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WO2006137773A1 - Procédé d'isolement de 4-(oxiranylméthoxy)benzonitriles - Google Patents

Procédé d'isolement de 4-(oxiranylméthoxy)benzonitriles Download PDF

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WO2006137773A1
WO2006137773A1 PCT/SE2006/000693 SE2006000693W WO2006137773A1 WO 2006137773 A1 WO2006137773 A1 WO 2006137773A1 SE 2006000693 W SE2006000693 W SE 2006000693W WO 2006137773 A1 WO2006137773 A1 WO 2006137773A1
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compound
formula
mixture
alkyl
compounds
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Silke Erbeck
Oscar-Paul Kiriacescu
Anders Kronström
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AstraZeneca AB
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AstraZeneca AB
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—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
    • C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
    • C07D303/02—Compounds containing oxirane rings
    • C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
    • C07D303/18—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by etherified hydroxyl radicals
    • C07D303/20—Ethers with hydroxy compounds containing no oxirane rings
    • C07D303/22—Ethers with hydroxy compounds containing no oxirane rings with monohydroxy compounds

Definitions

  • the invention relates to novel processes for the isolation of inter alia 4-(oxiranyl- methoxy)benzonitriles from a mixture comprising such benzonitriles and closely related "dimeric" compounds (such as l,l-di(4-cyanophenoxymethyl)methanol).
  • a process is also provided for the isolation of the "dimeric" compounds from such mixtures.
  • the benzonitriles obtained via the process of the invention may be employed as intermediates in the preparation of N-substituted oxabispidines having antiarrhythmic activity.
  • Oxiranyhnethoxyarene and oxiranylmethoxyheteroarene compounds are useful intermediates in the preparation of biologically active molecules, for example, those containing the 3-aryloxy-2-hydroxypropyl moiety.
  • the antiarrhythmic compound tert-butyl 2- ⁇ 7-[(2 ⁇ S)-3-(4-cyanophenoxy)-2-hydroxy- propylJ-P-oxa-SjT-diazabicyclop.S.lJnon-S-ylJethylcarbamate is prepared using 4-(oxiranylmethoxy)- benzonitrile, which is exactly such an epoxide intermediate.
  • a "dimeric" impurity e.g. a l,l-di(aryloxymethyl)methanol compound
  • Methods for the separation of the target epoxide from this dimeric impurity are not disclosed in the above- mentioned prior art.
  • VOCs volatile organic compounds
  • R 1 represents H or C 1-6 alkyl
  • R 2 represents phenyl or pyridyl, both of which groups are optionally substituted by one or more substituents selected from -OH, cyano, halo, nitro, C 1-6 alkyl (optionally terminated by -N(H)C(O)OR 3a ), C 1-6 alkoxy, -N(R 4a )R 4b , -C(O)R 4c ,
  • R 3a to R 3d independently represent C 1-6 alkyl
  • R 4a and R 4b independently represent H, C 1-6 alkyl or together represent C 3-6 alkylene, resulting in a four- to seven-membered nitrogen-containing ring;
  • R 4c to R 4 ° independently represent H or C 1-6 alkyl
  • selective dissolve when used herein in relation to compounds of formula I in crystalline form includes references to dissolving crystalline material, greater than 75% of which is a compound of formula I (e.g. greater than 85%, preferably greater than 90% (such as greater than 91, 92, 93, 94 or, particularly, 95%) of which is a compound of formula I).
  • isolation includes references to obtaining the compound of formula I in a form that is substantially (e.g. 95, 96, 97 or 98% or, particularly, at least 99%) free of the compound of formula II.
  • aromatic hydrocarbon includes references to one or more aromatic hydrocarbons such as benzene and mono-, di- or tri- alkylbenzenes (e.g. mesitylene, xylene, or toluene).
  • a particularly preferred aromatic hydrocarbon is toluene.
  • alkyl groups and alkoxy groups as defined herein may be straight-chain or, when there is a sufficient number (i.e. a minimum of three) of carbon atoms be branched-chain, and/or cyclic. Further, when there is a sufficient number (i.e. a minimum of four) of carbon atoms, such alkyl and alkoxy groups may also be part cyclic/acyclic.
  • alkyl and alkoxy groups may also be saturated or, when there is a sufficient number (i.e. a minimum of two) of carbon atoms, be unsaturated and/or interrupted by one or more oxygen and/or sulfur atoms. Unless otherwise specified, alkyl and alkoxy groups may also be substituted by one or more halo, and especially fluoro, atoms.
  • alkylene groups as defined herein may be straight- chain or, when there is a sufficient number (i.e. a minimum of two) of carbon atoms, be branched-chain. Such alkylene chains may also be saturated or, when there is a sufficient number (i.e. a minimum of two) of carbon atoms, be unsaturated and/or interrupted by one or more oxygen and/or sulfur atoms. Unless otherwise specified, alkylene groups may also be substituted by one or more halo atoms.
  • aryl when used herein, includes C 6-13 aryl (e.g. C 6-10 ) groups. Such groups may be monocyclic, bicyclic or tricylic and, when polycyclic, be either wholly or partly aromatic.
  • C 6-13 aryl groups that may be mentioned include phenyl, naphthyl, 1,2,3,4-tetrahydrona ⁇ hthyl, indanyl, indenyl, fluorenyl and the like.
  • the point of attachment of substituents on aryl groups may be via any carbon atom of the ring system.
  • aryl groups may be substituted by one or more substituents selected from -OH, cyano, halo, nitro, C 1-6 alkyl, C 1-6 .alkoxy, -N(R 4a )R 4b , -C(O)R 4c , -C(O)OR 4d , -C(O)N(R 4e )R 4f , -N(R 4g )C(O)R 4h , -N(R 4m )S(O) 2 R 3b , -S(O) 2 N(R 4B )(R 4 °), -S(O) 2 R 30 and/or -OS(O) 2 R 3d , (wherein R 3b to R 3d and R 4a to R 4m are as hereinbefore defined).
  • aryl groups are preferably substituted by between one and three substituents.
  • halo when used herein, includes fluoro, chloro, bro
  • the compounds employed in or produced by the process of the invention may also contain one or more asymmetric carbon atoms and may therefore exhibit optical and/or diastereoisomerism.
  • the process of the invention thus encompasses the use or production of such compounds in any of their optical or diastereoisomeric forms, or in mixtures of any such forms.
  • Preferred compounds of formula I and II include those in which: R 1 represents H or C 1-3 alkyl;
  • R represents phenyl or pyridyl, both of which groups are optionally substituted by one or more substituents selected from cyano, halo, nitro, C 1-6 alkyl, C 1-6 alkoxy, -NH 2 , -C(O)N(R 4e )R 4f , -N(R 4g )C(O)R 4h , and -N(R 4m )S(O) 2 R 3b ; R 3b represents C 1-3 alkyl;
  • R 4e to R 4m independently represent H or C 1-4 alkyl.
  • More preferred compounds of formula I and II include those in which: R 1 represents H or methyl; R 2 represents pyridyl or phenyl, which latter group is optionally substituted by one to three substituents selected from cyano, nitro, C 1 ⁇ alkoxy, NH 2 and -N(H)S(O) 2 CH 3 .
  • R 1 represents H
  • R 2 represents phenyl, substituted by cyano in the ortho- and/or, in particular in the para-position relative to the point of attachment to the rest of the molecule (e.g. para-cy anophenyl) .
  • Especially preferred compounds of formula I include 4-(oxiranylmethoxy)- benzonitrile, such as 4-[(2>S)-oxiranyhnethoxy]benzomtrile (i.e.
  • groups R and R take the same definition at each occurrence (i.e. for the compound of formula I and compound of formula II).
  • the solvent system utilised in step (1) of process (a) comprises an aromatic hydrocarbon, but may further comprise other organic solvents, such as C 2-6 alkyl alcohols, di(C 1 - 6 alkyl) ethers (such as di(C 1-4 alkyl) ethers, e.g. diethyl ether and/or diisopropyl ether), C 1-6 alkyl acetates (such as C 1-4 alkyl acetates, e.g. ethyl acetate), chlorinated hydrocarbons (e.g. chlorinated C 1-4 alkanes such as dichloromethane, chloroform and carbon tetrachloride), hexane and/or petroleum ether.
  • these other organic solvents preferably comprise less than 50% v/v (such as less than 25% and, more particularly, less than 15% (e.g. less that 5%) v/v) of the solvent system.
  • the solvent system employed in step (1) i.e. that used to dissolve the compounds of formula I and II
  • the solvent system employed in step (1) consists essentially of an aromatic hydrocarbon.
  • the co-crystallisation is effected by cooling the solution obtained from step (1) to any temperature from -10 to 4O 0 C, preferably to a sub-ambient temperature (e.g. to any temperature from -5 to 15°C, such as to any temperature from 6 to 12°C and/or any temperature from -5 to 2°C (e.g. about 0 0 C)).
  • the co-crystallisation may effected by cooling the solution obtained from step (1) to any temperature from -40 to 5°C, preferably to any temperature from -35 to 0 0 C, such as to any temperature from -30 to -1O 0 C (e.g. any temperature from -25 to -15°C, such as about -20 0 C).
  • the selective dissolution of crystalline compound of formula I is preferably effected by warming the mixture of crystalline material and mother liquor to any temperature from 10 to 35 0 C, such as from 15 to 25 0 C (e.g. from 18 to 25°C, such as about 2O 0 C).
  • step (4) of process (a) the crystalline and solvent phases may be separated by standard methods known to those skilled in the art (e.g. by decanting or, preferably, by filtering the mixture).
  • step (5) of process (a) may be effected from any solvent system, but is preferably performed in a solvent system comprising a C 2-6 alkyl alcohol and, optionally, up to 50% v/v of an aromatic hydrocarbon.
  • step (5) of process (a) maybe identical to process (b) above.
  • step (5) is performed using a solvent system consisting essentially of a C 2-6 alkyl alcohol and up to 25% v/v (e.g. up to 20%, such as up to 15% or, particularly, up to 10%) of an aromatic hydrocarbon.
  • C 2-6 alkyl alcohols that may be employed in the solvent system used in step (5) of process (a) include ethanol, n-propanol, n-butanol, isobutanol, s-butanol, or, particularly, isopropanol.
  • the solution of the compound of formula I may be cooled to sub-ambient temperature, such as to any temperature from -15 to 2O 0 C (e.g. from -10 to 1O 0 C, such as from -5 to 5°C or, particularly, about 0 0 C).
  • sub-ambient temperature such as to any temperature from -15 to 2O 0 C (e.g. from -10 to 1O 0 C, such as from -5 to 5°C or, particularly, about 0 0 C).
  • cooling of the (co-)crystallisation mixtures of steps (2) and (5) may take place over any period of time from 10 minutes to 20 hours, such as from 30 minutes to 5 hours (e.g. about 5 or 6 hours for step (2) and about 2 hours for step (5)), although the skilled person will appreciate that the cooling period will depend upon inter alia the temperature from and to which the crystallisation mixture is cooled and upon the volume and type of solvent employed.
  • step (D) isolating the crystalline compound of formula II obtained from step (C).
  • preferred compounds of formulae I and II include those indicated hereinbefore in respect of processes (a) and (b).
  • steps (A) to (C) of this process are equivalent to steps (1) to (3) of process (a) and so may be performed in the same manner as previously indicated for those steps (i.e. the same preferences apply).
  • Isolation of the compound of formula II may be performed using known techniques (e.g. by decanting solvent or, preferably, by filtration). .
  • a second embodiment of the present invention involves the isolation of a compound of formula I (from a mixture with a compound of formula II) by crystallisation from a solvent system comprising a C 2-6 alkyl alcohol.
  • the C 2-6 alkyl alcohols that may be utilised in this embodiment of the invention include ethanol, n-propanol, isopropanol, n-butanol, isobutanol, s-butanol, t-butanol, pentanol (including n-pentanol) and 4-methyl-2-pentanol.
  • Particularly preferred alcohols include C 3-4 alcohols such as isopropanol and n-butanol.
  • the solvent system employed in step (i) of process (b) comprises a C 2-6 alkyl alcohol, but may further comprise other organic solvents, such as di(C 1-6 alkyl) ethers (such as di(C 1-4 alkyl) ethers, e.g. diethyl ether and/or diisopropyl ether), C 1-6 alkyl acetates (such as Ci -4 alkyl acetates, e.g. ethyl acetate), chlorinated hydrocarbons (e.g. chlorinated Ci -4 alkanes such as dichloromethane, chloroform and carbon tetrachloride), hexane and/or petroleum ether.
  • these other organic solvents preferably comprise less than 50% v/v (such as less than 25% and, more particularly, less than 15% (e.g. less than 5%) v/v of the solvent system.
  • the solvent system consists essentially of C 2-6 alkyl alcohol and, optionally, up to 25% v/v of an aromatic hydrocarbon. More particularly, the aromatic hydrocarbon may be present at up to 15% (such as up to 10 or, more particularly, 5%) v/v.
  • the solvent system of step (i) of process (b) consists essentially of a C 2-6 alkyl alcohol and no more than 3% v/v of an aromatic hydrocarbon.
  • step (i) of process (b) i.e. the preparation of a solution
  • the mixture of compounds of formulae I and II and the solvent system may be heated (e.g. to any temperature from 35 0 C to reflux, such as from 35 to 80 0 C (e.g. from 35 to 6O 0 C)) in order to effect substantial dissolution of the compounds.
  • Step (ii) of process (b) involves a selective crystallisation of the compound of formula I.
  • the crystallisation of the compound of formula I is "selective" in that the crystalline material obtained is a compound of formula I that is substantially free of the compound of formula II.
  • the crystallisation of step (ii) of process (b) is promoted by cooling the solution obtained from step (i).
  • the crystallisation may be promoted by cooling to any temperature from -10 to 4O 0 C, such as from 10 to 30 0 C (e.g. from 15 to 25°C or, more particularly, from 20 to 25°C (e.g. 23 or 25 0 C)).
  • cooling of the crystallisation mixture may take place over any time period from 30 minutes to 20 hours, such as from 5 to 15 hours (e.g. about 10 hours), although the skilled person will appreciate that the cooling period will depend upon inter alia the temperature from and to which the crystallisation mixture is cooled and upon the volume and type of solvent employed.
  • crystals of the compound of formula I formed using process (b) above may be isolated by means known to those skilled in the art (e.g. by filtration and/or evaporation of solvents). Such crystals may then also be washed with solvent, such as a di(C 1-6 alkyl) ether (e.g. diisopropyl ether, which is a low-boiling solvent that provides for facile drying of the crystalline product).
  • solvent such as a di(C 1-6 alkyl) ether (e.g. diisopropyl ether, which is a low-boiling solvent that provides for facile drying of the crystalline product).
  • the mixture of compounds of formulae I and II (i.e. the mixture that is separated by the processes described above) is prepared by reaction of a compound of formula III,
  • L 1 represents a leaving group and R 1 is as hereinbefore defined.
  • Preferred compounds of formula III include those in which R is as hereinbefore defined in respect of compounds of formulae I and II.
  • Preferred compounds of formula IV include those in which:
  • R 1 is as hereinbefore defined in respect of compounds of formulae I and II;
  • L 1 represents halo (especially chloro); the compound of formula IV is in enantiomerically enriched or enantiomerically pure (e.g. S- or, particularly, R- form).
  • reaction between compounds of formula III and IV may be performed under conditions known to those skilled in the art, such as those described in WO 01/28992 and WO 02/83690, the disclosures of which are hereby incorporated by reference.
  • the reaction may be performed in the presence of a suitable solvent (e.g. acetonitrile) and a suitable base (e.g. potassium carbonate) at elevated temperature (e.g. reflux).
  • a suitable solvent e.g. acetonitrile
  • a suitable base e.g. potassium carbonate
  • the reaction is performed using a biphasic solvent system comprising an aromatic hydrocarbon and aqueous base.
  • preferred bases include alkali metal hydroxides, alkali metal carbonates and/or alkali metal hydrogencarbonates.
  • Particularly preferred bases include alkali metal hydroxides, such as sodium hydroxide.
  • the quantity of base employed is preferably at least equimolar compared with the quantity of the compound of formula III employed.
  • the stoichiometric ratio of base to the compound of formula III is preferably any value from 1:1 to 3:1, such as any value from 1:1 to 2:1 (e.g. about 12:10).
  • the stoichiometric ratio of the compound of formula III to the compound of formula IV is preferably any value from 1:1 to 1:3. In particular, it is preferred that a molar excess of the compound of formula IV is employed and, in this respect, the stoichiometric ratio is most preferably between 1 : 1 and 1 :2 (e.g. about 10:18).
  • acids and bases that provide or accept only one mole of hydrogen ions per mole of acid or base, respectively.
  • the use of acids and bases having the ability to donate or accept more than one mole of hydrogen ions is contemplated and requires corresponding recalculation of the quoted molar equivalents and stoichiometric ratios.
  • the acid employed is diprotic
  • a dibasic compound e.g. Na 2 CO 3
  • a monobasic compound e.g. NaHCO 3
  • the reaction between the compounds of formula III and IV may be performed at elevated temperature, such as at any temperature from 30°C to reflux or, preferably, from 45°C (e.g. 60 0 C) to reflux. When a mixture of toluene and water are employed as the solvent system, the reaction is most preferably performed at about 7O 0 C.
  • the base may be introduced to the reaction vessel in substantially one portion or, preferably, in multiple portions. Further, the base may be introduced to the reaction vessel before, at the same time as or, preferably, after the solvent and compounds of formulae III and TV. It is preferred that the base is added to a mixture of solvent and compounds of formulae II and III over any time period from 30 minutes to 12 hours, such as from 2 to 8 (e.g. 6) hours.
  • the phases are separated when the reaction between the compounds of formulae III and IV is substantially complete.
  • the organic (e.g. aromatic hydrocarbon) phase obtained after such separation will contain a mixture of compounds of formulae I and II and, as such, may be employed in any of the isolation processes described above.
  • a solution in an aromatic hydrocarbon is obtained by way of such separation, this may be employed directly in process (a) above (optionally following reduction of the volume of solvent, for example by reduced pressure distillation).
  • such a solution may be employed in the process for isolating the compound of formula II.
  • any of the embodiments of the invention may, if desired (e.g. to further reduce traces of compounds of formula II), include an additional recrystallisation step (after isolation of the compound of formula I) using any of the solvent systems identified above in respect of crystallisation of compounds of formula I.
  • Suitable protecting groups for hydroxy include trialkylsilyl and diarylalkyl- silyl groups (e.g. tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl and alkylcarbonyl groups (e.g. methyl- and ethylcarbonyl groups).
  • the processes of the invention may have the advantage that the compounds of formulae I and/or II is/are produced in higher purity, in a more convenient (i.e. easy to handle) form, from more convenient (i.e. easy to handle) precursors, at a lower cost and/or with less usage and/or wastage of materials (including reagents and solvents) compared to the procedures disclosed in the prior art.
  • the processes of the invention allow for the production of a compound of formula I in acceptable purity and by way of a route avoiding the use of VOCs and large stoichiometric excesses of epihalohydrins.
  • substantially when used herein, may mean greater than 50%, preferably greater than 75%, for example greater then 95%, and particularly greater than 99%.
  • relative volume refers to the volume (in millilitres) per gram of reagent employed.
  • the toluene layer was then concentrated (by reduced pressure distillation at a temperature of less than 65°C) such that the volume of toluene was reduced by 1 relative volume.
  • the remaining toluene phase was then filtered (whilst still hot (55 to 60 0 C)) to a clean vessel and the volume of toluene was then reduced by 5 relative volumes through a further reduced pressure distillation (in the above-described manner).
  • ra-Butanol (9 relative volumes) was then added and the combined solvent phase was reduced in volume (by another 5 relative volumes) by yet another reduced pressure distillation (in the above-described manner).
  • step (b) Purification The solvent phase remaining from step (a) above was cooled to ambient temperature, which promoted crystallisation of the title compound (optionally aided by seeding). The crystalline compound was washed with diisopropyl ether (3 x 3 relative volumes), dried on the filter and then dried in vacuo at 50°C. This provided the title compound in 63% yield (18.5 g), with the ratio of title compound: undesired dimer being 99.49:0.51.
  • the biphasic solution was heated to 7O 0 C ⁇ 3 0 C and aqueous sodium hydroxide (30% w/w, 125.4 g, 94 mL, 0.9405 mole, 1.12 eq.) was added over a period of 6 hours.
  • the reaction mixture was cooled to 25°C and the two phases were allowed to settle for 30 minutes.
  • An analytical sample was taken from the organic phase and was analyzed by GC.
  • the organic phase was then separated and concentrated under reduced pressure (100 mbar) to a residual volume of 850 mL.
  • the internal temperature was between 42 0 C and 45°C and Hie vapour temperature was between 35°C and 4O 0 C.
  • the mixture was filtered and toluene (86.7 g, 100 mL) was added.
  • the mixture was concentrated under reduced pressure (100 mbar) until a residual volume of 430 mL.
  • the internal temperature was between 45°C and 50°C and the vapour temperature was between 43°C and 45°C.
  • Butan-1-ol (729.0 g, 900 mL) was added and the mixture was concentrated under reduced pressure (100 mbar to 70 mbar) to a residual volume of 850 mL.
  • the internal temperature was between 50°C and 55 0 C and the vapour temperature was between 43 0 C and 52 0 C.
  • step (b) Purification Reactor N°l: A portion of the solution generated in step (a) above (166 g) was added to the preheated vessel and stirred at 6O 0 C for 1.5 hours. Then the solution was cooled to 40 0 C in 30 minutes, seeded and stirred at this temperature for 30 minutes. Finally, the solution was cooled to 25°C in 1 hour and directly filtered.
  • step (a) above A portion of the solution generated in step (a) above (166 g) was added to the preheated vessel and stirred at 6O 0 C for 1.5 hours. Then the solution was cooled to 40°C in 30 minutes, seeded and stirred at this temperature for 30 minutes. Finally, the solution was cooled to 25°C in 4 hour and directly filtered. The collected product was washed three times with of diisopropyl ether (3 x 75 mL) to give 27.2 g of a white solid. This solid was dried under vacuum at 50°C for 18 hours to yield 21.6 g (58.7 %) of compound.
  • step (a) above 166 g was added to the preheated vessel and stirred at 6O 0 C for 1.5 hours. Then the solution was cooled to 40 0 C in 30 minutes, seeded and stirred at this temperature for 30 minutes. Finally, the solution was cooled to 25°C in 1 hour and directly filtered. The collected product was washed three times with of diisopropyl ether (3 x 75 mL) to give 27.8 g of a white solid. This solid was dried under vacuum at 50 0 C for 18 hours to yield 21.6 g (58.7 %) of compound.
  • the crude mixture was prepared by combining the products obtained from the following two reactions (in which relative weights and volumes are determined by reference to the initial quantity of 4-cyanophenol utilised (36.0 kg in each case)).
  • a 1000 L reaction vessel was charged with 4-cyanophenol (36.0 kg, 0.30222 kmole, 1.00 wt), toluene (237.2 kg, 273.6 L, 7.60 rel. vol.) and demineralized water (205.2 kg, 205.2 L, 5.70 rel. vol.) at 22.5 0 C ⁇ 2.5°C.
  • 4-cyanophenol 36.0 kg, 0.30222 kmole, 1.00 wt
  • toluene 237.2 kg, 273.6 L, 7.60 rel. vol.
  • demineralized water (205.2 kg, 205.2 L, 5.70 rel. vol.
  • Aqueous sodium hydroxide (30% w/w, 44.3 kg, 33.3 L, 0.33244 kmole, 1.10 equiv.) was added at 70°C ⁇ 2°C over approximately 6 hours, then the mixture was cooled to 22.5°C ⁇ 2.5°C and settled. The phases were separated (the aqueous layer was discarded) and the organic phase was washed with demineralized water (72.0 kg, 72.0 L, 2.00 rel. vol.). The crude toluene solution (299.8 kg, ⁇ 315.5 L) was discharged into drums and analyzed by GC, using an external standard (solution found to be -14.46% w/w cyanoepoxide, i.e.
  • reaction vessel was rinsed with toluene (31.2 kg, 36.0 L, 1.00 rel. vol.), giving a total weight of toluene solution (after the rinse) of 331.0 kg.
  • a second batch of crude material was prepared according to the procedure described above for Reaction 1, and this afforded 301.5 kg ( ⁇ 317.4 L) of a toluene solution (GC analysis using an external standard showed this to be -14.50% w/w cyanoepoxide, i.e. 43.7 kg, which equates to a yield of 82.5%), which, after the toluene rinse rose to a total weight of toluene solution of 332.7 kg.
  • a 1000 L reaction vessel was charged with the toluene solutions of crude products from Reactions 1 and 2 of step (a) above (total of 663.7 kg, -698.6 L).
  • the solution was then concentrated in vacuo (at a pressure in the region of 1 to 7 kPa (10 to 70 mbar)), at between 53°C and 58°C, to provide a residue volume of approximately 1.47 rel. vol.
  • Toluene (312.1 kg, 360.0 L, 5.00 rel. vol.) was added to the oily residue and the solution concentrated again in vacuo (at a pressure in the region of 1 to 7 kPa (10 to 70 mbar)), at between 53°C and 58°C, to again provide a residue volume of approximately 1.47 rel.
  • the mixture thereby obtained was then heated to between 18°C and 25°C over 1 hour, celtrox (7.2 kg, 0.1 rel. wt.) was added and the suspension stirred at the same temperature for additional 3 hours.
  • the mixture was filtered through a lens filter equipped with a bed of celtrox (3.6 kg, 0.05 rel. wt.) overlying a glass fibre paper (GF 92) intermediate layer and a 0.8 micron filter paper (1575) base layer (in this filtration step, Celite® can be used in place of celtrox).
  • the filtrate was then passed through a cartridge filter having an absolute porosity of 0.3 microns.
  • the line was washed with toluene (31.2 kg, 36.0 L, 0.50 rel.
  • the resulting mixture was seeded with pure, crystalline 4-[(25)-oxiranylmethoxy]-benzonitrile, at between 32 and 36°C, stirred at the same temperature for 1 hour, cooled to 0 ⁇ 2°C, and finally stirred at this temperature for additional 2 hours (to achieve complete crystallization).
  • the resulting mixture was centrifuged, the line and the crystalline product washed twice with cold isopropanol (2 x 28.3 kg, 2 x 36.0 L, 2 x 0.50 rel. vol.) and then the wet product was dried in vacuo at 50 ⁇ 2°C to provide 73.8 kg (69.7%) of the title compound.
  • n-, s-, i-, t- and tert- have their usual meanings: normal, secondary, iso, and tertiary.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un procédé d'isolement d'un composé de formule I, [Formule chimique à insérer ici. Voir exemplaire papier] I ou d’un solvate dudit composé, à partir d'un mélange comprenant un composé de formule I et un composé de formule II, [Formule chimique à insérer ici. Voir exemplaire papier] II, le mélange des composés de formule I et de formule II pouvant être préparé par réaction d'un composé de formule III, R2-OH III avec un composé de formule IV, [Formule chimique à insérer ici. Voir exemplaire papier] IV, où R1, R2 et L1 sont tels que définis dans la description de l’invention.
PCT/SE2006/000693 2005-06-20 2006-06-12 Procédé d'isolement de 4-(oxiranylméthoxy)benzonitriles Ceased WO2006137773A1 (fr)

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SE0501430 2005-06-20
SE0501430-3 2005-06-20

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WO2006137773A1 true WO2006137773A1 (fr) 2006-12-28

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AR (1) AR057364A1 (fr)
TW (1) TW200710087A (fr)
WO (1) WO2006137773A1 (fr)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS63174981A (ja) * 1987-01-14 1988-07-19 Yuka Shell Epoxy Kk エポキシ化合物の精製方法
DD283501A7 (de) * 1988-07-29 1990-10-17 Veb Arzneimittelwerk Dresden,Dd Verfahren zur herstellung von reinem 1-(4-nitrophenoxy)-2,3-epoxy-propan
EP0435068A2 (fr) * 1989-12-27 1991-07-03 Daiso Co., Ltd. Procédé pour la production d'aténolol optiquement actif et un intermédiaire de celui-ci
EP0930307A1 (fr) * 1996-09-18 1999-07-21 Daiso Co., Ltd. Procede de preparation d'ethers glycidyliques
JP2000239346A (ja) * 1999-02-17 2000-09-05 Yuka Shell Epoxy Kk エポキシ化合物の精製方法
WO2002083690A1 (fr) * 2001-04-12 2002-10-24 Astrazeneca Ab Preparation d'oxabispidines

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS63174981A (ja) * 1987-01-14 1988-07-19 Yuka Shell Epoxy Kk エポキシ化合物の精製方法
DD283501A7 (de) * 1988-07-29 1990-10-17 Veb Arzneimittelwerk Dresden,Dd Verfahren zur herstellung von reinem 1-(4-nitrophenoxy)-2,3-epoxy-propan
EP0435068A2 (fr) * 1989-12-27 1991-07-03 Daiso Co., Ltd. Procédé pour la production d'aténolol optiquement actif et un intermédiaire de celui-ci
EP0930307A1 (fr) * 1996-09-18 1999-07-21 Daiso Co., Ltd. Procede de preparation d'ethers glycidyliques
JP2000239346A (ja) * 1999-02-17 2000-09-05 Yuka Shell Epoxy Kk エポキシ化合物の精製方法
WO2002083690A1 (fr) * 2001-04-12 2002-10-24 Astrazeneca Ab Preparation d'oxabispidines

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DATABASE WPI Week 198834, Derwent World Patents Index; Class A21, AN 1988-240157, XP003005086 *
DATABASE WPI Week 200065, Derwent World Patents Index; Class A21, AN 2000-667291, XP003005087 *

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AR057364A1 (es) 2007-11-28
TW200710087A (en) 2007-03-16

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