WO2006072963A1

WO2006072963A1 - Process for preparing simvastatin from lovastatin amine salts in three steps

Info

Publication number: WO2006072963A1
Application number: PCT/IN2005/000066
Authority: WO
Inventors: Sudhir Vaid; Pradeep Dr. Narula
Original assignee: Concord Biotech Limited
Priority date: 2005-01-10
Filing date: 2005-02-25
Publication date: 2006-07-13

Abstract

The application describes a new process for preparing Simvastatin from Lovastatin amine salts in three steps. Lovastatin was hydrolysed to acid form and then isolated in the form of amine salt like cyclopropyl or t-octyl amine etc. The salts isolated were methylated directly without any protection and deprotection of hydroxy groups. The Simvastatin ammonium salt was produced directly, converted to Simvastatin by conventional methods & then purified to Simvastatin.

Description

PROCESS FOR PREPARING SIMVASTATIN FROM LOVASTATIN AMINE SALTS IN THREE STEPS

TECHNICAL FIELD:

The present invention relates to a novel process and a Novel intermediates for preparing of Simvastatin (Ha) starting from the materials Lovastatin Amine Salts or any other salts of Mevinolinic Acid.

KEY INTERMEDIATES IN THE MANUFACTURE OF SIMV ASTATIN

• REFERENCE TO RELATED APPLICATION

This patent application is related to a patent application entitled PROCESS FOR MANUFACTURING SIMV AST A TIN FROM LOV AST A TIN OR MEVINOLINIC ACID assigned Ser. No. 08/816,573, and filed on Mar 13, 1997.

• BACKGROUND OF THE INVENTION

Compounds of structure I shown below are very active antihypercholesterolemic agents that function to limit cholesterol biosynthesis

(Ia) : R — CH3 : Lovastatin (Ib) : R — H : Compactin by inhibiting the enzyme HMG-CoA reductase.

Compounds of structure I include the natural fermentation product mevinolin (structure Ia where R=CH3, disclosed in U.S. Pat. No. 4,231,938, and also known as lovastatin), compactin (structure Ib where R=H, disclosed in U.S. Pat. No. 3,983,140), and a variety of semi-synthetic and totally synthetic analogs thereof, all having the natural 2-methylbutyrate side chain.

Compounds of structure II shown below having a 2,2-dimethylbutyrate side chain (e.g., simvastatin, structure Ha where R=CH3) are known to be more active inhibitors of HMG-CoA reductase than their 2-methylbutyrate analogs, and thus of greater utility in the treatment of atherosclerosis, hyperlipemia, familial hypercholesterolemia, and similar disorders.

(Ha) : R' = CH₃ : Simvastatin

Simvastatin (II), a more potent HMG-COA reductase inhibitor than lovastatin (Ia), has provide a need for a high yielding process which is more economically efficient and environmentally sound than those disclosed in the prior art.

Compounds of structure (II (e.g., simvastatin) with the 2,2-dimethylbutyrate side chain, and processes for their preparation are disclosed in U.S. Pat. No. 4,444,784 and EPO published patent application No. 33538. The process disclosed therein involves four distinct chemical steps:

• De-Esterification of the 2-methylbutyrate side chain;

• Protection of the 4-hydroxy group of the pyranone ring;

• Re-esterification of the side chain to form the desired 2,2- dimethylbutyrate; and

• Deprotection of the 4-hydroxy group.

This route is tedious and gives low overall yields.

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

U.S. Pat no. 4,582,915 (1986) discloses the direct methylation of the natural 2- (S)-methyl butyryloxy side chain of mevinolin in a single chemical step using a metal alkyl amide and a methyl halide to give simvastatin. This process suffers from poor conversion rate of the C-methylation step. Additionally, many side reactions take place due to methylation at other sites of the molecule. The C-methylation conversion rate may be improved to some extent by a second or a third charge of the amide base and methyl halide. Even so, the overall yields are moderate. Also, the purity of simvastatin obtained by this process is close to borderline for use as a human health-care product.

U.S. Pat. No. 4,820,850 (1989) discloses a process wherein high conversion C-methylation of the 2-(S)-methyl butyrloxy side chain of mevinolin takes place with a single charge of amide base and alkyl halide. The process described in this patent comprises six steps and is not economical as it involves the protection and deprotection of the two hydroxy groups of the intermediate lovastatin butyl amide using an expensive silylating agent, tertbutyldimethylsilyl chloride.

U.S. Pat. No. 5,763,646 (1998) discloses a process wherein high conversion C-methylation of the 2-(S)-methyl butyrloxy side chain of mevinolin takes place with a single charge of amide base and alkyl halide. The process described herein did not involve any protection and deprotection of hydroxy groups. However in this process the starting material Lovastatin amide is oily in nature and it also require six steps to get Simvastatin.

SUMMARY OF THE INVENTION

The present invention provides a novel process and novel intermediates for the preparation of simvastatin (Ha). The novel process may be depicted by the following reaction scheme: The starting material Lovastatin amine salt can be prepared from Lovastatin or any other salt of Mevinolinic acid.

(Ilia) : R = -cyclopropyl (HIb) : R = -t-octyl

Salient Features of the invention include:

(a) Simvastatin may be prepared from a salt of mevinolinic acid as the stating material rather than lovastatin.

(b) Simvastatin is prepared in a four step process which does not include the protection and deprotection of the two hydroxy groups of the open pyranone ring. Here the first intermediate is isolated as crystalline solid , the methods described in the prior art describe the first intermediate as oils and then methylation via protection of the hydroxy groups as essential steps for the preparation of simvastatin.

(c) In a preferred embodiment, the novel intermediate lovastatin amine salt (III a/b/c) is prepared from the starting material (lovastatin or a salt form of mevinolinic acid). This novel intermediate is then converted into a second novel intermediate (IV).

Simvastatin prepared by the inventive process has certain advantages in commercial manufacture. The purity and yield of simvastatin from the inventive process is high, with less consumption of reagents, time, labor, and cost, and in fewer steps. DETAILED DESCRIPTION OF THE INVENTION

According to the novel process of the present invention, simvastatin (Ha) is prepared by reacting lovastatin (Ia) or mevinolinic acid (Ic), preferably in the salt form where R₁= Na₅K₅NH₄ to amine salt form using alkyl amines or a cycloalkylamine of formula R₂-NH₂, wherein R₂ is C₃-Cg. Preferably, the amine R₃- NH₂ is t-octylamine or cyclopropylamine and the intermediate that is formed is lovastatin cyclopropylamine salt (III a or III b). The intermediate amine salt Ilia or IHb thus prepared is dissolved in dry tetrahydrofuran and is added to a solution of alkali metal amide, e.g., lithium pyrrolidide in THF at a temperature of about-35° C. to -40° C Lithium pyrrolidide is generated in situ by the reaction of n-BuLi with pyrrolidine in THF. The solution of intermediate amine salt Ilia or IHb₅ and the in situ generated base is aged at about -30° C to -25°C. for 1 hour, and dried alkyl halide, preferably methyl iodide (2 to 3 mol.eq.), is added in a single charge. The contents are stirred at about -30° C. for 1 hour, warmed to -10° C. and aged at this temperature for 20 minutes. Water is added to the reaction mixture and the layers are separated. The THF layer is washed with a mineral acid, preferably hydrochloric acid, and then with ammonium chloride solution. The THF layer concentrated under vacuum at 40-45° C to almost dryness. The oily residue was then dissolved in ethyl acetate. From the solvent phase the compound is directly isolated as Simvastatin ammonium salt by adding methanolic solution of ammonium hydroxide.

The compound was now directly converted to crude Simvastatin by heating in a hydrocarbon solvent such as toluene. The mixture is suspended in toluene, heated and stirred at about 100°-110° C. for 2 to 10 hours, preferably at about 105° for 5 hours, under a sweep of nitrogen gas. The mixture is then cooled to about 35° C, carbon treated, filtered, and the filtrate is concentrated under reduced pressure at about a 60° C. bath temperature to one-tenth of its original volume. The lactone is crystallized from a hydrocarbon solvent such as cyclohexane to give simvastatin (Ha) of high purity.

The following examples further illustrate the present invention: EXAMPLE: - 1

Preparation of Mevinolinic Acid cyclopropyl Salt (Ib) Using Cyclopropylamine

Step- 1: N-Cyclopropyl-7[l,2,6,7,8,8a®-hexahydro-2(S),6(R)-dimethyl-8(S)- [l2(S)-methylbutanoyl]oxy]-l(S)-naphthyl]-3(R),5(R)-dihydroxyheptanoic acid amine salt (IHb).

Lovastatin (12.5 g, 0.031moles) was suspended in methanol (25 ml). To the reaction mixture was added solution of sodium hydroxide in water(1.25 g in 50 ml of water).The mixture was heated and stirred at 35°-40°C for 45 minutes till hydrolysis is deemed complete. Added 50 ml of water and the pH of the reaction mixture is now adjusted to 4.0-4.2.The compound is now converted as acid was extracted in ethyl acetate(50ml) twice. The ethyl acetate layer separated was dried over sodium sulphate. To the E.A layer separated added cyclopropyl amine (2.15 ml) and acetone(20 ml) . The compound precipitated as ammonium salt was filtered and washed with acetone (20ml). The compound was dried under vacuum at 40-45° C to give 13 g of ammonium salt. HPLC purity=99.63%; IHNMR (CDCL₃, 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(CHCL₃) λ max 3500-3300 (b), 3000, 1740, 1660, 1530, 1450, 1210, 860, 760 cm-¹.

The above mentioned amine can also be prepared directly from Mevinolinic acid or it's salt form by above mentioned method.

Step-2: N-Cyclopropyl-7-[l,2,6,7,8,8a(R)-hexahydro-2(S),6(R)-dimethyl-

8(S)-[[2,2-dimethyl-butanoyl]oxy]-l(S)-naphthyl]-3(R),5(R)- dihydroxyheptanoic acid amine salt

Pyrrolidine (13.5 ml, 0.140 moles) in THF (50 ml) was cooled to -45° C. and n-butyl lithium in hexane (1.6M, 96 ml, 0.102 moles) was added under nitrogen at such a rate so as to maintain a temperature of -30° to -25° C. The mixture was stirred at -30° to -25° C for 60 minutes after the completion of addition.

A solution of compound IIIb(13 g ,0.02 mole) in THF (130 ml) was then slowly added via a cannula maintaining the temperature -35° to -3O⁰C. The solution was aged at -35° to -30° C. for 1 hour. Sieve dried methyl iodide (3.75 ml, 0.060 moles) was added in a single lot at -30 to -20⁰C. The off- white, cloudy solution thus obtained was stirred for 1 hour at -30° to -20° C then warmed to -10° C. and aged for 20 minutes. Distilled water (100 ml) was added to the reaction mixture and the contents vigorously stirred for 5 minutes. The layers were separated and the upper THF layer was treated with IN HCL (50 ml). The THF layer was concentrated at reduced pressure to a volume of about 20 ml to give Simvastatin acid in oil form. The acid was dissolved in ethyl acetate(50 ml) and added methanolic solution of ammonium hydroxide 5 ml in 10 ml of methanol. Simvastatin acid is precipitated as ammonium salt. HPLC purity 99.10% Lovastatin acid content is 0.60% IH NMR (CDCL₃, 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=O.1, 9.5 Hz, IH), δ 5.9 (d, J=9.6 Hz, IH), δ 6.2 (bt, J=5.3 Hz, IH); IR(CHCL₃) λ max 3500-3300 (b), 3000, 1740, 1660, 1530, 1450, 1210, 860, 760 cm^"1.

Step-3: 6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-2(S),6(R)-dimethyl- l,2,6,7,8,8a(R)-hexahydro-l(S)-naphthyl]ethyl]-4(R)-hydroxy-3,4,5,6- tetrahydro-2H-pyran-2-one (Ha) (Simvastatin)

The crude ammonium salt (V) from the previous step (1Og, 0.023 moles) was suspended in toluene (100 ml). The mixture was heated and stired at 105° C. under a sweep of nitrogen for 5 hours. The solution was cooled at 35° C, activated charcoal (0.5 g ) was added, stirred for 0.35 hour, and then filtered through celite bed. The filtrate was concentrated in vacuum to a volume of 40 ml at 60° C. bath temperature. Cyclohexane (40 ml) was added and the solution again refluxed for 15 minutes, cooled for 1 hour to 25° C, and further cooled to 10°-12° C. for 30 minutes, filtered and washed with cold cyclohexane (50 ml), dried in vacuum at 35° C. to give white crystalline product (Ha) which was further crystallized from absolute ethanol to afford the title product of >99% purity.

While the invention has been described by reference to specific embodiments, this was for purposes of illustration only. Numerous alternative embodiments will be apparent to those skilled in the art and are considered to be within the scope of the claims.

Claims

Claims: We claim;

1. A Process of producing a compound of structural formula II a

(Ua) : R' = CH₃ : Simvastatin

comprising treating a compound of formula Ia or Ic

(Ia) : R = CH₃ : Lovastatin

R, : M-It / K / Na

and R₂ is hydrogen ,sodium,,K or ammonium with an alkyl amine having the formula R₁ NH₂ ,where in Rj is a C₃-Cs n-alkyl or cycloalkyl grouρ,to produce a compound of structural formula III.

( I I I a) : R₁ = - cycl opr o

( I I I b) : R₁ = - t - oct yl

including R₁ as all amines from C₃ to C₈.

2. Treating said compound of structural formula III with a methylating agent to produce a compound of structural formula (Ic).

3. The process of claim 1 wherein step(ii) is performed without protecting or deprotecting the two hydroxy groups of the open pyranone ring of said compound of structural formula III.

4. The process of claim 1, wherein the compound of structural formula III is directly converted to compound of structural formula IV.

5. The process of claim 3, wherein said organic solvent is ethyl acetate and acetone.

6. The process of claim 1, wherein R₃ is Na, K, NH4 group.

7. The process of claim 1, wherein R₂ is a cyclopropyl or t-octyl group .

8. The process of claim 1, wherein said methylating agent is methyl halide.

9. The process of claim 7, wherein said methylating agent is methyliodide.

10. The process of claim 8, wherein said compound of structural formula III is treated with said methyl halide in the presence of a base.

11. The process of claim 9, wherein said base is lithium pyrrolidine.

12. The process of claim 10, wherein R₃ is NH₄