SK285772B6 - Process for preparation of simvastatin - Google Patents

Abstract

It is described a process for the preparation of a compound of formula (I) by acylation of the protected diol lactone of formula (IIa) in the presence of imidazole and dimethylaminopyridine in an organic solvent at a temperature of -10 °C to a temperature boiling point of used solvent.

Description

The invention is in the field of pharmaceutical chemistry. It relates to a process for the production of simvastatin, which is used as an HMG-CoA reductase inhibitor in the treatment of hypercholesterolemia.

BACKGROUND OF THE INVENTION

The known processes for the preparation of simvastatin and its derivatives can in principle be divided into two synthetic processes. The first group includes direct methylation processes of the methylbutyryl side chain in the lovastatin skeleton. In the second group are called. transesterification procedures.

The first type of reaction - direct alkylation of the methylbutyryl side chain is described in EP-B-137445 and EP-B-299656. These processes use metal alkyl amides and methyl halides. A disadvantage of these processes is the incomplete conversion of the starting lovastatin to simvastatin and its presence in the final product. Simvastatin and lovastatin molecules differ only by methyl, so it is very difficult to separate them from the mixture containing both simvastatin and lovastatin by conventional separation methods.

The second type of reaction is described in EP-B-33538 and consists of hydrolysis of lovastatin, lactonization, introduction of a silyl protecting group, acylation, desilylation. The acylation proceeds at 100 ° C in the presence of 4-pyrrolidino pyridine or dialkylaminopyridine for 18 to 36 hours. These reaction conditions lead to the formation of a substantial amount of unwanted by-product (dehydroderivative as a result of the elimination of the tert-butyldimethylsilyloxy radical which serves as the hydroxyl protecting group in the δ-valerolactone skeleton.

EP-B-287340 describes an improved acylation process for the preparation of antihypercholesterolemic compounds using a suitable acyl chloride in combination with an alkali metal bromide and a dialkylaminopyridine. The reaction is carried out at a relatively high temperature of 70 ° C in a solvent, preferably pyridine. The amount of dehydroderivative is up to 2%.

WO 00/32585 describes a process for the acylation of a protected diollactone with an acyl chloride activated metal halide in an organic solvent in the absence of dimethylaminopyridine. A disadvantage is that the protected diollactone is not completely converted to the protected simvastatin.

In US 6,252,091, N-methylimidazole is used in the selective acylation of protected diollactone, which serves as both a base and a solvent. The reaction proceeds at a low temperature of 0 to 30 ° C. The amount of undesirable dehydroderivative is below 1%. The disadvantage of this procedure is an extended reaction time of 42 hours and the use of commercially unavailable N-methylimidazole.

In WO 01/72734 A1, the protected diollactone is selectively acylated with a carboxylic acid which is activated with a trialkylphosphine and a halogen compound. The amount of dehydroderivative is in the range of 1 to 2%. The disadvantage is an extended reaction time - 20 hours and work with trialkylphosphine.

In WO 01/45484 A2 the protected diollactone derivative is acylated with an acyloxy triphenylphosphonium salt for 10 hours. The disadvantage is the prolonged reaction time and the need to prepare an acylating agent which is not commercially available.

These difficulties in industrial implementation can be overcome by the process according to the invention using commercially available raw materials.

SUMMARY OF THE INVENTION

The present invention provides a process for the preparation of a compound of formula (I)

wherein R is a C 1 to C 12 alkyl group,

R 1 is a protecting group, by reaction of a protected diollactone of formula (II)

wherein R 1 is a protecting group, and an acylating agent in the presence of imidazole and dimethylaminopyridine in an aromatic hydrocarbon or chlorinated aliphatic hydrocarbon solvent at -10 ° C to the boiling point of the solvent used.

The compounds of formula (I) are potent antihypercholesterolemic compounds, including simvastatin. In formula (I), the R group may be a C 1 -C ₂ branched or straight alkyl group, preferably a C ₅ alkyl and, in the case of simvastatin, a CH ₃ -CH ₂ -C (CH ₃ ) ₂ - group.

A suitable example of the protecting group R 1 is. are groups generally used to selectively protect hydroxy groups such as silyl groups. Preferred are trialkylsilyl groups such as e.g. isopropyldimethyl, triphenylmethyl, dimethylsilyl, tert-butyldiphenylsilyl, methyldiisopropylsilyl, tribenzylsilyl, triisopropylsilyl, most preferably the tert-butyldimethylsilyl group.

The acylating agent is a suitable activated form of the acid of formula (III)

R-CO-OH (III) wherein the R group is the same as in Formula (I).

Preferred activated acid forms are the acid halides or anhydrides, which are commercial raw materials, making the process available and suitable for industrial use, or the in situ formed intermediate of formula (IIIc) (R-CO-Imidazole) ⁺ X '(IIIc) )

Wherein X is chlorine, bromine or an acid radical R-COO, R is a C 1 to C ₁₂ alkyl group, preferably a CH ₃ -CH ₂ C (CH ₃ ) ₂ - group.

The solvent is any inert solvent from the group of aromatic hydrocarbons, preferably toluene, or chlorinated aliphatic hydrocarbons, preferably dichloroethane.

Prior art processes of acylation of a protected diollactone of formula (II) in an organic solvent at elevated temperature or at the boiling point of the solvent also using dimethyl aminopyridine type catalysts, alkali metal halides, 4-pyrrolidinopyridine and in the presence of an pyridine type organic base triethylamine unwanted side reaction products, in particular a dehydroderivative (unsaturated lactone), the removal of which from the reaction mixture is laborious and causes problems, e.g. in the crystallization of the ammonium salt of simvastatin.

Surprisingly, it has been found that the use of imidazole as a base in a solvent at an elevated or boiling point of the solvent and in the presence of a dimethyl aminopyridine catalyst provides a reaction mixture with a low by-product side reaction reaction, particularly a dehydroderivative (typically below 0.8%). acylation (typically above 98%). The selectivity of the reaction is achieved by carrying out batches of solvent raw materials, silyldiollactone, imidazole, dimethylaminopyridine and an acylating agent at -10 ° C to 10 ° C. Furthermore, it has been found that the use of imidazole and the configuration of the reaction conditions of the subject matter of the patent have an effect on an amount of acylating agent that is lower than the hitherto known processes for acylating the protected diollactone of formula (II). To achieve the conversion of the protected diollactone of formula (II) to the compound of formula (I), a 1.5-3 molar excess of the acylating agent to the protected diollactone of formula (II) used, preferably a 2.3 molar excess, is used. The reaction proceeds at room temperature, but requires an extended reaction time. Increasing the reaction temperature to the boiling point of the organic solvent shortens the time required to convert the protected diollactone to the corresponding acyl derivative, without affecting the selectivity of the reaction.

The processing of the reaction mixture after the acylation is complete is very simple due to the organic solvent used in which the acylation product is soluble. The unreacted acylating agent is quenched by addition of excess water, a C 1 -C ₂ alkanol or a mixture thereof and the imidazole salt is isolated from the reaction mixture by filtration or extraction with water. Removal of the R 1 protecting group in the compound of formula (I) may be converted by known methods, in the case of simvastatin e.g. using tetrabutylammonium fluoride in acetic acid (EP-B-33 538) or using BF ₃ etherate (EP-A-444 888) or concentrated hydrochloric acid in THF, 1,4-dioxane, 1,3-dioxane, methoxyethane, diethyl ether (WO 01/45484 A2).

The advantage of the process according to the invention is, compared to known processes, a high product yield of formula (I), typically above 98%, high process reproducibility, significant suppression of side reactions and reduction of unwanted impurities especially dehydroderivative (unsaturated lactone). the process becomes applicable on an industrial scale.

The main advantage of the process according to the invention is the high purity of the product of formula (I), which makes it possible to use less demanding purification operations in isolation e.g. Simvastatin, making the process of producing high purity simvastatin economical. Reducing the amount of acylating agent has contributed significantly to the ecology and economy of simvastatin production.

The process according to the invention is illustrated by the following non-limiting examples.

DETAILED DESCRIPTION OF THE INVENTION

Example # 1 Preparation 6 (R) - [2 [8 (S) - (2,2-Dimethylbutyryloxy) -2 (S), 6 (R) -dimethyl-1,2,6,7,8a (R) -hexahydronaphthyl- 1 (S)] -4 (R) -tert-Butyldimethylsilyloxy-3,4,5,6-tetrahydro-2H-pyran-2-one

300 ml of toluene, 40 g of silyldiollactone (0.092 mol), 15.15 g of imidazole (0.22 mol), 0, 85g of N are successively charged to a 1 liter three-necked flask equipped with a stirrer, reflux condenser, while stirring and cooling to -10 ° C. , N-dimethylaminopyridine (0.007 mol) and 29.6g of 2,2-dimethylbutyryl chloride (0.22 mol). The mixture was heated to reflux (111-114 ° C) under gentle inert gas inlet and stirred at this temperature for 6 hours. The conversion of silyldiollactone to silylsimvastatin is monitored by HPLC. The purity of silylsimvastatin is 98.12 area%, dehydrosimvastatin 0.55 area%.

The resulting silylsimvastatin is isolated from the reaction mixture and can be converted to simvastatin by removal of the silyl protecting group by known methods.

Measured NMR spectra of silylsimvastatin according to Example 1:

1 H-NMR (300 MHz, CDCl 3) in ppm

NMR sotktrum

Teb, NMR of Silylsimvastatin

(10.1 μ ^ / ml in mciwrolc) λ [nm] Λ ηΓ ........ 0.2Ϊ74

239 0.31,18

247 0.2? 9l

SK 285 772 B6

Example # Preparation 6 (R) - [2 [8 (S) - (2-Methylpropanoyloxy) -2 (S), 6 (R) -dimethyl-1,2,6,7,8a (R) -hexahydronaphthyl-1 ( (S)] - 4 (R) -tert-Butyldimethylsilyloxy-3,4,5,6-tetrahydro-2H-pyran-2-one (product)

300 ml 1,2-dichloroethane, 40 g silyldiollactone (0.092 mol), 15.15 g imidazole (0.22 mol) are successively charged to a 1 It three-necked flask equipped with a stirrer, reflux condenser, while stirring and cooling to -10 ° C, 0.85g of N, N-dimethylaminopyridine (0.007mol) and 23.44g of 2-methylpropionyl chloride (0.22mol). The mixture was heated to reflux (85-87 ° C) under gentle inert gas inlet and stirred at this temperature for 24 hours. Conversion of silyldiollactone to 6 (R) - [2 [8 (S) - (2-methylpropanoyloxy) -2 (S), 6 (R) -dimethyl-1,2,6,7,8a (R) -hexahydronaphthyl-1] (S)] -4 (R) -tert-Butyldimethylsilyloxy-3,4,5,6-tetrahydro-2H-pyran-2-one is monitored by HPLC. The purity of the product is 97.5% by area, the dehydroderivative is 0.8% by area.

The resulting product is isolated from the reaction mixture and can be converted to 6 (R) - [2 [8 (S) - (2-methylpropanoyloxy) -2 (S), 6 (R) -dimethyl-1,2,6,7,7] 8a (R) -hexahydronaphthyl-1 (S)] - 4 (R) -hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one by removal of the silyl protecting group by known methods.

foioha ^J C

d in ppm d ppm * J / Hz J 68.0 326 27.5 5.37 m 42 - 2.39 m 4 129.7 5 51 m 4a 131.6 5 128.4 6 00 d 9.7 6 133.1 5 78 dd 9.7.6.2 7 33.8 2.42 2.39 m 8 36.8 1.60 m 8a 374 2.20 m 9 10 C-3 CH 23.9 33.0 22.8 1.07 d 7.4 C-7-CI1, 13 9 0.89 d 7.0 I ' 76.3 4.64 m y 4 ' 36.0 62.5 4.36 m 5 ' 38.6 2.69 dd 17.5,5.0 6 ' 1 ' 170.6 177.4 2.58 ddd 1.6 2 34.5 3 ' 18.6 ÍJ5d 4.5 19.5 1.13 d 4.5

Industrial usability

where R is a C 1 to C ₁₂ alkyl group, in the case of simvastatin, a CH ₃ - CH ₂ - C (CH ₃ ) ₂ - group,

R is trialkylsilyl, a triarylsilyl group of a protected diollactone of formula (II),

wherein R 1 is as defined above, characterized in that the reaction is carried out by treating the protected diollactone of formula (II) with an acylating agent, wherein the acylating agent used is in a 1.5 to 3 molar excess of the protected diollactone of formula (II) used. imidazole and dimethylaminopyridine in a solvent selected from the group of aromatic hydrocarbons, preferably toluene, or chlorinated aliphatic hydrocarbons, preferably dichloroethane, at a temperature of -10 ° C to the boiling point of the solvent used.

Claims (1)

A process for the preparation of a compound of formula (I) according to claim 1, characterized in that the acylating agent is an acyl halide of formula (IIIa) R-CO-halogen (IIIa) or an acid anhydride of formula (IIIb) (R-CO) ₂ O (IIIb), or an in situ intermediate of formula (IIIc) (R-CO-Imidazole) ⁺ X '(IIIc) ), wherein X is chloro, bromo or the radical R-COO, R is C 1 to a C ₁₂ alkyl group, preferably a CH ₃ - CH ₂ C (CH ₃ ) ₂ - group. The invention is useful in the pharmaceutical industry for the industrial manufacture of the substance simvastatin, which is subsequently used as an HMG-CoA reductase inhibitor for the manufacture of dosage forms for the treatment of hypercholesterolemia. End of document PATENT CLAIMS 1. Process for the preparation of a compound of formula (I)