EP1753717A1 - Prodede de production de derives de diphenylazetidinone - Google Patents

Prodede de production de derives de diphenylazetidinone

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Publication number
EP1753717A1
EP1753717A1 EP05743217A EP05743217A EP1753717A1 EP 1753717 A1 EP1753717 A1 EP 1753717A1 EP 05743217 A EP05743217 A EP 05743217A EP 05743217 A EP05743217 A EP 05743217A EP 1753717 A1 EP1753717 A1 EP 1753717A1
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European Patent Office
Prior art keywords
aryl
alkyl
och
general formula
mmol
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EP05743217A
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German (de)
English (en)
Inventor
Heiner Jendralla
Guenter Billen
Wendelin Frick
Bernd Junker
Theodor Andreas Wollmann
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Sanofi Aventis Deutschland GmbH
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Sanofi Aventis Deutschland GmbH
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Publication of EP1753717A1 publication Critical patent/EP1753717A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention relates to the production of 1,4-diphenyl-azetidinone derivatives by cyclization of certain ß-arjriino-carboxamides or ß-amino-carboxylic acid esters.
  • ezetimibe blocks the absorption of cholesterol from the intestine, so that both lower LDL values and fewer triglycerides are observed in patients. It is the 1- (4-fluorophenyl) -3 (R) - [3- (4-fluorophenyl) -3 (S) -hydroxypropyl] -4 (S) - (4-hydroxyphenyl) -2-azetidinone of the following formula (see claim 8 in EP 0720 599 B1).
  • Trialkylphosphine / Dialkylazodicarboxylat a phase transfer catalyst
  • DialkylcUo hosphaiVTefra-n-butylammonium hydrogen sulfate or dichlorobenzoyl chloride / NaH e.g. Trialkylphosphine / Dialkylazodicarboxylat, a phase transfer catalyst, DialkylcUo hosphaiVTefra-n-butylammonium hydrogen sulfate or dichlorobenzoyl chloride / NaH, or
  • esters (R x is, for example, alkyl) of the general formula below with imines in the presence of strong bases,
  • a silylating agent and a fluoride ion catalyst as the cyclizing agent or a salt of the chiral compound (G + salt), in particular with bis (trimethylsilyl) acetamide and tefra-n-butylammonium fluoride.
  • LAG alkylene
  • a disadvantage of this process is the use of large amounts of silylating agents such as N, O-bis (trimethylsilyl) acetamide, since the workup produces acetamide, which is classified as carcinogenic.
  • the diastereoselectivity is rather moderate during the addition reaction stage using enolate and 1 min, which means that additional separation stages are necessary.
  • R 1 OH, OCH 3
  • R 2 F, CH 2 CH 3 , CH 2 NHR 4
  • R 5 OH, NH-CH 2 - [CH (OH) -] m CH 2 OH
  • R 8 R 2 , CH 2 N [Si (alkyl) 0 (aryl) p ] CO 2 CH 2 (C 6 H 5 ), CH 2 N [Si (alkyl) 0 (aryl) p ] CO 2 tert-butyl .
  • a typical reaction sequence - including the precursors - is shown below as an example.
  • 5- (4-Fluoro-phenyl) -5-oxopentanoic acid methyl ester (V ⁇ ) can be prepared from fluorobenzene as described in tetrahedron (volume 49, pages 3193-3202, 1993).
  • the keto group is reduced to the alcohol (VTIT), the S-enantiomer, using a chiral reducing agent.
  • VTIT the keto group
  • a chiral reducing agent All methods known to the person skilled in the art can be used here. Examples of this are the (R) -methyl-CBS-catalyzed reduction with borane-dimethylsulfide complex or borane-tetrahydrofuran complex (see, for example, WO 00/34240) and the ruthenium ( ⁇ ) -catalyzed asymmetric hydrogenation (analogously to J. Am. Chem Soc. 1996, 118, 2521 to 2522).
  • This asymmetric hydrosilylation has a number of advantages over the oxazaboroHdin-catalyzed reduction with borane in the starting situation [ ⁇ -keto ester (VII), which is specifically present in the process according to the invention], and in terms of feasibility, environmental compatibility and economy on an industrial scale Complexes and towards asymmetric hydrogenation.
  • the preferred reducing agent poly (methylhydrosiloxane) (PMHS) is very inexpensive on an industrial scale (cheapest known silane), not very volatile (bp> 177 ° C), safe to handle and environmentally friendly.
  • the borane-THF or DMS complex is significantly more expensive, much more volatile, the safe technical handling requires some effort and these substances are considerably polluting.
  • borane complexes in production requires e.g. B. a continuous exhaust air incinerator, since both the borane itself, as well as the dimethyl sulfide are strongly odorous. Furthermore the reduction with borane complexes is accompanied by the formation of hydrogen during the various phases of the reaction and work-up process. So that there are no detonating gas explosions in the pipes to the exhaust air combustion system, large amounts of nitrogen must be fed in continuously so that the explosion limit cannot be reliably reached. In addition, the commercial (R) -methyl-CBS solution is expensive and the reaction is moderately catalytic.
  • asymmetric hydrosilylation succeeds at high concentration in the solvent toluene (see Examples 32 and 33), while the CBS reduction is usually carried out at a larger dilution and in less technically desirable solvents such as dichloromethane or THF.
  • the advantage of asymmetric hydrosilylation over Noyori's asymmetric Ru (H) -catalyzed hydrogenation mainly consists in the low catalyst costs.
  • the asymmetric hydrosilylation takes place over a chirally complexed CuH catalyst that is generated in situ from an inexpensive copper ( ⁇ ) salt (e.g. CuCl), the ligand and the silane, preferably PMHS, in the reaction solvent (e.g. toluene).
  • the catalyst costs, irrespective of the S / C ratio achieved, only play a minor role as long as the S / L ratio is acceptably high.
  • the ruthenium precatalyst for the asymmetric Noyori hydrogenation of a non-chelating aryl ketone is made from a suitable ruthenium (H) compound, an optically pure diamine and an optically pure diphosphane.
  • H ruthenium
  • the asymmetric hydrosilylation can be carried out in the temperature range from -78 to + 30 ° C, preferably at -50 ° C to + 10 ° C, particularly preferably at -20 ° C to 0 ° C.
  • aprotic solvents which are inert to the silane used can be used, preference is given to the class of ethers, and chlorinated, saturated or aromatic hydrocarbons, particularly preferably toluene, THF, fluorobenzene, chlorobenzene, dichloromethane, cyclohexane, heptane or pentane, especially toluene.
  • a (more) stoichiometric reducing agent is a silane such as polymethylhydrosiloxane (PMHS), diphenylmethylsilane (Ph 2 MeSiH), diphenylsilane (Ph 2 SiH 2 ), phenylsilane (PhSiH 3 ), tetramethyldisiloxane (TMDS), tert-butyl-dimethyl-dimethyl TBS-H), triethylsilane (TES-H), preferably PMHS, Ph 2 MeSiH or TMDS, particularly preferably PMHS.
  • the silane is used in excess, based on the starting material, preferably 1.2 to 6.0 equiv., Particularly preferably 2.0 to 5.0 equiv.
  • the catalytically active species is probably a chelate complex of copper (I) hydride with a chiral diphosphane.
  • This catalytic species is preferably generated in situ in the reaction mixture from a suitable copper compound, a strong base, a chelating chiral diphosphane and the silane.
  • CuCl, CuCl 2 , CuF 2 , or Stryker reagent [(PPh 3 ) CuH] 6 are preferably used as the copper compound, particularly preferably CuCl or Stryker reagent.
  • the copper compound is used in an amount of 0.01 mol% to 10 mol% based on the starting material (ketone), preferably in an amount of 0.1 mol% to 3 mol%, particularly preferably in an amount of 0.5 to 1.0 mol%.
  • the strong base is preferably an alkali alcoholate or alkali hexamethyldisilazane, particularly preferably sodium tert-butoxide, sodium methoxide or NaHMDS.
  • the base is used either equimolar or in excess of the copper compound, preferably 1.0 to 10.0 equiv., Particularly preferably 1.0 to 6.0 equiv. based on the copper compound.
  • a chiral, chelating diphosphane is used as the ligand, the enantioselectivity of the catalytic hydrosilylation and the productivity of the catalyst often being higher the smaller the dihedral angle in the chiral diphosphane.
  • Preferred ligands come from the diphosphine classes B1NAP, DuPHOS, FerroTANE, JOSJPHOS, WALPHOS, BrriANP, B ⁇ PHEMP, MeO-BJPHEP and SEGPHOS.
  • Particularly preferred ligands are BINAP, Cy 2 PF-PCy 2 , BLTIANP, 5-xyl-MeO-BIPHEP, 4-MeO-3,5-DTBM-MeO-BIPHEP, DM-SEGPHOS, DTBM-SEGPHOS, very particularly preferably 5- Xyl-MeO-BIPHEP, 4-MeO-3,5-DTBM-MeO-BIPHEP, DM-SEGPHOS, DTBM-SEGPHOS.
  • the free one is , uncomplexed portion of the CuH is thermally unstable.
  • this decomposition is suppressed by carrying out the in-situ production of the CuH (for example from CuCl) in the presence of one equivalent of triphenylphosphine based on CuH, or alternatively using preformed Stryker reagent as the precatalyst.
  • the CuH-PPh 3 complex which is initially present, is thermally stable in the range from -20 ° C to 0 ° C, but does not commit a significant reduction in keto groups under these conditions. It is only when this "CuH bearing layer" meets the few chiral diphosphine molecules in the reaction mixture that the chiral, highly reactive CuH complex is formed, which in a ligand-accelerated reaction reduces the keto groups to optically active alcohols.
  • the asymmetric hydrosilylation of the ketone can be carried out in such a way that the reaction product is either isolated directly from the free, optically active alcohol, or its silyl ether, which can then be deprotected to give the free alcohol can, or can continue to implement in the protected form.
  • Use of PMHS and direct isolation of the free, optically active alcohol often gives better results and is therefore preferred.
  • the use of other silanes, e.g. B. TBS-H or TES-H, followed by the isolation of the tert-butyldimethylsilyl ether or the triethylsilyl ether of the chiral alcohol but also belongs to the embodiments of the present invention.
  • Silyl protective groups the trityl, the THP, the 1-ethoxyethyl and the alkoxymethyl protective groups, and the tert are particularly preferred.
  • the protective groups are introduced by methods known to the person skilled in the art, such as, for. B. in "Protective Groups in Organic Synthesis” Third Edition [TW Green, PGM Wuts (Editor), John Wiley & Sons, Inc., 1999] are described.
  • ester (IX) is then converted to the amide (XI) using (+) - (lS, 2S) -pseudoephedrine (X).
  • All methods known to the person skilled in the art can be used here. Examples of this are from A.G. Myers et al described in J. Am. Chem. Soc. (1997, volume 119, pages 6496 - 6511, 656 - 673) and in Organic Synthesis (1999, volume 76, pages 57 to 76).
  • a reliable and mild, but multi-step method for converting the ester (IX) into the amide (XI) is to first hydrolyze the methyl ester to the free carboxylic acid, the latter then with about 1.0 equivalents of a suitable carboxylic acid chloride, e.g. Pivalic acid chloride, or a chloroformate, e.g. Isobutyl chloroformate, in the presence of a suitable base, preferably about 2.2 equivalents of the base triethylamine, in a suitable solvent, preferably dichloromethane, acetone or toluene at about 0 ° C., to convert to the mixed anhydride, which then, preferably in a one-pot reaction approx. 0 ° C, with the addition of approx. 1.0 equiv. (+) - (lS, 2S) -pseudoephedrine (X) reacted to the amide (XI).
  • a suitable carboxylic acid chloride
  • the amide (XI) can also be obtained in one stage by direct condensation of ephedrine with the methyl ester (LX) under basic conditions in accordance with one of the two following variants.
  • This one-step synthesis of the pseudoephedrine amide (XI) is believed to be based on an original transesterification reaction of the methyl ester with the secondary hydroxy group of the pseudoephedrine followed by an intramolecular O -> N acyl shift.
  • the imine component (DI) required for the subsequent addition is obtained from the corresponding aniline derivative and aldehyde by known methods.
  • the water formed in the reaction can be removed, for example, by azeotropic distillation with toluene.
  • the enolate is produced from the amide (XI) with the appropriate bases and this is added to the lnine (DI).
  • General examples of this are described in J. Org. Chem. (2001, volume 66, pages 9030-9032), Organic Letters (2001, volume 3, pages 773-776 and 2000, volume 2, pages 3527-3529).
  • the conversion of the amide (XI) into the Mannich product (XU) is a one-pot reaction in which 2 to 4 phases are carried out, which are described below. All phases of the reaction are carried out in a fairly polar solvent with ether properties, which must have good solubility properties for lithium salts and good stability to lithium bases.
  • Preferred solvents are tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, diethoxymethane (DEM, formaldehyde diethylacetal), 1,1-dimethoxymethane (methylal), diglyme (diethylene glycol dimethyl ether), triglyme (triethylene glycol dimethyl ether) and dichloromethane.
  • Tetrahydrofuran and diethoxymethane, in particular tetrahydrofuran are particularly preferred.
  • Lithium diisopropylamide (LDA) or 1,1,1,3,3,3-hexamethyldisilazane lithium salt (LiHMDS, bis-trimethylsilyl lifhiumamide) are suitable as bases. LDA is preferred. Either the commercially available bases can be used, or they can be used in situ by adding a scarce equivalent of n-BuLi solution to dissolve diisopropylamine or 1,1,1,3,3,3- Hexamethyldisilazane (HMDS, bis-trimethylsilylamine) available lithium bases.
  • LDA Lithium diisopropylamide
  • LiHMDS 1,1,1,3,3,3-hexamethyldisilazane lithium salt
  • the solution of the amine in one of the above-mentioned dry solvents with ether properties, particularly preferably THF, is initially introduced under inert gas in a well-dried reaction vessel.
  • the lithium salt, preferably lithium chloride, required in phase 4 can already be dissolved / partially suspended.
  • 0.92 to 0.99 equivalents, based on the amine, of a 1.5 to 10.0 molar solution of n-butyllithium in hexane, preferably about 0.95 equivalents of an about 2.5 molar solution are at -78 ° C to + 10 ° C, preferably at -30 ° C to 0 ° C, particularly preferably at -20 ° C, slowly added. The mixture is allowed to warm to 0 ° C. and is stirred for a further 5 to 10 minutes at this temperature.
  • Phase 2 [conversion of the amide (XI) into the lithium enolate]:
  • the deprotonation of the pseudoephedrinamide (XI) to the lithium enolate is carried out with 2.0 to 3.2 equiv. the lithium base, preferably with approximately 2.05 equiv. LDA, as far as the amide (XI) contains no other unprotected protic function (OH, NHR) apart from the hydroxy group of pseudoephedrine. Otherwise, the amount of lithium base necessary to deprotonate this function must also be used.
  • the lithium salt, preferably lithium chloride, required in phase 4 can optionally already be dissolved / partially suspended in the reaction mixture.
  • the deprotonation of the amide (XI) to the lithium enolate with LDA is carried out at -78 ° C to + 40 ° C, preferably at -20 ° C to + 20 ° C. It is particularly preferred to drop the solution of the amide (XI) slowly at about -20 ° C. within about 30 minutes to 1 hour to the LDA solution which may optionally additionally contain lithium chloride. The mixture is stirred for approx. 15 to 30 minutes at -20 ° C., allowed to warm to 0 ° C. within approx. 30 minutes and stirred at this temperature for a further 15 minutes. Normally the enolization is rapid at 0 ° C. and therefore to this Time completed.
  • the solution of LiHMDS preferably about 3.2 equiv., Is slowly added dropwise at -5 ° C. to 0 ° C. to the solution of the amide (XI), optionally about 4 equiv. Can contain lithium chloride. Then it is stirred for another hour at 0 ° C.
  • Phase 3 [optional re-metalation of the amide lithium enolate]: Before the Mannich addition to the imine (DI) to the titanium enolate, the lithium enolate of the pseudoephedrinamide (XI) can Boron enolate, zinc enolate can be metal-plated, or alternatively can be used directly for Mannich addition (phase 4) without prior metal-metalation.
  • the direct use of the lithium enolate or the metal transition to the zinc enolate are preferred, the use of the lithium enolate without metal conversion is particularly preferred.
  • the solution of the lithium enolate obtained in phase 2 is cooled and the solution of 2 equivalents of anhydrous zinc chloride in THF is added at -78 ° C. to 0 ° C., preferably at -20 ° C. to 0 ° C. If the ZnCl 2 was added at - 78 ° C, the mixture was then stirred at this temperature for 1 hour. If the addition was carried out at -20 ° C to 0 ° C, the subsequent stirring time is only 30 to 10 minutes.
  • Phase 4 [Mannich addition of the amide enolate to the imine (DT)]:
  • the enolate of the pseudoephedrinamide (XI) produced in phase 2 or phase 3 is added to the imine (DI) to form the 2,3-anti-3- arylamino-carboxamides (XD) with high anti syn and ⁇ -side diastereoselectivity.
  • the ratio of the desired diastereomer (XD) to the sum of all other diastereomers was> 85% de in the examples examined, in some cases up to 97% de.
  • the addition is carried out in the presence of 3 to 8 equivalents of lithium salt, preferably lithium chloride, particularly preferably in the presence of 4 to 6.5 equivalents of lithium chloride.
  • 1.1 to 5.0 equivalents of imine (DI) based on the amide enolate are used, preferably 1.3 to 4.0 equiv., Particularly preferably 1.5 to 2.0 equiv.
  • the Mannich addition is used in 20 ° C to + 30 ° C, preferably at -10 ° C to + 20 ° C, particularly preferably at 0 ° C to + 10 ° C.
  • 1.5 to 2.0 equiv. a 1 molar solution of imine (DI) in THF at 0 to + 10 ° C within 10 minutes to 1 equiv. a 0.2 to 0.5 molar solution of lithium enolate in THF, the 6 to 6.5 equiv. Lithium chloride contains and then stirred for 1 to 3 hours at this temperature.
  • the reaction mixture is worked up and the Mannich product (XD) is isolated by the customary methods which are well known to those skilled in the art.
  • Pseudoephedrine can be split off by acid hydrolysis with protonic acids or with Lewis acid. But pseudoephedrinamides can also be split by basic hydrolysis or in boiling water. Examples of this can be found in the publications by AG Myers mentioned above, and in D. Badia et al, J. Org. Chem. 2001, 66, 9030-9032 and Org. Lett. 2001, 3 (5), 773-776.
  • amide cleavage of the ⁇ -alkyl-substituted ß-aryl-ß-arylammo-propionic acid pseudoephedrinamides (XD) of the present invention basic hydrolysis is preferred because under acidic conditions, impurities due to elimination reactions can arise and because the amide splitting in boiling water is very slow.
  • Basic amide cleavage in boiling aqueous-ethanolic, sodium hydroxide solution can lead to a more or less large extent to the epimerization of the ⁇ -position, which must be suppressed as much as possible.
  • the amide hydrolysis is slow and the degree of ⁇ -epimerization is high, the more nonpolar the inert protective group R 10 is.
  • the pseudoephedrine can also be cleaved using an amide-cleaving enzyme.
  • Another alternative is amide cleavage with palladium (D) perchlorate tetrahydrate in 0.1 M phosphate buffer solution at pH 7.0 and 25 ° C., according to NM Kostic et al, J.Am.Chem.Soc. 2004, 126, 696-697.
  • the protective groups can optionally be reintroduced into the product of the amide cleavage reaction (formula XID) using methods known to the person skilled in the art [see “Protective Groups in Organic Synthesis” (TW Green, PGM Wuts (editor), John Wiley & Sons, Inc. , 1999)].
  • R 9 then (C 1 -C 4 ) alkyl, CO (C 1 -C 4 ) alkyl, COO (CC) alkyl, SO 2 -Aryl - be converted into the ß-lactam (XIV). This can also be done directly from (XD).
  • An overview of the possible reaction conditions can be found in "Methods of Organic Chemistry (Houben-Weyl)" (Volume 16b, pages 60 to 114, Georg Thieme Verlag Stuttgart, New York, 1991).
  • This cyclization with 1 to 2 equivalents of the base LitWum-bis (trimethylsilyl) amide ( LHMDS) in the solvent THF
  • LHMDS base LitWum-bis (trimethylsilyl) amide
  • the cyclization is carried out in the temperature range from -40 ° C. to + 50 ° C., preferably at -20 ° C. to + 25 ° C., particularly preferably at -10 ° C. to 0 ° C.
  • the protective groups can finally be split off by methods known to the person skilled in the art.
  • Alkyl (-CC 4 ) alkyl, preferably (-C- 8 ) alkyl, unbranched or branched;
  • Aryl (C 6 -C 10 ) aryl; p in front of a substituent like "pOCH 3 " means position 4 am
  • the process according to the invention ensures that the diphenyl azetidinone derivatives known per se can be prepared in good yield and without the disadvantages of the prior art, such as the use of auxiliary reagents which lead to undesired by-products.
  • Examples 1 to 14 and 18 to 35 show the preparation of preliminary or intermediate products, Examples 15 to 17 the production of diphenyl azetidinones or their deprotection. A reference example VI is also given for comparison purposes.
  • TLC control (ethyl acetate / n-heptane 1: 1) only shows a trace of starting material.
  • the suspension is filtered through 200 g of silica gel 60 (Merck, 0.035-0.07 mm), which have been filled in a column in a 500 ml mixture of dichloromethane. It is washed with 2 times 250 ml of ethyl acetate (eluted). The combined organic phases are concentrated in vacuo and the residue is dried under HV. 136.5 g (400 mmol by weight) of light yellow oil are obtained.
  • the total yield (pale yellow resin) is thus 23.4 g (49.4 mmol, 92% HPLC [column: 250 x 4.6 mm (R, R) -Whelk 01; eluent: n-hexane / iPrOH 90:10; flow: 1 ml / min; temp .: 25 ° C ; Det .: 210 n, t ret 5 (S) -silanyloxy diastereomer 8.4 min .; peak of the same UV spectrum (probably 5 (R) -D iastereomer): t re t 7.4 min.] gives a diastereomeric purity of 96% de (de is the abbreviation for the diastereomeric excess "diastereomeric excess").
  • Lithium chloride (99%) is dried for 3 hours at 150-200 ° C / 4 x 10 "3 mbar.
  • Diisopropylamine (99.5%) is freshly distilled off from CaH 2 and then contains 0.02% by weight of water According to Karl Fischer titration, tetrahydrofuran (THF) is degassed using bubbling, dried argon and contains ⁇ 0.005% by weight of water according to Karl Fischer titration.
  • the mixture is allowed to warm to 0 ° C., the reaction mixture becoming very cloudy at -30 ° C., and stirring is continued for a further 5 minutes at 0 ° C. It is cooled again to -78 ° C, forming a thick, difficult to stir porridge.
  • a solution of 18.9 g (40.0 mmol) of the pseudoephedrinamide (from Example 3) in 80 ml of THF is added dropwise in a dropping funnel within 30 minutes.
  • the cold bath is initially removed briefly, the Indoor temperature rises to a maximum of -50 ° C.
  • the mixture quickly becomes thinner so that the reaction flask can be immersed in the cooling bath again.
  • the mixture is stirred at -78 ° C for 1 hour.
  • the reaction mixture becomes one in a 4L flask under nitrogen poured to 0 ° C and mechanically vigorously stirred mixture of 1.6 L 10% aqueous acetic acid and 1.6 L dichloromethane, the color brightens to yellow.
  • the mixture is allowed to warm to room temperature, the organic phase is separated off and the aqueous phase (pH 3-4) is extracted with 2 ⁇ 600 ml of dichloromethane.
  • the combined organic phases are washed with a total of 1.4 L of saturated aqueous NaHCO 3 solution, washing solution being added until the pH of the aqueous phase remains at pH 7-8 after shaking.
  • the organic phase is dried over potassium carbonate, filtered, concentrated in vacuo and the residue is dried under HV.
  • the contents can be determined from the HPLC peak areas of the imine-protected Mannich product or imine-deprotected Mannich product generated by these samples be read.
  • the crude product accordingly contains 57% by weight of imine-protected Mannich product and 8% by weight of nin-deprotected Mannich product. This corresponds to a yield of 23.8 g (28.6 mmol, 71.4% of theory) of protected Mannich product and 3.3 g (4.6 mmol, 11.6% of theory) imine deprotected Mannich product.
  • the overall yield of Mannich product is 33.2 mmol (83% of theory).
  • 0.84 (*, s, 9H, tBu), 1.4-2.05 (m, 5H, CH and 2 x CH 2 ), 2.30 (*, s, 3H, NCH 3 ), 2.5 (s, very broad, 3H, NH 2 and NH), 2.84 (#, s, 3H, NCH 3 ), 3, 07 (*, -qui, IH, NHCH), 3.20 (#. -Qui, IH, NHCH), 3.55 (#, AB system, 2H, CHaNH ⁇ , 3.66 (*, s, 2H , CH9NH9).
  • the anisaldehyde is completely removed by extraction with 4 x 30 ml of n-heptane.
  • 30 ml of dichloromethane are added to the acidic water phase and adjusted to pH 11 with vigorous stirring with 19.5 ml of 1N aqueous sodium hydroxide solution.
  • the organic phase is separated off and the aqueous phase is extracted with 2 ⁇ 30 ml of dichloromethane.
  • the combined dichloromethane extracts are dried over sodium sulfate, filtered, concentrated in vacuo and the residue is dried under high pressure. 1.09 g (1.53 mmol, 87% of theory) of pure product are obtained as a beige, amorphous solid.
  • Complete removal of the anisaldehyde before basing the aqueous phase is essential. If anisaldehyde residues remain, the corresponding amount of the starting material is formed again.
  • the reaction mixture is cooled, 20 ml of water are added and the mixture is then concentrated in vacuo to a total volume of about 20 ml in order to remove the ethanol.
  • Another 20 ml of water are added to the aqueous residue and the mixture is concentrated again.
  • the cloudy aqueous residue is washed with 2 x 20 ml of diethyl ether and then contains the products in a purity of 96 area% and in a ratio of 5: 1 according to HPLC analysis.
  • the aqueous phase is in an ice bath with 14 ml of 2N Hydrochloric acid adjusted to pH 7, whereby a fluffy, yellow precipitate precipitates soon after the addition has started.
  • the product is also chromatographed with an authentic sample from reference example 1. At -15 ° C., a further 135 ⁇ l (0.143 mmol) of 1.06 M solution of lithium bis (trimemylsilyl) amide in THF are added. HPLC control now shows complete conversion of the starting material into the product.
  • the reaction mixture is mixed with 3 ml of saturated aqueous sodium hydrogen carbonate solution and extracted with 3 x 3 ml of dichloromethane. The organic phase is filtered, concentrated in vacuo and the residue is dried under HV. Yield: 90 mg (0.135 mmol, 94% of theory) of a yellow solid.
  • the imino protective group is split off in analogy to example 6 by dissolving
  • Analytical HPLC (system as in Example 5): The starting material (t ret 19.9 min.) Completely passes into the product (t ret 17.1 min.).
  • HPLC analysis shows, in addition to pyridine (t ret 4.8 min.) And 1.5 area% starting material (t r et 9.8 min.), The product in the form of two diastereomers (ratio approx. 1: 1, t r et 14.1 and 14.4 min.).
  • the reaction solution is concentrated in vacuo to 70 ml, diluted with 100 ml of diethyl ether and washed with 1 x 100 ml and 2 x 50 ml of water.
  • the organic phase was concentrated in vacuo and the residue dried in the HV. 9.70 g of a slightly yellowish oil are obtained which, according to HPLC, has a purity of 76 area%.
  • HPLC analysis shows collidine (step 8.1 min.) And trityl chloride (t ret 14.3 min.), Product (t ⁇ 17.8 min.) And traces of starting material (t « * 9.8 min.).
  • the mixture is cooled, diluted with 300 ml of dichloromethane, washed with 1 x 200 and 2 x 100 ml of 10% aqueous acetic acid, then with 2 x 100 ml saturated aqueous NaHCO 3 solution followed by 2 x 100 ml water.
  • 100 ml of n-heptane are added to the organic phase (turbidity) and then concentrated in vacuo. An oil precipitates, which crystallizes after a short time.
  • HPLC (system as in Example 5) shows in addition to pseudoephedrine (t ret 4.2 min.) Only traces of the two diastereomeric starting materials (t ret 14.1 and 14.4 min.), And formation of the product as a pair of diastereomers (t ret 13.3 and 13.5 min.) And a by-product (t ret 9.0 min.).
  • the mixture is cooled with ice, and 45 ml of water are first added very slowly, then more rapidly. Two phases are formed. The bulk of THF is in vacuum distilled off.
  • the oil is extracted from the water phase with 3 x 25 ml of ethyl acetate, the pH being adjusted to 6-7 with 6 ml of 10% acetic acid in order to achieve an acceptable phase separation rate.
  • the combined extracts are washed with 20 ml saturated NaHCO 3 solution and with 20 ml water, then the solvent is distilled off in vacuo.
  • the residue is dried in an HV. 13.0 g of crude product are obtained as a pale yellow, voluminous solid foam which, according to HPLC, has a purity of 76 area%.
  • the mixture is cooled with ice and 30 ml of water are first added very slowly, then more rapidly. Two phases are formed. The majority of THF is distilled off in vacuo. The oil is extracted from the water phase with 3 x 15 ml of ethyl acetate, the pH being adjusted to 6 with 4 ml of 10% aqueous acetic acid in order to achieve a sufficient phase separation rate. The combined extracts are washed with 15 ml of saturated aqueous NaHCO 3 solution and with 15 ml of water, then the solvent is distilled off in vacuo. The residue is dried in an HV. 13.2 g of crude product are obtained as a yellow, voluminous solid foam which, according to HPLC, has a purity of 72 area%.
  • a 3-necked flask with magnetic stirrer, septum and thermometer are used under argon to dissolve 1.91 g (44.7 mmol) of anhydrous lithium chloride and 3.74 g (22.2 mmol) of 98% (+) - pseudoephedrine in 30 ml of absolute THF at 0-2 ° C. in the course of 10 minutes using a syringe pump 3.56 ml (8.91 mmol) of a 2.5 molar solution of n-butyllithium in hexane were added dropwise.
  • the mixture is cooled with ice and 30 ml of water are first added very slowly, then more rapidly. Two phases are formed.
  • the majority of THF is distilled off in vacuo and the oil which separates is extracted with 1 x 30 ml and 2 x 15 ml of ethyl acetate, the pH being set to 6 with 4 ml of 10% aqueous acetic acid in order to achieve a sufficiently rapid phase separation.
  • the combined organic extracts are washed with 15 ml of saturated aqueous NaHCO 3 solution and with 15 ml of water, concentrated in vacuo and the residue is dried under HV. 8.40 g of a yellowish oil is obtained, which slowly crystallizes.
  • Lithium chloride (99%) is dried for 3 hours at 150-200 ° C / 4 x 10 "3 mbar.
  • Diisopropylamine (99.5%) is freshly distilled off from CaH 2 and then contains 0.02% by weight of water According to Karl Fischer titration, THF is degassed using bubbling, dried argon and contains ⁇ 0.005% by weight of water according to Karl Fischer titration.
  • the ice-cold reaction mixture is poured into 112 ml of ice / water with nitrogen and stirring, whereupon it turns yellow and two phases form. It is extracted with 1 x 80 ml and 2 x 35 ml dichloromethane. The combined extracts are concentrated in vacuo and the residue is dried under HV. 12.0 g of yellow, amorphous, sticky foam are obtained which, according to HPLC, consists of 45 area% I in-protected Mannich product, 6 area% pseudoephedrinamide (starting material) and diimine. This crude product is subjected to chromatographic purification with simultaneous removal of the imine protective group.
  • a glass column (diameter 7.0 cm, length 46 cm) is filled with 1770 ml (approx. 900 g) silica gel 60 (Merck, 0.04 - 0.063 mm) in a book medium pressure system.
  • the column is conditioned at a flow of 130 ml / min with 1.5 L CH 2 C1 2 / MeOH / NfttOH (25%) 9: 1.5: 0.3, then with 2 L CH 2 C1 2 .
  • the crude product, dissolved in 15 ml of CH 2 C1 2 is then applied to the column.
  • Non-polar impurities are treated with 1 L CH 2 C1 2 followed by 0.5 L CH 2 C1 2 / MeOH 99: 1 followed by 0.5 L CH 2 C1 2 / MeOH 98: 2 followed by 0.5 L CH 2 C1 2 / MeOH 95: 5.
  • the product, which is deprotected on the column, is then treated with 1 L CH 2 C1 2 / MeOH / NH 4 OH (25%) 9: 0.5: 0.1, followed by 3 L CH 2 C1 2 / MeOH / NH4OH (25%) 9: 1: 0.2, followed by 2 L CH 2 C1 2 / MeOH / NH 4 OH (25%) eluted 9: 1.5: 0.3. Approx.
  • Lithium chloride (99%) is 3 hours at 150-200 ° C / 4 x 10 ° ⁇ 3. mbar dried.
  • Diisopropylarnine (99.5%) is freshly distilled off from CaH 2 and then contains 0.02% by weight of water according to the Karl Fischer titration.
  • THF is degassed using bubbling, dried argon and contains ⁇ 0.005% by weight of water according to the Karl Fischer titration.
  • the column is conditioned at a flow of 130 ml / min with 1.5 L CH 2 C1 2 / MeOH / NE OH (25%) 9: 1.5: 0.3, then with 2 L CH 2 C1 2 ,
  • the crude product, dissolved in 15 ml of CH 2 C1 2 is then applied to the column.
  • Non-polar impurities are treated with 1 L CH 2 C1 2 followed by 0.5 L CH 2 C1 2 / MeOH 99: 1 followed by 0.5 L CH 2 C1 2 / MeOH 98: 2 followed by 0.5 L CH 2 C1 2 / MeOH 95: 5 eluted.
  • the toluene prevents the product from being left behind from the ammonia when it is concentrated in water residues, in which it would suffer a retro Mannich reaction.
  • the solvents are removed in vacuo and the residue is dried in an HV. 5.30 g of brown, amorphous, solid foam are obtained, which according to HPLC is 97% by area. Yield: 6.11 mmol corresponding to 63% of theory.
  • Lithium chloride (99%) is dried for 3 hours at 150-200 ° C / 4 x 10 "3 mbar.
  • Diisopropylamine (99.5%) is freshly distilled off from CaH 2 and then contains 0.02% by weight of water According to Karl Fischer titration Tetrahydrofuran (THF, Fluka) is degassed using bubbling, dried argon and contains ⁇ 0.005% by weight of water according to Karl Fischer titration.
  • the column is conditioned at a flow of 130 ml / min with 3 L CH 2 C1 2 / MeOH / NH 4 OH (25%) 9: 1.5: 0.3, followed by 2 L CH 2 C1 2 . Then the crude product, dissolved in 30 ml CH 2 C1 2 , is applied to the column. Nonpolar associations are made with 1 L CH 2 C1 2 followed by .0.5 L CH 2 C1 2 / MeOH 99: 1 followed by 0.5 L CH 2 C1 2 / MeOH 98: 2 followed by 0.5 L. CH 2 C1 2 / MeOH 95: 5 eluted.
  • Fractions 13-24 containing the pure Mannich main product, are combined with the introduction of toluene.
  • the toluene prevents the product from being left behind from the ammonia when it is concentrated in water residues, in which it would suffer a retro Mannich reaction.
  • the solvents were removed in vacuo and the residue was dried in an HV. 5.56 g of light brown, amorphous, solid foam are obtained, which according to HPLC is 99% by area. Yield: 8.37 mmol corresponding to 65% of theory.
  • the aqueous solution is washed with 2 x 20 ml of diethyl ether.
  • the aqueous solution is cooled in an ice bath and, by slowly adding dropwise 14.4 ml of 2N aqueous hydrochloric acid under control with a pH electrode starting from pH 13.2 to pH 7.5, an increasingly thick slurry of solid precipitates. It is suctioned off, washed with water and dried in an HV over phosphorus pentoxide.
  • This crude product (2.57 g, 160% of theory) contains silicates which result from the action of the hot sodium hydroxide solution on the flask wall.
  • the crude product is mixed with 125 ml of ethanol and the suspension is stirred for 2 hours at room temperature.
  • the aqueous phase is cooled in an ice bath and slow 12.5 ml of 2N aqueous hydrochloric acid are added dropwise under control with a pH electrode starting from pH 13.2 to pH 7.5, an increasingly thick slurry of solid precipitating. It is suctioned off, washed with water and 1 dried in an HV over phosphorus pentoxide.
  • This crude product (2.38 g, 136% of theory) contains silicates which result from the action of the hot sodium hydroxide solution on the flask wall.
  • the crude product is mixed with 125 ml of ethanol and the suspension is stirred for 2 hours at room temperature. The undissolved residue is filtered off with a glass frit and washed several times with ethanol.
  • the filtrate is cooled in an ice bath and, by slowly adding dropwise 13.4 ml of 2N aqueous hydrochloric acid under control with a pH electrode starting from pH 13.3 to pH 7.5, an increasingly thick yellow solid slurry precipitates. It is suctioned off, washed with water and dried in an HV over phosphorus pentoxide.
  • This crude product (2.25 g, 146% of theory) contains silicates which were formed by the action of the hot sodium hydroxide solution on the flask wall.
  • the crude product is mixed with 125 ml of ethanol and the suspension is stirred for 2 hours at room temperature.
  • the undissolved colorless residue is filtered off with a glass frit and washed several times with ethanol.
  • HPLC of the ether phases shows pseudoephedrine and possibly only slight traces of the product.
  • HPLC of the aqueous phase shows the desired carboxylic acid and its epimer in a ratio of 87:13 in 99.5 area% purity.
  • the aqueous phase is adjusted from pH 14.1 to pH 7 to 8 with ice cooling with about 8 ml of 2 N hydrochloric acid (control with glass electrode), an oil precipitating from about pH 11, which crystallizes with the addition of a seed crystal.
  • the commercial sodium tert-butoxide is sublimed in a high vacuum and stored under argon until it is used shortly afterwards in a desiccator.
  • the toluene used is degassed over a predried molecular sieve (0.4 nm) for 5 minutes in an ultrasonic bath. Glass flasks are heated with hot air under a stream of argon. The solids are weighed in under a slight argon countercurrent. Solvents are added and samples are taken via a septum in the flask by means of syringes, which are kept in phosphorus pentoxide until they are used in the desiccator.
  • reaction mixture is poured onto 200 ml of ice-cooled 1% acetic acid (beaker) and stirred vigorously for 30 minutes. 50 ml of toluene are added, the ice bath is removed and the mixture is stirred vigorously at about 20 ° C. for a further hour.
  • the clear, colorless, aqueous phase (bottom) is separated off and the light yellow, cloudy organic phase (top) is stirred vigorously for a further 1 hour with 50 ml of 1% aqueous acetic acid.
  • the aqueous phase is separated off and the organic phase is dried over sodium sulfate.
  • the commercial sodium tert-butoxide is sublimed in a high vacuum and stored under argon until it is used shortly afterwards in a desiccator.
  • the toluene used is degassed over a predried molecular sieve (0.4 nm) for 5 minutes in an ultrasonic bath. Glass flasks are heated with hot air under a stream of argon. The solids are weighed in under a slight argon countercurrent. Solvent addition and sampling are carried out via a septum in the flask by means of syringes / cannulas, which are kept over phosphorus pentoxide until use in the desiccator.

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Abstract

L'invention concerne un procédé de production de dérivés de diphénylazétidinone de formule générale (I) ou des formes, dans lesquelles les substituants X, R<1> et/ou R<2> sont protégés, formule dans laquelle les symboles, les substituants et les indices ont la signification suivante : X = H, OH ; R<1> = OH, OCH3 ; R<2> = F, CH2CH3, CH2NHR<4> ; R<3> = H, F ; R<4> = H, CO-(CH2-)nCO-R<5>, CO-(CH2-)nNHR<6> ; n = un nombre entier de 4 à 16 ; R<5> = OH, NH-CH2-[CH(OH)-]mCH2OH ; R<6> = H, CO-[CH(OH)-]mCH2OH et m = un nombre entier de 1 à 5. Ledit procédé consiste à faire réagir de nouveaux composés de formule générale (II), dans laquelle Y = H, H ; H, OH ; H, OAc ; H, OSi(alkyle)o(aryle)p ; o, p = 0, 1, 2 ou 3 et o + p = 3 ; H, OTHP ; H, OC(aryle)3 ; H, OCH2Oalkyle ; H, OCH(Oalkyle)CH3 ; H, Oalkyle ; H, OCH2aryle ; OAlkyle, OAlkyle ; un cétal cyclique tel que O-(CH2-)q-O et q = 2 ou 3, avec des imines de formule générale (III), dans laquelle R<7> = R<1> et un groupe protecteur O et R<8> = p. ex. R<2>.
EP05743217A 2004-05-21 2005-05-20 Prodede de production de derives de diphenylazetidinone Withdrawn EP1753717A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102004025072A DE102004025072A1 (de) 2004-05-21 2004-05-21 Verfahren zur Herstellung von Diphenyl-azetidinon-Derivaten
PCT/EP2005/005497 WO2005113495A1 (fr) 2004-05-21 2005-05-20 Prodede de production de derives de diphenylazetidinone

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JP (1) JP2007538041A (fr)
CN (1) CN100582092C (fr)
AR (1) AR049283A1 (fr)
AU (1) AU2005245123A1 (fr)
CA (1) CA2567481A1 (fr)
DE (1) DE102004025072A1 (fr)
IL (1) IL178993A0 (fr)
MX (1) MXPA06013258A (fr)
TW (1) TW200611895A (fr)
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WO (1) WO2005113495A1 (fr)

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DE50111751D1 (de) * 2000-12-21 2007-02-08 Sanofi Aventis Deutschland Neue diphenzylazetidinone, verfahren zu deren herstellung, diese verbindungen enthaltende arzneimittel und deren verwendung zur behandlung von lipidstoffwechselstörungen
GB0215579D0 (en) 2002-07-05 2002-08-14 Astrazeneca Ab Chemical compounds
EP1699759B1 (fr) 2003-12-23 2010-10-20 AstraZeneca AB Derives diphenylazetidinone a activite inhibitrice de l'absorption du cholesterol
UY29607A1 (es) 2005-06-20 2007-01-31 Astrazeneca Ab Compuestos quimicos
AR057072A1 (es) 2005-06-22 2007-11-14 Astrazeneca Ab Compuestos quimicos derivados de 2-azetidinona, formulacion farmaceutica y un proceso de preparacion del compuesto
SA06270191B1 (ar) 2005-06-22 2010-03-29 استرازينيكا ايه بي مشتقات من 2- أزيتيدينون جديدة باعتبارها مثبطات لامتصاص الكوليسترول لعلاج حالات فرط نسبة الدهون في الدم
AR060623A1 (es) 2006-04-27 2008-07-02 Astrazeneca Ab Compuestos derivados de 2-azetidinona y un metodo de preparacion
JP5059355B2 (ja) * 2006-08-01 2012-10-24 壽製薬株式会社 オキサゾリジン誘導体の製造方法
CZ302395B6 (cs) * 2007-03-02 2011-04-27 Zentiva, A. S. Zpusob výroby (3R,4S)-1-(4-fluorfenyl)-3-[(3S)-3-(4-fluorfenyl)-3-hydroxypropyl)]-4-(4-hydroxyfenyl)-2-azetidinonu
CA2675312A1 (fr) 2007-03-06 2008-09-12 Teijin Pharma Limited Derives de 1-biarylazetidinone
US20090047716A1 (en) * 2007-06-07 2009-02-19 Nurit Perlman Reduction processes for the preparation of ezetimibe
DE102007054497B3 (de) * 2007-11-13 2009-07-23 Sanofi-Aventis Deutschland Gmbh Neue kristalline Diphenylazetidinonhydrate und Verfahren zu deren Herstellung
US9388440B2 (en) 2009-04-01 2016-07-12 Mylan Laboratories Limited Enzymatic process for the preparation of (S)-5-(4-fluoro-phenyl)-5-hydroxy-1morpholin-4-yl-pentan-1-one, an intermediate of Ezetimibe and further conversion to Ezetimibe
WO2015039675A1 (fr) 2013-09-23 2015-03-26 Pharmathen S.A. Nouveau procédé de préparation d'intermédiaires d'ézétimibe

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HUT67341A (en) * 1991-07-23 1995-03-28 Schering Corp Substituted beta-lactam compounds useful as hypocholesterolemic agents, pharmaceutical compositions containing the same and process for the production thereof

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Title
See references of WO2005113495A1 *

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US7563888B2 (en) 2009-07-21
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CA2567481A1 (fr) 2005-12-01
UY28913A1 (es) 2005-12-30
TW200611895A (en) 2006-04-16
AU2005245123A1 (en) 2005-12-01
CN100582092C (zh) 2010-01-20
DE102004025072A1 (de) 2005-12-15
MXPA06013258A (es) 2007-02-28
CN1956951A (zh) 2007-05-02
US20070149501A1 (en) 2007-06-28
WO2005113495A1 (fr) 2005-12-01
JP2007538041A (ja) 2007-12-27

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