WO2003008383A1 - Production of enantiomer pure 3r, 5s- (+) natrium erythro- (e) 7-'4-(4-fluorophenyl)-2, 6-diisopropyl-5-methoxymethyl-pyrid-3-yl!-3, 5-dihydroxy-hept-6-e-noate - Google Patents

Abstract

The invention relates to a method for the production of enantiomer pure 3R,5S-(+)-natrium-erythro-(E)-7-[4-(4-fluorphenyl)-2,6-diisopropyl-5-methoxymethyl-pyrid-3-yl]-3,5-dihydroxy-hept-6-enoate.

Description

PRODUCTION OF ENANTIOMER-PURE 3R, 5S- (+) -NATRIUM ERYTHRθ - (- E) -7- * 4- (4- FLUOROPHENYL) -2, 6-DIISOPROPYL-5-METHOXYMETHYL-PYRID-3 -YL! -3,5-DIHYDROXY- HEPT-6-E-NOAT

The present invention relates to a process for the production of enantiomerically pure 3R, 5S - (+) - sodium erythro- (E) -7- [4- (4-fluorophenyl) -2,6-diisopropyl-5-methoxymethyl pyrid-3-yl] -3,5-dihydroxy-hept-6-enoate.

Processes for the preparation of this compound or its precursors are known and are described in EP-A-325 130, EP-A-491 226, EP-A-617 019, WO-

10 98/57917 and O-98/45230.

The task was to provide a new, simplified process in order to obtain the target compound with higher selectivity, purity and space / time yield.

15

It was found that 3R, 5S - (+) - sodium-erythro- (E) -7- [4- (4-fluoφhenyl) - 2,6-diisopropyl-5-methoxymethyl-pyrid-3-yl] - 3,5-dihydroxy-hept-6-enoate can be prepared if the compounds of the formula (I)

In the first step reacted with sodium macetoacetic ester in the presence of n-hexyllithium and / or t-butyllithium and in particular n-butyllithium and worked up, and the racemate of the compound of the formula (II) thus obtained

At the second step

with triethylborane,

in an inert organic solvent mixture in the presence of sodium borohydride and, if appropriate after working up, the erythro racemate of the formula (III) thus obtained

im dritten Schritt

in the third step

with bases such as, in particular, sodium hydroxide solution at 0 ° C. to 70 ° C., in particular 20 ° C. to 30 ° C., and then adjusted to a pH of 1 to 7 with mineral acid, in particular hydrochloric acid, so that the erythro racemate obtained corresponds to the corresponding one Acid of formula (IV)

either directly or after cleaning

in the fourth step

after suspension in toluene, special gasoline 80/110, special gasoline 140/160, n-heptane, cyclohexane or isohexane, heated under reflux for 1 to 5 hours and, if appropriate after processing and purification, receives the racemate of the formula (V),

(Racemate) (V)

im fünften Schritt

in the fifth step

the racemate of the formula (V) is converted into the enantiomers as the stationary phase by chromatography on Baychiral PM-D®,

and in the sixth step

the enantiomerically pure lactone hydrolyzes.

The starting compound of formula (I) is known and is described in DE-A-38 01 406.

The reaction in the first step is preferably carried out in anhydrous tetrahydrofuran (THF), the water content preferably being below 0.1%.

For working up, the reaction solution is mixed with water and ammonium chloride or with aqueous ammonium chloride solution and then adjusted to a pH of 4 to 8, preferably 6-7 with mineral acid, preferably hydrochloric acid.

The mixture is extracted with toluene, petroleum spirit 40/60, special spirit 80/110, isohexane, Isopar C or especially n-heptane. The crude product thus obtained is used for the following reaction without and preferably after further purification.

The reaction in the first step is preferably carried out by undertaking a suspension of under inert gas, preferably nitrogen, at room temperature (RT)

Sodium acetoacetic ester in anhydrous THF (water content preferably less than or equal to 0.1%). After cooling to 0 to -20 ° C. at a temperature of -5 to -10 ° C., a 15% mixture of n-butyllithium or t-butyllithium in n-hexane is added dropwise to this suspension. Then pyridylacrolein dissolved THF is added dropwise at a temperature of about -20 to 0 ° C. The reaction solution is mixed with a solution of ammonium chloride in water or with water and solid ammonium chloride and then adjusted to a pH of 6 to 7 with dilute mineral acid. The mixture is extracted with toluene, petroleum spirit 40/60, special spirit 80/110, isohexane, Isopar C or preferably n-heptane, the organic phase is washed with water if necessary and concentrated. The crude product obtained in this way can be used in the next stage without further purification. After adding toluene, petroleum spirit 40/60, special spirit 80/110, isohexane, Isopar C or preferably n-heptane, the mixture is cooled and stirred. The product crystallizes out, if appropriate, after the addition of seed crystals and is isolated, for example, by means of a nutsche, centrifuge, pressure nutsche or nutsche dryer and, if appropriate, washed with cold petroleum spirit 40/60, special spirit 80/110, isohexane, Isopar C or n-heptane and optionally dried.

The advantage of this procedure is that, compared to the prior art, the use of sodium hydride can be dispensed with. This enables a large-scale implementation of this process stage.

The reaction in the second step is preferably carried out by adding to a dry solvent mixture of THF / MeOH, which is initially introduced under an inert gas, preferably nitrogen, in a mixing ratio of 2: 1 to 6: 1 at RT to -110 ° C.

4.6 to 32.8 mmol triethylborane, preferably in the form of a 0.4 to 4 molar Solution in THF, admits. A solution of 17 mmol of the compound of the formula (II) in an anhydrous solvent mixture of THF / MeOH in a mixing ratio of 2: 1 to 6: 1 is added dropwise at -50 to -110 ° C., the sequences being 1. triethylboron, 2. NaBH4, 3. 3-Ketoheptenester or 1. 3-Ketoheptenester 2. Triethylbor, 3. NaBH4 are also possible. Then 4 to 27 mmol

Sodium borohydride added in one or more portions and stirred. After heating, an approx. 1 to 10% solution of sodium hydrogen carbonate in water and then an approx. 1 to 35% aqueous hydrogen peroxide solution are added. The mixture is extracted with toluene, petroleum spirit 40/60, special spirit 80/110, isohexane, Isopar C or preferably n-heptane, and the organic phase is washed, if necessary, with about 1 to 20% aqueous sodium sulfite solution.

By carrying out the reaction according to the invention, a higher selectivity is achieved compared to the prior art.

The reaction in the third step is preferably carried out by concentrating the organic phase of the second step and, after adding THF and an approximately 5-20% alkali metal base, preferably sodium hydroxide solution, for approximately 0.5 to 12 hours at 0 to 50 ° C. stir. After cooling, a pH of 1 to 7, preferably 3-5, in particular 4, is set with mineral acid. The crude product obtained in this way can optionally be used in the subsequent step without further purification.

The crude product is preferably purified by adding petroleum gasoline 40/60, special gasoline 80/110, isohexane, Isopar C or preferably n-heptane and optionally water and stirring. The product crystallizes out and is isolated, for example by means of a centrifuge, pressure filter, suction filter dryer or suction filter, and optionally washed with water and petroleum spirit 40/60, special spirit 80/110, isohexane, Isopar C or preferably n-heptane and optionally dried. This procedure, in particular in combination with the work-up, gives crystalline product without the need for complex phase separations and extractions.

The reaction in the fourth step is preferably carried out by suspending the compound of the formula (III) in special gasoline 80/110, special gasoline 40/160, n-heptane, cyclohexane, isohexane or preferably toluene and then about 1 to 5 hours, preferably 2 heated to reflux on the water separator for up to 3 hours. If necessary, the solution is filtered and concentrated. The remaining residue can optionally be used directly for the next stage or is dissolved in toluene, MTBE and petroleum spirit 40/60, special spirit 80/110, isohexane, Isopar C or preferably n-heptane and optionally filtered. After cooling, the product which has crystallized out is isolated, for example, on a suction filter, centrifuge, pressure suction filter, suction filter dryer and, if appropriate, washed with petroleum gasoline 40/60, special gasoline 80/110, isohexane, Isopar C or preferably n-heptane and optionally dried.

Compared to the prior art, the reaction time will be significantly shortened by carrying out the reaction.

The enantiomer separation in the fifth stage is preferably carried out by using a column (preferably 10 to 70 cm in diameter and a length of over 40 cm) with an upper (pore size: approx. 10 μm) and lower distributor plate (pore size: approx. 10 μm) ) filled with dry or Baychiral PM-D® (N-Acryloyl-S-Phenylalamin-d-menthyl ester / Bayer) slurried in Tomol / THF. The column is preferably conditioned in that the eluent mixture toluene / THF, tert-amyl methyl ether or methyl tert-butyl ether (3: 1 to 6: 1) is used for several hours from below and from above with a pump and a flow of approx. 0.5 cm / min. pumps through the column (resulting bed height: approx. 40 to 50 cm). Alternatively, the column can be packed directly with moist Baychiral PM-D®. The distance between Distribution plate and chromatography bed is set to 0 to 5, preferably 0 to 1 cm.

A 5-30% solution of the compound of formula (V) in the eluent mixture is optionally after filtration through a 0.2 μm filter, in several portions (one

Portion preferably contains 3 to 30 g of the compound of formula (V) per kg of Bayhiral PM-D) applied to the column, for example by means of a pump. The mixture is then eluted at a running speed of 2.5 cm to 0.05 cm / min, preferably 0.4 to 1.0 cm / min. This results in the separation of the (+/-) isomers and other by-products. The individual components are detected by the rotation value (αo), possibly supplemented by UN absorption or HPLC measurements. The measured values are used for fractionation in 2 or more fractions. Three fractions are preferably separated, whereby

Fraction 1 as

Main component:

(-) - trans- (E) -6- (2,6-diisopropyl-4- (4-fluoφhenyl) -3-methoxymethyl-pyrid-5-yl) - ethenyl) -3, 4,5, 6-tetrahydro -4-hydroxy-2H-pyran-2-one.

Fraction 2 (mixed fraction A) as

Main components:

(+) - trans- (E) -6- (2,6-diisopropyl-4- (4-fluoφhenyl) -3-methoxymethyl-pyrid-5-yl) - ethenyl) -3, 4,5, 6-tetrahydro -4-hydroxy-2H-pyran-2-one

(-) - trans- (E) -6- (2,6-diisopropyl-4- (4-fluoφhenyl) -3-methoxymethyl-pyrid-5-yl) - ethenyl) -3,4,5,6-tetrahydro -4-hydroxy-2H-pyran-2-one and

Fraction 3 as the main component:

(+) - trans- (E) -6- (2,6-diisopropyl-4- (4-fluoφhenyl) -3-methoxymethyl-pyrid-5-yl) - ethenyl) -3,4,5,6-tetrahydro -4-hydroxy-2H-pyran-2-one. It takes about 1 to 3 hours to separate a portion. The column can already be coated with a new portion of the racemate to be separated during an ongoing separation.

The entire fraction 2 (mixed fraction A) is concentrated, the remaining residue (toluene moisture) is dissolved in the mobile phase mixture and then filtered as a 5-30% strength by weight solution through a 0.2 μm filter and again chromatographed as described above. This process is repeated if necessary. The solvent mixtures of fractions 1 and 2 are preferably recovered and used again.

The entire fraction 3 is concentrated in vacuo. The recovered solvent can be used again. The remaining residue is dissolved in toluene, MTBE and petroleum spirit 40/60, special spirit 80/110, isohexane, Isopar C and / or preferably n-heptane and optionally filtered. After cooling, the crystallized product is isolated, for example on a nutsche, centrifuge, pressure nutsche, nutsche dryer, if necessary washed several times with petroleum spirit 40/60, special spirit 80/110, isohexane, Isopar C and / or preferably n-heptane and, for example, using a ball dryer, pressure nutsche, Vacuum dryer or vacuum drying cabinet dried.

This procedure leads to a significantly higher loading of the column and thus a better space / time yield. In addition to the separation of enantiomers, other by-products are also separated off, thereby achieving a higher purity.

The hydrolysis in the sixth step is carried out in a customary manner using bases in organic solvents, preferably by the processes described in WO-98/57917. The following example serves to explain the invention. The invention is not limited to the example.

example

a) first stage

Methyl- (E) -7- (3-methoxymethyl-2,6-diisopropyl-4- (4-fluorophenyl) pyrid-5-yl)) - 5-hydroxy-3-oxo-hept-6-enoate

(Racemat)

(Racemate)

A suspension of 46.8 g (339 mmol) of sodium acetoacetate in 320 ml of dry THF is prepared under nitrogen at RT. 152.5 g (358 mmol) of 15% n-butyllithium in n-hexane are added dropwise to this suspension at a temperature of -5 ° C. to -10 ° C. 85.8 g (241 mmol) of pyridylacrolein are then added dropwise at a temperature of about -5 ° C. The reaction solution is mixed with the solution from 106.2 g of ammonium chloride in 390 ml of water and then with approx.

10% hydrochloric acid adjusted to pH = 6.9. The mixture is extracted with 480 ml of n-heptane, the organic phase is washed with 480 ml of water and then a volume of about 600 ml is concentrated in vacuo. After adding 560 ml of n-heptane (total volume: approx. 1160 ml), the mixture is cooled to RT and then to 0 ° C. The crystallized product is isolated on a suction filter, washed with cold n-heptane and dried in a vacuum drying cabinet. Yield: 100 g (88% of theory) b) second stage

Methyl erythro- (E) -7- (3-methoxymethyl-2,6-diisopropyl-4- (4-fluoro-phenyl) pyrid-5-yl)) - 3,5-dihydroxy-hept-6-enoate

(Racemat)

(Racemate)

16 g (18.4 mmol) of a 1 M (approx. 11.5% by weight) triethylborane solution in THF are added at RT to 37 g of an anhydrous solvent mixture of THF / MeOH (4: 1) introduced under nitrogen. After cooling the solution to -70 to -75 ° C, a solution of 8 g (17 mmol) of 3-ketoheptene ester in 12 g of anhydrous solvent mixture of THF / MeOH (4: 1) is added dropwise at -70 to -75 ° C. Then 0.55 g (14.5 mmol) of sodium borohydride are added in one or more portions and the mixture is subsequently stirred at -70 to -75 ° C. for about 90 minutes. Then a 7.5% solution of sodium hydrogen carbonate in water and then 38.3 g of an approximately 11% aqueous hydrogen peroxide solution are added. This mixture is extracted with 50 g of n-heptane and the organic phase is washed with about 15% aqueous sodium sulfite solution. Yield: approx. 90 g solution (100% of theory) c) third stage

Erythro- (E) -7- (3-methoxymethyl-2,6-diisopropyl-4- (4-fluorophenyl) pyrid-5-yl)) - 3,5-dihydroxy-hept-6-enoic acid, (DHH- Acid)

(Racemate)

The organic phase from the second stage is concentrated in vacuo. After adding 16 g of THF and 16.5 g (29 mmol) of an approximately 7% sodium hydroxide solution, the mixture is stirred at RT for about 90 minutes. A pH of 4 is then set with approximately 13.5% hydrochloric acid. 28 g of n-heptane and 5 g of water are added. The crystallized product is isolated on a suction filter, washed with water and with n-heptane and dried in a vacuum drying cabinet. Yield: 7.4 g (95% of theory)

d) fourth stage

(+/-) - trans- (E) -6- (2,6-diisopropyl-4- (4-fluorophene) -3-methoxymethyl-pyrid-5-yl) -ethenyl) -3,4,5,6 -tetrahydro-4-hydroxy-2H-pyran-2-one, (pyridine lactone)

(Racemat)

(Racemate)

20.5 g (54.4 mmol) of DHH acid are suspended in 238 ml of toluene. The mixture is then heated under reflux for about 2.5 hours on a water separator. The solution is filtered. After concentration, the remaining residue (approx. 24.5 g) is dissolved in 10.25 g, toluene, 20.5 g MTBE and 82 g n-heptane. After cooling, the crystallized product is isolated on a suction filter, washed with n-heptane and dried in a vacuum drying cabinet. Yield: 17.1 g (87% of theory)

e) fifth stage

(+) - trans- (E) -6- (2,6-diisopropyl-4- (4-fluoφhenyl) -3-methoxymethyl-pyrid-5-yl) - ethenyl) -3,4,5,6-tetrahydro -4-hydroxy-2H-pyran-2-one

A glass column (0 = 10cm, length = 60 cm) with an upper (pore size: approx. 10 μm) and lower distribution plate (pore size: approx. 10 μm) is filled with approx. 1000 g dry Baychiral PM-D. Then the eluent mixture is toluene / THF (5: 1) for several hours from below and from above with a pump and a flow of approx. 40 ml / min. (i.e. approx. 0.5 cm / min.) pumped through the glass column and the stationary phase conditioned (resulting bed height: approx. 45 cm). The distance between the distribution plate and the chromatography bed is set to approx. 0.5 cm.

500 g (1.13 mol) of pyridine lactone racemate are dissolved in 3200 ml of eluent mixture toluene / THF (5: 1) and the solution is then filtered through a 0.2 μm filter. An aliquot of this solution (contains 22.5 g of pyridine lactone racemate) is pumped and a flow of 40 ml / min. applied to the conditioned chromatography column. Then using a pump and a flow of

40 ml / min. eluted, which leads to the separation of the isomers and other by-products. The individual components are detected by the rotation value (CX _D ), possibly supplemented by UV absorption or HPLC measurements. The measured values are used for automatic computer-controlled fractionation in 3 fractions. Fraction 1: main component:

(-) - trans- (E) -6- (2,6-diisopropyl-4- (4-fluoφhenyl) -3-methoxymethyl-pyrid-5-yl) - ethenyl) -3, 4,5, 6-tetrahydro -4-hydroxy-2H-pyran-2-one.

Fraction 2 (mixed fraction A): main components:

(+) - trans- (E) -6- (2,6-diisopropyl-4- (4-fluoφhenyl) -3-methoxymethyl-pyrid-5-yl) - ethenyl) -3, 4,5, 6-tetrahydro -4-hydroxy-2H-pyran-2-one

(-) - trans- (E) -6- (2,6-diisopropyl-4- (4-fluoφhenyl) -3-methoxymethyl-pyrid-5-yl) - ethenyl) -3,4,5,6-tetrahydro -4-hydroxy-2H-pyran-2-one

Fraction 3: main component:

(+) - trans- (E) -6- (2,6-diisopropyl-4- (4-fluoφhenyl) -3-methoxymethyl-pyrid-5-yl) - ethenyl) -3, 4,5, 6-tetrahydro -4-hydroxy-2H-pyran-2-one Separation takes about 3 hours.

A separation takes about 3 hours. The separation time is reduced to approx. 1.5 hours if the next job on the column is already started, if the previous separation has not yet been completed.

This separation is repeated until the entire amount of pyridine lactone has been separated. This requires approx. 22 separation cycles.

The entire fraction 2 (mixed fraction A) is concentrated, the remaining residue (approx. 90 g, toluene-moist) is dissolved in 900 ml of the solvent mixture of toluene / THF (5: 1; v: v) and the solution is then passed through a 0.2 μm -Filter filtered. An aliquot of this solution (contains approx. 16 g pyridine lactone racemate) is pumped and a flow of 40 ml / min. on the conditioned chromatography column wear. Then with a pump and a flow of 40 ml / min. eluted, which leads to the separation of the isomers and other by-products. Detection: see above Fractionation: see above This separation is repeated until the entire amount resulting from fraction 2 (mixed fraction A) has been separated. About 5 separation cycles are required for this.

The entire fraction 1 is concentrated to recover the eluent mixture toluene / THF (5: 1; v: v) (option).

The entire fraction 2 (mixed fraction B) is concentrated to recover the solvent mixture toluene / THF (5: 1; v: v) (option). If necessary, the residue can be redissolved and chromatographed as described above.

The entire fraction 3 is concentrated in vacuo. The recovered solvent can be used again. The remaining residue (approx. 275 g, toluene-moist) is dissolved in 475 g toluene, 70 g MTBE and 980 g n-heptane. After filtration and cooling, the crystallized product is isolated on a suction filter, washed with n-heptane and dried in a vacuum dryer. Yield: 225 g (45% of theory)

Claims

claims 1. Process for the preparation of 3R, 5S - (+) - sodium erythro- (E) -7- [4- (4-fluorophenyl) -2,6-diisopropyl-5-methoxymethyl-pyrid-3-yl ] -3,5-dihydroxy-hept-6-enoate, characterized in that the compounds of the formula (I)

In the first step reacted with sodium acetoacetic ester in the presence of n-hexyllithium, t-butyllithium and / or n-butyllithium and worked up and the racemate of the compound of the formula (II) thus obtained

At the second step with triethylborane, in an inert organic solvent mixture in the presence of sodium borohydride and, if appropriate after working up, the erythro-racemate of the formula (III) thus obtained

in the third step with bases at 0 ° C. to 70 ° C., and then adjusted to a pH of 1 to 7 with mineral acid, so that the erythro-racemate of the corresponding acid of the formula (IV) obtained either directly or after cleaning in the fourth step after suspension in toluene, special gasoline 80/110, special gasoline 140/160, n-heptane, cyclohexane or isohexane, heated under reflux for 1 to 5 hours and, if appropriate after processing and purification, receives the racemate of the formula (V) (Racemate) (V)

in the fifth step the racemate of the formula (V) is converted into the enantiomers as the stationary phase by chromatography on Baychiral PM-D®, and in the sixth step the enantiomerically pure lactone hydrolyzes. Process for the preparation of compounds of formula (II)

characterized in that compounds of the formula (I)

with sodium acetoacetic ester in the presence of n-hexyllithium, t-butyllithium and / or n-butyllithium. Process for the preparation of compounds of formula (III)

characterized in that compounds of the formula (II)

with triethylborane, in an inert organic solvent mixture in the presence of sodium borohydride. Process for the preparation of compounds of formula (IV)

characterized in that compounds of the formula (III)

with bases at 0 ° C to 70 ° C, and then adjusted to a pH of 1 to 7 with mineral acid. Process for the preparation of compounds of formula (V), (Racemate) (V)

characterized in that compounds of the formula (IV)

after suspension in toluene, special gasoline 80/110, special gasoline 140/160, n-heptane, cyclohexane or isohexane heated under reflux for 1 to 5 hours. Process for the enantiomer separation of racemic compounds of the formula (V), (Racemate) (V)

characterized in that the racemate of the formula (V) is chromatographed on the chiral phase Baychiral PM-D® as the stationary phase.