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WO2003008383A1 - Production de 3r,5s-(+)-natrium-erythro-(e)-7-[4-(4-fluorophenyl)-2,6-diisopropyl-5-methoxymethyl-pyrid-3-yl]-3,5-dihydroxy-hept-6-enoate enantiomeriquement pur - Google Patents

Production de 3r,5s-(+)-natrium-erythro-(e)-7-[4-(4-fluorophenyl)-2,6-diisopropyl-5-methoxymethyl-pyrid-3-yl]-3,5-dihydroxy-hept-6-enoate enantiomeriquement pur Download PDF

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Publication number
WO2003008383A1
WO2003008383A1 PCT/EP2002/007479 EP0207479W WO03008383A1 WO 2003008383 A1 WO2003008383 A1 WO 2003008383A1 EP 0207479 W EP0207479 W EP 0207479W WO 03008383 A1 WO03008383 A1 WO 03008383A1
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WO
WIPO (PCT)
Prior art keywords
formula
racemate
compounds
erythro
pyrid
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP2002/007479
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German (de)
English (en)
Inventor
Mathias Berwe
Karl-Heinz Duchene
Joachim Rehse
Hermann Schutt
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Bayer AG
Original Assignee
Bayer AG
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Filing date
Publication date
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Publication of WO2003008383A1 publication Critical patent/WO2003008383A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/55—Acids; Esters

Definitions

  • 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.
  • the task was to provide a new, simplified process in order to obtain the target compound with higher selectivity, purity and space / time yield.
  • the reaction in the first step is preferably carried out in anhydrous tetrahydrofuran (THF), the water content preferably being below 0.1%.
  • THF anhydrous tetrahydrofuran
  • 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.
  • 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 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.
  • an inert gas preferably nitrogen
  • 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.
  • 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.
  • 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.
  • 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 ⁇ m) and lower distributor plate (pore size: approx. 10 ⁇ m) ) filled with dry or Baychiral PM-D® (N-Acryloyl-S-Phenylalamin-d-menthyl ester / Bayer) slurried in Tomol / THF.
  • a column preferably 10 to 70 cm in diameter and a length of over 40 cm
  • an upper pore size: approx. 10 ⁇ m
  • lower distributor plate pore size: approx. 10 ⁇ m
  • PM-D® N-Acryloyl-S-Phenylalamin-d-menthyl ester / Bayer
  • 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).
  • 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 ⁇ m 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 ( ⁇ o), 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
  • the column can already be coated with a new portion of the racemate to be separated during an ongoing separation.
  • 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 ⁇ m 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.
  • 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.
  • 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.
  • 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.
  • 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)
  • 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.
  • 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.
  • the entire fraction 1 is concentrated to recover the eluent mixture toluene / THF (5: 1; v: v) (option).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne un procédé de production de 3R,5S-(+)-natrium-érythro-(E)-7-[4-(4-fluorophényl)-2,6-diisopropyl-5-méthoxyméthyl-pyrid-3-yl]-3,5-dihydroxy-hept-6-énoate énantiomériquement pur.
PCT/EP2002/007479 2001-07-18 2002-07-05 Production de 3r,5s-(+)-natrium-erythro-(e)-7-[4-(4-fluorophenyl)-2,6-diisopropyl-5-methoxymethyl-pyrid-3-yl]-3,5-dihydroxy-hept-6-enoate enantiomeriquement pur Ceased WO2003008383A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE2001135013 DE10135013A1 (de) 2001-07-18 2001-07-18 Herstellung von Pyridylverbindungen
DE10135013.9 2001-07-18

Publications (1)

Publication Number Publication Date
WO2003008383A1 true WO2003008383A1 (fr) 2003-01-30

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PCT/EP2002/007479 Ceased WO2003008383A1 (fr) 2001-07-18 2002-07-05 Production de 3r,5s-(+)-natrium-erythro-(e)-7-[4-(4-fluorophenyl)-2,6-diisopropyl-5-methoxymethyl-pyrid-3-yl]-3,5-dihydroxy-hept-6-enoate enantiomeriquement pur

Country Status (2)

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DE (1) DE10135013A1 (fr)
WO (1) WO2003008383A1 (fr)

Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0306929A2 (fr) * 1987-09-08 1989-03-15 Warner-Lambert Company 6-[[Pyridin-3-yl substituées]alkyl]-et alkényl]-tétrahydro-4-hydroxypyran-2-ones-inhibiteurs de biosynthèse de cholestérol
EP0325130A2 (fr) * 1988-01-20 1989-07-26 Bayer Ag Pyridines substituées
EP0325129A2 (fr) * 1988-01-20 1989-07-26 Bayer Ag Pyridines disubstituées
EP0356788A2 (fr) * 1988-08-29 1990-03-07 E.R. SQUIBB & SONS, INC. Quinoléine et pyridine ancres pour des inhibiteurs de HMG-CoA reductase
US4950675A (en) * 1988-12-21 1990-08-21 Warner-Lambert Company Pyridine di-mevalono-lactones as inhibitors of cholesterol biosynthesis
EP0247633B1 (fr) * 1986-05-30 1991-01-30 Warner-Lambert Company Inhibiteurs de la synthèse du cholestérol du type trans[(carboxamido-3 ou 4-pyrrolyl-1 substitué)-2 alkyl]-6 hydroxy-4 pyranone-2
US4997837A (en) * 1987-09-08 1991-03-05 Warner-Lambert Company 6-(((substituted)pyridin-3-yl)alkyl)-and alkenyl)-tetrahydro-4-hydroxypyran-2-one inhibitors of cholesterol biosynthesis
US5064841A (en) * 1989-08-03 1991-11-12 Bayer Aktiengesellschaft HMG-COA reductase-inhibiting imino-substituted pyridines
WO1998045230A1 (fr) * 1997-04-08 1998-10-15 Bayer Aktiengesellschaft Separation chromatographique par enantiomeres de lactones
EP0617019B1 (fr) * 1993-03-24 2000-05-31 Bayer Ag Procédé de préparation de 3R,5S-(+)-érythro-(E)-7-4-(4-fluorophényl)--2,6-diisopropyl-5-méthoxyméthyl-pyrid-3-yl-3,5 dihydroxy-hept-6-énoate de sodium

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0247633B1 (fr) * 1986-05-30 1991-01-30 Warner-Lambert Company Inhibiteurs de la synthèse du cholestérol du type trans[(carboxamido-3 ou 4-pyrrolyl-1 substitué)-2 alkyl]-6 hydroxy-4 pyranone-2
EP0306929A2 (fr) * 1987-09-08 1989-03-15 Warner-Lambert Company 6-[[Pyridin-3-yl substituées]alkyl]-et alkényl]-tétrahydro-4-hydroxypyran-2-ones-inhibiteurs de biosynthèse de cholestérol
US4997837A (en) * 1987-09-08 1991-03-05 Warner-Lambert Company 6-(((substituted)pyridin-3-yl)alkyl)-and alkenyl)-tetrahydro-4-hydroxypyran-2-one inhibitors of cholesterol biosynthesis
EP0325130A2 (fr) * 1988-01-20 1989-07-26 Bayer Ag Pyridines substituées
EP0325129A2 (fr) * 1988-01-20 1989-07-26 Bayer Ag Pyridines disubstituées
EP0356788A2 (fr) * 1988-08-29 1990-03-07 E.R. SQUIBB & SONS, INC. Quinoléine et pyridine ancres pour des inhibiteurs de HMG-CoA reductase
US4950675A (en) * 1988-12-21 1990-08-21 Warner-Lambert Company Pyridine di-mevalono-lactones as inhibitors of cholesterol biosynthesis
US5064841A (en) * 1989-08-03 1991-11-12 Bayer Aktiengesellschaft HMG-COA reductase-inhibiting imino-substituted pyridines
EP0617019B1 (fr) * 1993-03-24 2000-05-31 Bayer Ag Procédé de préparation de 3R,5S-(+)-érythro-(E)-7-4-(4-fluorophényl)--2,6-diisopropyl-5-méthoxyméthyl-pyrid-3-yl-3,5 dihydroxy-hept-6-énoate de sodium
WO1998045230A1 (fr) * 1997-04-08 1998-10-15 Bayer Aktiengesellschaft Separation chromatographique par enantiomeres de lactones

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DE10135013A1 (de) 2003-01-30

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