SK283319B6 - Process for manufacturing simvastatin from lovastatin or mevinolinic acid - Google Patents

Abstract

A process for preparing simvastatin from lovastatin or mevinolinic acid in salt form comprises treating either starting material with cyclopropyl or butyl amide, the pyranone ring thereby being opened when lovastatin is the starting material, adding a methyl group to the 2-methylbutyrate side chain, and thereafter closing the open pyranone ring to produce simvastatin. The process is performed without protecting and deprotecting the two hydroxy groups of the open pyranone ring. In a preferred embodiment, the starting material is treated with cyclopropyl amine, which produces simvastatin via the novel intermediate lovastatin cyclopropyl amide.

Description

Technical field

The invention relates to a process for the production of simvastatin from lovastatin or mevinolinic acid.

BACKGROUND OF THE INVENTION

The compounds of structure (I) shown later are very potent antihypercholesterolemic agents whose function is to reduce cholesterol biosynthesis by inhibiting the enzyme HMG-

Compounds of formula (I) include the natural fermentation products mevinoline (structure (Ia), where R is CH ₃ , published in US Patent No. 4,231,938 and also known as lovastalin), compactin (structure (1b), wherein R is H No. 3,983,140), as well as a variety of semisynthetic or wholly synthetic analogs thereof, all of which have a natural side 2-methylbutyrate chain.

The compounds of formula (II) shown later have a 2,2-dimethylbutyrate side chain (for example, simvastatin of structure (IIa), wherein R is CH ₃ ). They are known to be more potent inhibitors of HMG-CoA reductase than their 2-methylbutyrate analogs and are therefore more useful in the treatment of atherosclerosis, hyperlipemia, familial hypercholesterolemia, and related disorders.

The recent introduction of simvastatin (Ha) as a more potent HMG-CoA reductase inhibitor than lovastatin (1a) has led to the need to develop a method that provides higher yield and is economically efficient and environmentally friendly than the methods disclosed in state of the art.

Compounds of structure (II) (e.g., simvastatin) with a 2,2-dimethylbutyrate side chain and methods for their preparation are disclosed in U.S. Pat. No. 4,444,784 and EPO published in patent application no. 33538. The disclosed method involves different chemical steps. These are de-esterification of the 2-methylbutyrate side chain, protection of the 4-hydroxy group of the pyranone ring, re-esterification of the side chain while forming 2,2-dimethylbutyrate, and deprotection of the 4-hydroxy group. This road is cumbersome and results in lower overall yields.

Simvastatin has also been prepared by α-alkylation of the ester moiety as described in U.S. Pat. 4,582,915 and 4,820,850.

With regard to obtaining simastatin, U.S. Pat. No. 4,582,915 (1986) direct methylation of the natural side chain of 2- (S) -methylbutyryloxy chain of mevinoline in one chemical step, using a metal alkyl amide and a methyl halide. A disadvantage of this procedure is the low conversion rate in the C-methylation step. Furthermore, a number of side reactions occur on methylation in other parts of the molecule. The rate of C-methylation conversion can be improved to some extent by the second or third batch of the basic amide and methyl halide. Nevertheless, the overall yields are average. Also, the purity of simvastatin obtained by this process approaches the limit of its use as a treatment product.

U.S. Pat. No. 4,820,850 (1989) discloses a process that involves a rapid C-methylation conversion of the mevinoline side 2- (S) -methylbutyryloxy side chain, running with a single dose of a basic amide and an alkylhylogenide. The process described in this patent involves six steps and is not economically advantageous as it involves protecting and deprotecting the two hydroxy groups of the lovastatin butylamide intermediate using an expensive silylating agent, i. j. t-butyldimethylsilyl.

SUMMARY OF THE INVENTION

The invention provides a novel process and novel by-products for the preparation of simvastatin (IIa). The new process can be described in the reaction scheme.

ACTION SCHEME

An essential feature of the invention is that the preparation of simvastatin can be carried out from the salt of mevinolinic acid, as a starting material, better than from lovastatin. Simvastatin is prepared in four steps, which do not involve the protection or deprotection of the two hydroxy groups of the open pyranone ring, which was necessary for the preparation of simvastatin for the prior art processes described so far. A preferred embodiment of the invention is that the novel intermediate lavostatin cyclopropylamide (IIIb) is prepared from a starting material (lavostatin or mevinolinic acid salt forms). This new intermediate is then converted to a second new intermediate (IVb).

Simvastatin prepared by the process of the invention has certain advantages in commercial production. The purity and yield of simvastatin prepared by the process of the invention is high, while at the same time consuming low reagent consumption, time, labor and expense, and produced using fewer steps.

DETAILED DESCRIPTION OF THE INVENTION

The starting material of the process according to the invention is lovastatin (Ia) or mevinolinic acid (Ic), which is later an open form of lovastatin. Mevinolinic acid is produced by Aspergillus terreus (see U.S. Patent No. 4,231,938). Typically, either lovastatin (Ia) or the salt form of mevinolinic acid (Ic) is used as the starting material. Unless otherwise specified, the term "mevinolinic acid" includes suitable salt forms thereof. Any salt form which does not interfere with the other reagents or conditions under which the invention is practiced is acceptable. Alkali metal salts such as Na and K or preferably an ammonium salt may be used.

Lovastatin is obtained from mevinolinic acid by lactonization, by methods well known in the art, and isolated by crystallization techniques in which losses occur. When naturally occurring mevinolinic acid is converted to lovastatin, there is probably a 20% loss of material. One object of the invention is to eliminate this loss by using mevinolinic acid as the starting material better than lovastatin.

According to the method of the invention, simvastatin (IIIa) is prepared by reacting lovastatin (Ia) or mevinolinic acid (Ic), which is preferably in the form of an ammonium salt, with n-alkylamine or cycloalkylamine of formula R ³ -NH 2 wherein R ³ is C 3 to C ₅ .

Preferably, the amine R ^{3 is} -NH 2 cyclopropylamine and the intermediate which is formed is lovastatin cyclopropylamide (IIIb). Optionally, the amine R ³ -NH 2 n-butylamine and the intermediate that is formed is lovastatin n-butylamide (IIIa).

The cyclic intermediates thus prepared, amides (IIIa) and (IIIb), are dissolved in dry tetrahydrofuran and added to a solution of an alkyl metal amide such as lithium pyrrolidide in tetrahydrofuran at a temperature of about -35 ° C to -40 ° C. Lithium pyrrolidide is formed in situ by reaction of n-BuLi with pyrrolidine in tetrahydrofuran. A solution of the intermediate, amide (IIIa) or (IIIb) and the in situ base is allowed to stand for one hour at about -35 to -40 ° C and then dry alkyl halide, preferably methyl iodide (2 to 3.5 molar) is added in one portion. eq). The contents were stirred at about -30 ° C for 1 hour, further heated to -10 ° C and allowed to stand for 20 minutes. Water was added to the reaction mixture and the layers were separated. The tetrahydrofuran layer is washed with a mineral acid, preferably hydrochloric acid, and then concentrated to an oily matter containing intermediates (IVa) or (IVb).

To a solution of intermediate (IVa) or (IVb) in methanol, 2 N NaOH is added without prior purification, and the mixture is refluxed at about 80 ° C to 81 ° C for 2 to 6 hours, preferably 2 hours. The mixture was cooled to about 50 ° C and methanol was removed under reduced pressure and then diluted with water. The mixture is then acidified at about 10 ° C by the careful addition of 2N HCl while maintaining pH 6, further extracted with ethyl acetate while further acidifying to pH 4. The ethyl acetate layer is separated and the hydrolyzed product precipitates as a crystalline substance in the form of of ammonium salt (V) by slowly adding methanolic ammonium hydroxide over about 22 minutes at about 22 ° C to 25 ° C, followed by cooling to 5 ° C.

The ammonium salt (V) is re-lactonized by heating in a hydrocarbon solvent such as toluene. The mixture is suspended in toluene, heated and stirred at about 100 ° C to 110 ° C for 2 to 10 hours, preferably at about 105 ° C for 5 hours under a stream of nitrogen gas. The mixture is then cooled to about 35 ° C and carbon is added. The mixture is filtered and the filtrate is concentrated under reduced pressure at a bath temperature of about 60 ° C to one-tenth of its original volume. The lactone is crystallized from a hydrocarbon solvent such as cyclohexane to give simvastatin (IIIa) of high purity.

The most preferred embodiment of the process according to the invention is that the ammonium salt of mevinolinic acid (Ic) is used as the starting material and is converted to lovastatin cyclopropylamide (IIIb). The mevinolinic acid salt is suspended in toluene and refluxed for 5-6 hours at about 100 ° C to 110 ° C, and preferably at about 105 ° C to 107 ° C. The resulting solution was concentrated to one-tenth of its volume by distilling toluene under reduced pressure at a bath temperature of about 55 ° C to 57 ° C. Cyclopropylamide is added at 30 ° C and the mixture is again heated at about 40 ° C to 50 ° C for 5-6 hours. Toluene and unreacted cyclopropylamide were distilled off under reduced pressure to give lovastatin cyclopropylamide (IIIb) in quantitative yield. The cyclic amide thus prepared is used in a subsequent C-methylation step similar to that described above without protecting the dihydroxy system to obtain simvastatin (IIa).

The following examples further illustrate the invention.

Example 1

Preparation of simvastatin (IIIa) from the ammonium salt of mevinolinic acid (Ib) using cyclopropylamine

Step 1: N-cyclopropyl-7- [1,2,6,7,8,8a (R) -hexahydro-2 (S), 6 (R) -dimethyl-8 (S) - [[2 (S) amide] 1-methylbutanoyl] oxy] -1 (S) -naphthyl] -3 (R), 5 (R) -dihydroxyheptanoic acid (IIIb)

The mevinolinic acid ammonium salt (Ic) (12.5 g, 0.296 mol) was suspended in toluene (400 mL). The mixture was heated and stirred at 105 ° C to 107 ° C for 5 hours under a stream of nitrogen. Then the temperature was lowered to 60 ° C and about 350 ml of toluene was distilled off. Cyclopropylamine (12 mL, 0.172 mol) was added at 30 ° C and the solution was stirred again at 40 ° C to 45 ° C for 4 hours. Under reduced pressure and at a bath temperature of 55 ° C, toluene was slowly removed to give the title compound as a resin. HPLC purity corresponds to 99.63%, Ή NMR (CDCl 3, 300 MHz): δ 0.495 (m, 2H), δ 0.50 (m, 2H), δ 0.86 (m, 6H), δ 1.08 ( m, 6H), δ 2.3 (d, 2H), δ 2.6 (m, IH), δ 3.7 (m, IH), δ 4.18 (m, IH), δ 5.4 ( m, IH), δ 5.5 (bt, J-3.0 Hz, IH), δ 5.7 (dd, J = 6.1, 9.5 Hz, IH), δ 5.9 (d, J = 9.6 Hz, IH), δ 6.2 (bt J = 5.3 Hz, IH); IR (CHCl 3): λ ™ 3500-3300 (b), 3000, 1740, 1660, 1530, 1450, 1210, 860, 760 cm ^-1 .

This resin was used directly in the next step without purification.

Step 2: N-cyclopropyl-7- [1,2,6,7,8,8a (R) -hexahydro2 (S), 6 (R) -dimethyl-8 (S) - [[2,2-dimethylbutanoyl] amide oxy] -1 (S) -naphthyl] -3 (R), 5 (R) -dihydroxyheptanoic acid (IVb)

Pyrrolidine (13.5 mL, 0.163 mol) in tetrahydrofuran (50 mL) was cooled to -45 ° C and n 3 was added under nitrogen.

-butyllithium in hexane (1.6 M, 100 mL, 0.163 mol) at such a rate as to maintain the temperature from -20 ° C to -15 ° C. After the addition was complete, the mixture was stirred at -20 ° C to -25 ° C for 40 minutes.

A solution of compound (IIIb) in tetrahydrofuran (300 mL) was prepared as described and then slowly added via cannula, maintaining the temperature below -35 ° C throughout the addition. The solution was allowed to stand at -35 ° C to -40 ° C for 1 hour. Sieved, dry methyl iodide (4.82 mL, 0.077 mol) was added in one portion. The thus obtained, not completely white, cloudy solution was stirred at -35 ° C to -40 ° C for 1 hour, then warmed to -10 ° C and allowed to stand for 20 minutes. Distilled water (105 mL) was added to the reaction mixture, and the contents were stirred vigorously for 5 minutes. The layers were separated and the upper tetrahyrofuran layer was treated with 1N HCl (105 mL). The tetrahydrofuran layer was concentrated under reduced pressure to a volume of about 40 mL to yield the title compound (IVb) where r ₃ is cyclopropyl.

Step 3: 6 (R) - [2- [8 (S) - (2,2-dimethylbutyryloxy) -2 (S), 6 (R) -dimethyl-1,2,6,7,8,8a (R)] 1-Hexahydro-1 (S) -naphthyl] ethyl] -4 (R) -hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one (IIIa) (simvastatin)

To a concentrated solution from the previous step containing compound (IVb) was added aqueous NaOH (2N, 25 mL) and methanol (175 mL). The mixture was refluxed at 80 ° C to 81 ° C for 2 hours and cooled to 50 ° C. The maximum of methanol was removed under reduced pressure and the mixture was dissolved in water (90 mL). Acidification of the solution was accomplished by careful addition of 2N HCl (pH 6). 200 mL of ethyl acetate was added and the mixture was vigorously stirred while further acidification continued to pH 4. The ethyl acetate layer was separated from the aqueous layer. A 1: 1 solution of ammonium hydroxide and methanol (10 mL) was slowly added over 30 minutes at 22 ° C to 25 ° C. The precipitates were stirred at 25 ° C for 1.5 hours, cooled to 5 ° C and stirred at this temperature for 30 minutes. Filtration was followed by washing with cold ethyl acetate (25 mL) and drying under vacuum at 35 ° C to give the ammonium salt (V).

The crude ammonium salt (V) from the previous step (10 g, 0.022 mol) was suspended in toluene (350 mL). The mixture was heated and stirred at 105 ° C under a stream of nitrogen for 5 hours. The solution was cooled to 35 ° C, activated carbon (0.5 g) was added with stirring for 0.35 hours, and then the solution was filtered through a pad of celite. The filtrate was further concentrated in vacuo to a volume of 40 mL at a 60 ° C bath. 125 ml of cyclohexane were added and the solution was refluxed again for 15 minutes and cooled to 25 ° C for 1 hour and further cooled to 10 ° C to 12 ° C for 30 minutes. The precipitates were stirred at 10-12 ° C for 30 minutes, filtered and washed with cold cyclohexane (50 mL), dried in vacuo at 35 ° C to give a white crystalline product (IIIa), which was further crystallized from anhydrous ethanol to obtained the title product with a purity greater than 99%.

Example 2 Preparation of simvastatin (IIIa) from lovastatin (Ia) using cyclopropylamine

Step 1: N-cyclopropyl-7- [1,2,6,7,8,8a (R) -hexahydro-2 (S), 6 (R) -dimethyl-8 (S) - [2 (S) amide] -dimethylbutanoyl] oxy] -1 (S) -naphthyl] -3 (R), 5 (R) -dihydroxyheptanoic acid (IVb)

Lovastatin (Ia) (12.5 g, 0.03 mol) was suspended in cyclopropylamine (13 mL, 0.174 mol) at 25 ° C. The mixture was slowly heated to 40 ° C to 45 ° C and stirred at this temperature for 5 hours. The excess amine was evaporated under reduced pressure and a 40 ° C bath to afford the title compound as a resin. This resin was used directly in the next step without prior purification.

Step 2, 3: the compound (IIIb) obtained from the previous step was converted to simvastatin (IIIa) by the same procedure as described in Example 1.

Examples 3 and 4

Preparation of simvastatin (IIa) from lovastatin (1a) and the ammonium salt of mevinolinic acid (Ic) as starting materials

The same steps as described in Examples 1 and 2 were followed, but an equimolar amount of n-butylamine was used instead of cyclopropylamine.

Specific embodiments of the invention are illustrative only. Numerous embodiments that will be apparent to those skilled in the art are within the scope of the claims.

Claims (20)

A process for the preparation of simvastatin of formula (IIa), characterized in that the compounds of formula (I ') comprise i) a reaction and R ² is -H, Na *, K ⁺ or NH 4 ⁺ , together with an alkylamine having the formula R ³ NH 2, R ³ is a C ₃ -C ₆ n-alkyl or cycloalkyl group to form a compound of formula (III) ii) which reacts with a methylating agent to give a compound of formula (IV) wherein R ³ is as defined iii) followed by removal of R ³ and closing the open pyranone ring of the compound Of formula (IV) to form simvastatin of formula (IIa). The process according to claim 1, wherein the R ³ group is removed without protecting or deprotecting the two hydroxy groups of the open pyranone ring of the compound of formula (IV). The process according to claim 1, wherein the R ³ group is removed by reacting a compound of formula (IV) with a base and then converting the resulting compound in an organic solvent to give simvastatin of formula (11a). Process according to claim 3, characterized in that the group R ³ is cleaved by reacting a compound of formula (IV) with a strong base, followed by reaction with ammonium hydroxide to give a compound of formula (V) which is then converted in toluene to give simvastatin of formula (IIa) according to claim 1, which is purified by crystallization from a hydrocarbon solvent. The process according to claim 4, wherein the strong base is sodium hydroxide. The process according to claim 3, wherein the organic solvent is toluene. A process according to claim 1, wherein R ³ is a cyclopropyl group. A process according to claim 1 wherein R ³ is an n-butyl group. The process of claim 1 wherein the methylating agent is a methyl halide. The method of claim 9, wherein the methylating agent is methyl iodide. The process according to claim 9, wherein the compound of formula (III) is reacted with a methyl halide in the presence of a base. The process according to claim 11, wherein the base is lithium pyrrolidide. The process of claim 1 wherein R ^{2 is} NH ₄ ⁺ . A process for producing simvastatin of formula (IIa), characterized in that the compounds of structural formula (I ') comprise i) reaction and R ² is -H, Na ⁺ , K ⁺ or NH ₄ ⁺ with cyclopropylamide to form a compound of formula III wherein R ³ is a cyclopropyl group, ii) which reacts with a methyl halide to form a compound of formula (IV) wherein R ³ is defined iii) followed by removal of the R ³ group and closing the open pyranone ring of a compound of formula (IV) to form simvastatin IIIa), according to claim 1. 15. The method according to claim 14, characterized in that r ² is NH ₄ ^+. 16. The process of claim 14 wherein the methyl halide is methyl iodide. Process according to claim 16, characterized in that the compound of formula (III) is reacted with methyl iodide in the presence of lithium pyrrolidide. The process of claim 14, wherein the R ³ group is removed by reacting a compound of formula (IV) with a base, followed by converting the resulting compound in an organic solvent into the simvastatin of formula (II) according to claim 1. The process of claim 18, wherein the base comprises sodium hydroxide followed by ammonium hydroxide. 20. The process of claim 18 wherein the organic solvent is toluene.