Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Reexamination Certificate
2001-04-24
2003-01-14
Rotman, Alan L. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
C560S107000, C560S256000, C560S185000, C560S119000, C549S292000, C562S501000
Reexamination Certificate
active
06506929
ABSTRACT:
TECHNICAL FIELD
This invention relates to novel processes for the manufacturing of simvastatin using lovastatin as staring material.
BACKGROUND ART
Simvastatin is an antihypercholesterolemic agents which inhibits cholesterol biosynthesis by inhibiting the enzyme HMG-Co A reductase. Animal and clinical data suggest simvastatin is twice as potent as lovastatin. The pharmacology and clinical use of simvastatin has been reviewed (V. E. Mauro, J. L. {overscore (M)}acDonald, DICP, The Annuals of Pharmacotherapy, 1991, 25, 257). The synthesis of simvastatin and related compounds was reviewed by Y. Chapleur in Recent Prog. Chem. Synth. Antibiot. Relat. Mircob. Product, 1993, p.829-937; editor: Lukacs, Gabor; publisher: Springer, Berlin, Germany.
Simvastain is an approved oral antihyperlipidemic medication and has been prepared by two general methods taught in Canadian patents 1,199,322 and 1,287,063. In a strict chemical sense, there are three potential methylation sites in lovastatin. These are 13-OH, 14-C and 2′-C. In its open form the 11-OH function provides an additional methylation site. A successful process requires the selective C-methylation of the 2′-position of side chain of lovastatin with minimum protection of other potentially reactive functional groups in lovastatin.
In the method taught in Canadian Patent 1,199,322, lovastatin is first treated with LiOH to give the triol VII which is re-lactonized to diol VIII. Selective silylation of the hydroxyl function at C-13 produces the silyl ether IX which is treated with 2-dimethylbutyryl chloride to give compound X. Desilylation of compound X leads to simvastatin VI (Scheme 1).
The overall yield is less than 40%. Variations of his method are disclosed in U.S. Pat. Nos. 5,159,104, 4,450,171, and 4,444,784.
In U.S. Pat. No. 4,582,915, lovastatin is reacted with potassium hydroxide ant is converted into a potassium salt of a dihydroxy acid compound. The potassium salt is then enolized with lithium pyrrolidide and the enolate intermediate is alkylated with methyl iodide to produce a dihydroxy acid compound with the 2,2-dimethylated side chain. The dihydroxy acid is then heated and water is azeotropically removed to produce simvastatin (Scheme 2).
The process is laborious and affords simvastatin only moderate yields. Furthermore, from the teachings of a subsequent U.S. Pat. No. 4,820,850 at column 1, lines 53 to 68 to column 2, lines 1 to 20 and its corresponding Canadian patent 1,287,063 at page 3, this process appears to have numerous disadvantages.
Canadian patent 1,287,063 states at page 3 that U.S. Pat. No. 4,582,915 “disclosed a novel route to the dimethylbutyate side chain via direct alkylation of the &agr;-carbon of the naturally available methylbutyrate side-chain using a metal amide and a methyl halide. However this process has been found to have certain disadvantages in the commercial manufacture of a pharmaceutical”.
Repeated addition of the amide base and methyl halide are necessary to improve the yield of the alkylation step. This is costly, inefficient and time-consuming.
A selective hydrolysis is necessary to reduce the level of unmethylated starting material to less than 0.7%. This step is time consuming since the hydrolysis of unconverted starting material is very slow and normally requires 20 hours.
The overall yield of the process is low when the starting material is mevinolin.
In addition to unconverted starting material a number of other impurities are generated during the methylation and hydrolysis steps. These include, when the starting material is mevinolin, des-butyratemevinolin and bis-methylated compounds wherein the &agr;-lactone carbon is methylated in addition to that on the &dgr;-C-ester side chain, and a methyl ether wherein the ring oxygen of the lactone now in the open form has been methylated.
The purity of the final product isolated from the overall process is close to be unsatisfactory for use as a drug substance.
In an attempt to overcome the shortcomings of U.S. Pat. No. 4,582,915, another method disclosed in Canadian patent 1,287,063 was devised.
Canadian patent 1,287,063 teaches that the lactone ring of lovastatin is reacted with an amine to give the amide XI. The diol of the amide XI is protected as a disilyated ether XII. Alkylation of compound XII with methyl iodide and base produces compound XIII. Deprotection of the diol XIII, followed by lactonization afforded simvastatin (Scheme 3).
More particularly, Canadian patent 1,287,063 discloses that lovastatin is specifically reacted with butylamine to produce lovastatin buytlamide XI. The two hydroxy groups in the butylamide are protected with tert-butyldimethylsilyl chloride to produce a disilyated lovastatin buytlamide XII. The disilyated lovastatin buytlamide is enolized with lithium pyrrolidide and the enolate is alkylated with methyl iodide to produce a disilyated simvastatin butylamide on aqueous work up XIII. The silyl protecting groups are removed using hydrofluoric acid to produce simvastatin butylamide XIV. The simvastatin butylamide is hydrolysed using sodium hydroxide and following acidification, the dihydroxyacid form of simvastatin XV is obtained. The dihydroxy acid compound XV is reacted with ammonium hydoxide to produce an ammonium salt XVI which is then relactonized by heating to produce simvastatin.
In an improved variation of this approach, phenyl boronic acid was used by Kubela, et al. for the protection of the diol resulting in a solid phenylboronate which can be subjected to purification by crystallization (U.S. Pat. No. 5,393,893).
Other variations of the method depicted in Scheme 3 are reported in U.S. Pat. Nos. 4,820,850, and 5,223,415.
In both methods discussed above the 13-OH is protected as a silyl ether. In the first process, the silyl group is removed after the introduction of the acyl group at the 1-OH position. In the second process, the silyl group is removed after the introduction the methyl group at 2′-position.
In Canadian patent 1,287,639 and its U.S. equivalent U.S. Pat. No. 4,916,239 a process for the lactonization of XVI produced as illustrated in Scheme 3 to simvastatin is disclosed. The ammonium salt XVI is suspended in an organic solvent with a strong acid catalyst. After the hydroxy acid-lactone equilibrium is established, water is gradually added to effect complete crystallization of simvastatin from the reaction medium (Scheme 4).
All the processes disclosed in the prior art involves numerous steps thereby contributing to the obtention of simvastatin in relatively low yield. Accordingly, a process that will overcome the disadvantages taught by the prior art will represent a considerable advance in the art.
The object of the present invention is to overcome these disadvantages. The process of the present invention is illustrated in Scheme 5.
Accordingly, an object of the invention is to reduce the number of steps thereby allowing the production of simvastatin in higher yields (Process A, three steps).
Furthermore, by the process developed in the present invention, the C-methylation of the 2′-position group is highly regioselective and does not require the protection/deprotection of 13-OH group of lovastatin (processes A and B), nor does it involve the hydrolysis of the lactone moiety and re-lactonization.
Other advantages of the process of the present invention can be briefly listed:
(i) it avoids the use of expensive reagents such as tert-butyldimethylsilyl chloride and lachrymators such as 2,2-dimethylbutyryl chloride and hydrofluoric acid;
(ii) as the number of steps has been reduced, the process generates fewer impurities which simplifies the isolation of simvastatin of desirable level of purity;
(iii) it provides a simpler and a more economical method of manufacturing simvastatin and is therefore amendable to industrial scale production.
BRIEF SUMMARY OF INVENTION
A process for the manufacture of simvastatin which comprises:
(A) step 1. Selectively reducing the carbonyl function of the lactone moiety of lovastatin to a hemiacetal of formula II:
step 2. reacti
Doucette Gary
Karimian Khashayar
Li Yiwei
Tam Tim Fat
Tao Yong
Apotex Inc.
Hughes Ivor M.
Hughes Neil H.
Reyes Hector M.
Rotman Alan L.
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