Nothing Special   »   [go: up one dir, main page]

WO2002079174A2 - Enantioselective synthesis of azetidinone intermediate compounds - Google Patents

Enantioselective synthesis of azetidinone intermediate compounds Download PDF

Info

Publication number
WO2002079174A2
WO2002079174A2 PCT/US2002/009123 US0209123W WO02079174A2 WO 2002079174 A2 WO2002079174 A2 WO 2002079174A2 US 0209123 W US0209123 W US 0209123W WO 02079174 A2 WO02079174 A2 WO 02079174A2
Authority
WO
WIPO (PCT)
Prior art keywords
formula
compound
acid
catalyst
present
Prior art date
Application number
PCT/US2002/009123
Other languages
French (fr)
Other versions
WO2002079174A3 (en
Inventor
Xiaoyong Fu
Timothy L. Mcallister
T. K. Thiruvengadam
Chou-Hong Tann
Original Assignee
Schering Corporation
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Priority to KR1020037012486A priority Critical patent/KR100590342B1/en
Priority to DE60206365T priority patent/DE60206365T2/en
Priority to PL363864A priority patent/PL205952B1/en
Priority to IL15755202A priority patent/IL157552A0/en
Priority to EA200300970A priority patent/EA006898B1/en
Priority to JP2002577801A priority patent/JP4145663B2/en
Priority to MXPA03008803A priority patent/MXPA03008803A/en
Priority to EEP200300464A priority patent/EE05453B1/en
Priority to AT02728561T priority patent/ATE305459T1/en
Priority to AU2002258605A priority patent/AU2002258605B2/en
Priority to SK1186-2003A priority patent/SK287408B6/en
Priority to EP02728561A priority patent/EP1373230B1/en
Priority to BRPI0208384A priority patent/BRPI0208384B1/en
Priority to HU0303526A priority patent/HU230229B1/en
Application filed by Schering Corporation filed Critical Schering Corporation
Priority to UA2003109666A priority patent/UA75644C2/en
Priority to CA002442219A priority patent/CA2442219C/en
Priority to NZ527852A priority patent/NZ527852A/en
Priority to SI200230193T priority patent/SI1373230T1/en
Publication of WO2002079174A2 publication Critical patent/WO2002079174A2/en
Publication of WO2002079174A3 publication Critical patent/WO2002079174A3/en
Priority to IL157552A priority patent/IL157552A/en
Priority to BG108168A priority patent/BG66189B1/en
Priority to HR20030760A priority patent/HRP20030760B1/en
Priority to HK04100111A priority patent/HK1057546A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2
    • C07D263/22—Oxygen atoms attached in position 2 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to other ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2
    • C07D263/26—Oxygen atoms attached in position 2 with hetero atoms or acyl radicals directly attached to the ring nitrogen atom
    • 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

Definitions

  • This invention relates to a process for producing intermediates for hydroxy- alkyl substituted azetidinones.
  • Hydroxy-alkyl substituted azetidinones for example, 1- (4-fluorophenyl)-3(R)-[3(S)-hydroxy-3-(4-fluorophenyl)propyl)]-4(S)-(4-hydroxyphenyl)- 2-azetidinone, are described in US Patent No. 5,767, 115. These compounds are useful as hypocholesterolemic agents in the treatment and prevention of atheroschlerosis. Processes for preparing the corresponding azetidinone without the 3-hydroxy substituent are claimed in US Patent No. 5,728,827 and US Patent No.
  • the intermediate compound of Formula I is protected with a suitable hydroxy-protecting group, such as a silyl protecting group such as that derived from chlorotrimethylsilane (TMSCI) or t- butyldimethyl-silyl chloride (TBDMSCI).
  • a silyl protecting group such as that derived from chlorotrimethylsilane (TMSCI) or t- butyldimethyl-silyl chloride (TBDMSCI).
  • TMSCI chlorotrimethylsilane
  • TDMSCI t- butyldimethyl-silyl chloride
  • BSA bistrimethylsilyl acetamide
  • a cyclizing agent such as a quaternary alkyl-, aryl-alkyl or arylalkyl-alkylammonium fluoride salt is then added to cause an intra-molecular cyclization of the previously silylated compound of Formula I.
  • the protecting groups are removed from the cyclizied compound using conventional methods, such as treatment with a dilute acid, in order to form the hypocholesterolemic azetidinone having the Formula
  • This invention provides an improved, simple, high yielding process for preparing an intermediate compound useful in the production of azetidinones.
  • the intermediate a compound of Formula I:
  • step b) combining the mixture of step a) with a catalyst selected from either (A) a compound selected from the group of compounds represented by Formula III, or (B) a compound of Formula IV,
  • R 1 of Formula III is a (C ⁇ -C 6 )alkyl and wherein R and S indicate stereochemistry at the chiral carbons; c) reducing the ketone adjacent to the p-fluorophenyl with a borane- tetrahydrofuran complex; and d) quenching the reaction with MeOH.
  • the process comprises: a) mixing a compound of Formula II in tetrahydrofuran in the presence of an acid to form a mixture; b) combining the mixture of step a) with a catalyst selected from either (A) a compound selected from the group of compounds represented by Formula III, or (B) a compound of Formula IV
  • R 1 of Formula III is a (C ⁇ -C- 6 )alkyl and wherein R and S indicate stereochemistry at the chiral carbons; c) reducing the ketone adjacent to the p-fluorophenyl with a borane- tetrahydrofuran complex; and d) quenching the reaction with MeOH.
  • alkyl represents a straight or branched saturated hydrocarbon chain having the designated number of carbon atoms. Where the number of carbon atoms is not specified, 1 to 6 carbons are intended.
  • the acid in step a) is selected from the group consisting of BF 3 *OEt 2 , BCI 3 , p- toluene sulfonic acid, trifluoroacetic acid, methanesulfonic acid and camphorsulfonic acid.
  • the catalyst of Formula IV If the catalyst of Formula IV is employed, it must be used in the presence of a trialkyl borate, preferably a trimethyl borate.
  • the ratio of the acid to the compound of Formula II is in a mole % of 1-10%, preferably 1-5%, more preferably in a mole % of 2-3%.
  • the ratio of the catalyst to the compound of Formula II of step b) is in a mole percent of 0.1-10%, preferably 1-5%, more preferably in a mole % of 2-3%.
  • the temperature of the reduction step c) is generally between -15 and 65°C, preferably between -10 and 55°C, more preferably between 0° and 30°C and typically between 23° and 28°C.
  • step a) dissolving a compound of Formula II in tetrahydrofuran to form a mixture; b) combining the mixture of step a) with a catalyst selected from either (A) a compound selected from the group of compounds represented by Formula III, or (B) a compound of Formula IV
  • R 1 of Formula III is a (C ⁇ -C 6 )alkyl and wherein R and S indicate stereochemistry at the chiral carbons; c) reducing the ketone adjacent to the p-fluorophenyl with a borane- tetrahydrofuran complex; and d) quenching the reaction with MeOH.
  • the temperature of the reduction step c) is between 23 and 28°C.
  • the ratio of the catalyst to the compound of Formula II of step b) is in a mole % of 0.1-10%, preferably 1-5%, more preferably in a mole % of
  • the present invention discloses a novel chemo selective and stereo selective reduction of the ketone adjacent to the p-fluorophenyl using a BH 3 -THF complex.
  • U.S. Patent No. 6,207,822 B1 the disclosure of which is incorporated herein by reference thereto, there is disclosed a reduction of said ketone using BH 3 Me 2 S (BMS) complex as a reducing agent.
  • BMS BH 3 Me 2 S
  • use of said BMS complex may lead to environmental concerns.
  • the replacement of BMS with borane tetrahydrofuran complex eliminates the environmental issues raised by use of the BMS complex.
  • the new process calls for adding BH 3 -THF to the solution of Formula II and (R)-tetrahydro-1-methyl-3,3-diphenyl-1 H,3H-pyrrolo[1 ,2-c] [1 ,3,2] oxazaborolidine (abbreviated as (R)-MeCBS) catalyst in THF (from Sigma-Aldrich, St. Louis, Missouri).
  • (R)-MeCBS oxazaborolidine
  • the batch was sampled for HPLC to monitor the progress of the reaction. After the reaction was judged complete, 20 mL of MeOH was slowly charged to keep the temperature below 25°C in order to quench the reaction. The batch was concentrated under vacuum to afford a batch volume of about 100 mL at a temperature below 40°C. 250 mL of toluene and a solution of 5 mL sulfuric acid in 100 mL water was charged. The mixture was agitated for about 10 min. and the batch was allowed to settle. The bottom acid layer was split off. 100 mL of water was charged to wash the batch twice. The batch was concentrated under vacuum at below 50°C to afford a volume of about 100 mL. Results varied, but in general, yields of -99% and 95% de were obtained.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Health & Medical Sciences (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Urology & Nephrology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Vascular Medicine (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Steroid Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Catalysts (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

The application relates to a process for preparing a compound of Formula I (Chemical formula should be inserted here as it appears on abstract in paper form)This compound is an intermediate used to produce compounds that are useful as hypocholesterolemic agents in the treatment and prevention of atheroschlerosis.

Description

ENANTIOSELECTIVE SYNTHESIS OF AZETIDINONE INTERMEDIATE
COMPOUNDS
BACKGROUND OF THE INVENTION
This invention relates to a process for producing intermediates for hydroxy- alkyl substituted azetidinones. Hydroxy-alkyl substituted azetidinones, for example, 1- (4-fluorophenyl)-3(R)-[3(S)-hydroxy-3-(4-fluorophenyl)propyl)]-4(S)-(4-hydroxyphenyl)- 2-azetidinone, are described in US Patent No. 5,767, 115. These compounds are useful as hypocholesterolemic agents in the treatment and prevention of atheroschlerosis. Processes for preparing the corresponding azetidinone without the 3-hydroxy substituent are claimed in US Patent No. 5,728,827 and US Patent No. 5,561 ,227. Other processes for preparing 1-(4-fluorophenyl)-3(R)-[3(S)-hydroxy-3-(4- fluorophenyl)-propyl)]-4(S)-(4-hydroxyphenyl)-2-azetidinone are disclosed in US Patent No. 5,631 ,365, US Patent No. 5,739,321 and US Patent No. 6,207,822 B1 (the '822 patent).
As per the procedure described in the '822 patent, the intermediate compound of Formula I, is protected with a suitable hydroxy-protecting group, such as a silyl protecting group such as that derived from chlorotrimethylsilane (TMSCI) or t- butyldimethyl-silyl chloride (TBDMSCI). This silylated product is further reacted with a silyl-enol ether silylating agent such as bistrimethylsilyl acetamide (BSA). A cyclizing agent such as a quaternary alkyl-, aryl-alkyl or arylalkyl-alkylammonium fluoride salt is then added to cause an intra-molecular cyclization of the previously silylated compound of Formula I. Finally, the protecting groups are removed from the cyclizied compound using conventional methods, such as treatment with a dilute acid, in order to form the hypocholesterolemic azetidinone having the Formula
Figure imgf000002_0001
SUMMARY OF THE INVENTION This invention provides an improved, simple, high yielding process for preparing an intermediate compound useful in the production of azetidinones. The intermediate, a compound of Formula I:
Figure imgf000003_0001
Formula I
is prepared by a process which comprises:
a) mixing a compound of Formula I!
Figure imgf000003_0002
Formula II
in tetrahydrofuran in the presence of an acid, or alternatively in tetrahydrofuran in the absence of an acid, to form a mixture; b) combining the mixture of step a) with a catalyst selected from either (A) a compound selected from the group of compounds represented by Formula III, or (B) a compound of Formula IV,
Figure imgf000004_0001
Figure imgf000004_0002
Formula IV wherein R1 of Formula III is a (Cι-C6)alkyl and wherein R and S indicate stereochemistry at the chiral carbons; c) reducing the ketone adjacent to the p-fluorophenyl with a borane- tetrahydrofuran complex; and d) quenching the reaction with MeOH.
DETAILED DESCRIPTION
In one embodiment, there is described herein a process for preparing a compound of Formula I
Figure imgf000004_0003
Formula which comprises the steps (a)-(d) shown above.
In a preferred embodiment, the process comprises: a) mixing a compound of Formula II in tetrahydrofuran in the presence of an acid to form a mixture; b) combining the mixture of step a) with a catalyst selected from either (A) a compound selected from the group of compounds represented by Formula III, or (B) a compound of Formula IV
Figure imgf000005_0001
Formula
Figure imgf000005_0002
Formula IV wherein R1 of Formula III is a (Cι-C-6)alkyl and wherein R and S indicate stereochemistry at the chiral carbons; c) reducing the ketone adjacent to the p-fluorophenyl with a borane- tetrahydrofuran complex; and d) quenching the reaction with MeOH.
Except where stated otherwise, the following definitions apply throughout the present specification and claims. These definitions apply regardless of whether a term is used by itself or in combination with other terms. Hence the definition of "alkyl" applies to "alkyl" as well as to the "alkyl" portions of "alkoxy", "alkylamino" etc. "Alkyl" represents a straight or branched saturated hydrocarbon chain having the designated number of carbon atoms. Where the number of carbon atoms is not specified, 1 to 6 carbons are intended.
The acid in step a) is selected from the group consisting of BF3*OEt2, BCI3, p- toluene sulfonic acid, trifluoroacetic acid, methanesulfonic acid and camphorsulfonic acid.
If the catalyst of Formula IV is employed, it must be used in the presence of a trialkyl borate, preferably a trimethyl borate.
In another embodiment of the present invention, the ratio of the acid to the compound of Formula II is in a mole % of 1-10%, preferably 1-5%, more preferably in a mole % of 2-3%.
In another embodiment of the present invention, the ratio of the catalyst to the compound of Formula II of step b) is in a mole percent of 0.1-10%, preferably 1-5%, more preferably in a mole % of 2-3%.
In further embodiments of the present invention, the temperature of the reduction step c) is generally between -15 and 65°C, preferably between -10 and 55°C, more preferably between 0° and 30°C and typically between 23° and 28°C.
In another embodiment of the invention, there is described a process for preparing a compound of Formula I
Figure imgf000006_0001
Formula 1 which process has no acid in step (a). The process, thus, comprises:
a) dissolving a compound of Formula II in tetrahydrofuran to form a mixture; b) combining the mixture of step a) with a catalyst selected from either (A) a compound selected from the group of compounds represented by Formula III, or (B) a compound of Formula IV
Figure imgf000007_0001
Figure imgf000007_0002
Formula IV wherein R1 of Formula III is a (Cι-C6)alkyl and wherein R and S indicate stereochemistry at the chiral carbons; c) reducing the ketone adjacent to the p-fluorophenyl with a borane- tetrahydrofuran complex; and d) quenching the reaction with MeOH.
In a preferred embodiment of the alternate process (with no acid in step (a)) described immediately above, the temperature of the reduction step c) is between 23 and 28°C.
In another embodiment of the alternate process (with no acid in step (a)) described immediately above, the ratio of the catalyst to the compound of Formula II of step b) is in a mole % of 0.1-10%, preferably 1-5%, more preferably in a mole % of
2-3%.
Figure imgf000008_0001
Formula II Formula I
The present invention discloses a novel chemo selective and stereo selective reduction of the ketone adjacent to the p-fluorophenyl using a BH3-THF complex. In a previous process patent, U.S. Patent No. 6,207,822 B1 (the '822 patent), the disclosure of which is incorporated herein by reference thereto, there is disclosed a reduction of said ketone using BH3 Me2S (BMS) complex as a reducing agent. However, use of said BMS complex may lead to environmental concerns. The replacement of BMS with borane tetrahydrofuran complex eliminates the environmental issues raised by use of the BMS complex.
However, simple replacement of BH3 Me2S with BH3-THF in the reduction generated a substantial amount of over-reduction of the amide bond, compared to the reduction of the ketone adjacent to the p-fluororophenyl, thus resulting in poor selectivity. Thus, initial experiments with BH3-THF yielded a desirable % of desired enantiomer (SS) to the undesired enantiomer (SR), however, the solution yield was not optimized due to the production of the above-noted over-reduced by-product from the amide. Applicants found, in the present process, that reversing the addition sequence surprisingly overcame the poor chemoselectivity in the reduction. The production of the over-reduced by-product from the amide was significantly reduced while at the same time resulting in high diasteroselectivity in the product.
The new process calls for adding BH3-THF to the solution of Formula II and (R)-tetrahydro-1-methyl-3,3-diphenyl-1 H,3H-pyrrolo[1 ,2-c] [1 ,3,2] oxazaborolidine (abbreviated as (R)-MeCBS) catalyst in THF (from Sigma-Aldrich, St. Louis, Missouri). Several experiments yielded results where the over-reduced by-product was minimized to <1 % with diastereoselectivity of 97:3. In fact, the molar equivalent (eq) of BH3-THF was kept to -0.6 eq, while % molar yields were generally over 97%.
Similar results could be obtained with a "in-situ" prepared catalyst using the compound of Formula IV (R-diphenylprolinol) and trimethylborate. (See reference: M.
Masui, T. Shioiri, Synlett, 1997, 273).
The following examples used to prepare the compound of Formula I illustrate the present invention, although such examples should not be construed as limiting the scope of the invention. Alternative reagents and analogous processes within the scope of the invention will be apparent to those skilled in the art. The product solutions of the following examples (which contain the compound of Formula I) can be directly used as such in subsequent process steps to make hydroxy-alkyl substituted azetidinones, or in the alternative, the compounds of Formula I can be crystallized or isolated using methods known and recognized by one of ordinary skill in the art.
Examples
Abbreviations which are used in the description of the schemes, preparations and the examples are:
(R)-MeCBS = (R)-tetrahydro-1-methyl-3,3-diphenyl-1 H,3H-pyrrolo[1 ,2-c] [1 ,3,2] oxazaborolidine
THF = tetrahydrofuran HPLC = High Performance Liquid Chromatography
MeOH = methanol
Atm = atmospheres mL = milliϋters g = grams PTSA = p-toluene sulfonic acid
CSA = (1S)-(+)-10-camphorsulfonic acid
TFA = trifluoroacetic acid de = difference between SS% and SR% Example 1 (Acid absent in step(a))
Fifty (50) g of the compound of Formula II was charged into a 1000 mL three necked round bottom flask equipped with a thermometer, N2 inlet and addition funnel. 500 mL THF was charged to dissolve the 50 g of the compound Formula II at about 20° to 25°C. The batch was concentrated at 1 atm to a batch volume of about 150 mL. The temperature was adjusted to about 20° to 25°C. 4.2 mL of lab pre-formed (R)-MeCBS catalyst in toluene (3 mole%) was charged. 70.4 mL of 1M borane THF complex in THF solution (from Aldrich Chemical Company, Milwaukee, Wisconsin) was slowly charged over 1.5 hrs at temperature between about 23° and 28°C. The batch was sampled for HPLC to monitor the progress of the reaction. After the reaction was judged complete, 20 mL of MeOH was slowly charged to keep the temperature below 25°C in order to quench the reaction. The batch was concentrated under vacuum to afford a batch volume of about 100 mL at a temperature below 40°C. 250 mL of toluene and a solution of 5 mL sulfuric acid in 100 mL water was charged. The mixture was agitated for about 10 min. and the batch was allowed to settle. The bottom acid layer was split off. 100 mL of water was charged to wash the batch twice. The batch was concentrated under vacuum at below 50°C to afford a volume of about 100 mL. Results varied, but in general, yields of -99% and 95% de were obtained.
Example 2 (Acid (pTSA) present in step (a))
Fifty (50) kg of the compound of Formula II and 0.8 kg of p-toluene sulfonic acid (PTSA) was charged into a 300 gallon glass lined reactor equipped with a thermocouple, N2 inlet and feed tank. 267 kg of dry THF was charged to dissolve the 50 kg of the compound Formula II and the p-toluene sulfonic acid at about 20 to 25°C. The batch was concentrated at 1 atm to a batch volume of about 185 liters. The temperature was adjusted to about 20 to 25°C. 200 liters of THF was charged to the batch. The batch was concentrated at 1 atm to a batch volume of about 185 liters. The temperature was adjusted to about 20 to 25°C. 3.4 kg of pre-formed (R )-MeCBS catalyst in toluene (3 mole %) was charged. 70.3 kg 1 M of borane THF complex in THF solution was slowly charged over 1.5 hours at a temperature range between about 23 and 28°C. The batch was sampled for HPLC to monitor the progress of the reaction. After the reaction was judged complete, using the same subsequent procedure as described in Example 1 (i.e. quenching with MeOH, vacuum concentration of the batch, etc., but in appropriate ratios of reagents for this example), the compound of Formula I was obtained in an average yield of 98.4%. A percentage yield of -97 %, a solution yield of 100% and de of 93.6% was obtained.
Example 3 (Acid present in step (a))
Fifteen (15) kg of the compound of Formula II was charged into a 50 gallon glass lined reactor equipped with a thermocouple, N2 inlet and feed tank. 150 liters of dry THF was charged to dissolve the 15 kg of the compound Formula II at about 20 to 25°C. The batch was concentrated at 1 atm to a batch volume of about 55 liters. The temperature was adjusted to about 20 to 25°C. 1.5 kg of preformed (R)-MeCBS catalyst in toluene (3 mole %) was charged. 18.55 kg of 1M borane THF complex in THF solution was charged over 1.5 hours at a temperature range between about 23 and 28 °C. The batch was sampled for HPLC to monitor the progress of the reaction. After the reaction was judged complete, using the same subsequent procedure as described in Example 1 (i.e. quenching with MeOH, vacuum concentration of the batch, etc., but in appropriate ratios of reagents for this example), the compound of Formula I was obtained in a yield of 100% with- a de of 95.4%.
Example 4 Acid (CSA) present in step (a))
Thirty (30) g of the compound of Formula II and 0.386 g (2 mole %) of (1S)-(+)-10- camphorsulfonic acid (CSA) was charged in a 500 mL 3 necked round bottom flask equipped with a thermometer, N2 inlet and addition funnel. 111 mL of dry THF was charged to dissolve the 30 g of the compound Formula II, and the (1 S)-(+)-10- camphorsulfonic acid at about 20 to 25°C. 2.2 mL of pre formed (R )-MCBS catalyst in toluene (3 mole %) was charged. 39.9 mL of 1 M borane THF complex in THF solution was slowly charged over 1.5 hours at a temperature range between about 23 and 28°C. The batch was sampled for HPLC to monitor the progress of the reaction. After the reaction was judged complete, using the same subsequent procedure as described in Example 1 (i.e. quenching with MeOH, vacuum concentration of the batch, etc., but in appropriate ratios of reagents for this example), the compound of Formula I was obtained. Results varied, but in general, -99% yield and -94% de were obtained.
Example 5
Using the method described above in example 4, other acids were substituted for CSA. This group of other acids included BF3»OEt2, BCI3, trifluoroacetic acid (TFA) or methansulfonic acid. Results varied, but in general, all yielded results with favorable SS:RS ratios of -95-97% to -3-5% and a % de range from -91 to - 93.8%. In general, chemical yields close to 97% and over were obtained.

Claims

We claim:
A process for preparing a compound of Formula I
Figure imgf000013_0001
Formula
is prepared by a process which comprises:
a) mixing a compound of Formula II
Figure imgf000013_0002
Formula II
in tetrahydrofuran in the presence of an acid, or alternatively in tetrahydrofuran in the absence of an acid, to form a mixture; b) combining the mixture of step a) with a catalyst selected from either (A) a compound selected from the group of compounds represented by Formula III, or (B) a compound of Formula IV,
Figure imgf000014_0001
Formula III
Figure imgf000014_0002
Formula IV wherein R1 of Formula III is a (Cι-C6)alkyl and wherein R and S indicate stereochemistry at the chiral carbons; c) reducing the ketone adjacent to the p-fluorophenyl with a borane- tetrahydrofuran complex; and d) quenching the reaction with MeOH.
2. The process of claim 1 wherein the acid in step a) is BF3«OEt2, BCI3, p-toluene sulfonic acid, trifluoroacetic acid, methanesulfonic acid, or camphorsulfonic acid.
3. The process of claim 2 wherein the catalyst of Formula IV is employed in the presence of a trialkyl borate.
4. The process of claim 3 wherein said trialkyl borate is a trimethyl borate.
5. The process of claim 2 wherein said acid is present in a 1-10 mole percent ratio with respect to said compound of Formula II.
6. The process of claim 2 wherein said acid is present in a 1-5 mole percent ratio with respect to said compound of Formula II.
7. The process of claim 2 wherein said acid is present in a 2-3 mole percent ratio with respect to said compound of Formula II.
8. The process of claim 1 wherein said catalyst is present in a 0.1-10 mole percent ratio with respect to said compound of Formula II.
9. The process of claim 1 wherein said catalyst is present in a 1-5 mole percent ratio with respect to said compound of Formula II.
10. The process of claim 1 wherein said catalyst is present in a 2-3 mole percent ratio with respect to said compound of Formula II.
11. The process of claim 1 wherein the temperature in the reduction step c) is between -15 and 65°C.
12. The process of claim 1 wherein the temperature in the reduction step c) is between -10 and 55°C.
13. The process of claim 1 wherein the temperature in the reduction step c) is between 0 and 30°C.
14. The process of claim 1 wherein the temperature in the reduction step c) is between 23 and 28°C.
15. The process of claim 1 , wherein acid is present in step (a).
16. The process of claim 1 , wherein acid is absent in step (a).
17. The process of claim 16 wherein the temperature in the reduction step c) is between 23 and 28°C.
18. The process of claim 16 wherein said catalyst is present in a 0.1-10 mole percent ratio with respect to said compound of Formula II.
19. The process of claim 16 wherein said catalyst is present in a 1-5 mole percent ratio with respect to said compound of Formula II.
20. The process of claim 16 wherein said catalyst is present in a 2-3 mole percent ratio with respect to said compound of Formula II.
21. A compound of Formula I
Figure imgf000016_0001
Formula formed by the process of claim 15.
22. A compound of Formula I
Figure imgf000016_0002
Formula formed by the process of claim 16.
PCT/US2002/009123 2001-03-28 2002-03-25 Enantioselective synthesis of azetidinone intermediate compounds WO2002079174A2 (en)

Priority Applications (22)

Application Number Priority Date Filing Date Title
BRPI0208384A BRPI0208384B1 (en) 2001-03-28 2002-03-25 enantioselective synthesis of azetidinone intermediate compounds
PL363864A PL205952B1 (en) 2001-03-28 2002-03-25 Enantioselective synthesis of azetidinone intermediate compounds
IL15755202A IL157552A0 (en) 2001-03-28 2002-03-25 Enantioselective synthesis of azetidinone intermediate compounds
EA200300970A EA006898B1 (en) 2001-03-28 2002-03-25 Enantioselective synthesis of azetidinone intermediate compounds
JP2002577801A JP4145663B2 (en) 2001-03-28 2002-03-25 Enantioselective synthesis of azetidinone intermediate compounds
MXPA03008803A MXPA03008803A (en) 2001-03-28 2002-03-25 Enantioselective synthesis of azetidinone intermediate compounds.
EEP200300464A EE05453B1 (en) 2001-03-28 2002-03-25 Process for the preparation of azetidinone intermediates
AT02728561T ATE305459T1 (en) 2001-03-28 2002-03-25 METHOD FOR THE ENANTIOSELECTIVE SYNTHESIS OF AZETIDINONE INTERMEDIATE PRODUCTS
AU2002258605A AU2002258605B2 (en) 2001-03-28 2002-03-25 Enantioselective synthesis of azetidinone intermediate compounds
SK1186-2003A SK287408B6 (en) 2001-03-28 2002-03-25 A process for preparing intermediate compounds to the synthesis of azetidinone
DE60206365T DE60206365T2 (en) 2001-03-28 2002-03-25 PROCESS FOR THE ENANTIOSELECTIVE SYNTHESIS OF AZETIDINONE INTERMEDIATE PRODUCTS
KR1020037012486A KR100590342B1 (en) 2001-03-28 2002-03-25 Enantio-Selective Synthesis of Azetidinone Intermediate Compounds
EP02728561A EP1373230B1 (en) 2001-03-28 2002-03-25 Enantioselective synthesis of azetidinone intermediate compounds
HU0303526A HU230229B1 (en) 2001-03-28 2002-03-25 Enantioselective synthesis of azetidinone intermediate compounds
UA2003109666A UA75644C2 (en) 2001-03-28 2002-03-25 Enantioselective synthesis of azetidinone intermediate compounds
CA002442219A CA2442219C (en) 2001-03-28 2002-03-25 Enantioselective synthesis of azetidinone intermediate compounds
NZ527852A NZ527852A (en) 2001-03-28 2002-03-25 Enantioselective synthesis of azetidinone intermediate compounds
SI200230193T SI1373230T1 (en) 2001-03-28 2002-03-25 Enantioselective synthesis of azetidinone intermediate compounds
IL157552A IL157552A (en) 2001-03-28 2003-08-24 Enantioselective synthesis of azetidinone intermediate compounds
BG108168A BG66189B1 (en) 2001-03-28 2003-09-09 Enantioselective synthesis of azetidinone intermediate compounds
HR20030760A HRP20030760B1 (en) 2001-03-28 2003-09-19 Enantioselective synthesis of azetidinone intermediate compounds
HK04100111A HK1057546A1 (en) 2001-03-28 2004-01-07 Enantioselective synthesis of azetidinone intermediate compounds.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US27928801P 2001-03-28 2001-03-28
US60/279,288 2001-03-28

Publications (2)

Publication Number Publication Date
WO2002079174A2 true WO2002079174A2 (en) 2002-10-10
WO2002079174A3 WO2002079174A3 (en) 2003-02-27

Family

ID=23068350

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2002/009123 WO2002079174A2 (en) 2001-03-28 2002-03-25 Enantioselective synthesis of azetidinone intermediate compounds

Country Status (29)

Country Link
US (1) US6627757B2 (en)
EP (1) EP1373230B1 (en)
JP (1) JP4145663B2 (en)
KR (1) KR100590342B1 (en)
CN (1) CN1275949C (en)
AT (1) ATE305459T1 (en)
AU (1) AU2002258605B2 (en)
BG (1) BG66189B1 (en)
BR (1) BRPI0208384B1 (en)
CA (1) CA2442219C (en)
CZ (1) CZ304929B6 (en)
DE (1) DE60206365T2 (en)
DK (1) DK1373230T3 (en)
EA (1) EA006898B1 (en)
EE (1) EE05453B1 (en)
ES (1) ES2245733T3 (en)
HK (1) HK1057546A1 (en)
HR (1) HRP20030760B1 (en)
HU (1) HU230229B1 (en)
IL (2) IL157552A0 (en)
MX (1) MXPA03008803A (en)
NZ (1) NZ527852A (en)
PL (1) PL205952B1 (en)
RS (1) RS50386B (en)
SI (1) SI1373230T1 (en)
SK (1) SK287408B6 (en)
UA (1) UA75644C2 (en)
WO (1) WO2002079174A2 (en)
ZA (1) ZA200306612B (en)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7135556B2 (en) 2002-07-19 2006-11-14 Schering Corporation NPC1L1 (NPC3) and methods of use thereof
EP1918000A2 (en) 2003-11-05 2008-05-07 Schering Corporation Combinations of lipid modulating agents and substituted azetidinones and treatments for vascular conditions
US7470678B2 (en) 2002-07-05 2008-12-30 Astrazeneca Ab Diphenylazetidinone derivatives for treating disorders of the lipid metabolism
US7842684B2 (en) 2006-04-27 2010-11-30 Astrazeneca Ab Diphenylazetidinone derivatives possessing cholesterol absorption inhibitor activity
US7871998B2 (en) 2003-12-23 2011-01-18 Astrazeneca Ab Diphenylazetidinone derivatives possessing cholesterol absorption inhibitory activity
US7893048B2 (en) 2005-06-22 2011-02-22 Astrazeneca Ab 2-azetidinone derivatives as cholesterol absorption inhibitors for the treatment of hyperlipidaemic conditions
US7901893B2 (en) 2004-01-16 2011-03-08 Merck Sharp & Dohme Corp. NPC1L1 (NPC3) and methods of identifying ligands thereof
US7910698B2 (en) 2006-02-24 2011-03-22 Schering Corporation NPC1L1 orthologues

Families Citing this family (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040132058A1 (en) 2002-07-19 2004-07-08 Schering Corporation NPC1L1 (NPC3) and methods of use thereof
AR040588A1 (en) 2002-07-26 2005-04-13 Schering Corp PHARMACEUTICAL FORMULATION INCLUDING AN INHIBITOR OF CHOLESTEROL ABSORPTION AND AN INHIBITOR OF A HMGCO TO REDUCTASE
US20060069080A1 (en) * 2004-09-29 2006-03-30 Veltri Enrico P Combinations of substituted azetidinones and CB1 antagonists
US7700597B2 (en) 2004-12-03 2010-04-20 Schering Corporation Substituted piperazines as CB1 antagonists
US8308559B2 (en) * 2007-05-07 2012-11-13 Jay Chun Paradise box gaming system
TW200726746A (en) 2005-05-06 2007-07-16 Microbia Inc Processes for production of 4-biphenylylazetidin-2-ones
BRPI0611531A2 (en) * 2005-05-09 2010-09-21 Microbia Inc organometal benzenophosphonate coupling agents and carbon-carbon bond generation method
WO2006122216A2 (en) * 2005-05-11 2006-11-16 Microbia, Inc. Processes for production of phenolic 4-biphenylylazetidin-2-ones
CA2609506A1 (en) * 2005-05-25 2006-11-30 Microbia, Inc. Processes for production of 4-(biphenylyl)azetidin-2-one phosphonic acids
DE602006010870D1 (en) * 2005-06-20 2010-01-14 Schering Corp PIPERIDINE DERIVATIVES SUITED AS ANTAGONISTS OF HISTAMINE H3
CA2616058A1 (en) * 2005-09-08 2007-03-15 Vinod Kumar Kansal Processes for the preparation of (3r,4s)-4-((4-benzyloxy)phenyl)-1-(4-fluorophenyl)-3-((s)-3-(4-fluorophenyl)-3-hydroxypropyl)-2-azetidinone, an intermediate for the synthesis of ezetimibe
HUP0501164A2 (en) * 2005-12-20 2007-07-30 Richter Gedeon Nyrt New industrial process for the production of ezetimibe
EP1973877A2 (en) 2006-01-18 2008-10-01 Schering Corporation Cannibinoid receptor modulators
CN101384532B (en) * 2006-02-16 2013-01-02 寿制药株式会社 Process for preparing optically active alcohols
WO2008030382A1 (en) * 2006-09-05 2008-03-13 Schering Corporation Pharmaceutical combinations for lipid management and in the treatment of atherosclerosis and hepatic steatosis
US20100197564A1 (en) * 2007-04-19 2010-08-05 Schering Corporation Diaryl morpholines as cb1 modulators
JP2010529148A (en) * 2007-06-07 2010-08-26 テバ ファーマシューティカル インダストリーズ リミティド Reduction method for the production of ezetimibe
RU2010102478A (en) * 2007-06-28 2011-08-10 Интэрвэт Интэрнэшнл Б.Ф. (NL) SUBSTITUTED PIPERASINS AS CB1 ANTAGONISTS
JP2010531874A (en) * 2007-06-28 2010-09-30 インターベット インターナショナル ベー． フェー． Substituted piperazines as CB1 antagonists
US20090093627A1 (en) * 2007-08-30 2009-04-09 Lorand Szabo Process for preparing intermediates of ezetimibe by microbial reduction
US20090312302A1 (en) * 2008-06-17 2009-12-17 Ironwood Pharmaceuticals, Inc. Compositions and methods for treating nonalcoholic fatty liver disease-associated disorders
US8273554B2 (en) 2008-08-29 2012-09-25 Codexis, Inc. Ketoreductase polypeptides for the stereoselective production of (4S)-3-[(5S)-5-(4-fluorophenyl)-5-hydroxypentanoyl]-4-phenyl-1,3-oxazolidin-2-one
EP2414529A2 (en) 2009-04-01 2012-02-08 Matrix Laboratories Ltd 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
US9102959B2 (en) 2009-08-19 2015-08-11 Codexis, Inc. Ketoreductase polypeptides for the preparation of phenylephrine
EP2566497B1 (en) 2010-05-04 2015-07-29 Codexis, Inc. Biocatalysts for ezetimibe synthesis
WO2012155932A1 (en) 2011-05-17 2012-11-22 Pharmathen S.A. Improved process for the preparation of ezetimibe
CN111518046B (en) * 2020-06-04 2022-04-15 中山奕安泰医药科技有限公司 Ezetimibe intermediate and preparation method of ezetimibe

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6207822B1 (en) * 1998-12-07 2001-03-27 Schering Corporation Process for the synthesis of azetidinones

Family Cites Families (53)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2046823A1 (en) 1970-09-23 1972-03-30 Farbwerke Hoechst AG vormals Meister Lucius & Brüning, 6000 Frankfurt New azetidinones (2) and processes for their preparation
JPS5628057A (en) 1979-08-13 1981-03-19 Isuzu Motors Ltd Front cab suspension device for tiltable cab
DE3006193C2 (en) 1980-02-19 1984-04-12 Siemens AG, 1000 Berlin und 8000 München Electrical connection of the electrodes of a gas discharge surge arrester
US4680391A (en) 1983-12-01 1987-07-14 Merck & Co., Inc. Substituted azetidinones as anti-inflammatory and antidegenerative agents
JPS61121479A (en) 1984-11-19 1986-06-09 Mitsubishi Electric Corp solar cell element
JPS61180212A (en) 1985-02-06 1986-08-12 Asahi Optical Co Ltd Rear stop type photographic lens
JPS62219681A (en) 1986-03-20 1987-09-26 Toshiba Corp Reference light source for optical-signal processing element
CN87107149A (en) 1986-10-03 1988-05-18 伊莱利利公司 The position replaces between 7-[() phenylglycocoll] 1-carbon generation-1-desulfuration cynnematin
US4803266A (en) 1986-10-17 1989-02-07 Taisho Pharmaceutical Co., Ltd. 3-Oxoalkylidene-2-azetidinone derivatives
EP0333268A1 (en) 1988-03-18 1989-09-20 Merck & Co. Inc. Process for synthesis of a chiral 3-beta hydrogen (3R) 4-aroyloxy azetidinone
IL89835A0 (en) 1988-04-11 1989-12-15 Merck & Co Inc Substituted azetidinones,their preparation and pharmaceutical compositions containing them
US4952689A (en) 1988-10-20 1990-08-28 Taisho Pharmaceutical Co., Ltd. 3-(substituted propylidene)-2-azetidinone derivates for blood platelet aggregation
US4876365A (en) 1988-12-05 1989-10-24 Schering Corporation Intermediate compounds for preparing penems and carbapenems
FR2640621B1 (en) 1988-12-19 1992-10-30 Centre Nat Rech Scient N-ARYL-AZETIDINONES, PROCESS FOR THEIR PREPARATION AND THEIR USE AS ELASTASE INHIBITORS
US4983597A (en) 1989-08-31 1991-01-08 Merck & Co., Inc. Beta-lactams as anticholesterolemic agents
US5120729A (en) 1990-06-20 1992-06-09 Merck & Co., Inc. Beta-lactams as antihypercholesterolemics
IL99658A0 (en) 1990-10-15 1992-08-18 Merck & Co Inc Substituted azetidinones and pharmaceutical compositions containing them
JPH04356195A (en) 1991-05-30 1992-12-09 Kyowa Hakko Kogyo Co Ltd Production of azetidinone derivative
US5561227A (en) 1991-07-23 1996-10-01 Schering Corporation Process for the stereospecific synthesis of azetidinones
US5688787A (en) 1991-07-23 1997-11-18 Schering Corporation Substituted β-lactam compounds useful as hypochlesterolemic agents and processes for the preparation thereof
US5688785A (en) 1991-07-23 1997-11-18 Schering Corporation Substituted azetidinone compounds useful as hypocholesterolemic agents
SK7994A3 (en) 1991-07-23 1994-07-06 Schering Corp Substituted beta-lactam compounds useful as hypocholesterolemic agents and processes of their preparation
LT3300B (en) 1992-12-23 1995-06-26 Schering Corp Combination of a cholesterol biosynhtesis inhibitor and a beta- lactam cholesterol absorbtion inhibitor
LT3595B (en) 1993-01-21 1995-12-27 Schering Corp Spirocycloalkyl-substituted azetidinones useful as hypocholesterolemic agents
JP2840452B2 (en) 1993-07-09 1998-12-24 シェリング・コーポレーション Method for synthesizing azetidinone
US5631365A (en) 1993-09-21 1997-05-20 Schering Corporation Hydroxy-substituted azetidinone compounds useful as hypocholesterolemic agents
US5627176A (en) 1994-03-25 1997-05-06 Schering Corporation Substituted azetidinone compounds useful as hypocholesterolemic agents
US5633246A (en) 1994-11-18 1997-05-27 Schering Corporation Sulfur-substituted azetidinone compounds useful as hypocholesterolemic agents
US5624920A (en) 1994-11-18 1997-04-29 Schering Corporation Sulfur-substituted azetidinone compounds useful as hypocholesterolemic agents
US5656624A (en) 1994-12-21 1997-08-12 Schering Corporation 4-[(heterocycloalkyl or heteroaromatic)-substituted phenyl]-2-azetidinones useful as hypolipidemic agents
US5631635A (en) * 1995-05-08 1997-05-20 Motorola, Inc. Message/response tracking system and method for a two-way selective call receiving device
US5618707A (en) 1996-01-04 1997-04-08 Schering Corporation Stereoselective microbial reduction of 5-fluorophenyl-5-oxo-pentanoic acid and a phenyloxazolidinone condensation product thereof
CA2235943C (en) 1995-10-31 2002-10-01 Schering Corporation Sugar-substituted 2-azetidinones useful as hypocholesterolemic agents
AU7472896A (en) 1995-11-02 1997-05-22 Schering Corporation Process for preparing 1-(4-fluorophenyl)-3(r)-(3(s)-hydroxy-3-({phenyl or 4-fluorophenyl})-propyl)-4(s)-(4-hydroxyphenyl)-2-azetidinon
JP2000505063A (en) 1995-12-08 2000-04-25 スミスクライン・ビーチャム・パブリック・リミテッド・カンパニー Azetidinone compounds for the treatment of atherosclerosis
BR9709196A (en) 1996-04-26 1999-05-25 Smithkline Beecham Plc Azetidinone derivatives for the treatment of atherosclerosis
US5739321A (en) 1996-05-31 1998-04-14 Schering Corporation 3-hydroxy γ-lactone based enantionselective synthesis of azetidinones
US5886171A (en) 1996-05-31 1999-03-23 Schering Corporation 3-hydroxy gamma-lactone based enantioselective synthesis of azetidinones
GB9611947D0 (en) 1996-06-07 1996-08-07 Glaxo Group Ltd Medicaments
AU4228997A (en) 1996-07-09 1998-02-02 Merck & Co., Inc. Method for treating homozygous familial hypercholesterolemia
AU4050797A (en) 1996-08-02 1998-02-25 Ligand Pharmaceuticals Incorporated Prevention or treatment of type 2 diabetes or cardiovascular disease with ppar modulators
US6139865A (en) 1996-10-01 2000-10-31 Eurand America, Inc. Taste-masked microcapsule compositions and methods of manufacture
US5756470A (en) 1996-10-29 1998-05-26 Schering Corporation Sugar-substituted 2-azetidinones useful as hypocholesterolemic agents
FR2758461A1 (en) 1997-01-17 1998-07-24 Pharma Pass PHARMACEUTICAL COMPOSITION HAVING HIGH BIOAVAILABILITY AND PROCESS FOR PREPARING THE SAME
CA2301543C (en) 1997-10-07 2005-05-17 Boehringer Ingelheim (Canada) Ltd. Azetidinone derivatives for the treatment of hcmv infections
US6133001A (en) 1998-02-23 2000-10-17 Schering Corporation Stereoselective microbial reduction for the preparation of 1-(4-fluorophenyl)-3(R)-[3(S)-Hydroxy-3-(4-fluorophenyl)propyl)]-4(S)-(4 -hydroxyphenyl)-2-azetidinone
US5919672A (en) 1998-10-02 1999-07-06 Schering Corporation Resolution of trans-2-(alkoxycarbonylethyl)-lactams useful in the synthesis of 1-(4-fluoro-phenyl)-3(R)- (S)-hydroxy-3-(4-fluorophenyl)-propyl!-4(S)-(4-hydroxyphenyl)-2-azetidinone
CA2353981C (en) 1998-12-07 2005-04-26 Schering Corporation Process for the synthesis of azetidinones
CN1249250C (en) 1999-04-05 2006-04-05 先灵公司 Stereoselective microbial reduction for prpn. of 1-(4-fluorophenyl)-3(R)-[3(s)-hydroxy-3-(4-fluorophenyl)propyl)-4(s)-(-4hydroxyphenyl)-2-azetidinone
WO2000063703A1 (en) 1999-04-16 2000-10-26 Schering Corporation Use of azetidinone compounds
DK1347987T3 (en) 2000-12-20 2005-01-31 Schering Corp Sugar-substituted 2-azetidinones useful as hypocholesterolemic agents
PL362379A1 (en) 2000-12-21 2004-10-18 Aventis Pharma Deutschland Gmbh Novel 1,2-diphenzylazetidinones, method for producing the same, medicaments containing said compounds, and the use thereof for treating disorders of the lipid metabolism
TWI291957B (en) 2001-02-23 2008-01-01 Kotobuki Pharmaceutical Co Ltd Beta-lactam compounds, process for repoducing the same and serum cholesterol-lowering agents containing the same

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6207822B1 (en) * 1998-12-07 2001-03-27 Schering Corporation Process for the synthesis of azetidinones

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
WALLBAUM S ET AL: "ASYMMETRIC SYNTHESES WITH CHIRAL OXAZABOROLIDINES" TETRAHEDRON: ASYMMETRY, ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, NL, vol. 3, no. 12, 1 December 1992 (1992-12-01), pages 1475-1504, XP002061997 ISSN: 0957-4166 *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7470678B2 (en) 2002-07-05 2008-12-30 Astrazeneca Ab Diphenylazetidinone derivatives for treating disorders of the lipid metabolism
US7135556B2 (en) 2002-07-19 2006-11-14 Schering Corporation NPC1L1 (NPC3) and methods of use thereof
EP1918000A2 (en) 2003-11-05 2008-05-07 Schering Corporation Combinations of lipid modulating agents and substituted azetidinones and treatments for vascular conditions
US7871998B2 (en) 2003-12-23 2011-01-18 Astrazeneca Ab Diphenylazetidinone derivatives possessing cholesterol absorption inhibitory activity
US7901893B2 (en) 2004-01-16 2011-03-08 Merck Sharp & Dohme Corp. NPC1L1 (NPC3) and methods of identifying ligands thereof
US7893048B2 (en) 2005-06-22 2011-02-22 Astrazeneca Ab 2-azetidinone derivatives as cholesterol absorption inhibitors for the treatment of hyperlipidaemic conditions
US7910698B2 (en) 2006-02-24 2011-03-22 Schering Corporation NPC1L1 orthologues
US8212016B2 (en) 2006-02-24 2012-07-03 Schering Corporation NPC1L1 orthologues
US7842684B2 (en) 2006-04-27 2010-11-30 Astrazeneca Ab Diphenylazetidinone derivatives possessing cholesterol absorption inhibitor activity

Also Published As

Publication number Publication date
US20020193607A1 (en) 2002-12-19
RS50386B (en) 2009-12-31
WO2002079174A3 (en) 2003-02-27
PL205952B1 (en) 2010-06-30
CN1500083A (en) 2004-05-26
BR0208384A (en) 2004-06-15
BG108168A (en) 2004-09-30
BRPI0208384B1 (en) 2016-05-31
MXPA03008803A (en) 2004-02-18
CN1275949C (en) 2006-09-20
DE60206365T2 (en) 2006-07-06
SK11862003A3 (en) 2004-04-06
CA2442219C (en) 2007-09-11
YU74803A (en) 2006-05-25
JP4145663B2 (en) 2008-09-03
CZ20032610A3 (en) 2004-03-17
BG66189B1 (en) 2011-12-30
EA200300970A1 (en) 2004-04-29
US6627757B2 (en) 2003-09-30
JP2004532210A (en) 2004-10-21
KR100590342B1 (en) 2006-06-15
CA2442219A1 (en) 2002-10-10
DK1373230T3 (en) 2005-11-07
HK1057546A1 (en) 2004-04-08
EE05453B1 (en) 2011-08-15
UA75644C2 (en) 2006-05-15
KR20030085573A (en) 2003-11-05
NZ527852A (en) 2005-03-24
SK287408B6 (en) 2010-09-07
HU230229B1 (en) 2015-10-28
PL363864A1 (en) 2004-11-29
ES2245733T3 (en) 2006-01-16
AU2002258605B2 (en) 2006-01-12
ATE305459T1 (en) 2005-10-15
IL157552A (en) 2009-08-03
HUP0303526A3 (en) 2004-11-29
EP1373230A2 (en) 2004-01-02
CZ304929B6 (en) 2015-01-28
DE60206365D1 (en) 2005-11-03
HUP0303526A2 (en) 2004-01-28
HRP20030760A2 (en) 2004-08-31
EP1373230B1 (en) 2005-09-28
EA006898B1 (en) 2006-04-28
ZA200306612B (en) 2004-10-12
IL157552A0 (en) 2004-03-28
EE200300464A (en) 2003-12-15
SI1373230T1 (en) 2005-12-31
HRP20030760B1 (en) 2011-07-31

Similar Documents

Publication Publication Date Title
EP1373230B1 (en) Enantioselective synthesis of azetidinone intermediate compounds
AU2002258605A1 (en) Enantioselective synthesis of azetidinone intermediate compounds
CN1124962A (en) Enantioselective 1,3,2-Oxazaboropentane Catalyst
JP5035863B2 (en) Process for the preparation of quinolone antibiotic intermediates
EP0191259B1 (en) Hexacoordinated silicon complexes, process for their preparation and their use
Hou et al. Reaction of phosphinoyl-activated imines: stereocontrolled synthesis of either trans-or cis-vinylaziridines
US20030204096A1 (en) Enantioselective synthesis of azetidinone intermediate compounds
WO2002012230A1 (en) Intermediate of carbapenem antibiotics and process for the preparation thereof
JPH05202074A (en) Method of catalytic alakylaton
JPH0673072A (en) Production of organooxysilane hydride
JP4807549B2 (en) Siloxanes, silanols and silanes, and methods for producing the same
JPS63135393A (en) Production of alkylsilyl cyanide
CN1017991B (en) Process for preparing 4-acetoxy-3-hydroxyethyl azetidin-2-one derivatives
JPH0441128B2 (en)
EP4403541A1 (en) Method for producing halogenobicyclo[1.1.1]pentane
JPH08143517A (en) Production of optically active 3-amino-1,2-butanediol derivative
TW202246275A (en) Methods of preparing carbanucleosides using amides
US20020049350A1 (en) Process for preparing thrombin receptor antagonist building blocks
EP0154867A1 (en) 2-Substituted-1,3-butadiene derivatives and process for producing same
JP2001131160A (en) New oxazolidinone derivatives and their uses
JPH0625193B2 (en) Epoxidation of α, β-unsaturated ketones
KR20120095567A (en) Process for the preparation of intermediate of penem antibiotic

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: P-748/03

Country of ref document: YU

AK Designated states

Kind code of ref document: A2

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CZ DE DK DM DZ EC EE ES FI GB GD GE HR HU ID IL IN IS JP KG KR KZ LC LK LR LT LU LV MA MD MG MK MN MX MZ NO NZ PH PL PT RO RU SE SG SI SK SL TJ TM TN TR TT TZ UA UZ VN YU ZA ZM

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
AK Designated states

Kind code of ref document: A3

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CZ DE DK DM DZ EC EE ES FI GB GD GE HR HU ID IL IN IS JP KG KR KZ LC LK LR LT LU LV MA MD MG MK MN MX MZ NO NZ PH PL PT RO RU SE SG SI SK SL TJ TM TN TR TT TZ UA UZ VN YU ZA ZM

AL Designated countries for regional patents

Kind code of ref document: A3

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

WWE Wipo information: entry into national phase

Ref document number: 157552

Country of ref document: IL

WWE Wipo information: entry into national phase

Ref document number: 2003/06612

Country of ref document: ZA

Ref document number: 200306612

Country of ref document: ZA

WWE Wipo information: entry into national phase

Ref document number: 527852

Country of ref document: NZ

ENP Entry into the national phase

Ref document number: 10816802

Country of ref document: BG

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: P20030760A

Country of ref document: HR

WWE Wipo information: entry into national phase

Ref document number: 2002258605

Country of ref document: AU

Ref document number: 2002577801

Country of ref document: JP

Ref document number: 11862003

Country of ref document: SK

WWE Wipo information: entry into national phase

Ref document number: 2442219

Country of ref document: CA

Ref document number: 1020037012486

Country of ref document: KR

WWE Wipo information: entry into national phase

Ref document number: PA/a/2003/008803

Country of ref document: MX

Ref document number: PV2003-2610

Country of ref document: CZ

Ref document number: 1524/CHENP/2003

Country of ref document: IN

WWE Wipo information: entry into national phase

Ref document number: 028075374

Country of ref document: CN

WWE Wipo information: entry into national phase

Ref document number: 2002728561

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 200300970

Country of ref document: EA

WWP Wipo information: published in national office

Ref document number: 2002728561

Country of ref document: EP

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

WWP Wipo information: published in national office

Ref document number: PV2003-2610

Country of ref document: CZ

WWP Wipo information: published in national office

Ref document number: 527852

Country of ref document: NZ

WWG Wipo information: grant in national office

Ref document number: 527852

Country of ref document: NZ

WWG Wipo information: grant in national office

Ref document number: 2002728561

Country of ref document: EP

WWG Wipo information: grant in national office

Ref document number: 2002258605

Country of ref document: AU