The present invention relates to a process lor manufacturing Sinivastalin (Formula V) from Lovastatin or Mevinolinic acid via the key intermediate having the Formula III shown in the accompanied drawings.
The Simvastatin is a very potent HMG-CoA reductase inhibitor to limit cholesterol biosynthesis and this compound is very effective in the treatment of alhcroschlcrosis, hyperlipemia, familial hypercholestrolemia and like disorders.
The recent introduction of Simvastatin (Formula V), a more potent HMG-CoA reductase inhibitor than lovastatin (Formula 1 having a side chain as shown in Formula (a) of the accompanied drawings) has provided a need for high yielding process which is economically efficient and environmentally sound than those realized by the prior art process.
Compounds of formula V (Simvastatin) with 2,2-dimethylbutyrate side chain and process for their preparation are disclosed in U.S. Pat. No. 4,444,784 (1984) and EPO published Patent Application No. 33538 (1981). The process disclosed therein involves four distinct chemical steps : (1) De-esterification of the 2-methylbutyrate side chain. (2) Protection of the 4-hydroxy group of the pyranone ring (3) Esterification to form the desired 2,2-dimethylbutyrate; and (4) Deprotection of the 4-hydroxy group. This route being tedious gives low overall yields.
Simvastatin has also been prepared by the a-alkylation of the ester moiety as described in U.S. Pat. Nos. 4,582,915 (1986) and 4,820,850 (1989).
The U.S. Pat. No. 4,582,915 (1986) discloses a process for the preparation of Simvastatin by direct methylation of the natural 2-(S)-methylbutryloxy side chain of Mevinolin. This process suffers from poor C-methylation and many side reactions due to methylation at other sites of the molecule. The C-methylation conversion was improved to some extent by second or third charge of the base and alkyl halide, but still the overall yields were moderate. Also the purity of Simvastatin obtained by this process was close to borderline for use as a human health-care product.
The U.S. Pat. No. 4,820,850 (1989) describes high conversion C-methylation of mevinolin side chain by a single charge of base and alkyl halide. This process comprises six steps and is not economical as it involves the protection and deprotection of the two hydroxy groups of the intermediate Lovastatin butylamide by using an expensive silylating agent, tert-butyldimethylsilyl chloride.
The present invention describes a process of the preparation of Simvastatin of Formula V from the intermediates of Formula II and III. Both these intermediates are new to the chemical world and the preparation of Simvastatin from these intermediates is not reported anywhere. Simvastatin prepared by this process will require less number of steps, less consumption of reagents, time, labour, cost and also elimination of some of the expensive raw materials like tert-butyldimethylsilyl chloride.
Accordingly, the present invention provides a novel process for the preparation of Simvastatin (Formula V) which comprises reacting compounds of Formula 1 wherein R, is a
side chain as shown in Formula la (Lovastatin) or R, is a side chain as shown in Formula Ib (Mevinolinic acid) where in R2 is Na, K or NH4 with alkylamine of the Formula R3NH2 wherein R3 is C3.6 (n-buryl or cyclopropyl group) to yield alkyl amide compounds of the Formula II wherein R3 is butyl or cyclopropyl group which is then reacted with a methylating agent like methyl iodide in the presence of a base like lithium pyrrolidide to give the compounds of the Formula III wherein R3 is butyl or cyclopropyl group which is further reacted with a strong base like sdium hydroxide to cleave the amide linkage and then treated with ammonium hydroxide to precipitate the ammonium salt (Formula IV) which on further heating with an organic solvent gives Simvastatin (Formula V).
Preferably the said organic solvent is toluene and R3 in Formula II and Formula III is a cyclopropyl group.
The Simvastatin prepared is crystallized from a hydrocarbon solvent such as cyclohexane to give Simvastatin of high purity.
The compound Simvastatin is prepared, according to the present invention, by reacting compounds of the Formula 1 wherein R! is a side chain as shown in Formula la (Lovastatin) or R, is a side chain as shown in Formula Ib (Mevinolinic acid) wherein R2 is Na, K or NH4, with n-alkylamine or cycloalkylamine R3NH2 wherein R3 is C3^ to yield alkylamide compound of the Formula II which is then reacted with a methylating agent like methyl iodide in the presence of a base like lithium pyrrolidide to give the compounds of the Formula III.
To the solution of compound of Formula III in methanol, is added sodium hydroxide and refluxed. It is then acifified and extracted with ethyl acetate. The ethyl acetate layer is separated and the hydrolysed product is precipitated out as a crystalline material in the form of ammonium salt (Formula IV) by addition of aqueous solution of ammonium hydroxide at 22-25T.
The ammonium salt (Formula IV) is lactonized by heating in an organic solvent such as toluene. The mixture is filtered and the filtrate is concentrated under reduced pressure at 60°C bath temperature. The lactone is crystallized from a hydrocarbon solvent such as cyclohexane to give Simvastatin (Formula V) of high purity.
The reaction scheme of the process, according to the present invention, is shown on sheet No. 3 of the accompanied drawings.
The compound Simvastatin prepared by the process as stated above requires less number of steps, less consumption of reagents, time, labour, cost and also elimiantion of some of the expensive raw materials like tert-butyldimethylsilyl chloride.
The preparation of the compound Simvastatin (Formula V), according to the present invention, is illustrated hi the following Examples :
Example I
Preparation of Simvastatin (Formula V) from Mevinolinic acid ammonium salt (Formula 1 having side chain of Formula l(b)) using Cyclopropylamine.
It comprises of the following steps :
Step-1 : Preparation of N-Cyclopropyl-7-[l,2,6,7,8,8a(R)-hexahydro-2(S),6(R)-dimethyI-8(S)- [[2(S)-methyl butanoyl]oxy]-l(S)-naphthyl]-3(R),5 (R)-dihydroxy-heptanoic acid amide (Formula-II wherein R3 is cyclopropyl)
Mevinolinic acid ammonium salt (12.5 g, 0.296 moles) was suspended in toluene (400 ml). Cyclopropylamine (12 ml, 0.172 moles) was added at 30°C and solution stirred at 40°-45°C for 4 hours. The toluene was removed to get the title compound prepared in gum like form. This gum was directly used in the next step. The spectroscopic data of the compound prepared revealed HPLC purity = 99.63%; 'H NMR (CDC13, 300 MHz): 8 0.495 (m, 2H), 8 0.50 (m, 2H), 8 0.86 (m, 6H) 8 1.08 (m, 6H), 8 2.3 (d, 2H), 8 2.6 (m, IH), 8 3.7 (m, IH), 8 4.18 (m, IH), 8 5.4 (m, IH), 8 5.5 (bt, J = 3.0 Hz, IH) 8 5.7 (dd, j = 6.1, 9.5 Hz, IH) 8 5.9 (d, J = 9.6 Hz, IH), 8 6.2 (bt, J = 5.3 Hz, IH); IR(CHC13) X max : 3500 - 3300 (b), 3000, 1740, 1660,1530,1450,1210,860,760 cnr1
Step-2 : Preparation of N-CyclopropyI-7-[l,2,6,7,8,8a(R)-hexahydro-2(S),6 (R)-dimethyl-8(S)-[[2^-dimethyl-butanoyl]oxy]-l(S)-naphthyl]3(R), 5(R)-dihydroxy-heptanoic acid amide (Formula-Ill wherein R3 is cyclopropyl)
Pyrrolidine (13.5 ml, 0.163 moles) in tetrahydrofuran (50 ml) was cooled to -45°C and n-butyl lithium in hexane (1.6 M, 100 ml, 0.163 moles) was added. After the addition was complete the mixture was stirred for 40 minutes. A solution of the alkyl amide (as prepared in Step-1) in tetrahydrofuran (300 ml) was prepared and then added to the reaction mixture. - The mixture was stirred and methyl iodide (4.82 ml, 0.077 moles) was added. The solution thus obtained was aged for 1 hour. Distilled water (105 ml) was added to the reaction mixture. Layers were separated and the upper tetrahydrofuran layer was acidified with IN HC1. The tetrahydrofuran layer was concentrated to a volume of about 40 ml., to yield compound of the Formula III wherein R3 is cyclopropyl).
Step-3 : Preparation of 6(R)-2[-[8(S)-2(2,2-dimethyIbutyryloxy)-2(S), 6(R)-dimethyl-l,2,6,7,7,8,8A (R)-hexahydro-l(S) napthyl] ethyl]-4-(R)-hydroxy-3,4,5,6-tetrahydro-2H]]- pyran-2-one (Simvastatin)
To the concentrated solution of the compound as prepared in Step-2 was added an aqueous solution of NaOH (2N, 25 ml) and MeOH (175 ml). The mixture was refluxed at 80°-81°C for 2 hours. The solution was acidified by adding 2N HC1. Ethyl acetate (200 ml) was added and mixture vigorously agitated while further acidifying. The ethyl acetate layer was separated from the aqueous one. An aqueous solution of NH4OH was slowly added at 22° -25°C. The precipitates were stirred for 1.5 hour, cooled to 5°C and stirred at this temperature
for 30 minutes. Filtration followed by washing with cold ethyl acetate and drying at 35°C afforded its ammonium salt (Formula IV).
The crude ammonium salt (10 g 0.022 moles) was suspended in toluene (350 ml) and refluxed for several hours till lactonization was complete. Contents were concentrated in vacuum to a volume of 40 ml. Cyclohexane (125 ml) was added and the solution further cooled to 10°-12°C. Precipitated product was filtered and washed with cyclohexane (50 ml) dried in vacuum at 35°C to give white crystalline product (Formula V) which was further recrystallized from absolute ethanol to afford the title product of > 99% purity.
Example II
Preparation of Simvastatin (Formula V) from Lovastatin (Formula 1 having side chain of Formula l(a)) using cyclopropylamine
It comprises of the following steps :
Step-1 : Preparation of N-Cyclopropyl-7-[l,2,6,7,8,8a(R)-hexahydro-2(S),6 (R)-dimethyl-8(S)-[[2(S)-methylbutanoyl]oxy]-l(S)-naphthyl]-3 (R),5(R)-dihydroxy-heptanoic acid amide (Formula-II wherein R3 is cyclopropyl)
Lovastatin (12.5 g, 0.03 moles) was suspended in cyclopropylamine (13 ml, 0.174 moles) at 25°C. The mixture was heated at reflux till the completion of the reaction. Excess amine was evaporated off at reduced pressure and 40°C bath temperature to afford the title compound in gum like form.
Step-2: Preparation of 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) -dihydroxy-heptanoic acid amide (Formula-Ill wherein R3 is cyclopropyl)
The alkyl amide obtained from the previous step was converted into the title compound by following the same procedure as described in Example-I.
Step-3 : Preparation of 6(R)-2[-[8(S)-2(2,2-dimethylbutyryloxy)-2(S), 6(R)-dimethyI-l,2,6,7,7,8,8A (R)-hexahydro-l(S) napthyl] ethyl]-4-(R)-hydroxy-3,4,5,6-tetrahydro-2H]]- pyran-2-one (Simvastatin)
Compound of Formula III wherein R3 is cyclopropyl obtained from the previous step was converted into Simvastatin (Formula V) by following the same procedure as described for Example I.
Example III & IV
Preparation of Simvastatin (Formula V) from Lovastatin (Formula 1 having side chain of Formula l(a)) and Mevinolinic Acid Ammonium Salt (Formula 1 having side chain of Formula l(b)) using n-butylamine.
Simvastatin (Formula V) was prepared from lovastatin and mevinolinic acid ammonium salt as starting materials following the same steps as described in Examples I and II but substituting equimolar quantities of n-butylamine in place of cyclopropylamine.
While the invention has been desribed 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 withn the scope of the present invention.

We Claim:
i) A novel process for the preparation of Simvastatin (Formula V) which comprises reacting compounds of Formula 1 wherein R, is a side chain as shown in Formula la (Lovastatin) or R, is a side chain as shown in Formula Ib (Mevinolinic acid) wherein R2 is Na, K or NH4 with alkylamine of the Formula R3NH2 wherein R3 is C^ (n-butyl or cyclopropyl group) to yield alkyl amide compounds of the Formula II wherein R3 is butyl or cyclopropyl group which is then reacted with a methylating agent like methyl iodide in the presence of a base like lithium pyrrolidide to give the compounds of the Formula III wherein R3 is butyl or cyclopropyl group which is further reacted with a strong base like sodium hydroxide to cleave the amide linkage and then treated with ammonium hydroxide to precipitate the ammonium salt (Formula IV) which on further heating with an organic solvent gives Simvastatin (Formula V).
2. The process as claimed in claim 1 wherein the said organic solvent is toluene.
3. The process as claimed in claims 1 and 2 wherein R3 in Formula II and Formula III is
a cyclopropyl group.
4. The process as claimed in claims 1 to 3 wherein the Simvastatin prepared is
crystallized from a hydrocarbon solvent such as cyclohexane to give Simvastatin of
high purity.
5. The novel process for the preparation of Simvastatin (Formula V) substantially as
herein described and illustrated in the Examples herein.