HRP970435A2 - Process for manufacturing simvastatin from lovastatin or mevinolinic acid - Google Patents

Description

Linked application

This patent application is related to patent application P-970436A, entitled "Key intermediates in the production of simvastatin", which was filed simultaneously with the subject application.

Background of the invention

The compounds of structural formula I shown below are highly active antihypercholesterolemic agents, which act to limit cholesterol biosynthesis by inhibiting the enzyme MMG-CoA reductase.

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Compounds of structural formula Ι include the natural fermentation products of mevinolin (structural formula Ιa, where R=CH3 and disclosed in US Patent No. 4,231,938, which is known under the name lovastatin), compactin (structural formula Ib, where R=H , and is disclosed in US Patent No. 3,983,140), and a group of their semi-synthetic and fully synthetic analogs, all of which have a naturally occurring 2-methylbutyrate side chain.

Compounds of structural formula II, shown below, having a 2,2-dimethylbutyrate side chain (ie simvastatin, structure IIa, where R=CH3) are better known as active HMG-CoA reductase inhibitors as are their 2-methylbutyrate analogs, and thus have greater utility in the treatment of arteriosclerosis, hyperlipemia, familial hypercholesterolemia, and similar diseases.

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The appearance of simvastatin (ΙΙa), a stronger inhibitor of HMG-CoA reductase than lovastatin (Ιa) on the market, created a need for a procedure that would have a greater economic effect and which would burden the environment as little as possible.

Compounds of structural formula II (ie, simvastatin), with a 2,2-dimethylbutyrate side chain, and processes for their production, were disclosed in US Patent No. 4,444,784 and in the EPO published application number 33538. The process shown in the mentioned documents includes four separate chemical steps:

1. de-esterification of the 2-methylbutyrate side chain;

2. protection of the 4-hydroxy group of the pyranone ring;

3. re-esterification of the side chain, to obtain the desired 2,2-dimethylbutyrate; you

4. deprotection of the 4-hydroxy group.

This method is weak and gives weak contributions.

Simvastatin was also prepared by α-alkylation of the ester moiety, which was already described in US patent no. 4,582,915 and 4,820,850.

US patent no. 4,582,915 (1986) discloses the direct methylation of the natural 2-(S)-methylbutyryloxy side chain of mevinoline in a single chemical step using a metal alkyl amide and a methyl halide to give simvastatin.

This procedure has a low conversion ratio of the C-methylation step. Many peripheral reactions are performed for methylation at other sites of the molecule. The C-methylation conversion ratio can be improved to some extent by second or third loading of the amide base and methyl halide. But even then, the total yields are very modest. Also, the purity of the thus obtained simvastatin is almost at the limit, allowed for the use of a product to improve human health.

US patent no. 4,820,850 (1989) discloses a procedure where high conversion C-methylation of the 2-(S)-methylbutyryloxy side chain of mevinoline occurs with a single charge of amide base and alkyl halide. The process described in that patent includes six steps and is not economical, as it involves the protection and deprotection of two hydroxyl groups of the lovastatin butylamide intermediate, using the expensive silylate agent, tertbutyldimethylsilyl chloride.

Summary of the invention

This invention describes a new process and new intermediates for the preparation of simvastatin (ΙΙa).

The new process can be described using the following reaction scheme:

REACTION SCHEME

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The main characteristics of this invention are:

a) Simvastatin can be prepared from the salt of mevinolinic acid, which serves us as a starting material, used instead of lovastatin.

b) Simvastatin is prepared in a four-step process, which does not include protection and deprotection of the two hydroxyl groups of the open pyranone ring. Thus, the methods described in the previous procedures require the protection and deprotection of hydroxy groups, which are essential steps in the preparation of simvastatin.

c) In a preferred embodiment of this invention, the new intermediate lovastatin cyclopropyl amide (IIIb) is prepared from the starting material (lovastatin or mevinolinic acid salt). This new junction is then converted into another new junction (ΙVb).

Simvastatin, prepared according to the new process, has some advantages in commercial production. Purity and yield of simvastatin using this procedure are high, with less consumption of reagents, time, labor, and less costs, it takes place in fewer steps.

Detailed description of the invention

The starting material for anchin according to the present invention is lovastatin (Ιa) or mevinolinic acid (Ιc), with the latter being the open ring form of lovastatin. Mevinolinic acid is produced by fermentation of Aspergillus terreus (see US Patent No. 4,231,938). Lovastatin (Ιa) or mevinolinic acid salt (Ιc) will typically be used as the starting material. The term "mevinolinic acid", unless otherwise indicated, includes exemplary salt forms thereof; any salt is allowed, which does not mix with other reagents or conditions, which are used for the implementation of the subject invention.

Alkali metal salts, such as Na and K, or preferably ammonium salt forms are also usable.

We produce lovastatin from mevinolinic acid by means of lactonization, which we do using methods already known in the art, then we isolate it by crystallization techniques, which cause loss of material. On this occasion, about 20% of the material is lost, which is a consequence of the conversion of natural mevinolinic acid into lovastatin. One of the goals of this invention is the elimination of this loss, where we use lovastatin instead of mevinolinic acid as the starting material.

With regard to this new process according to the present invention, simvastatin (IIa) is prepared by the reaction between lovastatin (Ia) or mevinolinic acid (Ic), preferably in the form of an ammonium salt, with an n-alkylamine or cycloalkylamine of the formula R3-NH2, where R3 is equal to C3-C6. Preferably, the amine R3-NH2 is n-butylamine, and the intermediate formed is lovastatin n-butylamide (IIIa).

The cyclic amide, intermediate compound, IIIa or IIIb, which we prepared in this way, is dissolved in dry tetrahydrofuran (THF) and added to a solution of alkali metal amides, i.e. lithium pyrrolidine in THF at a temperature of about -35ºC to -40ºC. Lithium pyrrolidine is generated in situ by the reaction of n-BuLi with pyrrolidine in THF. Let the solution between the amide IIIa or IIIb in situ generated base stand for 1 hour at –35ºC to –40ºC, and then add the dried alkyl halide, preferably methyl iodide (2 to 3.5 mol. eq.) in a single charge. The contents are then stirred for 1 hour at -30ºC, heated at -10ºC, and left to stand at that temperature for another 20 minutes. Then add water to the reaction mixture, and separate the layers from each other. The THF layer is washed with mineral acid, preferably hydrochloric acid, and then it is concentrated to an oily mass, which contains intermediate compound IVa or IVb.

Add 2.0 NaOH to the solution of intermediate compound ΙVa or ΙVb in methanol without purification, and then reflux everything together for 2 to 6 hours at a temperature of 80ºC to 81ºC, preferably only 2 hours. Cool the mixture to 50ºC, remove the methanol under reduced pressure, then dilute it with water. We then carefully add 2.0 N HCI to the mixture at a temperature of about 10ºC, making sure to maintain pH 6, and then carry out another extraction with ethyl acetate, until we bring it to pH 4. The ethyl acetate layer is then separated, the hydrolyzed product is precipitated as a crystalline material in the form of ammonium salt (V) with the slow addition of methanolic ammonium hydroxide for 30 minutes at a temperature of about 22º-25ºC, followed by cooling to 5ºC.

The ammonium salt (V) is then lactonized again by heating in a hydrocarbon solvent, such as toluene. The mixture is then suspended in toluene, heated and stirred at about 100º-110ºC for 2 to 10 hours, and best at about 105ºC for 5 hours, with a rapid passage of nitrogen gas. The mixture is then cooled to about 35ºC, treated with carbon, filtered, and then the filtrate is concentrated under reduced pressure at a bath temperature of about 60ºC to one tenth of the initial volume. The lactone is crystallized from a hydrocarbon solvent, such as cyclohexane, in order to obtain simvastatin (IIa) of high purity.

In the best embodiment of the new process according to the present invention, mevinolinic acid (Ιc) in the form of an ammonium salt is used as a starting material, and then it is converted into lovastatin cyclopropylamide (ΙΙΙb). Mevinolinic acid is suspended in toluene and refluxed for 5-6 hours at approx. 100º-110ºC, better at approx. 105º-107ºC. The resulting solution is concentrated to one tenth of its initial volume by distillation of toluene under reduced pressure, at a bath temperature of approx. 50º-55ºC. At a temperature of 30ºC, add cyclopropylamine, heat the mixture again for 4-5 hours at approx. 40º-50ºC. Toluene and unreacted cyclopropylamine are eliminated by distillation under reduced pressure, in order to obtain lovastatin cyclopropylamide (IIIb) in quantitative yield. The thus obtained cyclic amide is used in the next step of C-methylation as such, without prior purification, in a similar way, as described above without protection of the dihydroxy system, to obtain simvastatin (IIa).

The following examples further illustrate this invention:

Example 1

Preparation of simvastatin (ΙΙa) from the ammonium salt of mevinolinic acid (Ιb) using cyclopropylamine

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

The ammonium salt of mevinolinic acid (Ιc) (12.5 g, 0.296 mol) was suspended in toluene (400 ml). The mixture is heated and stirred at 105-107ºC with a rapid flow of nitrogen gas for 5 hours. For now, we lowered the temperature to 60ºC, and then we distilled approximately 350 ml of toluene. At 30ºC we then added cyclopropylamine (12 ml, 0.172 moles), and then the solution was stirred at 40-45ºC for 4 hours. The toluene was then slowly removed under reduced pressure and at a bath temperature of 55ºC, in order to obtain the title compound in the form of a rubber. HPLC purity = 99.63%;

1H NMR (CDCl3, 300 Mhz): σ 0.495 (m, 2H), σ 0.50 (m, 2H), σ 0.86 (m, 6H), σ 1.08 (m, 6H), σ 2.3 (d, 2H), σ 2.6 (m, 1H), σ 3.7 (m, 1H), σ 4.18 (m, 1H), σ 5.4 (m, 1H), σ 5.5 (bt, J=3.0Hz, 1H), σ 5.7 (dd, J =6.1, 9.5 Hz, 1H), σ 5.9 (dd, J=9.6 Hz, 1H), σ 6.2 (bt, J=5.3 Hz, 1H); IR(CHCl3):

χmax 3500-3300 (b), 3000, 1740, 1660, 1530, 1450, 1210, 860, 760 cm-1.

We then used that gum directly in the next step, without purification.

Step-2: amide N-Cyclopropyl-7-(1,2,6,7,8,8a (R)-hexahydro-2(S), 6(R)-dimethyl-8(S)-((2, 2-dimethyl-butanoyl)oxy)-1(S)-naphthyl)-3 (R), 5(R)-dihydroxyheptanoic acid (ΙVb)

Pyrrolidine (13.5 ml, 0.163 mol) in THF (50 ml) was cooled to -45ºC, and then n-butyl lithium hexane (1.6 M, 100 ml, 0.163 mol) was added under nitrogen in such a quantity that we maintained the temperature of - 20ºC to -15ºC. The mixture was then stirred at -20ºC to 25ºC for 40 minutes, after the addition was complete.

We prepared a solution of compound ΙΙΙb in THF (300 ml) as already described above, and then added it slowly through the tube, so that we maintained the temperature below -35ºC during the entire addition process. We then let the solution stand at -35ºC to -40ºC for 1 hour. Sieve-dried methyl iodide (4.82 ml, 0.077 mol) was added in one step. We stirred the white cloudy solution we obtained in this way for 1 hour at -35ºC, then heated it to -10ºC and let it stand for 20 minutes. We added distilled water (105 ml), and then stirred the contents vigorously for 5 minutes. The layers were then separated from each other, and then the upper THF layer was treated with 1N HCl (105 ml). The THF layer was concentrated under reduced pressure to a volume of 40 ml, in order to obtain the title compound ΙVb, where R3 was cyclopropyl.

Step-3: 6(R)-(2-(8(S)-(2,2-dimethylbutyryloxy)-2(S), 6(R)-dimethyl-1,2,6,7,8,8a( R)-hexahydro-1(S)-naphthyl)ethyl)-4(R)-

hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one (ΙΙa) (Simvastatin)

An aqueous solution of NaOH (2N, 25 ml) and MeOH (175 ml) was added to the concentrated solution from the previous step, which contained compound ΙVb. We refluxed the mixture at 80º-81ºC for two hours. The mixture was then cooled to 50ºC, and the maximum amount of MeOH was then scraped off under reduced pressure, and then further diluted with water (90 ml). Then, at a temperature of 10ºC, we brought the solution to pH by carefully adding 2N HCI. Ethyl acetate (200 ml) was added to the mixture, and then everything was vigorously agitated while further bringing the pH to a value of 4. Then we separated the ethyl acetate layer from the water layer. A solution of NH4OH and MeOH (1:1, 10 ml) was added slowly over a period of more than 30 minutes at a temperature of 22º-25ºC. The precipitates were then mixed at 25ºC for 1.5 hours, then cooled down to 5ºC, and mixed at the same temperature for another 30 minutes. Filtration was followed by washing with cold ethyl acetate (25 ml) and drying in a vacuum at 35ºC, with which we obtained the ammonium salt (V).

The crude ammonium salt (V) from the previous step (10g, 0.022 mol) was suspended in toluene (350 ml). The mixture was then heated and stirred at 105ºC with a rapid passage of nitrogen gas for 5 hours. We then cooled the solution to 35ºC, then added activated carbon (0.5 g), stirred for another 0.35 hours, then filtered through diatomaceous earth Celite (registered trademark). The filtrate was concentrated in a vacuum to a volume of 40 ml at a bath temperature of 60ºC. Then we added cyclohexane (125 ml), refluxed the solution again for 15 minutes, cooled for 1 hour at 25ºC, and then further cooled to 10º-12ºC, stirred for 30 minutes, filtered and then washed with cold cyclohexane (50 ml), dried in a vacuum at 35ºC, and thus obtained a white crystalline product (IIa), which was then further crystallized from absolute ethanol to obtain the title compound with >99% purity.

Example II

Preparation of simvastatin (ΙΙa) from lovastatin (Ιa) using cyclopropylamine.

Step-1: amide N-Cyclopropyl-7-(1,2,6,7,8,8a (R)-hexahydro-2(S), 6(R)-dimethyl-8)S)-(2(S )-methylbutanoyl)oxy)-1(S)-naphthyl)-3 (R), 5(R)-dihydroheptanoic acid (ΙΙΙb)

Lovastatin (Ιa) (12.5 g, 0.03 mol) was suspended in cyclopropylamine (13 ml, 0.174 mol) at 25ºC. The mixture was then slowly heated to 40-45ºC, and then stirred at that temperature for 5 hours. The excess amine was allowed to evaporate under reduced pressure at a bath temperature of 40ºC to obtain the title compound in the form of rubber. We then used that gum in the next step directly, without purification.

Steps 2-3: The compound (ΙΙΙb), obtained from the previous step, was converted into simvastatin (ΙΙa) using the procedure described for example Ι.

Examples ΙΙΙ and ΙV

Preparation of simvastatin (ΙΙa) and lovastatin (Ιa) and the ammonium salt of mevinolinic acid (Ιc) using n-butylamide Simvastatin (ΙΙa) was prepared from lovastatin (Ιa) and the ammonium salt of mevinolinic acid (Ιc), which served as starting materials as , that we followed the same sequence of steps described in example Ι and ΙΙ with the fact that we substituted equimolar amounts of n-butylamine instead of cyclopropylamine.

Although the subject invention has been described with reference to certain examples, the examples mentioned are intended for illustration only. Numerous other alternative applications, which are still within the scope of this invention, will be readily apparent to those skilled in the art.

Claims (20)

1. Procedure for the production of the compound with the structural formula IIa: [image] which is indicated by the fact that it contains a) treating the compound with the structural formula Ι': [image] where R is: [image] R2 is H, Na, K or NH4, with an alkyl amide having the formula R3NH4, where R3 is a C3-C6 n-alkyl or cycloalkyl group, to give a compound of the formula ΙΙΙ: [image] b) treating the mentioned compound of structural formula ΙΙΙ with a methylating agent, to obtain a compound of structural formula ΙV [image] where R 3 is as defined above c) elimination of the R3 group and closure of the pyranone ring of the mentioned group with the structural formula ΙV, in order to obtain the mentioned compound with the structural formula ΙΙa. 2. The method according to claim 1, characterized in that step c is performed without protection or deprotection of the hydroxy group of the open pyranone ring of the mentioned compound with structural formula IV. 3. The method according to claim 1, characterized in that step c is performed by treating the mentioned compound with structural formula IV with a base, in order to cleave the R3 group, and then the obtained compound is heated in an organic solvent, in order to obtain the mentioned compound with structural formula IIa . 4. The process according to claim 3, characterized in that the R3 group is cleaved off by treating said compound with structural formula IV with a strong base, followed by treatment with ammonium hydroxide, to obtain a compound with structural formula V: [image] 5. The method according to claim 4, characterized in that the mentioned strong base is sodium hydroxide. 6. The method according to claim 3, characterized in that said organic solvent is toluene. 7. The method according to claim 1, characterized in that R3 is a cyclopropyl group. 8. The method according to claim 1, characterized in that R3 is an n-butyl group. 9. The method according to claim 1, characterized in that said methylating agent is methyl halide. 10. The method according to claim 9, characterized in that the methylating agent is methyl iodide. 11. The method according to claim 9, characterized in that said compounds with structural formula III are treated with said methyl halide in the presence of a base. 12. The method according to claim 11, characterized in that said base is lithium pyrrolidine. 13. The method according to claim 1, characterized in that R2 is equal to NH4. 14. Procedure for the production of the compound with the structural formula IIa: [image] indicated by the fact that it contains a) treating the compound with the structural formula Ι': [image] where R is equal to: [image] R 2 is H, Na, K or NH 4 , with cyclopropyl amide to give a compound of structural formula ΙΙΙ; [image] where R 3 is a cyclopropyl group; b) treating the mentioned compound with the structural formula ΙΙΙ with methyl halide, in order to obtain the compound with the structural formula ΙV: [image] where R 3 is defined as above; c) elimination of the mentioned R3 group and closing of the open pyranone ring of the compound with the structural formula IV, to obtain the mentioned compound of the structural formula IIa. 15. The method according to claim 14, characterized in that R2 is equal to NH4. 16. The method according to claim 14, characterized in that said methyl halide is methyl iodide. 17. The process according to claim 16, characterized in that said compound with structural formula III is treated with methyl iodide in the presence of lithium pyrrolidide. 18. The method according to claim 14, characterized in that step c is performed by treating the mentioned compound with structural formula IV with a base, followed by heating in an organic solvent. 19. The method according to claim 18, characterized in that said base contains sodium hydroxide, followed by ammonium hydroxide. 20. The method according to claim 18, characterized in that said organic solvent is toluene.