. No. 5,278,313 describes a process for the preparation of (4R)-6-(2-aminoethyl)-2,2-dimethyl-l,3-dioxane-4- acetate from 4-chloro-3-hydroxybutyric acid.

<6> The above-described synthetic procedures for preparing (4R)-6-(2- aminoethyl)-2,2-dimethyl-l,3-dioxane-4-acetate include protecting 1,3-diol in the acetonide structure with acetone and toluenesulfonic acid or 2,2- dimethoxy-propane with dimethyl formamide(DMF) using toluenesulfonic acid to produce atorvastatin of Formula 3. However, it is not easy to obtain an optically pure substance from a protecting group in the acetonide structure.

<7> U.S. Pat. No. 6,867,306 discloses a process for the synthesis of a boronate compound. In the process, 1,3-diol is reacted with an industrially usable phenyl boronic acid in toluene and refluxed. Although the process may be able to synthesize an optical, high purity intermediate, its cost is very high and is thus industrially unfavorable.

<8> There are also many known methods to protect 1,3-diol. One of them is reacting benzaldehyde with zinc chloride or toluenesulfonic acid to obtain benzyl idene acetals, but its deprotection process is not much easy and is thus not useful in general. Besides, a si IyI protecting group is obtained readily by reacting di-t-butylsilyl-dichloride under conditions of acetonitrile, triethylamine, and hydroxybenzotriazole, but an industrial application thereof is rather difficult because it is easily hydrolyzed.

<9> J^'.Chem.Soc. , Perkin Trans. I 1863 (1981) mentions the synthesis of phenylboronates in use of phenyl, tolyl and nitrophenylboronic acid as a protecting group for boronic acid derivatives. However, their efficacies as a protecting group for other derivatives are not yet under study. <10>

[Disclosure] [Technical Problem] <π> It is, therefore, an object of an embodiment of the present invention to provide a key intermediate compound for the preparation of atorvastatin. <i2> It is another object of an embodiment of the present invention to provide a preparation method of a key intermediate compound to get atorvastatin.

<13>

[Technical Solution] <14> Accordingly, the present invention provides a compound of structure represented by Formula 1, [6-(2-amino-ethyl)-2-R-[l,3,2]dioxaborinane-4-yl]- acetic acid t-butyl ester. <i5> Another aspect of the present invention provides a preparation method of [6-(2-amino-ethyl)-2-R-[l,3,2]dioxaborinane-4-yl]-acetic acid t-butyl ester, which includes a step of reacting a boronic acid derivative with 6- cyano-3,5-dihydroxy-hexanoic acid t-butyl ester. <16> Preferably, a boronate compound of structure represented by Formula 2 is provided as another intermediate. <i7> Still another aspect of the present invention provides a preparation method of an atorvastatin intermediate of Formula 2(FIG. 2, where R is an alkyl having three or more, preferably from 3 to 12, carbon atoms, phenylethyl or a substituted phenylethyl) , which uses a boronate compound of

Formula 1 as an intermediate. [Advantageous Effects]

<I9> The present invention is therefore excellent in industrial utility in that it can synthesize a high purity atorvastatin with compounds of Formula 1 and Formula 2 as intermediates.

<20>

[Description of Drawings]

<2i> FIG. 1 is a Formula 1.

<22> FIG. 2 is a Formula 2.

<23> FIG. 3 is a Formula 3.

<24> FIG. 4 is a Reaction Formula 1.

<25> FIG. 5 is a Reaction Formula 2.

<26> FIG. 6 is a Reaction Formula 3.

<27> FIG. 7 is a Reaction Formula 4.

<28> FIG. 8 is a structural formula of the compound prepared in the example

1 of the invention.

<29> FIG. 9 is a structural formula of the compound prepared in the example

2 of the invention.

<30> FIG. 10 is a structural formula of the compound prepared in the example

3 of the invention.

<3i> FIG. 11 is a structural formula of the compound prepared in the example

4 of the invention.

<32> FIG. 12 is a structural formula of the compound prepared in the example

5 of the invention.

<33> FIG. 13 is a structural formula of the compound prepared in the example

6 of the invention.

<34> FIG. 14 is a structural formula of the compound prepared in the example

7 of the invention.

<35> FIG. 15 is a structural formula of the compound prepared in the example

8 of the invention.

<36> FIG. 16 is a structural formula of the compound prepared in the example

9 of the invention. <37>

[Best Mode]

<38> Diverse examples of boronic acids are prepared to find out the efficacy of a boronate as a selective protecting group for 1,3-diol.

<39> The inventors produced diverse kinds of boronic acids based on a method shown in Reaction Formula 1(FIG. 4), with reference to methods provided in J. Org. Chem. 45, 384-389 (1980), Bioorganic & Medicinal Chemistry, Vol. 2, No 1, 35~48 (1994) and so on.

<40> A vinyl derivative such as acetylene, a styrene derivative or the like is used for the Reaction Formula. Dibromoborane dimethylsulfide in an amount of 1.1 to 1.1 equivalent weight was refluxed for 10 - 15 hours, extracted with a suitable organic solvent such as ethylacetate or methylene chloride, and concentrated to give diverse kinds of boronic acid (1) of the Reaction Formula 1.

<4i> The boronic acid (1) obtained from the Reaction Formula 1 reacted with 1,3-diol compound (2) to obtain a boronate compound (3) as in Reaction Formula 2. Although the boronic acid (1) may be used in an amount of 0.5 to 2.5 equivalent weight, it is more preferable to use it in amount of 2.0 equivalent weight. Examples of the solvent include, but are not limited to, dichloromethane, carbon tetrachloride, acetonitrile, benzene, toluene, xylene, etc. Among them toluene is most preferably used. The reaction should continue for 10 ~ 40 hours at 40 - 130^°C, more preferably, 10 ~ 15 hours at 90 ~ 120^°C . A cyano group in the boronate (3) obtained from the Reaction Formula 2(FIG. 5) was then reduced to produce (4R)-6-(2-aminoe! hyl )- 2,2-dimethyl-l,3-dioxane-4-acetate.

<42> The 1,3-diol compound (2) of the Reaction Formula 2 was prepared by Reaction Formula 3(FIG. 6). As shown in the Reaction Formula 3, 4-cyano^~3- hydroxybutyric acid ethyl ester (4) was reacted with an acetate (5) to produce a beta-ketoester(6) . The acetate (5) was reacted with a base such as lithium di isopropylamide or butyl lithium in tetrahydrofuran(THF) at -40 ~ -70^°C to generate anions, and reacted with 4-cyano^~3-hydroxybutyric acid ethyl ester (4). Examples of the acetate (5) include, but are not limited to, methyl acetate, ethyl acetate, propyl acetate, n-butyl acetate, t-butyl acetate, isopropyl acetate, and so on. Among them t-butyl acetate is most preferably used. The beta-ketoester (6) was reduced with sodium borohydride in presence of tetrahydrofuran(THF) as the solvent to give a 1,3-diol compound (7) .

<43> Synthesis of atorvastatin using a boronate of Formula 1 suggested by the present invention was examined by conducting an experiment as in Reaction Formula 4.

<44> The compound of Formula 2 can be prepared easily by Paar-Knorr reaction between 2-[2-(4-fluorophenyl )-2-oxo-l-phenyl-ethyl ]-4-methyl-3-oxo-pentanoic acid phenylamide (8) in the Reaction Formula 4, a key substance for the synthesis of atorvastatin that is suggested in many studies and has been supplied industrially, and a boronate compound of Formula 1. Examples of a reaction solvent include, but are not limited to, acetonitrile, methylene chloride, THF, benzene, toluene, xylene, etc. Among them toluene or xylene is most preferably used. Meanwhile, a suitable use of an acid catalyst is desired to cause dehydration of two molecules. Examples of such acid catalyst include, but are not limited to, methanesulfonic acid, benzenesulfonic acid, and toluenesulfonic acid. Among them toluenesulfonic acid is most preferably used. Although vary depending on the solvent used, the reaction continues for 20 ~ 50 hours at 40 ~ 130^°C, more preferably, 25 ~ 35 hours at 90 ~ 130^°C.

<45> The boronate compound (9) in the Reaction Formula 4(FIG. 7) produces high purity atorvastatin by a suitable hydrolysis reaction. In detail, the boronate compound (9) in the Reaction Formula 4 was dissolved in ethyl acetate or dichloromethane, and a suitable base, preferably sodium hydroxide, was added thereto, and allowed to stand 2 - 5 hours for hydrolysis. When the reaction is over, hydrochloric acid was added to the resulting solution to acidify it. Finally, the acidic solution was treated with calcium hydroxide to give the target compound, i.e. atorvastatin calcium. <46>

[Mode for Invention]

<47> The invention will now be described in detail with reference to the following examples.

<48>

<49> EXAMPLE 1. Preparation of Phenylethylboronic acid(FIG. 8)

<50> 3 ml (26 mmol) of styrene and a solution of 26 ml (26 mmol) of dibromoborane dimethylsulfide in 1 M dichloromethane were put in a reactor and were refluxed over a period of 13 hours. Upon completion, 10 ml of water was added and stirred for 10 minutes. Then, the resulting mixture was extracted with 50 ml of ethyl acetate. The separated organic layer was concentrated and washed with 50 ml of n-hexane. The contents were stirred at 5^~10°C for a period of 2 hours, filtered, and dried to afford the title compound(2.25 g, 58%).

<51>

<52> EXAMPLE 2. Preparation of β-cyano-δ-hydroxy-S-oxo-hexanoic acid t-butyl ester(FIG. 9)

<53> 24 g of di isopropylamine was dissolved in 150 ml of THF in a reactor and cooled to -10^°C . Keeping the temperature, 170 ml of n-butyl lithium was added slowly and stirred for 30 minutes. The temperature was lowered to -40 ~ -35^°C , followed by slow addition of 45 ml of t-butyl acetate. The contents were stirred for 1 hour, while keeping the same temperature. At the same temperature, 12 g of 4-cyano-3-hydroxy butyric acid ethyl ester was then added slowly to the reactor and allowed to stand 2 hours at -20 ~ -15^°C . Upon completion, 200 ml of water was poured and the resulting mixture was stirred for 30 minutes, followed by the addition of 300 ml of ethyl acetate for extraction. Finally, the separated organic layer was concentrated in vacuo to afford the pale yellow compound in oil phase which was used for the next step.

<54>

<55> EXAMPLE 3. Preparat ion of 6-cyano-3 , 5-dihydroxy-hexanoi c aci d t-butyl ester(FIG. 10)

<56> To the oil compound, β-cyano-δ-hydroxy-S-oxo-hexanoic acid t-butyl ester, obtained from EXAMPLE 2, 200 ml of THF was added and cooled to -80^°C . Then, 5 g of sodium borohydride was added slowly thereto and stirred over a period of 6 hours at the same temperature. Upon completion, acetic acid was added for neutralization, followed by the addition of 100 ml of water and 200 ml of ethyl acetate for extraction. The separated organic layer was concentrated to afford the yellow compound in oil phase. The resulting compound was used for the next step, without further separation.

<57>

<58> EXAMPLE 4. Preparation of (6-cyanomethyl-2-phenethyl-[l,3,2]dioxaborinane-4- yl)-acetic acid t-butyl ester(FIG. 11)

<59> The 6-cyano-3,5-dihydroxy-hexanoic acid t-butyl ester obtained from EXAMPLE 3 was diluted with 100ml of toluene, followed by the addition of 5.2 g of phenyl ethyl boronic acid. The contents were then subjected to azeotropic distillation over a period of 5 hours to remove water. Upon completion, toluene was removed and the residue was treated with 100 ml of diethyl ether to afford the title compound(10 g) .

<60> ¹H NMR (CDCl₃ , 300MHz) : l . l(2H, t ) , 1.35C9H , s) , 1.58(2H, d) , 2.43C2H , d) , 2.60(2H , d) , 2.65(2H , t ) , 3.2( 1H, t ) , 3.9QH , m) , 7.2(5H , m) .

<61 >

<62> EXAMPLE 5. Preparation of (6-cyanomethyl-2-propyl-[l,3,2]dioxaborinane-4-yl)- acetic acid t-butyl ester(FIG. 12)

<63> The 6-cyano-3,5-dihydroxy-hexanoic acid t-butyl ester obtained from EXAMPLE 3 was diluted with 100 ml of toluene, followed by the addition of 3 g of propyl boronic acid. The contents were then subjected to azeotropic distillation over a period of 5 hours to remove water. Upon completion, toluene was removed and the residue was treated with 100 ml of diethyl ether to afford the title compound(7 g).

<64> ¹HNMR (CDCl₃, 300MHz):0.6(2H, t), 0.9(3H, t), 1.3(9H, s), 1.6(2H, t), 2.4(2H₁ d), 2.6(2H, d) , 3.2(1H, m), 3.9(1H, m) .

<65>

<66> EXAMPLE 6. Preparation of [6-(2-amino-ethyl)-2-phenethyl- [i,3,2]dioxaborinane-4-yl]-acetic acid t-butyl ester(FIG. 13)

<67> 10 g of the boronate compound obtained from EXAMPLE 4, 100 ml of ammonia-containing methanol, and 10 g of Ra nickel were put into a reactor, and the reaction was progressed with hydrogen. The reaction continued over a period of 8 hours under the pressure of 5 kg. The residue was filtered and the resulting filtrate was concentrated to afford the title compound(10 g).

<68> ¹H NMR (CDCl₃, 300MHz):l.l(2H, t), 1.4(9H₁ s), 1.6(2H, d), 1.7(2H, m),

2.60(2H, d), 2.65(2H, t), 3.2(1H, t), 3.9(1H, m), 7.2(5H,m).

<69>

<70> EXAMPLE 7. Preparation of [6-(2-amino-ethyl)-2-propyl-[l,3,2]dioxaborinane-4- yl]-acetic acid t-butyl ester(FIG. 14)

<7i> In a reactor, 10 g of the boronate compound obtained from EXAMPLE 5, 100 ml of methanol saturated with ammonia, and 10 g of Ra nickel were put and the reaction was progressed with hydrogen. The reaction continued over a period of 8 hours under the pressure of 5 kg. The residue was filtered and the resulting filtrate was concentrated to afford the title compound(7 g).

<?2> ¹H NMR (CDCl₃, 300MHz):0.6(2H, t), 0.9C3H, t), 1.4(9H, s), 1.5(2H, t),

1.6(2H, m), 1.7(2H, m), 2.4(2H₁ d), 2.6(2H, d), 3.2(1H, m), 3.9(1H, m).

<73>

<74> EXAMPLE 8. Preparation of (6-{2-[2-(4-fluoro-phynyl)-5-isopropyl-3-phenyl-4- pheny1carbamoyl-pyrrole-l-yl]-ethyl }-2-phenethyl-[1,3,2]dioxaborinane-4-yI)- acetic acid t-butyl ester(FIG. 15)

<75> 10 g of 2-[2-(4-fluoro-phenyl)-2-oxo-l-phenyl-ethyl]-4-methyl-3-oxo- pentanoic acid phenyl amide, 8.5 g of [6-(2-amino-ethyl)-2-phenethyl- [l,3,2]dioxaborinane-4-yl]-acetic acid t-butyl ester, and 150 ml of toluene were put into a reactor, and toluenesulfonic acid in a catalytic amount was added thereto. The reaction solution was refluxed at a reflux temperature and the water being produced was azeotroped off. By continuously dehydrating, the distillation was carried out over a period of 30 hours to remove the solvent completely. The concentrated oil compound was then treated with 100 ml of ethyl acetate and 100 ml of water and stirred for 30 minutes. The separated organic layer was concentrated and washed with 100 ml of n-Hexane to afford the title compound(15 g).

<76> ¹H NMR (CDCl₃ , 300MHz) : 0.9(2H, t ) , 1.2(2H , m) , 1.4(9H , s) , 1.5(6H ₁ d) ,

1.6(2H , m) , 2.3(2H , d) , 2.6(2H , t ) , 3.6( 1H , m) , 3.7QH , m) , 3.9( 1H , m) , 4.2(2H , m) , 7.2U9H , m) .

<77>

<78> EXAMPLE 9. Preparation of (6-{2-[2-(4-fluoro-phynyl)-5-isopropyl-3-phenyl-4- phenylcarbamoyl-pyrro1e-l-y1]-ethyl }-2-propy1-[1,3,2]dioxaborinane-4-y1 )- acetic acid t-butyl ester(FIG. 16)

<79> 10 g of 2-[2-(4-fluoro-ρhenyl)-2-oxo-l-phenyl-ethyl]-4-methyl-3-oxo- pentanoic acid phenyl amide, 6 g of [6-(2-amino-ethyl)-2-propyl- [l,3,2]dioxaborinane-4-yl]-acetic acid t-butyl ester, and 150 ml of toluene were put into a reactor, and toluenesulfonic acid in a catalytic amount was added thereto. The reaction solution was refluxed at a reflux temperature and the water being produced was azeotroped off. By continuously dehydrating, the distillation was carried out over a period of 30 hours to remove the solvent completely. The concentrated oil compound was then treated with 100 ml of ethyl acetate and 100 ml of water and stirred for 30 minutes. The separated organic layer was concentrated and washed with 100 ml of n-Hexane to afford the title compound(10 g).

<80> ¹H NMR (CDCl₃, 300MHz) :0.6(2H, t), 0.9(3H, t), 1.2(2H, m), 1.4(9H, s),

1.5(6H, d), 1.55(2H, m) , 1.6(2H, m) , 2.3(2H, dd), 2.6(2H, t), 3.6(1H₁ m) , 3.7QH, m), 3.9UH, m) , 4.2(2H, m), 7.2Q4H, m).

<81>

<82> EXAMPLE 10. Preparat ion of atorvastat in cal cium

<83> In a reactor , 15 g of (6-{2- [2-(4-f luoro-phynyl )-5-i sopropyl-3-phenyl- 4-phenylcarbamoyl-pyrrole-l-yl]-ethyl }-2-phenethyl-[1,3,2]dioxaborinane-4- yl)-acetic acid t-butyl ester was completely dissolved in 150 ml of ethyl acetate. Then, 50 ml of 1 N NaOH was added drop wise over a period of 30 minutes and the mixture was stirred. After that, pH of the solution was adjusted to 1 ~ 2 using 1 N HCl, followed by stirring for additional 30 minutes to separate the organic layer. The separated organic layer was washed with potassium acetate and stirred over a period of 2 hours. The resulting solid was filtered to afford the title compound(7 g).

<84>

[Industrial Applicability]

<85> Therefore, the present invention can be advantageously used in industry as an effective method for synthesizing a high purity atorvastatin using compounds of Formula 1 and Formula 2 as intermediates.

<86>

<87> While the present invention has been described with respect to the specific examples, it will be apparent to those skilled in the art that various changes and modifications may be made without departing from the spirit and scope of the invention as defined in the following claims.

Claims

[CLAIMS] [Claim 1]

<89> A preparation method of [6-(2-amino-ethyl)-2-R-[l,3,2]dioxaborinane-4- yl]-acetic acid t-butyl ester of Formula 1(FIG. 1, where R is an alkyl having three or more carbon atoms, phenylethyl or a substituted phenylethyl), comprising:

<90> reacting a boronic acid derivative with 6-cyano-3,5-dihydroxy-hexanoic acid t-butyl ester.

[Claim 2]

<9i> A preparation method of an atorvastatin intermediate of Formula 2(FIG. 2, where R is an alkyl having three or more, preferably from 3 to 12, carbon atoms, phenylethyl or a substituted phenylethyl) by using a boronate compound of Formula 1 as an intermediate.

[Claim 3]

<92> [6-(2-amino-ethyl )-2-R-[ l , 3 , 2]dioxabor inane-4-yl ]-acet i c ac id t-butyl ester of Formula 1.

[Claim 4] <93> A boronate compound of Formul a 2.