WO2005058861A1

WO2005058861A1 - Process for preparing simvastatin.

Info

Publication number: WO2005058861A1
Application number: PCT/KR2003/002754
Authority: WO
Inventors: Jong-Min Kim; Bong-Youl Chung; Joon-Seop Kim; Jae-Gu Choi; Shin-Wook Kang; Sang-Won Yi; Hyun-Jin Ahn
Original assignee: Uk Chemipharm Co., Ltd.
Priority date: 2003-12-16
Filing date: 2003-12-16
Publication date: 2005-06-30
Also published as: AU2003289546A1

Abstract

The present invention relates to a process for preparing simvastatin, comprising the steps of reacting a diol lactone of formula 4 with a di-substituted silyl dichloride (dichlorosilane) to produce a diol lactone dimer of formula 5, subsequently acylating the diol lactone dimer with 2,2-dimethylbutyryl chloride to produce a simvastatin dimer of formula 6, and deprotecting the simvastatin dimer to produce simvastatin. The process is simple in overall manufacturing steps, uses cheap protecting agent, and has an excellent productivity and economical effect.

Description

PROCESS FOR PREPARING SIMVASTATIN

Technical Field

The present invention relates to a process for preparing simvastatin in a high yield by hydrolyzing lovastatin with an inorganic base, forming a diol lactone, selectively protecting the diol lactone to form a lactone dimer, acylating the lactone dimer to produce simvastatin dimer, and then deprotecting the simvastatin dimer.

Background Art

Simvastatin, used as an HMG-CoA reductase inhibitor, is a kind of statin antihyperlipidemic. A process for preparing simvastatin from lovastatin is known in the art. Korean - Patent Publication No. 10-1985-669 and US Patent No. 4,444,784 disclose a method of preparing silyl derivative of simvastatin of formula B and then deprotecting it to produce simvastatin, as illustrated in the following Scheme 1. [Scheme 1]

Lovastatin A

Simvastatin The process of preparing simvastatin as shown in Scheme 1 is characterized in hydrolyzing lovastatin with lithium hydroxide as an inorganic base and then forming a diol lactone of formula B in toluene; and selectively introducing t-butylmethylsilyl protecting group into the secondary alcohol in 4- position of the diol lactone to produce an intermediate, a silyl derivative of simvastatin of formula B. In the process, however, the reaction time required for hydrolysis is so long as 72 hours, and the yield is a little low as 69 % in the step of silyl introduction. Further, the use of expensive t-butyldimethylsilyl chloride causes the increase of total cost of production. Also, tetrabutylammonium fluoride for desilylation is too expensive to be used in large quantities. Also, PCT Publication WO 03/057684 discloses a method of preparing simvastatin from lovastatin, which is similar to that disclosed in Korean Patent Publication No. 10-1985-669 and US Patent No. 4,444,784. In this method, a large quantity of rather expensive phase transfer agent is used in acylation step and the reaction carried out in organic solvent such as toluene at high temperature for a long time results in the production of lots of by-products. Further, tetrabutylammonium fluoride is used in large quantities in protecting t- butyldimethylsilyl and deprotecting it, which causes increase of cost of production. In addition, Korean Patent Laid-open Publication No. 10-2003-40858 discloses a process for preparing simvastatin characterized in that hydrolyzing lovastatin with an inorganic base through the medium of phase transfer agent and then heating with reflux to produce a diol lactone in a consecutive process without separation, and selectively introducing tetrahydropyranyl group into the secondary alcohol of pyranone ring to produce 4-THP-diol lactone. In this method, byproducts having two THP are produced in the protection step, which causes overall decrease of yield, and a purification step is required to remove the byproducts. In order to solve the above-mentioned problems, the present inventors have developed a new protecting group which is economical and safe in environment as well as ensures high yield of product, and studied its deprotection reaction; at last have succeeded to complete a new process for preparing simvastatin in high yield by introducing di-substituted silyl group into one secondary alcohol and removing efficiently the silyl protecting group in the presence of fluoride salt or acid catalyst in mild condition (0 ^°C or room temperature).

Disclosure of Invention

Technical Problem

It is an object of the present invention to provide a process for preparing simvastatin, which is useful antihyperlipidemic agent having excellent HMG- CoA reductase inhibiting activity, in a high yield under a mild condition without using an expensive reagent.

Technical Solution In accordance with one aspect of the present invention, it is provided a process for preparing simvastatin of formula 1, comprising the steps of: reacting a diol lactone of formula 4 with a di-substituted silyl dichloride (dichlorosilane) to produce a diol lactone dimer of formula 5; subsequently acylating the diol lactone dimer with 2,2-dimethylbutyryl chloride to produce a simvastatin dimer of formula 6; and deprotecting the simvastatin dimer to produce simvastatin. The diol lactone of formula 4 can be prepared by deacylating lovastatin of formula 2 with an inorganic base to obtain a triol acid of formula 3 and refluxing the triol acid in the presence of toluene. [Formula 1]

[Formula 2]

[Formula 3]

[Formula 4]

[Formula 5]

[Formula 6]

wherein Ri and R₂ are independently an alkyl or an aryl group, and preferably methyl, ethyl, isopropyl, t-butyl or phenyl. In the present invention, simvastatin is prepared from lovastatin in a high yield by hydrolyzing ester of lovastatin with an inorganic base, forming a diol lactone, selectively protecting the diol lactone to form a lactone dimer, introducing 2,2-dimethylbutyryl ester into the lactone dimer to produce a simvastatin dimer, and then deprotecting silyl group of the simvastatin dimer with fluoride salt or acid to produce simvastatin. The process for preparing simvastatin according to the present invention consists of the following four steps: (1) deacylating lovastatin of formula 2 with an inorganic base such as potassium hydroxide to produce a triol acid of formula 3; (2) refluxing the triol acid of formula 3 in toluene to produce a diol lactone of formula 4; (3) selectively protecting the secondary alcohol of the diol lactone of formula 4 with dialkyl (or diaryl or arylalkyl) silyl dichloride (R₁R₂SiCl₂, wherein Ri and R₂ are independently an alkyl or an aryl group, such as methyl, ethyl, isopropyl, t-butyl or phenyl) to produce a silyl-protected diol lactone dimer of formula 5, and subsequently (i.e., without interruption of reaction) acylating the diol lactone dimer with 2,2-dimethylbutyryl chloride to produce a silyl-protected simvastatin dimer of formula 6; and (4) removing the protecting silyl group from the simvastatin dimer of formula 6 in the presence of fluoride salt or acid catalyst to produce simvastatin of formula 1 in a high yield. Scheme 2 illustrates the above-mentioned process for preparing simvastatin according to the present invention. [Scheme 2]

The steps illustrated in Scheme 2 will be described more detail as follows. In step (1), lovastatin of formula 2 is added with an inorganic base such as potassium hydroxide and then heated with reflux for 5 to 15 hours to be deacylated and acidified, which results in the production of a triol acid of formula 3. In step (2), the triol acid of formula 3 is refluxed in toluene, successively removing water, to prepare a diol lactone of formula 4. In step (3), two secondary alcohols in two diol lactone molecules of formula 4 are selectively protected with dialkyl (or diaryl or arylalkyl) silyl group in the presence of base to obtain a silyl-protected diol lactone of formula 5. Successively, the silyl-protected diol lactone is directly subjected to coupling reaction with 2,2-dimethylbutyryl chloride in the presence of 4,4- dimethylaminopyridine catalyst to prepare a silyl-protected simvastatin dimer of formula 6 in the yield of 95 % or more. Suitable dialkyl (or diaryl or arylalkyl) silyl dichlorides which may be used in step (3) are dichlorosilanes having two alkyl or aryl substitutes which are same or different each other, such as dimethyl silyl dichloride, diethyl silyl dichloride, diisopropyl silyl dichloride, methylvinyl silyl dichloride, di-t-butyl silyl dichloride, diphenyl silyl dichloride, methylphenyl silyl dichloride, etc. Preferably, dimethyl silyl dichloride is used in an amount of 0.5 to 1.0 equivalent, since it is low in price and easily removed in the system. • Representative examples of the organic base used in step (3) are tertiary amine such as triethylamine, tributylamine, diisobutylethylamine, N- methylmorpholine, etc. and aromatic amine such as imidazole, 1- methylimidazole, pyridine, 2,6-lutidine, picoline, etc. Among the amines pyridine is preferred to be used. 4,4-dimethylaminopyridine used as catalyst for coupling reaction is preferred to be added within the range of 0.1 to 1 equivalent. By adjusting the amount of the catalyst to be used it is possible to improve the reaction and minimize side-reaction. Suitable reaction solvent in step (3) may includes pyridine, methylene dichloride, 1,2-dichloroethane, tetrahydrofuran, toluene, benzene, acetonitrile, etc. Methylene chloride is preferred to be used alone. In step (4), a silyl-protected simvastatin dimer of formula 6 is easily deprotected in the presence of fluoride salt or acid catalyst to produce simvastatin of formula 1 in a high yield. Suitable fluoride salts which may be used in step (4) include cesium fluoride, potassium fluoride, ammonium fluoride, pyridinium fluoride, triethylammonium fluoride, tetrabutylammonium fluoride, etc. Representative examples of the acid catalyst include hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, pyridinium p-toluenesulfonate, p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, etc. Preferably, ammonium fluoride is used in an amount of 0.5 to 2.0 equivalents.

Suitable reaction solvent in step (4) may includes acetonitrile, dimethylformamide, dimethylacetamide, methanol, ethanol, tetrahydrofuran, 1,4- dioxane, ethylacetate, benzene, toluene, or mixtures thereof. Ethylacetate is preferred to be used. Simvastatin of formula (1) may be crystallized by non-polar solvents such as hexane, cyclohexane, diethyl ether, petroleum ether, diisopropyl ether, t- butylmethyl ether, ethyl acetate/hexane, etc. Cyclohexane is preferred to be used alone. Best Mode

The present invention will hereinafter be described more specifically by preparations and examples. It is, however, to be borne in mind that the present invention is by no means limited to or by them.

Example 1: Synthesis of 3,5-dihydroxy-7-(8-hvdroxy-2,6-dimethyl- 1,2,6,7,8, 8a-hexahydro-naphthalen-l-yr)heptanoic acid [step 1] 10 g (24.7 mmol) of lovastatin was added with 70 ml of 2- propanol/ethanol and 8.16 g (123.5 mmol) of potassium hydroxide, and then the resultant was stirred at room temperature for 30 minutes. The solution was heated to the reflux temperature, and then stirred at the temperature for 6 hours. After the reaction was finished, the resultant was cooled to room temperature, and then completely dissolved by adding 300 ml of water. The solution was added with concentrated hydrochloric acid to adjust the pH to 3 or lower and then stirred to crystallize. After stirring for 1 hour, the resultant was filtrated and then dried completely to yield 7.53 g (90%) of the title compound as white crystal. The obtained substance was used in the next process without further recrystallization. 1H NMR(CDC1₃, 400MHz): δ5.94(d, 1H, J = 9.6Hz, naphtha C-4H),

5.75(dd, 1H, J = 9.6Hz, naphtha C-3H), 5.52(t, 1H, J = 3.0Hz, naphtha C-5H), 4.69(m, 1H), 4.36(q, 1H), 4.21(q, 1H), 2.62(dd, 2H, -CH₂-), 2.50-2.30(m, 2H), 2.13(m, 1H), 2.00-2.30(m, 12H), 1.46(m, 2H), 1.15(d, 3H, -CH₃), 0.86(s, 3H, - CH₃)

Example 2: Synthesis of 4-dihvdroxy-6-[2-(8-hydroxy-2,6-dimethyl- 1 ,2,6,7,8,8a-hexahydro-naphthalen- 1 -yl ethyll-tefaahydro-pyran-2-one [step 2] 7.53 g (22.25 mmol) of the triol acid produced in Example 1 was suspended in 40 ml of toluene, and then refluxed for 1 hour with successive removal of water. The resultant was distilled to leave 15 ml of toluene, and then stirred gently to cool down to room temperature. The crystal obtained by filtration was dried to yield 6.75 g (95%) of white diol lactone crystal. The obtained crystal was dried under reduced pressure and then directly used in the next process. 1H NMR(CDC1₃, 400MHz): δ5.93(d, 1H, J = 9.6Hz, naphtha C-4H), 5.77(dd, 1H, J = 9.6Hz, naphtha C-3H), 5.5 l(t, 1H, J = 3.0Hz, naphtha C-5H), 4.50-4.70(m, 2H), 4.25(m, 2H), 3.75(m, 1H), 3.48(m, 1H), 2.70-2.50(m, 2H),

2.50-1.30(m, 18H), 1.15(d, 3H, J=7.5Hz, CH₃), 0.86(d, 3H, J=7.5Hz, CH₃)

Example 3: Synthesis of simvastatin dimer [step 3] 6.75 g (21.1 mmol) of the diol lactone produced in Example 2 was dissolved in 40 ml of methylene chloride, and 2.78 ml (31.65 mmol) of pyridine was added thereto. The resultant was added slowly with 1.39 ml (11.6 mmol) of dimethylsilyl dichloride for 30 minutes, and then stirred for another 30 minutes. After the reaction was completed, the resultant was added with 772 mg (30 mol%) of 4-dimethylaminopyridine and 5.49 g (63.3 mmol) of lithium bromide, and then 8.59 ml (105.5 mmol) of pyridine was slowly added thereto at 0 °C . After stirring for 10 minutes, the mixture was added with 5.67 ml (42.2 mmol) of 2,2- dimethylbutyryl chloride and then refluxed for 5 hours. After the reaction was completed, the resultant was stirred with addition of an excess amount of saturated sodium bicarbonate solution, and then extracted with 30 ml of methylene chloride three times and dried with anhydrous magnesium sulfate. After the solvent was removed under reduced pressure, the extracted was dried under vacuum to obtain transparent oily simvastatin dimer. The product was used in the next process without further purification. 1H NMR(C₆D₆, 400MHz): 56.1 l(d, 1H, J = 9.6Hz, naphtha C-4H), 5.78(dd, 1H, J = 9.6Hz, naphtha C-3H), 5.48(m, 1H), 4.56(m, 1H), 4.15(m, 1H), 3.78(m, 1H), 2.39 and 2.14(dd, 2H, -CH₂-), 2.29(m, 2H), 2.04(m, 3H), 1.80- 1.50(m, 6H), 1.22(d, 3H, CH₃), l.ll(s, 3H, -CH₃, from ester), 1.10(s, 3H, -CH₃, from ester), 0.91(d, 3H, CH₃), 0.81(t, 3H, J = 7.4Hz, -CH₃, from ester), -0.08(s, 3H, SiCH₃)

Example 4: Synthesis of 2,2-dimethyl-butyric acid 8-r2-(3-hvdroxy-5- oxo-cvclohexylVethyl]-3,7-dimethyl-l,2,6,7.8.8a-hexahydronaphthalen-l-yl ester (simvastatin [step 2] 8.94 g (10.0 mmol) of the protected simvastatin dimer produced in Example 3 was dissolved in 90 ml of ethylacetate, and the mixture was added with 370 mg (10.0 mmol) of ammonium fluoride at 0 ^°C and then stirred for 3 hours. After the reaction was completed, organic layer was washed twice with 100 ml of saturated sodium chloride solution. The organic layer was separated, dried with anhydrous magnesium sulfate, and then concentrated under a reduced pressure to obtain semi-solid residue. The semi-solid residue was added with

100 ml of cyclohexane, heated to dissolve, and then slowly cooled to 10 to 15 ^°C to obtain 7.55 g (96%, purity > 99%) of white crystalline simvastatin. 1H NMR(CDC1₃, 400MHz): δ5.95(d, 1H, J = 9.6Hz, naphtha C-4H), 5.75(dd, 1H, J = 6.1, 9.6Hz, naphtha C-3H), 5.48(t, 1H, J = 3.0Hz, naphtha C-5H), 5.34(q, 1H), 4.58(m, 1H), 4.35(q, 1H), 2.75-2.55(m, 2H), 2.50(br s, 1H, -OH),

2.45-1.20(m, 14H), l.ll(s, 3H, -CH₃, from ester), 1.10(s, 3H, -CH₃, from ester), 1.05(d, 3H, J = 7.4Hz, -CH₃), 0.85(d, 3H, J - 7.4Hz, -CH₃), 0.81(t, 3H, J = 7.4Hz, -CH₃, from ester) As described above, the present invention provides new protection group which is low in price and can be easily removed under fluoride salt and acid condition in manufacturing simvastatin and proves its industrial availability. The characteristic features and excellency of the present invention are as follows: (1) In the conventional method of manufacturing simvastatin, a diol lactone of formula A is subjected to two-step reaction to produce simvastatin intermediate. According to the present invention, a diol lactone is protected and then directly subjected to one-step reaction to proceed acylation, which simplify the overall procedures; (2) In the present invention, a diol lactone of formula 4 is an intermediate compound and two secondary alcohols in two diol lactone molecules are selectively protected by using dialkyl (or diaryl or arylalkyl) silyl dichloride (RιR₂SiCl₂). That is, since protection is carried out by using dialkyl (or diaryl or arylalkyl) silyl dichloride under alkaline and mild condition (0 ^°C), side reactions such as opening of lactone ring or dehydration of alcohol in acidic condition are inhibited, which increases the yield up to 95%> or more. Further, protecting agent is used by half amount and low in price, which makes the present method economical. (3) The protecting silyl group, especially dialkyl (or diaryl or arylalkyl) silyl group is easily removed in the presence of fluoride salt or acid catalyst under a rather mild condition (room temperature or 0 ^°C) to produce simvastatin.

Further, by- product is easily removed in the recrystallization process. Therefore, simvastatin is obtained in a high purity (>99%>) and high yield (96%> or more). Industrial Applicability

As described above, the process for preparing simvastatin according to the present invention is simple in overall manufacturing steps and uses cheap protecting agent. Further, it has an excellent productivity and economical effect.

Claims

1. A process for preparing simvastatin of formula 1, comprising the steps of: reacting a diol lactone of formula 4 with a di-substituted silyl dichloride (dichlorosilane) to produce a diol lactone dimer of formula 5; subsequently acylating the diol lactone dimer with 2,2-dimethylbutyryl chloride to produce a simvastatin dimer of formula 6; and deprotecting the simvastatin dimer to produce simvastatin. [Formula 1]

[Formula 4]

[Formula 5]

[Formula 6]

wherein R_ and R₂ are independently an alkyl or an aryl group.

2. The process of claim 1, wherein the diol lactone of formula 4 is prepared by deacylating lovastatin of formula 2 with an inorganic base to obtain a triol acid of formula 3 and refluxing the triol acid in the presence of toluene. [Formula 2]

[Formula 3]

wherein Ri and R₂ are independently an alkyl or an aryl group.

3. The process of claim 1, wherein the dichlorosilane is selected from dimethyl silyl dichloride, diethyl silyl dichloride, diisopropyl silyl dichloride, methylvinyl silyl dichloride, di-t-butyl silyl dichloride, diphenyl silyl dichloride and methylphenyl silyl dichloride.

4. The process of claim 1, wherein the dichlorosilane is dimethyl silyl dichloride and is added in an amount of 0.5 to 1.0 equivalent.

5. The process of claim 1, wherein the diol lactone is reacted with the dichlorosilane in the presence of an organic base selected from triethylamine, tributylamine, diisobutylethylamine, N-methylmorpholine, imidazole, 1- methylimidazole, pyridine, 2,6-lutidine and picoline.

6. The process of claim 1, wherein the diol lactone dimer is acylated with 2,2-dimethylbutyryl chloride in the presence of 4,4-dimethylaminopyridine.

7. The process of claim 1, wherein the simvastatin dimer is produced in pyridine, methylene dichloride, 1,2-dichloroethane, tefrahydrofuran, toluene, benzene, acetonitrile, or mixtures thereof.

8. The process of claim 1, wherein the simvastatin dimer is deprotected in the presence of a catalyst selected from cesium fluoride, potassium fluoride, ammonium fluoride, pyridinium fluoride, triethylammonium fluoride, tetrabutylammonium fluoride, hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, pyridinium p-toluenesulfonate, p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid and trifluoromethanesulfonic acid.

9. The process of claim 1, wherein the simvastatin dimer is deprotected in the presence of acetonitrile, dimethylformamide, dimethylacetamide, methanol, ethanol, tefrahydrofuran, 1,4-dioxane, ethylacetate, benzene, toluene, or mixtures thereof.

10. The process of claim 1, wherein the simvastatin is recrystallized in the presence of hexane, cyclohexane, diethyl ether, petroleum ether, diisopropyl ether, t-butylmethyl ether, ethyl acetate, or mixtures thereof.