MXPA01001643A - Enantioselective synthesis - Google Patents

Abstract

A short practical commercial process for the efficient enantioselective synthesis of the non-steroidal antiestrogen of formula (I) or (XIV) or a pharmaceutically acceptable salt thereof.

Description

SYNTHESIS ENANTIOSELECTIVA BACKGROUND OF THE INVENTION The present invention relates to a short and effective enantioselective synthesis of the orally active antiestrogen of the formula I or XIV or a pharmaceutically acceptable salt thereof. The synthesis and anti-estrogenic activity of the compound of the formula I, ie 4 ', 7-bistrimethylacetate of (S) -7-hydroxy-3- (4'-hydroxyphenyl) -4-methyl-2- ( 4"- [2" '- (1-piperidino) -ethoxy] phen? I] - 2 H -benzopyran, in J. Med. Chem. 1997. 40, 2117-2122. See also U.S.A. Nos. 5,395,842 and 5,407,947 and J. Med. Chem., 1990, 33, 3216-3222. Each of the exposed synthetic schemes is a laboratory scale procedure that involves expensive steps not suitable for a practical procedure on a commercial scale. There is a need for a short and effective enantioselective synthesis suitable for the large-scale manufacture of the compounds of formulas I and XIV.

BRIEF DESCRIPTION OF THE INVENTION The present invention provides a process which consists in reacting the compound of the formula IV with the compound represented by the formula VII in the presence of piperidine, a hindered organic amine base and a C3-C6 alkanol at a temperature and for a time sufficient to produce the compound of formula IX essentially free of the cis isomer of the compound of formula IX, and of the calcona E and Z of formula VIII in which HPG is an acid labile hydroxylphenolic protecting group: IX The present invention also provides a method consisting of the steps of: ^^^ and ^^^^^^^^ * ^ ¡^^ > * (a) reacting the compound of the formula IV with the compound represented by the formula VII: in the presence of piperidine, a hindered organic amine base and a C3-C6 alkanol at a temperature and for a time sufficient to produce the compound of formula IX essentially free of the cis isomer of the compound of formula IX, and of the calcona E and Z of formula VIII in which HPG is an acid labile hydroxylphenolic protecting group: IX (b) reacting the compound of the formula IX with a stoichiometric excess of methyl lithium in an aprotic solvent for a time and at a temperature sufficient to produce the compound of the formula X: x (c) contacting the compound of formula X with a stoichiometric excess of (S) - (+) - camphor sulfonic acid in a solvent consisting of a CrC6 alkanol for a time and at a temperature sufficient to produce the addition salt of the R, S / S acid, racemic S of the formula XI; XI (d) contacting the racemic acid addition salt of formula XI with a catalytic amount of (S) - (+) - camphor sulfonic acid and in a solvent consisting of ethanol for a time and at a temperature sufficient to produce the S, S-diastereomeric acid addition salt of formula XII; XII substantially free of the opposite R, S-diastereomeric salt of formula XIII, XIII; and (e) (i) contacting the S, S-diastereomeric acid addition salt of compound XII with a stoichiometric excess of pivaloyl chloride in the presence of a tertiary organic base at a temperature and time sufficient to produce the compound of the formula I: : or (e) (!) contacting the S, S-diastereomeric acid addition salt of compound XII with a sufficient amount of a tertiary organic base at a temperature and time sufficient to produce a compound of formula XIV: ^^^ á ^^ Sm9msí ^^^^ XIV DETAILED DESCRIPTION OF THE INVENTION The method of the present invention provides a short and practical commercial process for the effective enantioselective synthesis of potent, orally active non-steroidal anti-estrogenic compounds of the formulas I and XIV, in the chemical essence and enantiomerically pure. By the term "enantioselective synthesis" as used herein with reference to the compounds of formulas I and XIV is meant that the process of this invention produces the S-enantiomer of formulas I and XIV in preference to the enantiomer of the R configuration opposite. The procedure, summarized in Schemes I and IA, comprises a selection of reagents and reaction conditions that avoid the use of separation techniques, such as fractional crystallization and chromatography, while providing chemical and enantiomerically pure compounds. Steps B and C of the procedure in Scheme I involve reactions and reaction conditions étJ *? É & It is necessary to change the balance of chalcone (compound VIII) / chromanone (compound IX) to produce essentially only 2,3-fra / 7s-diaryl-2,3-dihydro-4H- Phenyl-1-benzopyran-4-one of the formula IX, a precursor of the compound of the formula I. The conversion of this racemic precursor to a single S, S diastereomer of the formula XII is effected by a kinetic (dynamic) resolution in the step F. Specifically, the present invention provides conditions and reagents in steps B and C that allow the production of a simple trans compound of the formula IX in essentially chemically pure and essentially free of the cis isomer of the compound of the formula IX and free of the calconas E and Z of the formula VIII. By the term "chemically pure" as used herein is meant to be greater than 95%, preferably greater than 99%, free of other chemical substances, for example the chalcones E and Z of formula VIII. By the phrase "essentially free" of the cis isomer of the compound of the formula IX as used herein is meant that the compound of the formula IX contains less than about 2%, preferably less than about 1%, of the cis isomer of the compound of the formula IX. By the term "C3-C6 alkanol" is meant a straight or branched chain C3-C6 alkanol including isopropanol, isobutanol, isopentanol and isohexanol, and the secondary alcohols 2-butanol, 2-pentanol, 3-pentanol and 2-hexanol. The use of 2-butanol, isobutanol or isopropanol is preferred. The use of 2-butanol is more preferred. ^ - ^^^^. ^ "^^ i ^^^^^^^^ A ^^ ^ m ^^^^^^^? ^. ^.

By the term "acid-labile hydroxylphenolic protecting group" (HPG) as used herein, "protecting groups" that are separated under acidic conditions are meant, for example, conditions of step E of the present invention. Typically suitable acid-labile hydroxylphenolic protecting groups include phenolic protecting groups commonly employed in organic chemistry including, but not limited to, tetrahydropuranyl, methoxymethyl, methoxyethoxymethyl and cyclopropylmethyl. The introduction of hydroxylphenolic protecting groups is discussed in "Protecting Groups in Organic Synthesis, TW Greene, pp. 87-113, J. Wiley &Sons, NY, 1984. The use of tetrahydropyranyl as a hydroxylphenolic protecting group is preferred. Example 1) By the term "an hindered organic amine base" as used herein, "non-nucleophilic organic amines" are meant.The typically adequate hindered organic amine bases include 1,5-diazabicyclo [4.3.0] non-5-ene ("DBN"), 1,4-diazabicyclo [2.2.2.] octane ("Dabco ™), 1,8-diazabicyclo [5.4.0] undec-7-ene (" DBU ") and 1, 1, 3 ', 3'-tetramethylfuanidine ("TMG"). DBN, Dabco, DBU and TMG are obtainable from Aldrich, Milwaukee Wl 53233. The use of DBU and DBN is preferred. The use of DBU is more preferred. By the term "tertiary amine base" as used herein, C? -C6 trialkylamines, such as triethylamine, N-methyl-piperidine and N-methylmorpholine, are meant. The preferred tertiary amine base is triethylamine. & - < *, < $ Scheme I XV 10 Scheme IA Details of the steps of the I and IA schemes are provided below. Step A: The compound of formula IV can be prepared by the The reaction of the compound of the formula III with dihydropyran ("DHP") in the presence of p-toluenesulfonic acid ("p-tsa") in ethyl acetate. The compound of the formula III can be prepared as described in J. Med. Chem., 1997, 40, 2117-2122 on page 2117. Steps B and C: Step B, formation of the carbon-carbon double bond in the compound of formula VIII, it involves a knoevenagel condensation reaction of the ketone compound of formula IV with the aldehyde of formula VII in the presence of a solvent and a catalytic amount of piperidine. The preferred solvent is 2-butanol, but can be used also other C3-C6 alkanols, such as isopropanol or isobutanol. It is usually carried out the condensation reaction by heating the reaction mixture of the compounds IV and VII and piperidine in a C3-C6 alkanol to reflux temperature in an inert atmosphere such as nitrogen or argon. The Knoevenagel condensation is an equilibrium reaction and must be carried out by removing water from the reaction mixture. The separation of water is achieved by distilling an azeotropic mixture of alcohol and water. The water formed in the reaction must also be separated by the use of a drying agent such as molecular sieves or anhydrous sodium sulfate. HE can add the drying agent, if used, to the reaction or be contained in an external vessel, such as a column, through which the azeotropic distillate of alcohol and water passes, before being returned to the mixture. reaction. Alternatively, other solvents can also be used such as aromatic hydrocarbons, for example toluene or xylene, in which water is immiscible, as a solvent in the Knoevenagel reaction. When aromatic hydrocarbons are used as solvents, the water can be separated during reflux by means of a Dean-Stark siphon. If these aromatic hydrocarbon solvents are used, however, they should be replaced with a C3-C6 alkanol as described above, before carrying out the isomerization step C. This isomerization of the compounds of formula VIII to the compound of formula IX is also a method of balancing base catalyzed, in that the equilibrium position is dependent upon the temperature, solvent and base involved in The procedure. At the end 7h "- ^ -" i - ^ ^^^^ to ^^^^^^^^ - - '^ ^ ge of the Knoevenagel reaction, the ratio of VIII to IX is about 1.6: 1 to 2 : 1 depending on the solvent used It has been found that with the use of a strong hindered organic amine base, such as DBU or DBN, in a C3-C6 alcohol, preferably 2-butanol or 2-5-propanol, it can be raised this equilibrium ratio at about 6: 1. which is not yet high enough for a manufacturing process to avoid chromatography or other inefficient methods of purification to be commercially feasible it has further been found that if the concentration of VIII is adjusted and IX in the C3-C6 alkanol, so that the transi-chromanone of formula IX crystallizes during the isomerization, the equilibrium can be fully carried to compound IX.Finally, at the end of the isomerization step, the ratio of IX to VIII in the reaction mixture of approximately 98: 2 and in the prod The ratio of IX to VIII is greater than 99: 1. The use of a hindered organic amine base, such as DBU or DBN, in contrast to the prior art bases, for example sodium or potassium acetate, also advantageously reduces the byproducts arising from the deprotection of the hydroxy groups phenolic After the Knoevenagel reaction is complete, the reaction mixture is cooled and the concentration of the products adjusted by adding or separating the alcohol, as necessary. If a solvent other than a C3-C6 alcohol is used, this non-alcoholic solvent is then removed by distillation and replaced with a suitable C3-C6 alcohol. In step C, the thus formed mixture of cis-chromanones is stirred ^^^^^^^ ímifr ^^^^. * & * &? and trans of formula IX and chalcones E and Z of formula VIII at room temperature for a sufficient time - preferably at least 24 hours, but up to 48 hours - to complete the isomerization of the mixture to the pure trans compound of formula IX . Seeds of IX can be added, if necessary, to ensure that the crystallization of IX occurs. Filter IX and wash with isopropanol or 2-butanol. Normal DBU or DBN is added or preferably after the Knoevenagel condensation reaction is complete (ie after the reaction mixture has cooled to room temperature) and before the start of step C.

Optionally adding DBU or DBN with the piperidine at the start of step B. The catalytic amounts of piperidine and the strong hindered organic amine base used, such as DBU, are usually about one third of the stoichiometric amount of IV used in the reaction (see example 1). The prior art process described in J. Med. Chem, 1997, 40, 2117-2122 in 2118 produces a mixture of compounds IX and VIII in a ratio of 3: 2 (60% to 40%). According to the process of this invention, VIII is completely converted to a trans compound of formula IX which is essentially chemically pure and is essentially completely free (ie containing less than about 2 or even 1%) of the Cis isomer of the formula IX and the E and Z isomers of the formula VIII. Step D: The preferred organometallic reagent for methylation step D is methyl lithium, but methyl halide can also be used ^? ji¿y ^^ áíÉk? y ^. magnesium, preferably methyl magnesium chloride or bromide in the presence of ceric chloride (III). The use of methyl lithium ("MeLi") is preferred. It has been discovered that during step D, methylation of the compound of formula IX, compound IX is again somerized to the chalcones of formula VIII. In the presence of methylating agents, the chalcones of the formula VIII can give rise to compounds of the formula Q, ie products of addition 1, 4 to the enone.

Q Under the conditions of the prior art including the use of methylmagnesium halides in THF or ether (see U.S. Patent Nos. 5,395,842, or 5,407,947 and J. Med. Chem .. 1990, 33, pp. 3216-3222), VIII and Q are obtained in a ratio of approximately 7: 1 and are usually separated by chromatography. Mixtures of VIII and Q are also obtained with MeLi in THF alone (see J. Med. Chem., 1997, 40 pp. 2117-2122) and chromatography is usually required to separate these mixtures into pure compounds. It has been found that under certain conditions chromanones of formula IX can be methylated in such a way that less than about 3% of the compounds of formula Q are formed (the ratio of IX to Q is greater than about 27: 1). No chromatography is required, since the small amount of Q is conveniently separated for the next step, ie, step E, during the crystallization of XI. To achieve this low level of Q, methylation is carried out in a non-polar acyclic ether solvent using methyl lithium as the methylation reagent and a non-polar ether solvent such as diethyl ether, t-butyl methyl ether, dimethoxyethane, or diethoxymethane under anhydrous conditions. The preferred acyclic ether solvent is t-butyl methyl ether. The use of a cyclic ether, for example THF, as the sole solvent normally leads to a greater number of compounds of the formula Q. Other non-polar solvents, such as toluene or eumeno, can be used, but are not convenient as they have relatively high boiling points and are difficult to separate. Mixtures of the anhydrous acyclic esters listed above can also be used with anhydrous aromatic hydrocarbons, such as eumeno or toluene; preferably a mixture of eumeno and THF. Preferred aprotic solvents are pure anhydrous ethers, especially diethoxymethane ("DEM") and t-butylmethyl ether ("TMBE"). At step D is required at least about 2.8 equivalents, preferably about 3 equivalents of MeLi; minor amounts of MeLi lead to greater amounts of Q. The preferred methylation reagent is methyl lithium as an 8% solution in DEM. Other commercially obtainable sources of methyl lithium can be used, such as methyl lithium at 1.4 M in diethyl ether or methyl-lithium at 1.0 M in cumene THF (9: 1, v / v), but are less preferred, since they are more diluted, ie they have a lower concentration of the methylation reagent and also give more Q. Methylation is preferably conducted in a dry atmosphere, free of oxygen and inert, such as nitrogen or argon dry. The temperature of the methylation reaction is usually in the range of about -20 ° C to about 50 ° C, preferably about -20 ° C to 20 ° C and most preferably in the range of about 0 ° C to about 5 ° C. C under conditions of anhydrous and inert atmosphere. The methylation of the prior art was conducted at a temperature of -78 ° C. According to a preferred aspect of the process of this invention, methyl lithium is used as an 8% solution in diethoxymethane ("DEM") with tert-butyl methyl ether ("TBME") as the reaction solvent, to produce alkylation with methyl. -lite almost exclusively in carbonyl-carbon with less than 1-2% Q formed by Michael's 1,4-alkylation of VIII. The reaction is preferably conducted under an inert atmosphere of nitrogen or argon at a temperature in the range of about 0 to about 5 ° C. The reaction is distinguished with an aqueous acid solution - preferably aqueous ammonium chloride and the organic layer containing compound X is washed with saline and sent to the next step without further purification or chromatography, as taught in J. Med. Chem 1997. 40, 2117-2122 at 2117. Also J. Med. Chem. 1990 33 3216. Step E: the dehydration and deprotection procedure of the prior art (separation of acid labile phenolic hydroxyl protecting groups, from THP, preferred) of the compound of the formula X uses 90% of * $ faith * -. The acetic acid at 90 ° C is produced to produce the free base of the diphenol of the formula Z. This process of dehydration and deprotection of the prior art suffers from the difficulty of separating the acetic acid from the product of the formula Z and the production of the same. amorphous material of variable color from light pink to red, 5 due to the formation of impurities. The free base reaction product of formula Z contains large amounts of solvent and is also unstable. The high reaction temperature of the prior art is detrimental and causes the increased decomposition of the deprotected diphenol Z. The prior art process also requires chromatography to purify the free base compound 10 of the formula Z.

A novel process has been discovered by which dehydration and deprotection is effected in step E. The process is quick and conducted at room temperature to reduce the formation of impurities. In addition, diphenol, the free base of the formula Z once formed, is immediately converted without isolation of the addition salt of the racemic (S) -carboxyphosphonic acid of the formula XI which is more stable than the free base Z diphenolic. An additional advantage of step E is that the a ^ '' A * - ^ 'i ^ ?? r? f #? rífffstflÉÉ it - ** rfr * ¡r * * t¿? ** • ** composition of the formula XI as a solid crystalline material and it can be isolated with high yield and easily purified by crystallization directly from the reaction solvent, without need of expensive chromatography. The addition salt composition of the racemic (S) -camphorsulfonic acid of formula XI is a new composition of matter, not isolated or previously described. The procedure of step E is carried out as follows: the TBME solution of the compound of formula XI from step D above is concentrated and the residue thus formed is dissolved in an inert solvent, such as a lower alcohol, including for example methanol , ethanol or isopropanol or a acetone or a mixture of alcohols, preferably ethyl alcohol, most preferably a mixture of ethyl alcohol, methyl alcohol and isopropanol (18: 1: 1, v / v / v). The concentration of X is preferably in the range of about 1000 g / l to about 200 g / l, most preferably about 340 g / l. It is added at least approximately 1.0 to about 1.5 equivalents, preferably to about 1.1 equivalents of (S) -camphorsulfonic acid, and the solution is stirred at room temperature for 24-48 hours, preferably for about 24 hours, while the acid addition salt composition is crystallized (S) Racemic -CSA of formula XI. Can it be added Optionally an additional solvent, such as sodium propane, to maintain the fluidity during crystallization. The racemic R, S / S, S composition of formula XI is filtered off, washed with an alcohol solvent other than methanol, such as isopropanol, and dried. You drive the ^ ÍÁ? ^ S u ^ * ?? ^^^ > ^ ^ ^ ^ ^ ^ S ^^^^^ ^ ^^, Yy ..., YSsia procedure preferably in an inert atmosphere, such as argon or nitrogen. The isolation of the composition of formula XI as a crystalline solid has the additional advantage of allowing its use in a novel dynamic resolution procedure in step F described below. In a preferred embodiment of step E, the compound of formula X is dehydrated, deprotected and converted into diphenol thus formed in a mixture of diastereomeric acid addition salts of formula XI by contacting X with a stoichiometric excess at less about 1.0 to 1.5 equivalent, preferably about 1.1 equivalents of (S) -CSA at room temperature in a solvent consisting of ethanol, preferably ethanol denatured with 5% (v / v) of 5% methanol (v / v) ) of sopropanol. The reaction mixture thus formed is stirred for about 15 minutes and the mixture of diastereomeric acid addition salts of the formula XI is crystallized. When the crystallization is well advanced and the watery paste thickens considerably, 5 volumes of isopropanol are added and the slurry is stirred for at least 24 hours at about 20 ° C. the crystalline mixture of the diastereomeric acid addition salts of formula XI is isolated by filtration and dried in a blast furnace at less than 50 ° C to produce a 90% yield (of compound IX) of the mixture of salts of addition of S, SR, Sd¡astereomeric acid (S) -CSA of the formula XI which are 97.8% chemically pure.

Step F: In the prior art process, the separation of the racemic free base compound of the formula Z to its constituent R and S enantiomers was carried out either by expensive and time consuming chromatography using a chiral stationary phase or by a traditional resolution by means of fractional crystallization of a mixture of diastereomeric (S) -alphaforphosulonic acid salts which is prepared in situ by adding (S) -alphaforphosulphonic acid to the compound of the formula Z in a mixture of CH2Cl2 / DMF. Ester process of the prior art also uses chlorinated hydrocarbon CH2Cl2 which is expensive and dangerous. He The prior art resolution performance is low and the unwanted R, S diastereomer is wasted and must be recirculated by a prolonged procedure involving a racemization catalyzed by the lithium hydroxide base at high temperature to produce the compound of free base diphenol of the formula Z that must be converted again in situ to the racemic (S) -alphaforphosphonic acid salt of formula XI and then resolved as before. A novel dynamic resolution procedure (step F) has been invented for the compound of formula XI which not only avoids the advantages of the prior art process, but also gives superior optical and chemical performances. The present invention provides in Step F a novel higher dynamic resolution method which not only avoids the disadvantages of the prior art processes, but also provides the S, S diastereomer of the salt compound of the prior art.

Formula XII in performance and highest optical purity. A special feature of this dynamic resolution method is the simultaneous resolution of the diastereomeric mixture of (S) -camphor-sulfonic acid addition salts of the formula XI and the racemisation of the undesired R, S diastereomer of the compound of the formula XII, of such that up to 130% of the amount of diastereomer S, S of formula XII is obtained in the original starting mixture of R, SS, S-diastereomeric acid addition salts of formula XI. This dynamic resolution procedure avoids the disadvantages of the prior art methods described above, including the need for chromatography that is impractical on a very large scale and the need for a separate step of base catalyzed racemization, along with the requirement to reform the Diastereomeric (S) -alphaforphosulonic acid salt of the formula XI, in order to recover and recycle the undesired opposite R, S diastereomer of the compound of the formula XIII: XIII This improved dynamic resolution procedure also avoids the use of the CH2Cl2 / DMF solvent mixture of the prior art resolving process and at the same time increases the optical purity of the compound of formula XII by obtaining percent diastereomeric excess ("of ") - the prior art process produced only 92% -and the weight yield to more than 60% (compared to 41% of the prior art process). Step F of the process of the present invention is characterized in that a suspension of the diastereomeric mixture of the (S) -camphorsulfonic salts of the formula XII is heated in about 6 volumes (range of 4 to 8 volumes) of ethanol, preferably 2B ethanol anhydrous (95% ethanol-5% water) containing (S) -camphorsulfonic acid in a catalytic amount of about 0.15 molar equivalents to about 1.2 molar equivalents, preferably 0.5 to about 0.7 molar equivalents, most preferably 0.6 equivalents molars (at about 20% by weight) of (S) -alphaforphosulphonic acid at a temperature between 50 ° and the boiling point of ethanol, preferably a temperature in the range of about 70-80 ° C, more preferably and about 70 ° and 75 ° C for a time, until a portion S, S: R, S of the diastereomeric (S) -alphaforphosulonic acid salts of the formula XI in the Total reaction mixture is approximately 7: 1 (usually less than 24 hours). The reaction mixture is preferably stirred under an inert atmosphere, such as nitrogen or argon, during the heating and cooling process. The reaction mixture is cooled to room temperature during. about 4 to 24 hours, preferably for about 4 to 6 hours, the optically pure diphenol- (S) -alphaforphosphonic salt of the formula XII is then filtered off and washed with an alcohol such as ethanol or isopropanol, and dry It is believed that the undesired R, S diastereomer of the acid addition salt of formula XIII is solubilized during this acid-catalyzed process and is racemised at the 2-position of the 2H-benzopyran ring system to generate a mixture of salts of addition of S, S and R, S (S) -alphaforphosulphonic acid of the formula XI. The less soluble S, diatereomeric acid addition salt emerges by crystallizing allowing more diastereomer R, S to enter solution. In this way, the balance of salts R.S./S.S. is mainly forced to form S, S, namely the compound of formula XII. Step G: In the prior art process, the (S) -alphaforphosulphonic acid salt compound of formula XII was first converted to the enantiomer-free base compound (S) of formula Z by treatment with aqueous K2CO3 isolated by extraction to a solvent, dried and concentrated the solution thus formed. In a second step, the compound of free base of enantiomer (S) of the formula Z was converted by treatment with pivaloyl chloride and triethylamine in methylene chloride to the compound of the formula I. On a large scale, this method is uneconomical as to extraction solvent, it is a consumer of time and can lead to a decomposition of the unstable free base of the formula Z during the prolonged procedure. In addition, it has been observed that the compound of formula I reacts with CH2Cl2 to generate a chloromethyl quaternary salt of undesirable impurity of the formula Z2: Step H: In step H of scheme 1A, compound XV, the acid addition salt of hydrogen chloride and compound XIV, can be prepared directly from compound XII to form the free base of the salt (S) - camphor sulfonate (XII) to provide compound XIV which is converted, without isolation, to compound XV. It can be purified Optionally compound XV by recrystallization. The formation of free bases can be carried out by suspending the salt XII in a mixture of water and an immiscible organic solvent, in which the free base (compound XIV) is soluble and adding between one and two equivalents (preferably about 1.4 equivalents) from a base such as alkali metal carbonate or bicarbonate, Preferably a tertiary organic base, such as trialkylamine or pyridine, preferably tritylamine. The immiscible organic solvent can be an ether, an acetone, an ester, a halogenated hydrocarbon, preferably an ether or an ester, most preferably t-butyl methyl ether (t-BuOMe). The Y- ^ = ^^^ & The mixture thus formed, preferably at room temperature, until the complete solution is produced. The lower aqueous layer is separated and extracted with the organic solvent. All the organic solvent and the extracts containing Compound XIV are combined and washed with saline and filtered through the silica gel. The filtrate is concentrated and the solvent is replaced with a water miscible alcohol solvent, preferably ethanol. The alcohol solution of compound XIV is cooled, preferably at about 5 ° C and added slowly between one and two equivalents (preferably about 1.1 equivalents) of 2N hydrochloric acid, with stirring about 3. Stirring is continued for 30 minutes and then water is added. Stirring is continued for about 1 to 6 more hours, preferably for about 2 hours, during which time the temperature between About 0 and 25 ° C, preferably between about 5 and 10 ° C. The crystals of compound XV are filtered off, washed with water and dried at room temperature under vacuum with a little nitrogen flow. The compound XV can optionally be recrystallized from a water miscible alcohol solvent and water, preferably ethanol and water, most likely ethanol / water (1.4, v / v). The method of the present invention has been designed to avoid the disadvantages of the prior art described above in the sense that the (S) enantiomer of the free base of the formula Z is not isolated, in the process of the present invention, but instead is generated in situ from the precursor of formula XII and formula I is immediately converted to the (S) enantiomer of bispivaloate. The process of the present invention has the advantages further to produce the compound of the formula I with higher optical and chemical purities and also with higher yield than the prior art processes. Since the process of the present invention also avoids the use of methylene chloride, the compound of the formula I is not further contaminated with the impurity of the formula Z2. The procedure of step G is normally carried out by suspending the compound of formula XII in about 2-8 volumes of THF, preferably anhydrous THF. To this suspension is added a stoichiometric excess of triethylethylamine. From about 3 to about 6 equivalents, preferably from about 3 to about 4.5 equivalents and most preferably about 4.1 equivalents of triethylamine is used. The solution thus formed is cooled to a temperature of about -30 ° C to about 0 ° C, preferably and about -20 ° C to -15 ° C. A solution of about 2 equivalents to 4 equivalents, preferably about 2.9 equivalents in pivaloyl chloride (trimethylacetyl chloride) in about 1 volume of THF, preferably anhydrous THF (relative to the amounts of XII) is added to the cooled solution. The mixture is preferably stirred under an inert atmosphere, such as nitrogen or argon during the reaction. The reaction mixture is allowed to proceed until it is substantially complete, preferably keeping the temperature below about 15 ° C. The compound of the formula I is then conveniently isolated by diluting the reaction mixture with a water-immiscible, inert solvent (other than a halogenated hydrocarbon) below the boiling point, preferably t-butylmethyl ether, washing the reaction mixture with an aqueous solution of a light base, such as sodium bicarbonate or potassium carbonate, preferably sodium bicarbonate to destroy the pivaloyl chloride in excess The solvent is then usually removed by evaporation to obtain the compound of the formula I. The process of the present invention also encompasses a final purification step for the compound of the formula I. The purification step normally involves the crystallization of the compound of the formula l from alcohol other than methanol, such as sodium propane or 2-butanol, preferably 18 volumes of sodium propane. The crystallization optionally includes contacting the alcohol solution of the compound of formula I with activated charcoal, filtering the charcoal, concentrating and cooling the purified solution to obtain crystals of the compound of the invention. formula I that can be isolated by filtration. In this way, the compound of formula I is essentially chemically pure, ie 99.5% with less than 0.5% impurities, with optical purity greater than 99%. < A ^ aj Using the (R) -camphorsulfonic acid for step E and step F, the process for producing the racemic diastereomeric addition salt R, R / S, R of the formula XIV in step E can be modified. (example 6) and the addition salt of the R, R-diastereomeric acid of (R) -CSA of the formula XIV in step F (example 7) and the R enantiomer of the compound of the formula I in step G (example 8).

Description of an alternative conventional process for the resolution of diastereomeric (S) -alphaforphosulonic acid salts XII. The method of the present invention also contemplates that the composition of the formula XI can be reduced to provide the diastereomer S, S in optically pure essence of formula XII by means of a crystallization process in ethanol. This method advantageously avoids the use of methylene chloride and DMF. In addition, it is possible to recirculate advantageously racemization the source solutions containing mainly the undesired diastereomer R, S to the compound SS-diastereomeric of the formula XII under acidic conditions, thus avoiding the formation of the free base of the formula Z and the need to reform the acid salt (S) -CSA of the formula XI. The compound of the formula Xi generated by racemisation is then reduced again, as described hereinabove to provide additional amounts of XII. The compound of formula Xi is dissolved in ethanol, preferably 95: 5 (v / 7) ethanol: water by heating, preferably with stirring, under an inert atmosphere, such as nitrogen or argon. The amount of ethanol should be in the range of 25 to 35 volumes, preferably of about 30 volumes. When the complete solution is achieved, the solution is allowed to cool between about 15 and 25 ° C, preferably at about 20 ° C and is kept at this temperature for 1 to 24 hours, preferably for about 6 hours. The compound of formula XII is isolated by filtration and washed with ethanol. Preferably, and from about 0.5 to about 0.7 equivalents of (S) -camphorsulfonic acid are added to the source solutions containing mainly R, S-diastereomeric acid addition salt. These source solutions are heated between 50 ° C and the reflux temperature, preferably at about the reflux temperature until racemization is complete. The S, S / R, S ratio achieved in the compound of formula XI is usually about 47:53.

The concentration of the compound of the formula XI in ethanol and about 100 g / l to about 30 g / l, preferably to about 60 g / l, is adjusted by concentration at atmospheric pressure or optionally adding an additional amount of the acid addition salt of the formula XI. Heating is carried out preferably with stirring in an inert atmosphere, such as nitrogen or alcohol. After achieving the desired concentration of the compound of the formula XI, the solution is allowed to cool as before between about 15 and 25 ° C, preferably at about 20 ° C and is maintained at this temperature for one to 24 hours. hours, preferably for about 6 hours. The desired compound S, S of formula XII is isolated by filtration and washed with ethanol. The solutions of Gomo origin can be recirculated as described hereinabove.

EXAMPLE 1 (STEP A) Preparation of 2'-hydroxy-4'-tetrahydropyranyloxy-2- (4"-tetrahydropyranyloxyphene) acetophenone C14H12 ° 4 C24H28 ° 6 (24425) (41248) IV Procedure 1.- To a 500 ml 3-necked round bottom flask equipped with mechanical stirrer, thermometer, inlet conduit for nitrogen and condenser, charge 2 ', 4'-dihydro-2- (4"-hydroxyphen). L) acetophenone (48.85 g, 0.2 mol), 3,4-dihydropyran (Aldrich, 91.24 ml, 1.0 mol) and ethyl acetate (Fisher, 90 ml). fe - ^^^ feK ^ tft? Ai ^ r *, ^ a * ^ £ iifr 2.- Add p-toluenesulfonic acid monohydrate "p-tsa" (MCB, 30.4 mg, 0.16 mmol) and cover the reaction with nitrogen. It has exothermic reaction and temperature ranges from 21 ° C to about 55 ° C in about 5 minutes. 3.- Shake the reaction for about 3 hours until the conversion of the starting material to the product is complete. The course of the reaction can be followed by TLC or HPLC. 4.- When the reaction is complete, charge the triethylamine (Aldrich, 1.4 ml, 0.01 mmol) to the reaction mixture. 5.- Concentrate the mixture formed under deduced pressure and keep the internal temperature at 65 ° C until no more volatile materials are collected. 6.- When the distillation is complete, interrúmpase the partial vacuum with nitrogen and load 350 ml of isopropanol to the residual oil. 7.- Remove from the heating bath, allow the solution thus formed to cool to room temperature with agitation; then cool the solution with an ice bath. 8.- Shake the reaction mixture thus formed for about 1.5 hours and separate the product by filtration and wash with 250 ml of cold sopropanol until the washings are colorless. 9.- Dry the product from a blast furnace at 40 ° C to obtain 67.9 g (82% of the theory) of 2'-hydroxy-4'-tetrahydroxylamino-2- (4"- *; . tetrahydropyranylloxyphenol) acetophenone (purity 99%, area normalization by HPLC).

EXAMPLE 2 (STEPS B and C) Preparation of ± -fra / 7S-2- (4"-r 2" -piperidinethoxyphenyl) -3- (4'-tetrahydropyranyloxyphenyl) -7-tetrahydropyranxyloxy-2,3-dihydro -4H-1- benzopyran-4-one C24H2806 C14H19N02 (412 48) (233 31) IV Vil fifteen C38H45N07 (627 78) Procedure IX 1.- To a 500 ml 3-necked round bottom flask equipped with a mechanical stirrer, thermometer, nitrogen inlet duct and condenser, with an ejector, such as a Dean-Stark siphon, ^^^^ aat ^^^ a ^^^^ ^^^ a ^^^^ a ^ fea load the 4- (2'-p¡peridinoetox¡) benzaldehyde (36.75 g, 0.158 mol) and 160 ml of ( ±) -2-butanol (obtainable from Fischer Scientific). 2. Add 2'-hydroxy-4'-tetrahydropyranyloxy- (4-tetrahydro-pyranyloxy-phenyl) acetophenone produced according to Example 1 (61.87 g, 0.15 moles), piperidine (Aldrich, 99% pure, 4.26 g, 0.05 moles) and diazabicyclo [5.4.0] undec-7-one ("DBU") (obtainable from Aldrich, 97%, 7.61 g, 0. 05 moles), then cover the reaction with dry nitrogen. 3. Heat the reaction mixture thus formed with stirring to reflux (98 ° C) at atmospheric pressure. 4. When a gentle reflux has been achieved, slowly distil off to 80 ml of (±) -2-butanol for a period of about 2 hours. 5.- Continue heating the reaction mixture to reflux temperatures for about 2 more hours without additional concentration. 15 Monitor the reaction of Knoevenagel by HPLC. 6.- Cool the reaction mixture to 80 ° C and add 200 ml of sopropanol. 7.- Allow the reaction mixture thus formed to cool between 20 ° C and 25 ° C. Continue to stir the solution thus formed for 48 hours, during which time the intermediate chalcones (the compounds of formula VIII) are cyclized to the product of formula IX, (±) -fraps-2- (4"- [2"-piperidinoethoxy] phenyl) -3- (4'-tetrahydropyranxaloxyphenyl) -7-tetrahydro-pyridinium-2,3-dihydro-4H-1-benzopyran-4-one which is comes off by crystallization of the _ - *. ? ú¿¡tiá * ¿¿?? - * Í? A¿ solution. Seeds of the product of formula IX can be added if the crystallization has not started after 6 hours. The IX cis is rearranged to XI trans during this period. 8.- Collect the XI crystals by filtration and wash with 3 x 90 ml portions of isopropanol. 9.- Dry the crystalline product at a temperature between 40-50 ° C in a blast furnace to obtain 81.93 g (86.1% of the theory, corrected for purity) of the product of the formula IX (purity of 98.9%, by CLAR ).

EXAMPLE 3 (STEPS DYE) Preparation of (SM ±) camphor sulfonate of (2R, S) -7-hydroxy-3- (4'-hydroxyphenyl) -4-methyl-2- (4"-r2" -piperidinoethoxyphenyl-2H- 1-benzopyran (689.87) 5 Procedure 1.- To a 1-liter, 3-necked, round bottom flask equipped with mechanical stirrer, thermometer, inlet conduit for nitrogen and addition funnel, charge the (±) -raps-2 (4"- [2" '- 0 piperidinoethoxy] phenyl) -3- (4'-tetrahydropyranyloxy) phenyl) -7-tetrahydropyranyloxy-2,3-dihydro-4H-1-benzopyran-4-one (50.0 g, 0.0796 moles) of example 2. 2.- Charge the tert-butylmethyl ether (250 ml) and cover the reaction with dry nitrogen gas. 3. - Cool the suspension thus formed at 0 ° C with agitation. 4.- Charge a solution of 8% methyllithium in diethoxymethane (75.1 ml, 0.263 moles, 3.3 eq.) To the flask for a period of 30 minutes, while maintaining the temperature of the reaction mixture at less than 5 minutes. ° C. 5.- Keep the reaction mixture at 0 ° C for 15 minutes, remove the cooling bath and allow the solution formed at room temperature to warm up for a period of 45 minutes. 6.- Keep the reaction mixture thus formed for an additional 4 hours at room temperature and then cool the solution to 0 ° C. The reaction can be monitored by CLAR. 7.- Charge an aqueous solution of NH4Cl (13.1 g and 50 ml of H2O) dropwise to the reaction mixture, keeping the reaction mixture thus formed at a temperature below 15 ° C. 15 8.- Remove the cooling bath and shake the mixture thus formed for an additional 2 minutes at room temperature. 9.- Transfer the resulting clear solution to a 1-liter separatory funnel and separate the lower aqueous phase. 10. Wash the organic phase with 40 ml of saturated sodium chloride solution. 11.- Separate the lower aqueous phase. 12. - Charge the upper organic phase to a one-liter three-necked round bottom flask equipped with a stirrer, thermometer and distillation condenser. 13.- Concentrate the solution to 90 ml and keep the internal temperature below 76 ° C. 14.- Cool the residue formed at room temperature. 15.- Shake the reaction mixture thus formed and charge 50 ml of 2B ethanol (denatured with 5% by volume of methanol and 5% by volume of isopropanol) and (S) - (+) - camphorsulfonic acid. (20.5 g, 0.0876 moles, 1.1 eq.): 16.- Continue stirring the reaction mixture thus formed for about 15 minutes and charge 350 ml of isopropanol to the resulting yellowish thick slurry. Isopropanol should not be added until the crystallization is well advanced and the slurry thickens considerably. 17.- Agitate the slurry thus formed during 24 hours at approximately 20 ° C. 18.- Separate the crystals thus formed by filtration under nitrogen and rinse the flask with part of the original solution, if necessary. 19.- Wash the crystalline product with 50 ml of isopropanol. 20.- Dry the crystalline product in a blast furnace at less than 50 ° C for 24 hours to give 50.7 g (90% of theory) of (S) - (+) - camphor sulfonate of (2R, S) -7- hydro 3 <4'-hydroxyphenyl) -4-methyl-2- (4"- [2" '- piperidinoethoxy] phenyl) -2H-1-benzopyran (97.8% purity in relation to a reference standard as determined by CLAR on a YMC Basic 5 column (4.96 mm x 250 mm), 10 mM solution of mobile phase of 5 ammonium acetate in methanol / water (65:35), flow rate 1.0 ml / min, UV detection @ 240 nm, Vol Iny 20 μl, conc 10.4 mg / ml).

EXAMPLE 4 (STEP F) Preparation of (S) - (10) - (2S) -7-hydroxy-3- (4'-10-hydroxyphenyl) -4-methyl-2- (4"-r2") -alphaforphosphonate piperidino-ethoxy-1-phenyl) -2H-1-benzopyran X II Procedure 1.- Even a three-necked round bottom flask equipped with a mechanical stirrer, thermometer, condenser and nitrogen inlet conduit, charge (2R, S) -2- (p- [2"-piperidinyl ] ethoxyphenyl) -3- (4'-hydroxyphenyl) -4,5-methyl-7-hydroxychrom-3-ene (50 g, 0.0725 mol) of example 3, (S) - (+) - camphor-sulfonic acid (10 g, 0.043 moles) and 300 ml of 2B ethanol 2.- Cover the flask with nitrogen and heat the suspension at 63 ° C with stirring for 24 hours The ratio of diastereomers can be followed by the chiral HPLC (see step 6). 3. Continue stirring the suspension and allow to cool to room temperature for a period of 1 hour 4.- Continue stirring the suspension so formed at room temperature for another 4 hours 5.- Separate by filtration of crystals formed and wash 15 with (2B) cold ethanol 6.- Dry the crystalline product in a blast furnace at 50 ° C to obtain (S) - (+) - camphor sulfonate d e (2S) -7-hydroxy-3- (4'-hydroxyphenyl) -4-methyl-2- (4"- [2" '- piperidinoethoxy] phen?) -2H-1-benzopranol, 29 g, (58%), 98% determined by chiral HPLC using the method described above. 20 Optical purity was determined on a Chiralpak AD column (4.6 mm x 250 mm) (Daicel Chemical Industries Inc.), mobile phase: hexane / ethyl alcohol / diethylamine (85 15: 0.1), flow rate: 1.4 ml / min, UV detection @ 240 nm, Vol. Iny. 20 μl, conc. 0.5 mg / ml in the mobile phase, Column temperature 26 ° C.

EXAMPLE 5 (STEP G) Preparation of 4 ', 7-bistrimethylacetate of (S) -7-idroxy-3- (4'-hydroxyphenyl) -4-methyl-2- (4"-r 2", - (1-piperidino) ethoxy-1-phenyl) -2H -benzopyran (689 87) (625 81) 15 XII Procedure 1.- To a 1-L flask, charge the (S) - (+) - camphor sulfonate of (2S) -7-hydroxy-3- (4, -hydroxyphenol) -4-methyl-2- ( 4"[2," - piperidinoethoxy] phenyl) -2H-1-benzopyran (20 g, 0.029 mole) of Example 4 and 60 mL of dry tetrahydrofuran. 2.- Cover the suspension with nitrogen. - ** .- ^^^^^^^^ ¿^ ^ aife ^^ fe ^^^^^^^^^. 3. - Charge triethylamine (Aldrich, 99% pure, 16.5 ml, 0.119 moles, 4.1 equivalents) and shake the suspension thus formed between 15 ° and 25 ° C for about 10 minutes until the complete solution has been achieved. 4.- Cool the reaction mixture thus formed to a temperature between -20 ° C and -15 ° C. 5.- Charge a solution of trimethylacetyl chloride ("t-BuCOCI"), (Aldrich, 99% pure, 10.14 g, 0.084 mol, 2.9 equivalents) in 20 ml of dry tetrahydrofuran at a rate such that the temperature of the mixture of reaction thus formed does not exceed -10 ° C. 6.- Keep the temperature of the reaction mixture thus formed between -15 ° and -10 ° C for 15 minutes and then let the reaction mixture reach a temperature of 0 to 5 ° C for a period of 1 hour. 7.- Keep the reaction mixture at that temperature until the reaction is complete. The reaction is complete in approximately 1.5 hours and can be monitored by CLAR (column YMC Basic S-5) or TLOC. (Silica gel Analtec GF 250m, methylene chloride / methanol / ammonia 19ml: 1 ml: 4 drops, visualize with iodine). 8.- Charge to the reaction mixture 80 ml of t-butyl methyl ether and a solution of sodium bicarbonate (7.5 g in 150 ml of water) and shake the mixture thus formed during 15 minutes at room temperature and destroy the trimethylacetyl chloride. in excess. 9. - Separate the phases and wash the upper organic layer with a solution of 7.5 g of sodium chloride in 150 ml of water. 10.- Separate the phases and transfer the upper organic layer to a flask equipped with a distillation condenser. 11.- Charge 180 ml of isopropanol to the flask and concentrate the solution thus formed by atmospheric distillation. 12.- Take an additional 170 ml of isopropanol (as allowed by the space in the flask) and continue the solution being concentrated to a final volume of approximately 320 ml. 13.- Charge the Darco and Supercel to the flask and reflux the mixture thus formed for 15 minutes. Filter the mixture. This must be done quickly to avoid crystallization on the filter. 14.- Wash the Darco and Supercel on the filter with fresh isopropanol. 15.- Combine the filtrate and the washings and concentrate the combination at a final volume of 320 ml. The final volume is important to ensure adequate purity, ee and performance. Concentrate the solution to an atmosphere or add sopropanol to achieve this final volume. 16.- Separate the product by filtration and wash with 40 ml of cold isopropanol (0-5 ° C) and then with 108 ml of heptanes (available from Fisher Scientific). 17. - Dry the crystalline product at 60 ° -70 ° CD in a blast furnace for 12 hours to obtain 15 g (83% yield, 99% purity) of the compound of formula I, ie (S) -7-hydroxy -36- (4'-hydroxy-phenyl) -4-methyl-2- (4"- [2 '" - (1-piperidino) ethoxy] phenyl) -2H-benzopyran 4', 7-bistrimethylacetate ( 99% of 5 chemical purity per column YMC Basic S-5 from CLAR (4.96 mm x 250 mm), mobile phase: solution at 10 mM methanol / water ammonium acetate (85:15), flow rate: 1.0 ml / min, UV detection @ 240 nm, Vol. Iny. 10 ml, EXAMPLE 6 Preparation of (R) - (10) - (2R.S) -7-Hydroxy-3- (4'-hydroxyphenyl) -4-methyl-2- (4"-r2 '" - piperidinoethoxy1phenyl) -alphaforphosphonate) -2H-1-benzopyran (689 87) ¿3 > ** > * »* ¡IS» ~ .Z. - .. ^^^^^? ? M ^ ü ^ ^ ^^, Procedure 1.- To a round-bottomed, three-necked flask, 12 L, equipped with mechanical stirrer, thermometer, inlet conduit for nitrogen and addition funnel, charge the (±) -fraps-2- (4"- [2" '- piperidinoethoxy] -phenyl) -3- (4'-tetrahydropyranyloxyphenyl) -7-tetrahydropyranyloxy-2,3-dihydro-4H-1-benzopyran -4-one (666.3 g, 1.06 moles) of Example 2. 2.- Charge the tert-butylmethyl ether (4 L) and as is the flask with nitrogen. 3.- Cool the suspension at 0 ° C with agitation. 4.- Charge yourself with methyl lithium (8% solution in diethoxymethane, 1.0 L) to the flask in a period of 30 min, keeping the temperature below 5 ° C. 5.- After 15 minutes at 0 ° C, remove the cooling bath and allow the solution to warm to room temperature for a period of 45 minutes. 6.- After an additional 4 hours at room temperature, cool the solution to 0 ° C. 7.- Charge the saturated aqueous solution of NH4CI (666 ml) dropwise, keeping the temperature below 15 ° C. 8.- Remove the cooling bath and shake the batch for an additional 2 minutes at room temperature. 9.- Separate the lower aqueous phase. ^ * g jS &2 ¿^. { & 10.- Wash the organic phase with 666 ml of saturated sodium chloride solution. 11.- Separate the lower aqueous phase. 12.- Concentrate the upper organic phase approximately 1.2 L. 13.- Chill the residue at room temperature. 14. With stirring, charge 2.0 L of EtOH (denatured with 5% of MeOH and 5% of i-PrOH) and acid (R) -IO-camphor-sulfone-co (277 g, 1.19 mol). 15.- After approximately 15 min, charge isopropanol (2.66 L) to the resultant yellowish thick watery paste. 16.- Agitate the slurry for 48 h at approximately 20 ° C. 17.- Separate the crystals by filtration in nitrogen and rinse the flask with part of the original solution, if necessary. 18.- Wash the product with sodium propane. 19.- Dry the (R) - (10) -alphaforphosphonate of (2R, S) -7-hydroxy-3- (4'-hydroxyphenyl) -4-methyl-2- (4"- [ 2 '"- piper? D? Noetox?] - phen? L) -2H-1-benzopyran in a blast furnace at less than 50 ° C for 24 hr. To give 647 g, purity 97.4%, yield 88% (86% corrected for purity). Purity measured by CLAR using a YMC Basic S-5 micron column (4.6x250 mm). Mobile phase; solution at 10 mmol of ammonium acetate in methanol / water (65:35); flow rate, 1.0 ml / min; vo jjt? in injection, 20 L; concentration, Ó§ mg / ml in MeOH; UV detection @ 240 nm.

EXAMPLE 7 Preparation of (R) - (10) -a Ica nforsulf onate of (2R.S) -7-hydroxy-3- (4'-hydroxyphenyl) -4-methyl-2- (4"- [2 '" -piperidinoethoxy] phenyl) -2H-1-benzopyran Procedure 1.- To a 12 L round 3-necked flask equipped with a mechanical stirrer, thermometer, condenser and inlet duct for nitrogen, charge the acid salt (2R, S) -2- (p- [ 2"-piperidyl] ethoxy-phenyl) -3- (4'-hydroxyphenyl) -4-methyl-7-hydroxychrom-3-ene- (R) - (10) -20 camphorsulfonic acid (compound of example 6) (630 g , 0.913 mole), (R) - (-) - alkylphosphonic acid (12.8 g, 0.054 mole) and ethyl alcohol 2B (test 190) (2.55 L). 2. - Cover the flask with nitrogen and heat the suspension at 73 ° C (internal temperature) with stirring for 24 hours. 3.- Continue stirring and allow the solution to cool at 12 ° C for 1 hour. 4.- Continue stirring for 4 more hours. 5.- Separate by filtration the crystals and wash with cold ethanol of test 200. 6.- Dry the product in a blast furnace at 50 ° C to obtain 375.8 g (60% yield), d.e. 98% of (R) -2- (p- [2"-piperidyl] ethoxyphenyl) -3- (4'-hydroxyphenyl) -4-methyl-7-hydroxyrom-3-ene- (1 R) acid ) - (10) - sulfuric ketone column YMC Basic S-5 micron column, (4.6 x 250 mm).; 10 mmol solution of methanol / water ammonium acetate (65:35); flow rate 1.0 ml / min; injection volume, 20 ml; concentration, 0.4 mg / ml in MeOH; UV detection @ 240 nm. Optical purity was measured by CLAR using a column Chiralpak AD (250 mm x 4.6 mm) (Daicel Chemical Industries Inc.), mobile phase: hexanes: ethanol: diethylamine (85: 15: 0.1), flow rate, 1.4 ml / min; UV detection @ 240 nm, Vol. Iny. 20 ml, conc. 0.5 mg / ml in mobile phase, column temperature 26 ° C.

EXAMPLE 8 Preparation of (R) -7-hydroxy-3- (4, -hydroxyphenyl) -4-methyl-2- (4"-f2", - (1 • piperidino) ethoxy] phenyl) -2H-benzopyran 4'.7-bistrimethylacetate of C39H47N08S C39H47N06 (68987) (625.81) Procedure 1.- To a 3-neck flask of 5 I, charge (S) - (10) -alphaforphosphonate of (2R) -7-hydroxy-3- (4'-hydroxyphenyl) -4-methyl-2- (4"- [2 '" - (1-piperidinoethoxy] phenyl) -2H-1-benzopyran of (compound of Example 7) (370 g, 0.536 moles) and anhydrous tetrahydrofuran (1.4 I) 2.- Cover the suspension with nitrogen 3.- Load the triethylamine (310 ml, 0.222 mmol) and shake the suspension between 15 ° and 25 ° C for about 10 minutes until the complete solution is achieved 4.- Chill the mixture between -20 ° and -15 ° C.

. - Charge a solution of trimethylacetyl chlorine (195.8 g, 0.162 mol) in anhydrous tetrahydrofuran (370 ml) at a rate such that the reaction temperature does not exceed -10 ° C. 6.- Keep the temperature between -15 ° and -10 ° C for 15 minutes and then allow the batch to reach 0 ° to 5 ° C for one hour. 7 '.- Keep the temperature until the reaction is complete. 8.- Charge to 80 ml of t-butyl methyl ether (1.5 I) and a solution of sodium bicarbonate (141 g in 2.25 l of water) and shake the batch for 15 minutes at room temperature. 9.- Separate the phases and wash the upper organic layer with a sodium chloride solution (141 g in 2.25 I of water). 10.- Separate the phases and transfer the upper organic layer to a tras equipped with a distillation condenser. 11.- Charge isopropanol (3.5 I) and concentrate the solution by atmospheric distillation. 12.- As space permits, charge additional isopropanol (3.0 I) and continue concentrating the solution to a final volume of approximately 6.0 I. 13. Load the Darco (37 g) and the Supercel (37 g) and reflux during 15 minutes. 14.- Separate Darco and Supercel by filtration and wash with hot isopropanol (1.0 I).

. - Begin the centering and washing and concentrate to a final volume of approximately 6.0 L. 16.- With agitation, let cool in batch and crystallize overnight. 5 17.- Separate the product by filtration and wash with cold isopropanol. 18.- Dry the batch at 60 ° C in a vacuum oven. Performance of 4 ', 7-bistrimethylacetate of (R) -7-hydroxy-3- (4'-hydroxy-phenyl) -4-methyl-2- (4"- [2" - (1-piperidino) ethoxy] phenyl) -2H-benzopyran 294 g (88% yield, 99% ee, 10 99% purity). Chemical purity measured by CLAR using column YMC Basic S-5 micron (4.6 mm x 250 mm), mobile phase, solution at 10 mmole of ammonium acetate in methanol / water (85; 15), flow rate: 1.0 ml / min, UV detection @ 240 nm, Vol. Iny. 10 L, conc. 1 mg / ml. 15 Optical purity measured by CLAR using a Chiralpak column AD (250 mm × 4.6 mm) (Daicel Chemical Industries Inc.), mobile phase: hexanes: ethanol: isopropanol: diethylamine (95: 3: 2: 0.1), flow rate: 1.0 ml / min. UV detection @ 240 nm, Vol. Iny. 10 I, conc. 2 mg / ml in mobile phase, column temperature 26 ° C. ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ _ .. afea EXAMPLE 9 Preparation of (S) - (10) - (2S) -7-hydroxy-3- (4'-hydroxyphenyl) -4-methyl-2- (4"-f2" '- piperidinoethoxy | phenyl) -alphaforphosphonate) -2H-1-benzopyran C39H47N08S C39H47N08S (689 87) (689 87) Procedure 1.- To a 2-L Erlenmeyer flask, equipped with magnetic stirring bar 15, charge in (S) - (10) -alphaforphosphonate of (2R, S) -7-hydroxy-3- (4'-hydroxyphenyl) ) -4-methyl-2- (4"- [2" -piperidinoethoxy] phenyl) -2H-1-benzopyran (compounds of example 3) (25 g, 0.072 mol) and test ethanol 190 (750 ml) . 2.- Shake and heat the suspension until a clear solution is obtained. 3.- Remove the heat source and continue stirring, allowing the solution to cool to room temperature. & & J5EA 7"A.- If necessary, be seated with crystals of (S) - (10) - (2S) -7-hydroxy-3- (4O-hydroxyphenyl) -4-methyl-2-camphor-sulfonate. (4"- [2" - piperidinoethoxy] phenyl) -2H-1-benzopyran 5.- Continue stirring for 24 hours at room temperature 6.- Separate the crystals by filtration and wash with cold ethanol of test 190. 7 .- Dry the product in a blast furnace at 50 ° C. Yield (S) - (10) - (2S) -7-hydroxy-3- (4, -hydroxyphenyl) -4-methyl-2- ( 4"[4" - 10 [2"-piperidinoethoxy] phenyl) -2H-1-benzopyran 9.89 g, (39.6%, corrected for purity); 96.5% purity, of 96.6%. Purity was determined using the following CLAR system: column YMC Basic S-5, (4.6 x 250 mm). Mobile phase: solution at 10 mmole of ammonium acetate in methanol / water (65:35); flow rate, 1.0 ml / min; injection volume, 20 μl; concentration, 0.4 mg / ml in MeOH; detection UV @ 240 nm. Optical purity by CLAR using a Chiralpak AD column (250 mm x 4.6 mm) (Daicel Chemical Industries Inc.), mobile phase: hexanes: ethanol: diethylamine (85:15:01), flow rate: 1.4 ml / min, UV detection @ 240 nm, Vol. Iny. 20 μl, conc. 0.5 mg / ml in mobile phase, column temperature 26 ° C.

EXAMPLE 10 Preparation of (S) - (10) - 2- (S) -7-hydroxy-3- (4'-hydroxyphenyl) -4-methyl-2- (4"-f2" '- piperidinoethoxyphenyl) -alphaforphosphonate ) -2H-1-benzopyran a starting from the source solutions containing (S) - (10) - camphor sulfonate of 2- (R) -7-hydroxy-3- (4'-hydroxyphenin-4-methyl-2- (4"-r2" '- piperidinoethoxy] phenyl) -2H-1-benzopyran (S) -Xll C 3399HH4477NN008S (689 87) 20 Procedure 1.- Add acid (S) - (10) -alphafor sulfonic acid (0.25 g) to the original solutions and the yeasts of example 9 and concentrate on the solution by slow distillation at atmospheric pressure in nitrogen at approximately 225 ml. 2.- Continue stirring and reflux the solution until the ratio of diastereomeric camphorsulfonic acid salts is approximately 47: 543 (S, S: R, S). 3.- Remove the heat source and continue stirring, allowing the solution to cool to room temperature. 4.- If necessary, with crystals of (S) - (10) -alphaforphosphonate of (2S) -7-hydroxy-3- (4, -hydroxyphenyl) -4-methyll-2- (4"- [2, "- piperidinoethoxy] phenyl) -2H-1-benzopyran. 5.- Continue stirring for 24 hours at room temperature. 6.- Separate by filtration of crystals and wash with cold ethanol of test 190. 7.- Dry the product in a blast furnace at 50 ° C. Performance (S) - (10) - (2S) -7-Hydroxy-3- (4'-hydroxyphenyl) -4-methylene-2- (4"- [2m-piperidinoethoxy] ] phenyl) -2H-1-benzopyran of 3.5 g, (24%), purity 95%, of 96% Purity was determined using the following HPLC system: column of YMC Basic S-5, (4.6 x 250 mm Mobile phase, solution at 10 mmolar methanol / water ammonium acetate (65:35), flow rate, 1.0 ml / min, injection volume, 20μl, concentration, 0.4mg / ml in MeOH, UV detection ( a) 240 mn.

Diastereomer ratio measured by CLAR using a Chiralpak AD column (250 mm x 4.6 mm) (Daicel Chemical Industries Inc.), mobile phase: hexanes: ethanol: diethylamine (85: 154: 0.1), flow rate: 1.4 ml / min , UV detection @ 240 nm, Vol. Iny. 20 μl, conc. 0.5 mg / ml in mobile phase, column temperature 26 ° C.

EXAMPLE 11 Synthesis of (2S) -7-hydroxy-3- (4, -hydroxyphenyl) -methyl-2- (4"-r 2" - piperidino] ethoxyphenyl-2H-benzopyran hydrochloride (XV) A. Preparation of compound XV To a salt suspension of (2S) -7-hydroxy-3- (4'-hydrophenyl) -4-methyl-2- (4"- [2" -pi? Erdino] ethoxyphenyl) -2H-benzopyran- (1 S) -10-camphorsulfonic acid (compound XII) (400 g) in t-butyl methyl ether (5.5 I) and water The triethylamine (114 ml) was added to the sterile solution for injection (3.5 I) at room temperature. The mixture was stirred until the complete solution was produced. The lower aqueous layer was separated and extracted with t-butylmethyl ether (1.5 I). The t-butylmethyl ether layers were combined and washed with saline (2 I), and then concentrated under reduced pressure to 2L and filtered through silica gel (150 g); the silica gel was then washed with t-butylmethyl ether (1.5 I). The filtrate and the washes containing (2S) -7-hydroxy-3- (4-hydroxyphenyl) -4-methyl-2- (4"- [2" -piperidino] -ethoxyphenyl) -2H-benzopyran was combined (compound XIV) and the solvent was replaced with ethanol (inlet 190,) (1 .7 1). To this solution, cooled to approximately 5 ° C, HCl at 2N (320 ml) was added slowly with stirring for 30 minutes. Stirring was continued for 30 minutes and then sterile water for injection (4.5 I) was added. Stirring was continued for another 2 hours during which time the temperature was maintained between about 5 ° and 10 ° C. The crystals of the product (XV) were filtered off, washed with sterile water for injection (1.0 L) and dried at room temperature in vacuo with a slow flow of nitrogen. The yield of (2S) -7-hydroxy-3- (4'-hydroxyphenyl) -4-methyl-2- (4"- [2" "- piperidino] ethoxyphenyl) -2H-benzopyran hydrochloride (compound XV ) was 244 g (85%).

B. Recrystallization of compound XV (2S) -7-hydroxy-3- (4'-hydroxyphenyl) -4-methyl-2- (4-methyl-2 (4"- [2" piper?] Hydrochloride was dissolved. dino] ethoxyphenyl) -2H-benzopyran (compound XV) (4 g) in test ethanol at 190 (40 ml) under reflux, a mixture was filtered and the Compound XV purified, at room temperature, under vacuum with a slow flow of nitrogen. Yield 3.28 g (82%).

CLAR ISOCRATIC ASSAY FOR THE CHEMICAL PURITY OF THE COMPOSITE XV Mobile phase Ammonium acetate at 10 mM in methanol / water (65:35). YMC Basic column 5 mm 120 A (4.6 mm x 250 mm) maintained at 30 ° C. Flow rate 1.0 ml / min. Injection volume 10 ml. Sample repair 0.5 mg / ml Detector 240 nm.

CLAR TEST FOR THE OPTICAL PURITY OF (+) - XIV AND THE DENTURE (-) - R OF XIV Mobile phase Hexane / ethyl alcohol / diethylamine (80: 20: 0.2, v / v / v), Chiralpak AD column (4.6 mm x 250 mm) (Daicel Chemical Industries Inc.). Flow rate 1.0 ml / min. Injection volume 20 ml Sample repair 0.5 mg / ml Detector 240 nm.

Compound Typical retention time (+) - XIV 7.7 minutes Enantiomer S (enantiomer -) - R of XIV 9.2 minutes Similarly, the R-enantiomer of the compound XV of compound XVll of example 7.

Claims (21)

NOVELTY OF THE INVENTION CLAIMS

1. A process comprising reacting the compound of the formula IV with the compound represented by the formula VII in the presence of piperidine, a hindered organic amine base and a Ci-Cβ alkanol at a temperature and for a time sufficient to produce the compound of the formula IX in chemically pure essence and essentially Free of the cis isomer of the compound of the formula IX and substantially free of the chalcones E and Z of the formula VIII, characterized in that HGP is an acid labile phenolic hydroxyl protecting group: IX

2. - The process according to claim 1, further characterized in that the alkanol of (C2-C6) is 2-butanol, isopropanol or isobutanol.

3. The process according to claim 1, further characterized in that the hindered organic amine base is 1,8-diazabicyclo [5.4.0] undec-7-ene or 1,5-diazabicyclo [4.3.0] non-5-ene

4. The process according to claim 1, further characterized in that (a) the compound of the formula IV is contacted with the compound of the formula VII in the presence of piperidine, 2-butanol at the boiling point of 2- butanol for a sufficient time to substantially completely distill an azeotropic mixture of 2-butanol and water to form a reaction product comprising a mixture of the E and Z chalcones of formulas VIII and cis and trans IX, and (b) the reaction mixture is cooled to a temperature in the range of about 20-25 ° C and the hindered organic amine base, 1,8-diazabicyclo [5.4.0] undec-7-ene is added, and the contacting for a sufficient time to produce the compound of formula IX substantially free of chalcones E and Z of formula VIII and essentially free of the cis isomer of the compound of formula IX: IX

5. The process according to claim 1, further characterized in that the acid labile phenolic hydroxyl protecting group is tetrahydropyranyl.

6. The process according to claim 1, further comprising the step of reacting the compound of the formula IX with a stoichiometric excess of methyl lithium in an anhydrous acyclic ether as a solvent for a time and at a temperature sufficient to produce the compound of formula X: X

7. The process according to claim 6, further comprising contacting the compound of the formula X with a stoichiometric excess of (S) (+) - camphor sulfonic acid in a solvent consisting of ethanol for a while already a temperature sufficient to produce the addition salt of the R, S / S, S-diastereomeric acid of the formula IX: XI 8.- The addition salt of the crystalline racemic R, S / S, S-diastereomeric acid of the formula XI: XI essentially chemically pure and the addition salt of the R, S /

S, S-diastereomeric acid of formula XVI, essentially chemically pure: XVI ^ jaa ^^^^ fe ^^^^^ fc ^^ ate ^. ^

9. - The process according to claim 7, further comprising contacting the addition salt of the diastereomeric acid of the formula XI with a catalytic amount of (S) - (+) - camphor sulfonic acid in a solvent consisting of ethanol during a time and a temperature sufficient to produce the S, S-diastereomeric salt of the formula XII, substantially free of the addition salt of the R, S-diastereomeric acid of the formula XIII:

10. - The method according to claim 9, which 15 further comprises contacting the S, S-diastereomeric acid addition salt of compound XII with a stoichiometric excess of pivaloyl chloride in the presence of tertiary organic amine at a temperature and for a time sufficient to produce a compound of formula I : tWle ** JIM "- - ** - a ^« a ^^ 'i ^ S ^ -: .. AA, > Yi-A, - ^ t ^. ..., ".

11. The process according to claim 9, further comprising contacting the addition salt of S, S-diastereomeric acid of compound XII with an amount of a tertiary organic amine at a temperature and for a time sufficient to produce the compound of the formula XIV: XV

12. The process according to claim 10 or 11, further characterized in that the tertiary organic amine is trialkylamine of (d-Ce), pyridine or N-methylmorpholine.

13. The process according to claims 10 or 11, further characterized in that the organic amine is triethylamine.

14. The process according to claim 10, further characterized in that a suspension of the diastereomeric acid addition salt of the formula XII is contacted in acetonitrile or THF at a temperature in the range of about -20 ° to 20 ° C. ° C with triethylamine and a stequmetric excess of pivaloyl chloride for a sufficient time to produce the compound of the formula I:

15. - A process comprising the steps of: (a) reacting the compound of the formula IV with the compound represented by the formula VII in the presence of piperidine, a hindered organic amine base and a (C3-C6) alkanol at a temperature and for a time sufficient to produce the compound of formula IX essentially free of the cis isomer of the compound of formula IX and substantially free of the E and Z chalcones of the formula VIII, further characterized in that HPG is an acid labile phenolic hydroxyl protecting group; IX - 2, (b) reacting the compound of formula IX with a stoichiometric excess of methyl lithium in an anhydrous acyclic ether solvent or aromatic hydrocarbon for a time and at a temperature sufficient to produce compound X; 10 X (c) contacting the compound of the formula X with a stoichiometric excess of (S) - (+) - camphor sulfonic acid in a solvent consisting of ethanol for a time and at a temperature sufficient to produce the addition salt of the acid R , S / S, S-racemic of formula IX: XI ? -SBsSf? (d) contacting the addition salt of the R, S / S, S-racemic acid of formula XI with a catalytic amount of (S) - (+) - camphor sulfonic acid in a solvent consisting of ethanol for a time and at a temperature sufficient to produce a single addition salt of S, S-diastereomeric acid of formula XII; XII substantially free of the opposite addition salt of the R, S-diastereomeric acid of the formula XIII; XIII; Y ^^^^^^^^ fe_ (e) (i) contacting the S, S-diastereomeric acid addition salt of compound XII with a stoichiometric excess of pivaloyl chloride in the presence of a tertiary organic base at a temperature and for a sufficient time to produce the compound of the formula I: I; or (e) (!) contacting the S, S-diastereomeric acid addition salt of compound XII with an amount of a tertiary organic base at a temperature and for a time sufficient to produce a compound of formula XIV: XIV

16. The process according to claim 15, further characterized in that the hindered organic amine base is 1,8-diazabicyclo [5.4.0] undec-7-ene or 1,5-diazabicyclo [4.3.0] non- 5-ene

17. - The process according to claim 15, further characterized in that in step (b), (i) the compound of the formula IV is contacted with the compound of the formula VII in the presence of piperidine, and 2-butanol in the presence of boiling point of 2-butanol during a 5 sufficient time to substantially completely distill an azeotropic mixture of 2-butanol and water to form the reaction product consisting of a mixture of the compounds of the formulas VIII and IX, and (i) the reaction mixture is cooled at a temperature in the range of * approximately 20-25 ° C and a hindered organic amino base is added and * B 10 the contacting is continued for a sufficient time to produce the compound of the formula IX substantially free of the chalcones E and Z of the formula VIII and essentially free of the cis isomer of the compound of the formula IX.

18. The method according to claim 17, Further characterized in that the hindered amine base in step (a) is 1,8-diazabicyclo [5.4.0] undec-7-ene.

19. The process according to claim 15, further characterized in that in step (e) the tertiary organic base is trialkylamine of (C-i-Cß), pyridine or N-methylmorpholine.

20. The process according to claim 14, further characterized in that in step (e) the tertiary organic amine is triethylamine.

21. The process according to claim 14, further characterized in that in step (e) (ii) a suspension of the diastereomeric acid addition salt of the formula XII is contacted in a mixture of an immiscible organic solvent and water at a temperature in the range of about -20 ° to 25 ° C with a tertiary organic base and a stequimetric excess of aqueous hydrogen chloride for a time sufficient to produce the compound of the formula XV: XV