EP0858460A1 - Procede de preparation d'azetidinones a substitution - Google Patents

Procede de preparation d'azetidinones a substitution

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Publication number
EP0858460A1
EP0858460A1 EP96937014A EP96937014A EP0858460A1 EP 0858460 A1 EP0858460 A1 EP 0858460A1 EP 96937014 A EP96937014 A EP 96937014A EP 96937014 A EP96937014 A EP 96937014A EP 0858460 A1 EP0858460 A1 EP 0858460A1
Authority
EP
European Patent Office
Prior art keywords
recited
preparation
isocyanate
solvent
azetidinone
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP96937014A
Other languages
German (de)
English (en)
Inventor
Joseph S. Amato
Raymond Cvetovich
Frederick W. Hartner
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck and Co Inc
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Merck and Co Inc
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 claimed from GBGB9603560.5A external-priority patent/GB9603560D0/en
Application filed by Merck and Co Inc filed Critical Merck and Co Inc
Publication of EP0858460A1 publication Critical patent/EP0858460A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/54—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/58—Radicals substituted by nitrogen atoms

Definitions

  • Elastase is a member of the protease family of enzymes. Proteases from granulocytes and macrophages have been reported to be responsible for the chronic tissue destruction mechanisms associated with inflammation, including rhematoid arthritis and emphysema. Accordingly, specific and selective inhibitors of these proteases are candidates for potent anti-inflammatory agents useful in the treatment of inflammatory conditions resulting in connective tissue destruction, e.g.
  • rheumatoid arthritis rheumatoid arthritis, emphysema, bronchial inflammation, chronic bronchitis, glomerulonephritis, osteoarthritis, spondylitis, lupus, psoriasis, atherosclerosis, sepsis, septicemia, shock, myocardial infarction, reperfusion injury, periodontitis, cystic fibrosis and acute respiratory distress syndrome.
  • proteases from granulocytes, leukocytes or macrophages are related to a rapid series of events which occurs during the progression of an inflammatory condition:
  • lymphoid cells especially macrophages and polymorphonuclear leukocytes (PMN). It has been known that a variety of proteases are released from the macrophages and PMN, further indicating that the proteases do play an important role in inflammation.
  • proteases are an important family of enzymes within the peptide bond cleaving enzymes whose members are essential to a variety of normal biological activities, such as digestion, formation and dissolution of blood clots, the formation of active forms of hormones, the immune reaction to foreign cells and organisms, etc., and in pathological conditions such as the degradation of structural proteins at the articular cartilage/pannus junction in rheumatoid arthritis etc.
  • Elastase is one of the proteases. It is an enzyme capable of hydrolyzing the connective tissue component elastin, a property not contained by the bulk of the proteases present in mammals. It acts on a protein's nonterminal bonds which are adjacent to an aliphatic amino acid.
  • Neutrophil elastase is of particular interest because it has the broadest spectrum of activity against natural connective tissue substrates.
  • the elastase of the granulocyte is important because, as described above, granulocytes participate in acute inflammation and in acute exacerbation of chronic forms of inflammation which characterize many clinically important inflammatory diseases.
  • Proteases may be inactivated by inhibitors which block the active site of the enzyme by binding tightly thereto.
  • Naturally occurring protease inhibitors form part of the control or defense mechanisms that are crucial to the well-being of an organism. Without these control mechanisms, the proteases would destroy any protein within reach.
  • the naturally occurring enzyme inhibitors have been shown to have appropriate configurations which allow them to bind tightly to the enzyme. This configuration is part of the reason that inhibitors bind to the enzyme so tightly (see Stroud, "A Family of Protein-Cutting Proteins" Sci. Am. July 1974, pp. 74-88).
  • one of the natural inhibitors is a glycoprotein contained in human serum that has a wide inhibitory spectrum covering, among other enzymes, elastase both from the pancreas and the PMN. This inhibitor is hydrolyzed by the proteases to form a stable acyl enzyme in which the active site is no longer available. Marked reduction in serum al ⁇ antitrypsin, either genetic or due to oxidants, has been associated with pulmonary emphysema which is a disease characterized by a progressive loss of lung elasticity and resulting respiratory difficulty.
  • Rheumatoid arthritis is characterized by a progressive destruction of articular cartilage both on the free surface bordering the joint space and at the erosion front built up by synovial tissue toward the cartilage. This destruction process, in turn, is attributed to the protein- cutting enzyme elastase which is a neutral protease present in human granulocytes. This conclusion has been supported by the following observations:
  • a second aspect this invention concerns the use of novel azetidinones in the treatment of certain cancers including nonlymphoblastic leukemias, acute myelogenous leukemia (FAB Ml and FAB M2), acute promyelocytic leukemia (FAB M3), acute myelomonocytic leukemia (FAB M4), acute monocytic leukemia (FAB M5), erythroleukemia, chronic myelogenous leukemia, chronic myelomonocytic leukemia, chronic monocytic leukemia and conditions associated with leukemia involving activity of PMN neutral proteases e.g. disseminated intravascular coagulation.
  • PR-3 proteinase 3
  • leukemia such as nonlymphoblastic leukemias, acute myelogenous leukemia (FAB Ml and FAB M2), acute promyelocytic leukemia (FAB M3), acute myelomonocytic leukemia (FAB M4), acute monocytic leukemia (FAB M5), erythroleukemia, chronic myelogenous leukemia, chronic myelomonocytic leukemia, chronic monocytic leukemia and conditions associated with leukemia involving activity of PMN neutral proteases e.g. disseminated intravascular coagulation, comprising administration of a therapeutically effective amount of compound of formula I will result in remission of the disease state.
  • Administration may be either oral or parenteral.
  • the instant invention relates to the process for the preparation [S-(R*,S*)]- N-[ 1-(1, 3-benzodioxol-5-yl)butyl]-3 ,3-diethyl- 2-[4-[(4-methyl- 1 -piperazinyl)carbonyl]phenoxy] -4-oxo- 1 -azetidine- carboxamide, Formula I.
  • the convergent route utilizes a chiral ⁇ -lactam intermediate prepared using a resolution based procedure and a chiral isocyanate intermediate prepared using a chiral propylation of piperonal followed by azide inversion of the alcohol.
  • the base is an amine base, such as l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), or an inorganic base, such as l ,5-diazabicyclo[4.3.0]non-5-ene (DBN), and potassium carbonate.
  • DBU l,8-diazabicyclo[5.4.0]undec-7-ene
  • DBN inorganic base
  • potassium carbonate potassium carbonate.
  • the base is used in a catalytic amount in the range of about 1 mole % to about 100 mole %. A preferred range is about 5 mole % to about 25 mole %. When DBU was the base employed 10 mole % was used to effect the coupling reaction.
  • Another embodiment of this method is wherein the solvent is selected from acetonitrile, toluene, methyl t-butyl ether, and isopropylacetate.
  • the solvent used is acetonitrile.
  • the coupling reaction can be carried out at a temperature range of about -10°C to about to 25°C.
  • the preferred temperature for the coupling reaction is in the range of about 0°C to about 10°C.
  • (k) crystallizing the azetidinone using a solvent selected from ethyl acetate, propyl acetate and isopropyl acetate.
  • a solvent selected from ethyl acetate, propyl acetate and isopropyl acetate.
  • the base used in the displacement step is selected from the group consisting of: K2CO3 and CS2CO3.
  • the polar solvent system used in the displacement step is selected from the group consisting of: aqueous acetonitrile or dimethylformamide (DMF).
  • the noble metal catalyst used in the hydrogenolysis step is selected from the group consisting of: a palladium catalyst in the presence of cyclohexene, or a palladium catalyst under a hydrogen atmosphere.
  • An embodiment of the process for the preparation of the isocyanate wherein the base in the azide formation step is 1 ,8- diazabicyclo[5.4.0]undec-7-ene (DBU),l,4-diazabicyclo[2.2.2]octane (DABCO), triethylamine, 4-dimethylaminopyridine (DMAP), quinuclidine, pentamethylpiperidine, 2-t-butyl-l,l,3,3-tetramethyl- guanidine and pentamethylguanidine.
  • DBU diazabicyclo[5.4.0]undec-7-ene
  • DABCO alkylamine
  • DMAP 4-dimethylaminopyridine
  • quinuclidine pentamethylpiperidine
  • 2-t-butyl-l,l,3,3-tetramethyl- guanidine pentamethylguanidine.
  • An embodiment of the process for the preparation of the isocyanate wherein the solvent in the azide formation step is toluene, xylenes, tetrahydrofuran, methyl t-butylether, isopropyl acetate, and cyclohexane.
  • An embodiment of this embodiment of the process for the preparation of the isocyanate is when the base in the azide formation step is l ,8-diazabicyclo[5.4.0]undec-7-ene and the solvent is toluene.
  • An embodiment of the process for the preparation of the isocyanate wherein the organic solvent mixture in the resolution step consists of the second solvent selected from the group consisting of: isopropanol, ethanol, or methanol.
  • amide 4 was synthesized in four steps in 18% overall yield and 99.4% e.e. via the following sequence (see Scheme 1): reaction of 3,3-dimethyl-4-propionyloxy-2-azetidinone with benzyl 4-hydroxy benzoate mediated by Cs2C ⁇ 3; ester debenzylation; resolution with chiral methylbenzylamine to afford (S)-acid; and amide formation with N-methylpiperazine employing DCC. Isocyanate 9 was prepared in 57% overall yield and 98.2% e.e.
  • azetidinone 1 was prepared via the addition of chlorosulfonylisocyanate (CSI) to 2,2-diethylvinylpropionate in the presence or absence of a solvent (eg. toluene) the reaction having a t 1/2 of about 8 hours.
  • CSI chlorosulfonylisocyanate
  • solvent eg. toluene
  • the use of the 4-propionyloxy group vs the acetyl analogue was dictated by the instability of the latter analogue and the poor yields resulting from its displacement.
  • Other analogues, such as the isobutyloxy did not provide any yield advantages in displacement reactions.
  • Recrystallization then upgraded the purity of the (S,S)-MBA acid salt to give 94-96% e.e. in 24% recovery.
  • the mother liquours from each crystallization were combined, which generated an ⁇ 1 :1 mixture of enantiomers, and reprocessed through the resolution procedure to give an overall (S)-acid 3-(4S) recovery of 27% (54% of the available (S)-enantiomer).
  • Racemic amide 4 was also prepared by the displacement of ⁇ -lactam 1 with the N-methylpiperazinylamide of 4-hydroxybenzoic acid. Attempts to resolve this material produced mixed crystalline salts with negligible resolution.
  • the benzyl ester 2 was found to be a racemic mixture by X-ray crystallography, and thus can be resolved using continuous resolution by preferential crystallization. Then, the desired S-benzyl ester can be hydrogenolyzed to give the 3-(4S) acid, which is then reacted with DCC, HOBT and N-methylpiperazine in isopropyl acetate to give the amide 4.
  • the continuous resolution of a racemic mixture of the benzyl ester 2 can be performed using the methodology described in Dolling, U. H., et al. J. Org. Chem, Vol. 43, No. 9, pp. 1634 (1978) and citations contained therein.
  • the resolution can be carried out using an ethanol- water solvent mixture.
  • the isocyanate synthesis is described in Scheme 2 and begins with the Yoshioka procedure for the enantioselective addition of a dialkylzinc reagent to an aldehyde.
  • a chiral complex prepared from the bis- trifluorosulfonamide of trans-(R),(R)-l,2-diaminocyclohexane (di- triflamide) and titanium tetraisopropoxide catalyzes the addition of di-n- propylzinc to piperonal 5.
  • the reaction gave product in excellent yield (98%) and optical purity (>99%e.e.) and no effort was made to modify the equivalents of zinc reagent or catalyst employed.
  • Azide 7 was prepared by the procedure of Thompson and coworkers in which a toluene solution of the alcohol is treated with diphenylphosphoryl azide, followed by DBU. [A. Thompson, G. Humphrey, A. DeMarco, D. Mathre, E. Grabowski, J. Organic Chemistry, 58, 5886 (1993).] The reaction proceeded through an intermediate phosphate that was observable by NMR. The product was obtained as a toluene solution after workup in approximately 65% yield. Some racemization occurred during the transformation of the piperonal derived alcohol, resulting in an azide enantiomeric excess of 85% (down from >99% e.e. for alcohol 6).
  • the azide product as an oil or in toluene solution at typical operating concentrations, is potentially shock sensitive and has a heat release of over 1200 cal/gram.
  • the initial exotherm begins at approximately 50°C. Consequently, agitation should be limited and operating temperatures should be carefully monitored and controlled.
  • Amine 8 was obtained from the azide in approximately 95% yield by reduction with lithium aluminum hydride in tetrahydrofuran.
  • the aluminum salts produced in the reaction workup were separated by quenching with a solution of Rochelle's salt.
  • the amine was separated from neutral by-products, including (PhO)2P(0)NH2 formed by reduction of the excess (PhO)2P(0)N3, by extraction into dilute acid.
  • the azide may also be reduced with triphenylphosphine to give a phosphinimine, which is hydrolyzed with aq. NaOH to the amine. It is difficult to drive the hydrolysis to completion, however, and the product is obtained less pure than by LAH reduction. No other methods of reduction were explored.
  • the optical purity of amine 8 was improved by crystallization of the D-pyroglutamic acid salt from 20:1 EtOAc:EtOH. Amine 8 of 85% e.e. was upgraded to as high as 99.4% e.e. in 93% yield (based on (R)-amine) in lab experiments. The optical purity of the resolved amine ranged from 98.0-99.4% e.e. depending on the conditions of the resolution.
  • amine 8 was first converted into the hydrochloride salt, which reacted with phosgene but not with the desired product (isocyanate 9).
  • isocyanate 9 For lab scale reactions, three equivalents of phosgene were necessary to completely consume the amine. At the prep scale, less was needed, it is believed that the longer addition time of the reagent (2 h vs. 0.5 h) required the use of more reagent.
  • the toluene solution of product did not degrade during the aqueous workup, but traces of bicarbonate catalyzed the decomposition of the oil concentrate to a mixture of amine and symmetrical urea. No racemization of the chiral center occurred at this step.
  • the (S)-alcohol 6 can be prepared using a chiral borane reduction of the ketone, ⁇ -propylpiperonylketone, with (R)- oxazaborolidine-borane complex [(R)-OAB-BH 3 ] as depicted above.
  • the ketone can be prepared from readily available starting materials using a conventional Friedel Crafts acylation reaction of the 1,3-benzodioxazole with butyryl anhydride or oxidation of the racemic alcohol 6, available from a conventional Grignard addition to piperonal.
  • a chiral borane such as the one used in the above reaction scheme was utilized so as to effect the chiral reduction.
  • [S-(R*,S*)]- N-[ 1 -( 1 ,3-benzodioxol-5-yl)butyl]-3,3-diethyl- 2-[4-[(4-methyl- 1 -piperazinyl)carbonyl]phenoxy]-4-oxo-l -azetidine- carboxamide can be chromatographed using a 50:1 loading of silica gel 60, 230-400 mesh, by eluting with EtOAc, which removed neutral components, and then switching to EtOAc/MeOH/TEA 88/10/2, which elutes product and basic impurities.
  • CH3CN H2 ⁇ with 0.1 % H3PO4 in each; gradient elution 50:50 to 90: 10 over 30 min, 254 nm, 25°C, 2.0 mL/min.
  • tR Product, 12.0 min.; Benzyl paraben, 5.4 min.
  • the mixture was filtered through Solka-Floc ( 1 Kg) to remove the catalyst and the Solka-Floc cake was washed with ethanol (2 x 1 L).
  • the ethanol solution was combined with the second batch (same scale).
  • the combined batch was evaporated in vacuo (30°C, 29 in Hg) to a volume of 20 L.
  • the concentrate was diluted with methyl t-butyl ether (10 L) and reconcentrated in vacuo to a solid slurry. Methyl t-butyl ether (10 L) was added and the product was filtered, washed with methyl t- butyl ether (20 L) and dried with a nitrogen stream giving 8.77 Kg of product for an 82% yield.
  • Step A Crystallization of the R. R diasteriomeric salt (3-R.R salt .
  • the R,R salt was filtered, washed with iPrOH:CH3CN (1 :1, 7 L) and dried with a nitrogen stream to give 1.88 Kg (33 % yield), with the desired (S)-enantiomer enriched in the mother liquours as an 76:24 mixture.
  • Step B Crystallization of the S.S diasteriomeric salt (3-S.S salt)
  • Step D Recrystallization of a second crop
  • the batch was diluted with MTBE (4 L), concentrated in vacuo to a crystalline slurry which was diluted with MTBE (8 L), filtered, washed with MTBE (1 L), and dried with a nitrogen stream to give 1.7 Kg of racemic acid.
  • the above resolution was repeated to provide 502 g of purified S,S diasteriomeric salt.
  • HOBT Hydroxybenzotriazole hydrate
  • DCC dicyclohexylcarbodimide
  • the reaction mixture was cooled to 18°C and filtered.
  • the cake was washed with /PrOAc (3 L) and the filtrate (19.5 L) was concentrated in vacuo to a volume of 8-9 L (concentration of amide was 25-30 wt %).
  • the titanium catalyst mixture was transferred to the 22 L flask by cannula and nitrogen pressure directly to the 22 L flask. (Addition was exothermic.)
  • the septum on the 22 L flask was exchanged for an addition funnel.
  • the piperonal solution was added by cannula and nitrogen pressure to the addition funnel and then slowly (approximately 20 minutes) to the contents of the flask while maintaining a temperature of -5 to -2°C.
  • the mixture was stirred at -2 to 0°C for 2-4 h at which time HPLC indicated ⁇ 1 % piperonal.
  • reaction was quenched by the slow addition of cold 2N HCl (8.8 L) while maintaining a temperature of 0-5°C. Initially, the addition of 2N HCl is very exothermic.
  • the mixture was transferred to a 50 L extraction vessel, and the layers were separated.
  • the acidic aqueous layer was extracted with a 97/16448 PC17US96/17215
  • optical purity was determined on an aliquot of the product solution by HPLC using the following procedure.
  • a 50 L multi-neck reaction vessel was equipped with mechanical stirrer, N2 inlet, thermocouple, glycol cooling, and addition funnel.
  • DBU 1,8- diazabicyclo[5.4.0]undec-7-ene
  • the reaction was stirred at room temperature for 16 h, at which time the reaction was complete.
  • the two liquid layers were diluted with water (7 L) and separated.
  • the lower aqueous layer was extracted with toluene (1 L).
  • the combined organic extracts were washed sequentially with water (7 L), cold IN HCl (4 L), water (4 L), and 10% NaCl (4 L).
  • the organic layer was dried widi anhydrous Na2S04 (700 g) for 1-2 h and filtered.
  • the cake was washed with toluene (2 x 0.2 L). The filtrate and washes were combined and used as is in the next step.
  • a 50 L multi-neck reaction vessel equipped with mechanical stirrer, N2 inlet, thermocouple, glycol cooling, and addition funnel was charged under N2 with dry THF (6.3 L), and the solvent was cooled to approximately 10°C.
  • a solution of IM lithium aluminum hydride (LAH) in toluene (6.0 L, 6.0 mol) was transferred from a metal container to the addition funnel and then added to die THF.
  • the azide solution from the previous Example 6 (1.36 Kg, 6.20 mol., approximately 12 L) was charged to the addition funnel in portions and added to the LAH over 1-2 hour at such a rate as to maintain the temperature at 23 ⁇ 2°C.
  • the reaction was aged until gas evolution ceased. The addition is mildly exothermic.
  • N2 evolution lasts about 6 h.
  • the reaction mixture was cooled to 0°C, and the excess LAH was quenched by the slow addition of water (400 mL) while maintaining the temperature ⁇ 5°C.
  • a solution of potassium sodium tartrate (8.5 kg) in water (40 L) was prepared in a 200 L extraction vessel and two liters was added to the reaction mixture, and another 6 L was reserved for washing.
  • the reaction mixture was transferred to the 200 L vessel, and the vessel was washed with the 6 L of wash solution. The wash was added to the vessel, and the mixture was stirred at room temperature for 16 h.
  • the product may be analyzed by HPLC using the following procedure:
  • tR ⁇ -propyl piperonylamine, 5.1 min.; ethyl analogue, 4.3 min.; toluene, 14.7 min.
  • the ratio of enantiomers is also determined by HPLC as follows:
  • the solution is analyzed by HPLC. If there is unreacted amine, the mixture must be reheated to 100°C and additional phosgene added. The presence of unreacted amine is also indicated by the formation of solids upon cooling of the reaction solution.
  • Inertsil ODS-2 250 x 4.6 mm; 5 ⁇ , 210 nm; CH3CN: 10 mM pH 6.5 potassium phosphate buffer: MeOH; isocratic 64:30:6, 1.0 ml/min.
  • IR Amine, 4.9 min.; isocyanate, l ⁇ .4 mm.; ethyl analogue, 7.8 min.; symmetrical urea, 6.5 min.; toluene, 7.2 min.
  • Step A Preparation of [S-(R*,S*)]- N-[l-(l ,3-benzodioxol-5- yl)butyl]-3,3-diethyl-2-[4-[(4-methyI-l-piperazinyl)- carbonyllphenoxy. -4-oxo- 1 -azetidinecarboxamide
  • the mixture was aged for a total of 60 min, then poured into a stirring mixture of water (100 L, containing 1 wt% sodium chloride) and iPrOAc (50 L).
  • the upper organic phase was washed with water (2 x 20 L, containing 1 wt% sodium chloride) and saturated aqueous sodium chloride (10 L).
  • the organic phase was concentrated in vacuo to 40 L, diluted with iPrOAc (20 L) and reconcentrated, in order to dry the solution and remove acetonitrile. HPLC assay showed that no loss of material occurred.
  • the iPrOAc solution was filtered through a 5 ⁇ line-filter into a 20 L round bottomed flask, and concentrated in vacuo to -6 L.
  • the concentrate was diluted with MTBE (4 L), reconcentrated and diluted with MTBE (4 L). After dilution to 11 L total volume, the mixture was aged for lh at 20°C.
  • Step B [S-(R*,S*)]- N-[l-(l,3-benzodioxol-5-yl)butyl]-3,3-diethyl- 2-[4-[(4-methyl-l-piperazinyl)carbonyI]phenoxy]-4-oxo-l- azetidinecarhoxamide (I)
  • HPLC assav lnertsil ODS-2, 250 x 4.6 mm; CH3CN: Water (20 mM TEA + HOAc to pH 4.5); 1.5 mL/min; 25°C, 230 nm tR: Ethyl analogue, 8.06 min.; title compound, 12.16 min.
  • Example 1 The product of Example 1 can be resolved using a preferential crystallization method as disclosed in the Dolling, U. H., et al. J. Org. Chem, Vol. 43, No. 9, pp. 1634 (1978) and citations contained therein.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Cette invention porte sur un procédé de préparation d'azétidinone à substitution répondant à la formule (I) comprenant une synthèse convergente.
EP96937014A 1995-10-31 1996-10-28 Procede de preparation d'azetidinones a substitution Withdrawn EP0858460A1 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US608795P 1995-10-31 1995-10-31
US6087P 1995-10-31
GBGB9603560.5A GB9603560D0 (en) 1996-02-20 1996-02-20 Process for preparing substituted azetidinones
GB9603560 1996-02-20
PCT/US1996/017215 WO1997016448A1 (fr) 1995-10-31 1996-10-28 Procede de preparation d'azetidinones a substitution

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EP0858460A1 true EP0858460A1 (fr) 1998-08-19

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EP (1) EP0858460A1 (fr)
JP (1) JP3081250B2 (fr)
AU (1) AU701386B2 (fr)
CA (1) CA2234640A1 (fr)
WO (1) WO1997016448A1 (fr)

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KR100543614B1 (ko) * 1997-06-10 2006-01-20 신톤 비.브이. 4-페닐피페리딘 화합물
CH689805A8 (fr) * 1998-07-02 2000-02-29 Smithkline Beecham Plc Méthanesulfonate de paroxétine, procédé pour sa préparation et compositions pharmaceutiques le contenant.
WO2000012474A1 (fr) * 1998-08-31 2000-03-09 Du Pont Pharmaceuticals Company Procede efficace de preparation d'un inhibiteur d'elastase leucocytaire humaine

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Publication number Priority date Publication date Assignee Title
US5348953A (en) * 1991-06-25 1994-09-20 Merck & Co., Inc. Substituted azetidinones as anti-inflammatory and antidegenerative agents
US5149838A (en) * 1991-09-20 1992-09-22 Merck & Co., Inc. Intermediates for substituted azetidinones useful as anti-inflammatory and antidegenerative agents
CA2108584C (fr) * 1992-10-27 1998-11-24 James B. Doherty Utilisation d'azetidinones substituees comme anti-inflammatoires et agents anti-degeneratifs

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CA2234640A1 (fr) 1997-05-09
JPH10512593A (ja) 1998-12-02
AU701386B2 (en) 1999-01-28
AU7478596A (en) 1997-05-22
JP3081250B2 (ja) 2000-08-28
WO1997016448A1 (fr) 1997-05-09

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