MXPA05011753A - Processfot the preparation of (4-hydroxy-6-oxo-tetrahydropyran-2-yl) acetonitrile and derivatives thereof - Google Patents

Abstract

The invention relates to a process for the preparation of (4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-acetonitrile from 6-X-substituted-methyl-4-hydroxy-tetrahydro-pyran-2-one, wherein X stands for a leaving group, by reacting 6-X-substituted-methyl-4-hydroxy-tetrahydro-pyran-2-one with a cyanide ion in water and by subsequent lowering of the pH to a pH between 0 and 5. (4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-acetonitrile and other compounds obtainable from (4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-acetonitrile may suitably be used in the preparation of a pharmaceutical preparation, more in particular in the preparation of statins, more in particular in the preparation of Atorvastatine or a salt thereof, for instance its calcium salt. The invention also relates to (4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-acetonitrile and other compounds obtainable therefrom.

Description

PROCESS FOR THE PREPARATION OF (4-HYDROXY-6-OXO-TETRAHIDROPIRAN-2-IL) ACETONITRILO AND DERIVATIVES OF THE SAME FIELD OF THE INVENTION The invention relates to a process for the preparation of a compound of formula 1 BACKGROUND OF THE INVENTION The above-mentioned compound can suitably be used as an intermediary in the preparation of various pharmaceutical active ingredients, in particular in the preparation of HMG-CoA reductase inhibitors, more particularly in the preparation of statins, example in the preparation of Atorvastatin as described by A. Kleemann, J. Engel; pharmaceutical substances, synthesis, patents, applications 4th edition, 2001 Georg T ieme Verlag, p. 146-150.

SUMMARY OF THE INVENTION The compound of formula 1 is prepared according to the invention by reacting a compound of formula 2 (2) Where X is a leaving group with a cyanide ion in water and by subsequent lowering of the pH to a pH between 0 and 5. Compared with the known process for Atorvastatin, the process of the invention is an easy process, also efficient process and cash in costs.

Advantages of the present process are for example that it is scalable, does not require, for example, ultra-low temperature or dangerous reagents such as organometallic or alkylborane. Leaving groups X, which can be used in this reaction, include for example halogens, in particular Cl, Br, I; sulphonic acid ester groups, in particular tosylate, mesylate or benzene sulfonate groups, each of which may be optionally substituted with a nitro or a halogen group; acyloxy groups, in particular acetoxy or benzoyloxy. For practical reasons, X is preferably Cl. For the above reaction, the cyanide ions may, for example, be added to the reaction in the form of cyanide salts or as a combination of HCN and a base. In principle all cyanide salts known to a skilled person can be used. Examples of cyanide salts include: cyanide salts with an alkali metal such as cation, for example sodium cyanide, potassium cyanide or lithium cyanide; cyanide salts with a bulky cation, for example tetrabutylammonium cyanide or tetrabutyl phosphonium cyanide. For commercial use, sodium cyanide or potassium cyanide is preferred. Preferably the concentration of the cyanide ions is at least 1 mole per liter, more preferably at least 5 moles per liter and most preferably at least 10 mole per liter. The concentration of the cyanide ions is preferably chosen as high as possible. The temperature of the reaction in principle is not critical, for example, temperatures may be chosen between 0 and 100 ° C, more preferably between 30 and 70 ° C, more preferably between 50 and 60 ° C. The decrease in pH at a pH between 0 and 5, preferably between 2 and 4, can be made according to a manner known per se, for example by the addition of an acid, preferably a strong acid, for example with a pKa < 4, preferably with a p a < 2. If desired, before lowering the pH, the excess cyanide ions can be removed by oxidation with an oxidizing agent, for example with chlorine, with hypochlorite or with H202, for example as described in US 3,617,567. In a different embodiment of the invention, the compound of formula 2 can first be treated with a base before reacting with a cyanide ion. Both stages of the reaction can be carried out in the same reaction vessel. The selection of the base used in the conversion of the compound of the formula 2 into a compound of the formula 1, either in combination with HCN or before the reaction with a cyanide ion, is not critical in principle. Examples of bases that may suitably be used include: alkali metal (earth) hydroxides, for example, sodium or potassium hydroxide, alkali metal (earth) carbonates, for example sodium carbonate or magnesium carbonate, NH 4 OH or (alkyl) 4 OH, alcoholates, NH 3 or N (alkyl) 3 and carboxylates. The base is preferably used in a molar ratio of between 0.3 and 3 compared to the amount of compound of formula 2, more preferably in a molar ratio between 0.5 and 1.5, most preferably a dwarf molar ratio between 0.9 and 1.1. If the compound of formula 2 is first treated with a base, the molar ratio between the total amount of cyanide ion and the total amount of compound of formula 2 is preferably between 0.5 and 10, more preferably between 1 and 5, most preferably between 1.5 and 2.5. If the compound of formula 2 is not treated first with a base, the molar ratio between the total amount of cyanide ion and the total amount of compound of formula 2 is between 1 and 11, more preferably between 2 and 16, at most preferably between 2.5 and 3.5 molar equivalent. The compound of formula 1 can be reduced with a suitable copy agent to form the corresponding compound of formula 3: The reducing agent can be chosen from the group of reducing agents which is generally known to be applicable in the reduction of a nitrile to an amine. Examples of reducing agents include hydride reducing agents, for example dibalH (diisobutylaluminum hydride); reductote agents with hydrogen, for example Raney Nickel with H2, Rh / Al203 / NH2 or Pd (OH) 2 with H2. The compound of formula 2, wherein X is a leaving group, can, for example, be prepared by an aldol condensation in acetaldehyde and an aldehyde which is substituted in the 2-position by X, where X is as defined above, in the presence of an aldolase, for example as described in US 5,795,749 and by subsequent reaction of the compound formed of formula 4, where X is as defined above, with an oxidizing agent. Preferably, in the aldol condensation for the preparation of a compound of formula 4, the concentration of carbonyl - the sum of the concentration of aldehyde, of substituted aldehyde in the 2-position and the intermediate formed in the reaction between the aldehyde and the aldehyde 2-substituted (a 4-substituted 4-hydroxybutanal intermediate) -, is between 0.1 t 5 moles per liter of the reaction mixture, more preferably between 0. 6 and 4 moles per liter of the reaction mixture. The temperature and the reaction pH are not critical and both are chosen as a function of the substrate. Preferably the reaction is carried out in liquid phase. The reaction can be carried out for example at a reaction temperature between -5 and 45 ° C, preferably between 0 and 10 ° C and a pH between 5.5 and 9, preferably between 6 and 8. The reaction is preferably carried out at pH more or less constant, making use for example of a regulator or automatic titration. As a regulator, for example sodium bicarbonate and potassium, potassium and potassium phosphate, triethanolamine / HCl, bis-tris-propane / HCl and HEPES / KOH can be used. Preferably a potassium or sodium carbonate buffer is applied, for example in a concentration between 20 and 400 nmol / l of the reaction mixture. The molar ratio between the total amount of aldehyde and the total amount of 2-substituted aldehyde is not very critical and preferably falls between 1.5: 1 and 4: 1, in particular between 1.8: 1 and 2.2: 1. Preferably the aldolase used is 2-deoxyribose-5-phosphate aldolase (DERA, EC 4.1.2.4) or a mutant thereof, more preferably DERA of Escherichia coli or a mutant thereof. The amount of DERA used is not very critical and is chosen as the source of, for example, the reagents applied, the reagent concentrations, the desired reaction rate, the desired duration for the reaction, and other economic factors. The amount of DERA used falls between, for example, 50 and 5000 U / mmol of the substituted or unsubstituted aldehyde. 1 U (unit) is a measure of the enzymatic activity and corresponds to the conversion of 1 μmol of 2-deoxyribose-5-phosphate per minute at 37 ° C.

DETAILED DESCRIPTION OF THE INVENTION The process of the invention is especially advantageous since both the preparation of a compound of formula 2 from simple aldehydes and the subsequent conversion of the compound of formula 2 to a compound of formula 1 can be carried out in water. The use of water as a solvent has many advantages known to those skilled in the art, for example, that water is a cheap, widely available and environmentally benign solvent. As an oxidizing agent for use in the oxidation of the compound of formula 4, in principle all the oxidizing agents known to those skilled in the art, applicable in the oxidation of an alcohol to a ketone, can be applied. Examples of such oxidizing agents include: Br2, Cl2 / NaClO, Ni04, Cr03 and peroxides, for example, H202. The compound of formula 1 or a compound of formula 3 can be subsequently converted to a compound of formula 6, where R1 is CN or CH2NH2 and R2, R3 and R4 are each independently an alkyl with for example 1 to 12 carbon atoms., preferably 1-6 C atoms, an alkenyl with for example 1-12 C atoms, preferably with 1-6 C atoms, a cycloalkyl with for example 3-7 C atoms, a cycloalkenyl with for example 3-7 C atoms, an aryl with for example 6-10 C atoms or an aralkyl with for example 7-12 C atoms, each of R2, R3 and R4 can be substituted and where R2 and R3 can form a ring together with the C atom to which they are bound, making use of a suitable acetal-forming agent, in the presence of an acid catalyst, for example as described in WO 02/06266. The substituents on R2, R3 and R4 are for example halogens or hydrocarbon groups with for example 1-10 carbon atoms, optionally containing one or more heteroatoms, for example, Si, N, P, O, S, F, Cl, Br or I. The term "alkyl" refers to straight chain or branched saturated hydrocarbon chains. Examples of these are methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, hexyl and octyl. The term "alkenyl" is related to straight or branched unsaturated hydrocarbon chains, such as vinyl, allyl and i-butenyl. The term cycloalkyl comprises saturated hydrocarbon chains in the form of a ring. The term "aryl" refers to aromatic and heteroaromatic systems, as well as substituted variants thereof. Examples thereof are phenyl, p-methylphenyl and furanyl. The term "aralkyl" means a combination of aryl and alkyl with the aryl residue connected through an alkyl chain, for example benzyl. The groups R2, R3 and R4 preferably each independently are C 1-3 alkyl, more preferably methyl or ethyl. Preferably R4 is methyl. In practice, R2 = R3 = R4 is methyl is the most preferred. Examples of suitable acetal formers that can be applied in the process according to the invention include dialkoxypropane compounds, with the alkoxy groups each preferably having 1-3 carbon atoms, eg, 2,2-dimethoxypropane or 2, 2-diethoxypropane; alkoxypropene, with the alkoxy group having 1-3 carbon atoms, for example, 2-methoxypropene or 2-ethoxypropene. The most preferred is 2-dimethoxypropane. This can optionally be formed in situ from acetone and methanol, preferably having removed the water.

Acid catalysts can be used as acid catalysts known for the reactions of acetals, preferably strong organic acids, with a pka < 4, with a non-nucleophilic anion, for example, sulfonic acids, in particular p-toluenesulfonic acid, methanesulfonic acid or camphorsulfonic acid; or strong inorganic acids, with a pka < 4, with a non-nucleophilic anion, for example sulfuric acid, HC1, phosphoric acid: acidic ion exchangers, for example DOWEX; or solid acids, for example so-called etheropoly acids. The formation of acetal can be carried out without using a separate solvent; if desired, the reaction can also be carried out in an organic solvent. Examples of suitable organic solvents include ketones, in particular acetone, hydrocarbons, in particular aromatic hydrocarbons, for example toluene, chlorinated hydrocarbons, for example methylene chloride. The temperature at which the acetal formation reaction is carried out is not critical and preferably falls between -20 ° C and 150 ° C, in particular between 0 ° C and 100 ° C. The molar ratio of the acetal forming agent to the compound of formula 5 preferably falls between 1: 1 and 20: 1, in particular between 3: 1 and 5: 1. Using an organic solvent, the molar ratio is in particular between 1: 1 and 2: 1. The molar ratio between the acid catalyst and the compound of formula 5 preferably falls between 1: 1 and 0.001: 1, in particular between 0.05: 1 and 0.1: 1. The compound of formula 6, wherein R1 is CN or CH2NH2 and where R2, R3 and R4 are as defined above, can subsequently be hydrolyzed in the presence of a base and water to form the corresponding salt of formula 7, where Y is an alkali metal, for example lithium, sodium, potassium, preferably sodium; an alkaline earth metal, for example magnesium or calcium, preferably calcium; or a substituted or unsubstituted ammonium group, preferably a tetraalkyl ammonium group. Optionally hydrolysis is followed by conversion to the corresponding compound of formula 7, where Y is H, for example as described in WO 02/06266. The hydrolysis of the compound of formula 6 is preferably carried out with at least 1 equivalent of base, in particular of 1-1.5 equivalents of base, with respect to the compound of formula 6. In principle, a larger excess can be used, but this in the practice usually offers no advantages. The reaction is preferably carried out at a temperature between -20 ° C and 60 ° C, in particular between 0 ° C and 30 ° C. The hydrolysis can be carried out for example in water, in an organic solvent, for example an alcohol, in particular methanol or ethanol, an aromatic hydrocarbon, for example toluene, or a ketone, in particular acetone methyl isobutyl ketone (MIKB), or a mixture of an organic solvent and water, usually catalysed by a phase transfer catalyst (PTC) or addition of a cosolvent. The compound of the formula 6, wherein R1, R2, R3 and R4 are as defined above, can also be converted enzymatically to form the corresponding salt of formula 7, wherein R1, R2, R3 and Y are as defined above, for example as described in WO 02/06266. Examples of enzymes that can suitably be used in the conversion of a compound of formula 6 into the corresponding salt of formula 7 include enzymes with lipase or esterase activity, for example Pseudomonas enzymes, in particular Pseudomonas fluorescens, Pseudomonas fragi; Burkholderia, for example Burkholderia cepacia; Chromobacterium, in particular Chromobacterium viscosum; Bacillus, in particular Bacillus thermocatenulatus, Bacillus licheniformis, - Alcaligenes, in particular Alcaligenes faecalis; Aspergillus, in particular Aspergillus niger; Candida, in particular Candida antarctica, Candida rugosa, Candida lipolytica, Candida cilindracea; Geotrichum, in particular Geotrichum candidum; Humicola, in particular Humicola lanuginosa; Penicillium, in particular Penicillium cyclopium, Penicillium roque fortii, Penicillium camembertii; Rhizomucor, in particular Rhizomucor javanicus, Rhizomucor miehei; Mucor, in particular Mucor javanicus; Rhizopus, in particular Rhizopus oryzae, Rhizopus arhizus, Rhizopus delemar, Rhizopus niveus, Rhizopus japonicus, Rhizopus javanicus, porcine pancreas lipase, wheat germ lipase, bovine pancreatic lipase, pig liver stearase. Preferably, use is made of an enzyme of Rhizomucor miehei, Humicola lanuginosa, Candida rugosa or Candida antarctica or subtilisin. Such enzymes can be obtained using commonly known technologies and / or are commercially available. The salt of formula 7 can be converted into the corresponding ester of formula 8 where R1 is CN or CH2NH2, where R2 and R3 are as defined above and where R5 can represent the same groups as indicated above for R2, R3 and R4, in a manner known per se (for example as described in WO 02) / 06266). For example, R5 may represent a methyl, ethyl, propyl, isobutyl or tert-butyl group. An important group of esters of formula 8 that can be prepared with the process according to the invention are tert-butyl esters (R5 represents tert butyl). In a special aspect of the invention, the salt of formula 7 is converted into the corresponding ester of formula 8 by contacting the salt of formula 7 in an inert solvent, for example toluene, with an acid chloride forming agent. , by contacting the acid chloride formed with an alcohol of formula R5OH, wherein R5 is as defined above, in the presence of N-methylmorpholine (NMM). The acid chloride forming agent can be chosen from the group of reagents which is generally known as such. Suitable examples of acid chloride forming agents include oxalyl chloride, thionyl chloride, PC13, PC15, and POC13. Preferably, the acid chloride forming agent is used in excess with respect to the amount of the salt of formula 7, for example between 1 and 3 equivalents, more preferably between 1.2 and 1.8 equivalents. If desired, a catalyst may also be present in the formation of the acid chloride. The amount of catalyst can, for example, vary from 0-1, preferably 0-0.5 equivalents, calculated with respect to the amount of al in formula 6. Larger amounts of catalyst are also possible, but usually will not have extra advantageous effects. Preferably the amount of catalyst, if any, will be between 0.05 and 0.2 equivalents calculated with respect to the salt of formula 7. Suitable catalysts are the catalysts generally as accelerators of the formation of acid chlorides, for example dimethylformamide (DF) and N-methylpyrrolidone (NMP). The amount of alcohol of formula R5OH is not very critical in the conversion of the salt of formula 7 and is preferably between 1 and 15 equivalents calculated with respect to the amount of salt of formula 7, more preferably between 2 and 13 and most preferably between 3 and 6.

In practice in the conversion of the salt of formula 7, in this special aspect of the invention, a small amount of NMM is applied, efficient to eventually trap the free HCL, for example, 1.5 to 2.5, preferably 1.8 to 2.0 equivalents calculated with respect to the amount of salt of formula 7. When a large excess of acid chloride forming agent is used, larger amounts of NM are preferably used, and when a smaller excess of acid chloride forming agent is used, smaller amounts of NMM are preferably used. The salt of formula 7 is preferably contacted with the acid chloride forming agent at a temperature between -30 ° and 60 ° C, more preferably between 20 ° and 50 ° C. The conversion of the acid chloride to the ester of the formula 7 is preferably carried out at a temperature between 20 ° and 80 ° C, more preferably between 20 and 50 ° C. The conversion of the salt of formula 7 to the corresponding ester of formula 8 according to this special aspect of the invention can be carried out in one step. Preferably the first salt of formula 7 is converted into the corresponding acid chloride, and subsequently the acid chloride is contacted with the alcohol of formula R5OH and NMM. In a particularly preferred embodiment the acid chloride formed is neutralized with NMM and the alcohol of formula R5OH. Compounds in which R1 is CN as mentioned herein can be reduced with a suitable copy agent to form the corresponding compound which R1 represents CH2NH. Suitable reducing agents are the reducing agents known to a person skilled in the art as applicable in the reduction of a nitrile to an amine and examples of such reducing agents are given above. It is also possible to start from an enantiomerically enriched compound of formula 2 to prepare the corresponding enantiomerically enriched compounds. An enantiomerically enriched compound of formula 2 can be obtained, for example by an aldol condensation between acetaldehyde and an aldehyde which is substituted at the 2-position by X in the presence of DERA of Escherichia coli as described above. Starting from (4R, 65) -6-chloromethyl-tetrahydro-pyran-2,4-diol, via cyanation of its oxidized form (4R, 6S) - 6-chloromethyl-4-hydroxy-tetrahydro-pyran-2-one for form the corresponding ((2i? 4i?) -4-hydroxy-6-oxo-tetrahydro-pyran-2-yl) -acetonitrile and subsequent acetalization of ( {2R, R) -4-hydroxy-6-oxo-tetrahydro-pyran-2-yl) -acetonitrile, an ester of ((4J2, 6R) -6-cyanomethyl-2, 2-dimethyl- [ 1,3] dioxan-4-yl) -acetic, for example, its methyl ester, its ethyl ester or its tert-butyl ester can be formed. Preferably, the enantiomeric excess (e.e.) of the enantiomerically enriched compounds obtained is < 80% ee, more preferably > 90% ee, even more preferably > 95%, most preferably > 99% us If an enzyme is used in the conversion of the acid ester ((éR, 6R) -4-hydroxy-6-cyanomethyl-2,2-dimethyl- [1,3] dioxan-4-yl) -acetic acid to the corresponding salt enantioactive, there is even more enantiomeric enrichment during hydrolysis. The compounds prepared according to the process of the invention are particularly useful in the preparation of an active ingredient of a pharmaceutical preparation, for example of a statin. A particularly interesting example of such preparation is the preparation of Atorvastatin calcium as described by A. leemann, J. Engel; pharmaceutical substances, synthesis, patents, applications 4th edition, 2001 Georg Thieme Verlag, p. 146-150. The invention therefore relates to novel intermediates in such a preparation, for example the compounds (4-hydroxy-6-oxo-tetrahydro-pyran-2-yl) -acetonitrile, 6- (2-amino-ethyl) -4- hydroxy-tetrahydro-pyran-2-one, (6-cyanomethyl-2,2-dimethyl- [1,3] dioxan-4-yl) -acetic acid methyl ester, methyl ester, (6-cyanomethyl-2,2-dimethyl) - [1,3] dioxan-4-yl) -acetic acid, (6-cyanomethyl-2,2-dimethyl- [1,3] dioxan-4-yl) -acetic acid i-propyl ester, n-propyl ester of acid (6-cyanomethyl-2,2-dimethyl- [1,3] dioxan-4-yl) -acetic acid methyl ester [6- (2-amino-ethyl) -2,2-dimethyl- [1,3] dioxan-4-yl] -acetic acid [6- (2-amino-ethyl) -2,2-dimethyl-fl, 3] dioxan-4-yl] -acetic acid ethyl ester, [6-] (2-Amino-ethyl) -2,2-dimethyl- [1,3] dioxan-4-yl] -acetic acid, n-propylester of [6- (2-amino-ethyl) -2,2-dimethyl- [1, 3] dioxan-4-yl] -acetic. The invention also relates to a process, wherein a compound obtained in a process according to the invention is further converted into a statin, preferably Atorvastatin or a salt thereof, for example its calcium salt, in a well known manner in the technique.

Examples Example 1: Preparation of ((2J ?, 4R) -4-hydroxy-6-oxo-tetrahydro-pyran-2-yl) -acetonitrile (an enantiomerically enriched compound of formula 1). In a 250 ml round-bottomed 3-necked flask equipped with a dropping funnel, a mechanical stirrer and a cooling water bath, 42 g of (4R, 6S) -6-chloromethyl-4-hydroxy-tetrahydro- pyran-2-one (an enantiomerically enriched compound of formula 2 where X = Cl) in demineralised water (25 ml) with stirring. Drop by drop an aqueous solution of potassium hydroxide (28 g, 50% w / w) was added over a period of three hours. The dropping funnel was washed with water (4 ml) and removed. Solid potassium cyanide (26 g) was added at once and the flask was heated at 45 ° C (water bath temperature) for 5 h and subsequently at 50 ° C for another 30 minutes. The water bath was replaced by an ice bath and the excess cyanide was removed by the addition of copper (II) hydrate acetate (1 mg) and dropwise addition of aqueous hydrogen peroxide (8.1 ml, 50% p / p) during a period of 30 min (Tmax = 60 ° C). After stirring at 22 ° C for 1 h, the mixture was cooled with an ice bath, antifoam (Sigma type 204, 0.02 ml) was added and aqueous hydrochloric acid (35 ml, 37% w / w) was added dropwise for a period of 2.5 h. The acidified mixture was filtered through paper, and the residue in the filter was washed four times with water (10 ml each). The unified filtrate was extracted continuously with ethyl acetate for 1 day. Another portion of hydrochloric acid 3 ml, 37% w / w) was added to the aqueous phase, which was then extracted continuously with ethyl acetate for 2 days. The unified organic phases were dried over sodium sulfate, filtered and evaporated in vacuo, leaving even highly viscous orange oil containing the target compound ((2J ?, éR) -4-hydroxy-6-oxo-tetrahydro-pyran-2-yl) -acetonitrile (an enantiomerically enriched compound of formula 1) according to the CCD and NMR analyzes. Performance: (76%). A sample of the crude product (1.0 g) was purified by flash column chromatography (100 ml silica 60, mesh 230-400, column diameter 3 cm, elution with acetonitrile / dichloromethane 3/7, fraction size 20 ml) to analyze the compound. The purest fractions were unified and evaporated in vacuo, leaving 0.31 g of the objective compound (. {2R, 4R) -4-hydroxy-6-oxo-tetrahydro-pyran-2-yl) -acetonitrile as a white solid after drying to high vacuum. ^ -NMR (300 MHz, d6-DMSO, residual solvent not deuterated as internal standard: 2.51 ppm): d = 1.72-1.81 (m, 1 H, H-3), 1.88-1.97 (m, 1 H, H- 3), 2.44 (d "t", J = 17.5, ~ 2 Hz, 1 H, H-5), 2.70 (dd, J = 17.5, 4.7 Hz, 1 H, H-5), 2.95 (dd, " = 17.1, 6. 6 Hz, 1 H of CH2CN), 3.05 (dd, J = 17.1, 4.6 Hz, 1 H of C # 2CN), 4.15-4.21 (m, 1 H, H-4), 4.77-4.87 (m, 1 H, H-2), 5.37 (d, J = 3.4 Hz, 1 H, OH) 13C-NMR: (75.5 MHz, d6-DMSO, deuterated solvent as internal standard: 39.5 ppm): d = 23.5 (CH2CN), 33.9, 38.2 (C-3 / C-5), 60.9 (C-4), 71.05 (C-2), 117.2 (CN), 169.3 (C-6) Calculated elemental analysis (%) for C7H9N03 (155.15): C 54.19, H 5.85, N 9.03; found: C 54.4, H 5.8, N 9.0. aH-NMR and the results of the elemental analysis prove that the compound formed is ((2J ?, AR) ~ 4-hydroxy-6-oxo-tetrahydro-pyran-2-yl) -acetonitrile.

Example 2: Preparation of ((4J? 6R) -6-Cyanomethyl-2, 2-dimethyl- [1, 3] dioxan-4-yl) -acetic acid methyl ester (an enantiomerically enriched compound of formula 6 wherein R1 = CN and R2 = R3 = R4, Me). A round bottom flask equipped with a reflux condenser and a PTFE coated stir bar was charged with 0.56 g of crude ((2R, 4R) -4-hydroxy-6-oxo-tetrahydro-pyran-2-yl) -acetonitrile. as obtained in Example 1. 2,2-dimethoxypropane (3 ml) and p-toluenesulfonic acid hydrate (15 mg) were added, and heating was continued for a further 5 h. After cooling to room temperature, the mixture was diluted with ethyl acetate (230 ml) and washed with aqueous sodium bicarbonate solution / 5% w / w). The phases were separated, and the harassing phase was extracted with ethyl acetate (30 ml). The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and evaporated in vacuo, leaving a yellow oil containing the objective compound methyl ester of ((4R, 6R) -6-cyanomethyl- 2,2-dimethyl- [1,3] dioxan-4-yl) -acetic (an enantiomerically enriched compound of formula 6 wherein R1 = CN and R2 = R3 = R4 = Me) according to the CCD and NMR analyzes. Yield: 0.37 g (45%). ^ -NMR (300 MHz, CDCl3, residual non-deuterated solvent as internal standard: 7.26 ppm): d = 1.12-1.38 (m, 1 H, H-5) superimposed on 1.36 (s, 3 H, Me), 1.44 ( s, 3 H, Me), 1.75 (d "t", J = 12.6, ~ 2 Hz, 1 H, H-5), 2.39 (dd, J = 15.7, 6.1 Hz, 1 H of CH2CN), 2.49 ( center of system AB, 2 H, CH2COOMe) superimposed on 2.56 (dd, J = 15.7, 6.9 Hz, 1 H of CH2CN), 3.67 (s, 3 H, COOCH3), 4.13 (mc, 1 H, H-6) , 4.31 (mc, 1 H, H-4). 13 C-NMR: (75.5 MHz, CDC13, deuterated solvent as internal standard: 77.2 ppm): d = 19.6 (Me), 24.9 (CH2CN), 29.7 (Me), 35.3, 40.8 (C-5 / CH2COOMe), 51.7 (COOCH3), 65.0, 65.4 (C-4 / C-6), 99.5 (C-2), 116.8 (CN), 171.0 (COOMe). The results of XHRMN and 13C-NMR prove that the compound formed is the methyl ester of ((4J? 6R) -6-cyanomethyl-2,2-dimethyl- [1, 3] dioxan-4-yl) -acetic acid.

Example 3: Preparation of ((2J ?, 4R) -4-hydroxy-6-oxo-tetrahydro-pyran-2-yl) -acetonitrile on a larger scale than in example 1. In a 3-neck round bottom flask , 250 ml, equipped with a dropping funnel, a mechanical stirrer and a thermometer, 50 g of (4R, 6S) -6-chloromethyl-4-hydroxy-tetrahydropyran-2-one were suspended in demineralised water (30 ml) with agitation. An aqueous solution of potassium hydroxide (34 g, 50% w / w)) was added dropwise over a period of two hours. The dropping funnel was rinsed with water (4 ml) and removed. During the addition, the temperature of the reaction mixture rose from 25 ° C to 35 ° C. After stirring for an additional 45 min, solid potassium cyanide (35.6 g) was added in one portion. After two hours the temperature of the reaction mixture rose from 30 ° C to 65 ° C (no cooling or external heating was applied). Subsequently the temperature of the reaction was maintained between 50 and 55 ° C (with an oil bath) for two additional hours. The external heating was stopped and the reaction mixture was stirred at room temperature overnight. The thermometer was replaced by a gas outlet leading to a wash bottle filled with 50% w / w KOH (to trap the excess cyanide). Hydrochloric acid (42ml, 37% w / w) was added through a dropping funnel for two hours while a slight overpressure of nitrogen was applied. The pH of the reaction mixture was 3 at the end of the addition. Then the reaction mixture was purged for six hours with nitrogen to remove excess HCN. The acidified mixture was filtered through paper and the residue was washed four times with water (10 ml each). The unified filtrate was extracted continuously with ethyl acetate for one day. Another portion of hydrochloric acid (1 ml, 37% w / w) was added to the aqueous phase which was further extracted with ethyl acetate for two days. The unified organic phases were dried over sodium sulfate, filtered and evaporated in vacuo, leaving a highly viscous liquid containing the objective compound ((2R, 4R) -4-hydroxy-6-oxo-tetrahydropyran-2-yl) -acetonitrile . Yield: 36g (76%).

Example 4: Preparation of (4R, 6R) -6-Cyanomethyl-2,2-dimethyl- [1, 3] dioxan-4-yl) -acetic acid methyl ester on a larger scale than in Example 2. A bottom flask round, equipped with a reflux condenser and magnetic stirring bar coated with PTFE, was charged with 19 g of crude ((2R, 4R) -4-hydroxy-6-oxo-tetrahydropyran-2-yl) -acetonitrile as obtained in Example 1. 1. 2,2-Dimethoxypropane (133ml) was added and the mixture was heated to reflux (the solubility of the substrate was poor at low temperatures). P-toluenesulfonic acid hydrate (0.5g) was added and the heating continued for three hours. After cooling to room temperature, the mixture was diluted with ethyl acetate and poured into saturated aqueous sodium bicarbonate solution. The phases were separated and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and evaporated in vacuo leaving an orange oil which was purified by column chromatography over silica (solvent: petroleum ether / MTBE gradient). 5 + 1 to 1 + 1). The resulting yellow oil contained the objective compound methyl ester of ((4R, 6R) -6-cyanomethyl-2,2-dimethyl- [1,3] -dioxan-4-yl) -acetic acid yield: 12.7g (46%) .

Example 5: Preparation of ((4R, 6R) -6-cyanomethyl-2,, 2-dimethyl- [1, 3] -dioxan-4-yl) sodium acetate (an enantiomerically enriched compound of formula 7 where RX = CN, R2 = R3 = Me, Y = Na). A round bottom flask equipped with a magnetic stirring bar coated with PTFE was charged with 6.4 g of ((4R, 6R) -6-cyanomethyl-2,2-dimethyl- [1,3] -dioxan-4-methyl ester. -yl) -acetic as obtained in Example 4, toluene (10 ml), methanol (450 mg) and water (6 ml). Sodium hydroxide solution (32 w / w%, 3.9 g) was added dropwise over 10 minutes at room temperature. The resulting two-phase mixture was stirred at room temperature for four hours. The toluene phase was separated and discarded and most of the aqueous phase was evaporated in vacuo. The crude residue was used for the next reaction.

Preparation of ((4R, 6R) -6-Cyanomethyl-2,2-dimethyl- [1,3] -dioxan-4-yl) -acetic acid chloride: The crude residue (pH > 9) of Example 5 was transferred to a round bottom flask equipped with a magnetic stirring bar coated with PTFE and a Dean Stark trap. The residue was distilled by azeotropic evaporation with toluene. At the end of the drying process, 100 ml of toluene was left with the solid sodium salt. The trap of Dean Stark was removed. Oxalyl chloride (3.5 ml) was added dropwise through a syringe for 2.5 hours at room temperature while maintaining a constant flow of nitrogen through the flask. After the addition was complete, the reaction mixture was stirred at room temperature for four more hours. The orange suspension that formed was used in the next step.

Example 7: Preparation of 1,1-dimethylethyl acetate ((4R, 6R) -6-cyanomethyl-2,2-dimethyl- [1,3] -dioxan-4-yl) (an enantiomerically enriched compound of formula 8 wherein R1 = CN, R2 = R3 = Me, R5 = tert butyl): A round bottom flask equipped with a magnetic stirring bar coated with PTFE was charged with tert-butanol (10 ml) and N-methylmorpholine (8 ml). To this solution was added the toluene suspension at room temperature over 30 minutes. The resulting dark brown solution was stirred at room temperature for 12 hours. After dilution with toluene, the organic layer was washed three times with saturated aqueous sodium bicarbonate solution, once with saturated aqueous solution of ammonium chloride and once with saturated aqueous sodium chloride solution. The organic layer was dried with sodium sulfate, filtered and evaporated in vacuo leaving 7 g of a dark viscous oil, which was purified by column chromatography over silica (solvent: petroleum ether / ethyl acetate 8 + 1). The resulting solid contained the tert-butyl ester of ((4R, 6R) -6-cyanomethyl-2,2-dimethyl- [1,3] -dioxan-4-yl) -acetic acid tert-butyl ester yield: 3.3g (43%) ) in three stages. The NMR data of the target compound are identical to the literature data published for this compound (EP 1077212).

Claims (18)

1. NOVELTY OF THE INVENTION Having described the invention as above, property is claimed as contained in the following: CLAIMS 1. Process for the preparation of a compound of formula 1: (1) characterized in that a compound of formula 2 (2) wherein X is a leaving group, is reacted with a cyanide ion in water and where the pH is subsequently decreased to a pH between 0 and 5. Process according to claim 1 characterized in that the concentration of the cyanide ion is at least 1 mole per liter. Process according to claim 1 or claim 2, characterized in that the molar ratio between the total amount of the cyanide ion and the total amount of the compound of formula 2, is between 0.5 and 10. Process according to any of claims 1-3 , characterized in that the compound of formula 1 is first treated with a base before being reacted with a cyanide ion. Process according to claim 4, characterized in that the base is used in a molar ratio of between 0.3 and 3 compared to the amount of compound of formula 2. Process according to any of claims 1-5, characterized in that the compound of formula 1 is reduced with a suitable reducing agent to form the corresponding compound of formula 3: (3) Process according to any of claims 1-6, characterized in that the compound of formula 2, in which X is a leaving group, is prepared by an aldol condensation between acetaldehyde and an aldehyde which is substituted at the 2-position. by X, where X is as defined above, in the presence of an aldolase and by subsequent reaction of the compound formed of formula 4, where X is as defined above, with an oxidizing agent. Process according to claim 7, characterized in that the aldolase used is 2-deoxyribose-5-phosphate aldolase (DERA, EC 4.1.2.4) or a mutant thereof. Process according to any of claims 1-8, characterized in that a compound of formula 1 or a compound of formula 3 is converted into a compound of formula 6, where R1 is CN or CH2NH2 and R2, R3 and R4 each independently are a group, alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl or aralkyl and where R2 and R3 can form a ring together with the C atom to which they are linked use of a suitable acetal forming agent, in the presence of an acid catalyst and wherein the compound of formula 6 with R1 being CN is optionally reduced with a suitable reducing agent to form the corresponding compound of formula 6 with R1 being CH2NH2. Process according to claim 9, characterized in that a compound of formula 6, wherein R1 is CN or CH2NH2 and where R2, R3 and R4 are as defined above is subsequently hydrolyzed in the presence of a base and water to form the corresponding salt of formula 7, wherein Y is an alkali metal or a substituted or unsubstituted ammonium group, optionally followed by the conversion of the salt of formula 7 into the corresponding acid (the compound of formula 7 where Y is H) and wherein the salt or acid of formula 7 wherein R 1 is CN is optionally reduced with a suitable reducing agent APRA to form the corresponding salt or acid of formula 7 wherein R 1 is CH 2 NH 2. 11. Process according to claim 10, characterized in that the salt of formula 7 or the acid of formula 7 is converted into the corresponding ester of formula where R1 is CN or CH2NH2, where R2 and R3 are as defined above and where R5 can represent the same groups given above for R2, R3 and R4, in a manner known per se. 12. Process according to claim 11, characterized in that the salt of formula 7 is converted into the corresponding ester of formula 8 by contacting the salt of formula 7 in an inert solvent with an acid chloride forming agent to form the corresponding chloride of acid and contacting the acid chloride formed with an alcohol of formula R5OH, wherein R5 is as defined above, in the presence of N-methylmorpholine (NMM), and wherein the salt or acid of formula 7 in which R1 is CN is optionally reduced with a suitable reducing agent to form the corresponding salt or acid of formula one in which R1 is CH2NH2. Process according to any of claims 7-12 characterized in that the compound with a group (R1 is CN) is reduced with a suitable reducing agent to form the corresponding compound with an amino group (R1 is CH2NH2). Process according to any of claims 1-13, characterized in that the compound obtained is enantiomerically enriched. 15. Process according to any of claims 1-14, characterized in that the obtained compound is further converted to a statin, preferably Atorvastatin or its calcining salt in a manner known per se. 16. Use of a compound obtained by a process according to any of claims 1-15 in the preparation of a pharmaceutical composition, preferably a statin, more preferably Atorvastatin. 17. The compounds: (4-hydroxy-6-oxo-tetrahydro-pyran-2-yl) -acetonitrile, 6- (2-amino-ethyl) -4-hydroxy-tetrahydro-pyran-2-one, acid methyl ester (6- cyanomethyl-2,2-dimethyl- [1,3] dioxan-4-yl) -acetic acid ester (6-cyanomethyl-2,2-dimethyl- [1,3] dioxan-4-yl) -acetic, (6-cyanomethyl-2,2-dimethyl- [1,3] dioxan-4-yl) -acetic acid i-propylester, (6-cyanomethyl-2,2-dimethyl- [n-propylester] 1,3] dioxan-4-yl) -acetic acid [6- (2-amino-ethyl) -2,2-dimethyl- [1, 3] dioxan-4-yl] -acetic acid methyl ester, acid ethyl ester [6- (2-Amino-ethyl) -2,2-dimethyl- [1,3] dioxan-4-yl] -acetic acid [6- (2-amino-ethyl) -2-, 2-propylester] -dimethyl- [1,3] dioxan-4-yl] -acetic acid [z-propyl] -6- (2-amino-ethyl) -2,2-dimethyl- [1,3] dioxan-4-yl] -acetic. 18. Compound according to claim 17, characterized in that the compound is enantiomerically enriched.