MXPA99002644A - Process for producing simvastatin - Google Patents

Abstract

A process for manufacturing simvastatin is provided comprising reacting lovastatin with an organic boronic acid to produce a derivative of lovastatin with a hemiboronate group attached to the C-4 carbon of the pyranyl group, methylating the 2-methylbutyryloxy group on the lovastatin derivative to form a 2,2-dimethylbutyryloxy group on the lovastatin derivative and thereafter removing the hemiboranate group to produce simvastatin.

Description

PROCESS FOR PRODUCING SIMVASTATIN FIELD OF THE INVENTION This invention relates to the preparation of SIMVASTATIN. This invention also relates to the purification of intermediates that can be used in the preparation of simvastatin. More broadly, this invention relates to processes for the alkylation on an α-carbon of an ester (containing one or two α-hydrogens) in a molecule, which also contains a β-hydroxylactone functional group with one or two a-hydrogens. BACKGROUND OF THE INVENTION Mevastatin (also known as compactin) and lovastatin (also known as mevinolin) are naturally occng inhibitors of HMG-CoA reductase. These compounds have been used medicinally in the control of human serum cholesterol levels. Both compounds contain a (2S) -2-methylbutyryloxy substituent at the C-8 position of their hexahydronaphthalene nuclei and both produce medicinal analogues with increased potency towards the HMG-CoA reductase, when the above-mentioned 2-methylbutyryloxy side chain becomes a 2, 2-dimethylbutyryloxy group. The analogue that is obtained from lovastatin by such conversion is known as simvastatin. "A method for the commercial scale production of simvastatin from lovastatin is the subject of the present invention" BACKGROUND ART Various processes for the preparation of simvastatin from lovastatin are mentioned Two of these methods include a deacylation / reagelation process. The prior art discussed in US 4,444,784 (84) / CA 1,199,322 (86, Merck) teaches the conversion of lovastatin to various derivatives of 8-acyloxy, including simvastatin.Lovastatin is completely hydrolyzed to remove the 2-methylbutyryl side chain and to simultaneously open its 6-membered lactone ring to produce a trihydroxy acid The trihydroxy acid compound is then heated in order to effect relactonization and a dihydroxylactone is obtained The free hydroxy group in the lactone ring of dihydroxylactone it is protected as a tert-butyldimethylsilyl ether and then the hydroxy group in C-8 of the ring system or hexahydronaphthalene is esterified using 2, 2-dimethylbutyryl chloride. The t-butyldimethylsilyl protection group is then removed in the final step using tetrabutylammonium fluoride to produce simvastatin.

Production Diagram for US 4,444,784 (84) / CA 1,199,322 (86) In US 5,159,104 (92) / CA 2,067,722 (Merck), a deacylation / reacylation approach is also used, but an acyl group is used instead protection of a tert-butyldimethylsilyl group. The dihydroxylactone (obtained as above, from lovastatin) is acetylated in the most reactive lactone hydroxy group using acetic anhydride. The resulting acetate is then reacted with 2, 2-dimethylbutyryl chloride to produce simvastatin acetate. The acetate group is then removed by either of the two methods. In the first procedure, the simvastatin acetate is reacted with methanol under acidic conditions to produce a dihydroxymethyl ester. This methyl ether is then reacted with ammonium hydroxide to produce a dihydroxy ammonium salt. The ammonium salt is heated in order to cause relactonization and simvastatin is obtained.

Production Diagram for US 5,159,104 (92) / CA 2,067,722 (92) In the second procedure, simvastatin acetate is hydrolysed using an enzyme preparation. Previously, it has been reported that lovastatin (in its lactone form) can not be directly converted to simvastatin by an enolate alkylation reaction due to concnt alkylation in the lactone at position a (D. Askin, TR Verhoeven, H. Liu and I. Shinkai, J. Org. Chem, 1991, 56, 4929) due to the higher acidity (approximately 3 pKa units) of the a-hydrogens lactone compared to the α-hydrogenating side chain ester (KB iberg, K.E. Thus, the technologies treated in US 4,582,915 (86), US 4,820,850 (89) / CA 1,287,063 (91) and US 5,393,893 (95) share a common strategy, in which lovastatin is transformed into a protected intermediate compound in which the lactone residues of lovastatin have been intentionally opened This strategy is undertaken with the aim of intentionally altering the acidity of the hydrogen atoms, which are located in the position a of the lactone group of lovastatin The opening and protection of the ring of the lactone group then allows the treatment with a suitable base and therefore the removal of the proton a in the side chain 2-methylbutyryloxy. they are then methylated to produce a 2, 2-dimethylbutyryloxy side chain The protecting groups are then removed, and a thermal reaction is then used to effect lactonization to produce simvastatin. The technologies are discussed in more detail below. In the process described in US 4,582,915 (86, Merck), lovastatin is reacted with potassium hydroxide and converted to a potassium salt of a dihydroxy acid compound. The potassium salt is then enolized using 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 the water removed azeotropically to produce simvastatin.

Elaboration diagram for the US 4,582,915 (86) In US 5,393,893 (95, Apotex), lovastatin is reacted with cyclohexylamine to open the lactone ring and to produce a lovastatin dihydroxycyclohexylamide. The dihydroxy unit is protected by reacting the intermediate compound with phenylboronic acid to produce a cyclohexylamide boronate of lovastatin. The boronate is alkylated using lithium pyrrolidide and methyl iodide and, with an aqueous treated simvastatin, the hydrohexyl amide boronate is produced. The boronate group is removed by hydrolysis with sodium hydroxide to produce a cyclohexylamide of simvastatin. The amide group is removed and the lactone ring is reformed upon heating with acetic acid. Elaboration Chart for US 5,393,893 (95) In US 4,820,850 (89) / CA 1,287,063 (91, Merck), lovastatin is reacted with butylamine to produce lovastatin butylamide. The two hydroxy groups in the butylamide are protected with tert-butyldimethylsilyl chloride to produce a disilalylated lovastatin butylamide. The disilaged lovastatin butylamide is enolized with lithium pyrrolidide and the enolate is alkylated with methyl iodide to produce a disilalylated simvastatin butylamide in aqueous treatment. The silyl protection groups are removed using hydrofluoric acid to produce simvastatin butylamide. Simvastatin butylamide is hydrolyzed using sodium hydroxide, and following the acidification, the dihydroxy acid form of simvastatin is obtained. The dihydroxy acid compound is reacted with ammonium hydroxide to produce an ammonium salt which is then relativized by heating to produce simvastatin.

Elaboration diagram for US 4,820,850 (89) / CA 1,287,063 (91) These processes suffer from several disadvantages such as, excessive stages which include those involved with the ring opening of the lactone lovastatin group, the insertion and removal of the protection groups and the need for relactonization. It is therefore an object of this invention to provide a process (processes) for the preparation of simvastatin, which is more efficient by requiring fewer steps than in the processes of the prior art without the problems associated therewith. It is a further object of this invention to provide a process (processes) for the preparation of compounds containing a group of β-hydroxy lactone with available α-lactone hydrogens and also an aliphatic ester side chain with available α-hydrogens, in wherein the alkylation in the ester a-carbon requires fewer steps than in the processes of the prior art, without the problems associated therewith. Other objects of the invention will be realized by those skilled in the art from the following description of the invention, summary of the invention and examples thereof. EXPOSITION OF THE INVENTION The present invention relates to the unexpected incorporation of a hemiboronate group into lovastatin and its unexpected ability to act as a group that directs enolization. This targeting group binds to the free hydroxy group of lovastatin and directs the deprotonation with selectivity elevated otherwise in the thermodynamic position to the less acidic side-chain 2-methylbutyrate. Therefore, the result of the present invention is in contrast to the accepted rules of thermodynamic acidity. The present invention avoids the need for excessive steps involved with, the ring opening of the lactone lovastatin group, the insertion and removal of the protecting groups and the need for relactonization. The results of the present invention are also in contrast to the results that could be predicted using kinetic acidity information. During the enolization of the hemiboronate (II, see Summary), a metal salt must first be formed in the place of the free hydroxy group of the hemiboronate, due to its relatively high acidity. Such a metal salt of the hemiboronate has the ability to promote an induced, complex proximity effect (or CIPE); P. Beak and A.l. Meyers Acc. Chem. Res. 1986, 19, 356). The consequence of an operational CIPE would be known from the chemical literature to increase the kinetic acidity of the proximal a-lactone hydrogens in the present invention and therefore promote kinetic deprotonation in its place. Since this result is not clearly seen in the present invention, the present discovery is one of additional curiosity. The reason for the reversal in the selectivity of enolate formation in this system is not clearly obvious and it is recognized that a complete understanding of this chemistry will have broader implications in the areas of synthetic organic, mechanistic and physical chemistry. The group that directs hemiboronate, after serving as the controller of selectivity for the alkylation stage, can be removed to produce simvastatin, by using transesterification methods employing diols or polyols, which are well known in the literature (see for example , RJ Ferrier Advances in the Chemistry and Biochemistry of Carbohydrates (Advances in Carbohydrate Chemistry and Biochemestry,) "Carbohydrate Boronatos", 1978, 35, 31-80). It has also been observed that the group directing the hemiboronate can be removed by dissolving the hemiboronate in a solution comprised of an organic solvent and water, under high dilution conditions to produce simvastatin in its dihydroxy acid form. SUMMARY OF THE INVENTION According to one aspect of the invention, simvastatin can be made by reacting lovastatin with an organic boric acid to produce a lovastatin derivative with the hemiboronate group attached to the C-4 carbon of the pyranyl group, then methyl-group 2-methylbutyryloxy to form the 2, 2-dimethylbutyryloxy group and then removing the hemiboronate group (which the applicants believe acts as a steering group for the alkylation step). More broadly, according to another aspect of the invention, a compound containing a β-hydroxylactone group (with available α-lactone hydrogens) and also an aliphatic ester side chain (with available α-hydrogens) can be reacted with an organic boronic acid. The hemiboronate compound obtained therefrom can then be subjected to an alkylation of the subsequent enolate in the other way from the normally less acidic position of the side chain of the aliphatic ester allowed by the directing effect of the hemiboronate on said compound. After alkylation of the enolate of the compound, the hemiboronate group can be removed and the alkylated compound can be recovered. The present invention also relates to new intermediates used to carry out these processes and their use to make the compounds including simvastatin. One such compound has the following structural formula, general: wherein the a-b and c-d links are optionally single or double bonds; n = 1 to 4; R is an alkyl group of 1-6 carbon atoms; a cycloalkyl group of 3-7 carbon atoms, or an aryl group optionally substituted by 1-4 halogen substituents or lower alkyl in any combination; R1 is selected from hydrogen, alkyl of 1-6 carbons; cycloalkyl of 3-7 carbon atoms; OH; ORIV (RIV is, alkyl, cycloalkyl, aryl); R11 is selected from hydrogen, alkyl of 1-6 carbons, cycloalkyl of 3-7 carbon atoms; R111 is selected from hydrogen, alkyl of 1-6 carbons, cycloalkyl of 3-7 carbon atoms. Thus, the present invention relates to a new unexpected process for the production of simvastatin from lovastatin, the processes for the preparation of the intermediate compounds used herein, and the novel intermediates themselves.

The invention also relates to a process for the purification of lovastatin, through the formation of new crystalline (II) compounds. According to one aspect of the present invention, a process of the invention can be carried out as follows: alkylation using for example. 1) M + R1 R 2 - - 2) CH3X wherein R can be selected from an alkyl group of 1-6 carbon atoms, a cycloalkyl group of 3-7 carbon atoms, substituted or unsubstituted, or an aryl group optionally substituted by 1-4 halogen substituents or lower alkyl in any combination, Rx and R2 are selected from methyl, isopropyl, trimethylsilyl, cyclohexyl and cyclo- (CH2) 4, M is selected from lithium, sodium and potassium and X is selected from chlorine, bromine and iodine. Generally, to make simvastatin, lovastatin (I) is heated together with an equimolar amount of an alkyl boronic or aryl acid, preferably phenylboronic acid, in a non-polar solvent, preferably toluene, from which water and water can optionally be removed azeotropically. Lovastatin hemiboronate (II) which is formed is isolated by concentration of the reaction mixture and crystallization with a suitable cosolvent, preferably hexanes. The crystalline nature of (II) allows a method of purification of lovastatin, which is used in the process and thus provides a significant advantage over the previous prior art. In this way, upon recovering the lovastatin hemiboronate and removing the hemiboronate to make lovastatin in a manner similar to the removal of the hemiboronate from the simvastatin hemiboronate (III), as understood by those skilled in the art, lovastatin can be purified. According to another aspect of the invention, loyastatin can be stirred in the presence of a dehydrating agent, preferably molecular sieves, in an organic solvent, preferably tetrahydrofuran, at room temperatures and the lovastatin hemiboronate that is produced can be isolated by filtration and evaporation The lovastatin hemiboronate (II) is treated in a low temperature mode, between -30 ° C and -60 ° C, preferably -55 ° C, in an ether solvent, preferably tetrahydrofuran, with an alkali metal salt (selected lithium, sodium and potassium) of a secondary amine selected from dimethylamine, pyrrolidine, dicyclohexylamine, 1, 1, 3, 3, 3-hexamethyldisilazane and diisopropylamine, preferably pyrrolidine to produce an alkali metal enolate intermediate. The enolate intermediate is methylated with a suitable methyl halide, preferably methyl iodide, at temperatures between -10 ° C and -30 ° C to produce simvastatin hemiboronate (III). The reaction product is isolated by a concentration and acidic treatment. The simvastatin hemiboronate (III) is heated in the presence of a suitable diol solvent selected from ethylene glycol, 1,3-propanediol, or neopentyl glycol, under thermal conditions. The products are isolated by the concentration of the reaction mixture, dilution with water and extraction with an organic solvent. The organic solvent is concentrated to a minimum volume and simvastatin is isolated by the addition of a cosolvent and filtration. Alternatively, (III) can be stirred in a mixture of water and an organic solvent, preferably methanol, under high dilution conditions to produce simvastatin in its acid form. The simvastatin acid can be isolated by extraction or crystallization and relactonized to produce simvastatin. Alternatively, (III) can be dissolved in an organic solvent and recirculated onto a stationary phase of supported diol or polyol to which the hemiboronate residues of (III) are attached. The organic solution is concentrated to obtain simvastatin. Simvastatin can also be produced from (III) by reacting (III) with a stoichiometric amount of a diol selected from ethylene glycol, 1,3-propanediol, neopentyl glycol or several carbohydrate diols at. an organic solvent or combination of organic solvent / water under thermal conditions. The resulting solution of simvastatin is extracted with a second immiscible organic solvent to remove the cyclic boronate by-product. Simvastatin is isolated by concentration, the addition of a suitable cosolvent to effect crystallization, and filtration. The crude simvastatin obtained by the methods described above can be brought to pharmaceutically acceptable levels by recrystallization of suitable solvents or solvent combinations. EXAMPLES Example 1 - Preparation of Lovastatin Hemifenilboronate A suspension of lovastatin (350 g, 0.865 mmol), phenylboronic acid (110.8 g, 0.909 mmol) and toluene (1.75 1), was heated with stirring under a nitrogen atmosphere. A reflux temperature of 100-105 ° C was maintained for 55 minutes as the water was collected and separated from the reaction mixture. The solution was cooled and 1.39 1 of toluene were removed by vacuum distillation at 40-50 ° C. The concentrated solution was treated with hexanes (3.15 1) between 40-50 ° C. The resulting suspension was cooled to 0-5 ° C for 2 hours and the product was filtered and washed with hexanes at 0.5 ° C (350 ml). The product is dried at 35-40 ° C under vacuum to provide 427.9 g (97%) of lovastatin hemifenilboronate a > 99% purity by HPLC. Example 2 - Alkylation of Hemifenilboronate of Lovastatin using Lithium Pirrolidide. A flask with 3 2 1 necks was charged with pyrrolidine (56 ml, 0.67 mol) and dry THF (453 g) under a nitrogen atmosphere. N-butyllithium (419 ml, 1.6 M hexane solution, 0.67 mol) was added dropwise at a temperature between -20 and -25 ° C for a period of 1 hour. The solution was kept at its temperature for 30 minutes and then cooled to -55 ° C and -60 ° C. A solution of hemifenilboronate of lovastatin (101.7 g, 0.20 mol) in 274.7 g of THF was cooled to a temperature of -50 ° C and then added to the cold lithium pyrrolidide solution at a rate such that the internal temperature was between -50 and -55 ° C during the addition. The reaction was maintained at its temperature for 4 hours and then the methyl iodide (116.4 g, 0.82 mol) was added at a temperature below -55 ° C. The reaction was stirred for 13 hours at -15 to -20 ° C and then cooled with 500 ml of 2M HCl at a temperature below 0 ° C. After heating to 20 ° C, the layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were rinsed with 5% NaHS03 solution and deionized water. The solution was filtered through a Celite buffer and concentrated to yield 102.8 g (98.4%) of crude simvastatin hemifenilboronate a > 95% purity by HPLC. A portion of the above material (50.0 g) was charged into a flask purged with nitrogen with acetonitrile (100 ml). The suspension was heated at 110 ° C for 3 hours and then cooled from -5 to -10 ° C for 1 hour. The product was filtered and washed with 25 ml of acetonitrile at -5 ° C and dried under vacuum to provide 43.7 g of simvastatin hemifenilboronate a > 99% purity by HPLC. Example 3 - Alkylation of Lovastatin Hemimethylboronate using Lithium Pirrolidide. According to the method described in Example 2, from 8.9 g of lovastatin hemimethylboronate, simvastatin hemimethylboronate was obtained from > 90% purity in 96% production. Example 4 - Alkylation of Hemifenilboronate of Lovastatin using Lithium Dimethylamide. According to the method described in Example 2, from 10.2 g of lovastatin hemifenilboronate and lithium substitution dimethylamide for lithium pyrrolidide, 75% of simvastatin hemifenilboronate was obtained from > 95% purity. Example 5 - Preparation of Simvastatin from Simvastatin hemifenilboronate using 1,3-Propanediol. A suspension of hemifenilboronate of simvastatin (30.0 g) and 1,3-propanediol (450 ml) was heated, from 105 to 107 ° C in 0.2 mm Hg. After 1 hour, 182 ml of the distillate was collected and the reaction was cooled to 20 to 25 ° C. Deionized water (270 ml) was added and toluene (3x75 ml) was used to extract the mixture. The combined toluene layers were washed with water (2x30 ml). The organic solution was heated to reflux for 1 hour and the water removed azeotropically. The solution was concentrated to a final volume of 24 ml under vacuum at 40 to 50 ° C. To the concentrated solution were added hexanes (215 ml) for 10 minutes. The resulting mixture was cooled to 0 to 5 ° C and filtered. The crude simvastatin was washed with hexanes at 0 to 5 ° C and dried under vacuum to yield 21.0 g (88%) of simvastatin. Example 6 - Preparation of Simvastatin from Hemifenilboronate of Simvastatin using Glycol Neopentyl. A mixture of simvastatin hemifenilboronate (5.22 g, 0.010 mol), toluene (31 ml) and neopentyl glycol (1.11 g, 0.0107 mol), was heated under a nitrogen atmosphere of 77 to 79 ° C for 1 hour 40 minutes. The solution was concentrated under reduced pressure at a bath temperature of 60 ° C for a final volume of 5 ml and n-heptane (160 ml) was added at a temperature of 50-60 ° C. The crude simvastatin was filtered and washed with heptane to provide 3.17 g (76%) of simvastatin. By appropriate manipulation of the conditions and reagents, compounds such as the simvastatin compactin analog can be prepared. Since many changes can be made to the invention without departing from the scope thereof, it is intended that all material contained in the embodiments be construed as illustrative of the invention and not in a limiting sense.

Claims (30)

1. NOVELTY OF THE INVENTION Having described the present invention, it is considered as a novelty and therefore the property described in the following claims is claimed as property. 1. A process for the preparation of a compound of the formula (II) by reacting a compound of the formula (I) (i) with an alkyl, cycloalkyl or arylboronic acid, wherein R can be selected from an alkyl group of 1-6 carbons, 3-7 carbon cycloalkyl, substituted or unsubstituted, or aryl optionally substituted by 1-4 halogen or lower alkyl substituents or combinations thereof.
2. 2. A process for the purification of lovastatin by a process, characterized by the compound of the formula (II) wherein R can be selected from an alkyl group of 1-6 carbons, 3-7 carbon cycloalkyl, substituted or unsubstituted, or aryl optionally substituted by 1-4 halogen or lower alkyl substituents or combinations thereof, is recovered from the solution, the hemiboronate is removed and the lovastatin is recovered.
3. The process according to claim 1, characterized in that it further comprises reacting a compound of the formula (II) with a methyl halide, CH3X, in which X is a starting group, in the presence of an alkali metal salt of a secondary amine for (III) producing a compound of the formula (III):
4. 4. The process according to claim 3, characterized in that it further comprises reacting a compound of the formula (III): (lll) with a diol or polyol reagent to produce a compound of the formula (IV)
5. 5. The process according to claim 4, characterized in that the reaction of a compound of the formula (III) with the diol or polyol reagent is selected from the group of processes comprising one of the following processes: (i) heating (III) with the diol or polyol as a solvent, (ii) heating (III) with a stoichiometric amount of diol or polyol in an organic solvent, (iii) diluting (III) in a mixture of water and an organic solvent, (iv) circulating a solution of (III) on a stationary phase of diol or supported polio.
6. 6. A compound of the formula (II) wherein R is selected from alkyl of 1-6 carbons, cycloalkyl of 3-7 carbons, substituted or unsubstituted, or aryl optionally substituted by 1-4 substituents of halogen or lower alkyl or combinations of them
7. 7. A compound of the formula (III) wherein R is selected from alkyl of 1-6 carbons, cycloalkyl of 3-7 carbons, substituted or unsubstituted, or aryl optionally substituted by 1-4 substituents of halogen or lower alkyl or combinations of the same (lll)
8. 8. A process for making simvastatin comprising reacting lovastatin (I) with an organic boronic acid RB (OH2) to produce a lovastatin (II) derivative with a group or hemiboronate attached to the C-4 carbon of the pyranyl group, methylating the group 2-methylbutyryloxy of (II) to form the 2,2-dimethylbutyryloxy group of (III) and then removing the hemiboronate group to produce simvastatin (IV), wherein R can be selected from an alkyl group of 1-6 carbons, cycloalkyl 3-7 carbons, substituted or unsubstituted, or aryl optionally substituted by 1-4 halogen or lower alkyl substituents or combinations thereof.
9. 9. The process of making simvastatin (IV) through the following stages: (IV) (lll) wherein R can be selected from an alkyl group of 1-6 carbons, 3-7 carbon cycloalkyl, substituted or unsubstituted, or aryl optionally substituted by 1-4 halogen or lower alkyl substituents or combinations thereof.
10. The process according to claim 8 or 9, characterized in that it further comprises the step of recovering simvastatin.
11. 11. The process to produce the compound (III) (lll) from the compound (II) by metalation and methylation, wherein R can be selected from an alkyl group of 1-6 carbons, 3-7 carbon cycloalkyl, substituted or unsubstituted, or aryl optionally substituted by 1-4 halogen or lower alkyl substituents or combinations of same.
12. 12. The process according to claim 11, characterized in that the methylation comprises reacting (II) in the presence of (1) M + R1R2N ", wherein M is selected from lithium, sodium and potassium and RX, R2 is selected from: R1 = R2 = methyl, R1 = R2 = isopropyl, R- = R2 = cyclohexyl, RX = R2 = (CH3) 3 Si, R1 + R2 = cyclo- (CH2) 4 and (2) CH3X, where X is selected from chlorine , bromine and iodine
13. 13. The process according to claim 12, characterized in that it further comprises producing simvastatin by removing the hemiboronate group from the compound of the formula (III) and then recovering the simvastatin
14. 14. A process to hemiboronate a compound useful in the simvastatin preparation, said compound containing a β-hydroxylactone group (with available α-lactam hydrogens) and also an aliphatic ester side chain (with α-hydrogens available), the process comprising reacting said compound with an organic boronic acid of formula RB (OH) 2.
15. 15. The process according to claim 14, characterized in that the product resulting from claim 14 is subjected to an enolate alkylation reaction in the other, normally less acidic, form of the aliphatic ester side chain.
16. The process according to claim 15, characterized in that it further comprises debonding the compound of claim 15.
17. 17. The process according to claim 16, characterized in that it further comprises recovering the compound of claim 16.
18. 18. The process according to claim 8 , 9, 10, 11, 12, 13, 14, 15, 16 or 17, characterized in that the R group is alkyl, cycloalkyl or aryl, wherein the alkyl group contains 1-6 carbon atoms, the cycloalkyl group contains 3-7 carbon atoms and the aryl group is optionally substituted by 1-4 halogen or lower alkyl substituents or combinations thereof.
19. 19. The process according to claim 15, characterized in that the alkylation of the enolate is methylation and wherein the methylation comprises reacting (II) wherein R can be selected from an alkyl group of 1-6 carbons, 3-7 carbon cycloalkyl, substituted or unsubstituted, or aryl optionally substituted by 1-4 halogen or lower alkyl substituents or combinations thereof in the presence of (1) M + R1R2N ", wherein M is selected from lithium, sodium and potassium and RX, R2 is selected from: R1 = R2 = methyl, R- = R2 = isopropyl, R- = R2 = cyclohexyl, RX = R2 = (CH3) 3 Si; R- + R2 = cyclo- (CH2) 4 and (2) CH3X, wherein X is selected from chlorine, bromine and iodine
20. 20. The compound of the following structural formula: wherein the a-b and c-d links are optionally single or double bonds; n = 1 to 4; R is an alkyl group of 1-6 carbon atoms; a cycloalkyl group of 3-7 carbon atoms, or an aryl group optionally substituted by 1-4 halogen substituents or lower alkyl in any combination; R1 is selected from hydrogen, alkyl of 1-6 carbons; cycloalkyl of 3-7 carbon atoms; OH; 0RIV (RIV is, alkyl, cycloalkyl, aryl); R11 is selected from hydrogen, alkyl of 1-6 carbons, cycloalkyl of 3-7 carbon atoms; R111 is selected from hydrogen, alkyl of 1-6 carbons, cycloalkyl of 3-7 carbon atoms.
21. 21. The process according to claim 9, characterized in that the hemiboronate group arises from the compound RB (OH) 2, wherein R is selected from the substituted and unsubstituted alkyl and aryl groups.
22. 22. The process according to claim 21, characterized in that R is unsubstituted phenyl.
23. 23. The process according to claim 9 or 22, characterized in that the hemiboronate is removed using a diol or a polyol.
24. 24. The process to produce simvastatin as follows: Substituted or unsubstituted methylated group 2-methyl-
25. 25. The process to produce: by inserting a group of hemiboronate into (I) wherein R can be selected from an alkyl group of 1-6 carbons, 3-7 carbon cycloalkyl, substituted or unsubstituted, or aryl optionally substituted by 1-4 halogen or lower alkyl substituents or combinations thereof.
26. 26. The process for methylating the 2-methylbutyryloxy group of compound II to produce (lll) wherein R can be selected from an alkyl group of 1-6 carbons, 3-7 carbon cycloalkyl, substituted or unsubstituted, or aryl optionally substituted by 1-4 halogen or lower alkyl substituents or combinations thereof.
27. 27. The process to remove the hemiboronate from: (lll) to produce wherein R can be selected from an alkyl group of 1-6 carbons, 3-7 carbon cycloalkyl, substituted or unsubstituted, or aryl optionally substituted by 1-4 halogen or lower alkyl substituents or combinations thereof.
28. The process according to claim 25, characterized in that the hemiboronate group arises from the compound RB (0H) 2, wherein R is selected from alkyl and aryl groups, substituted or unsubstituted.
29. 29. The process according to claim 28, characterized in that R is unsubstituted phenyl.
30. 30. The process according to claim 27, characterized in that the hemiboronate is removed by using a diol or a polyol.