WO2006137773A1 - Process for the isolation of 4-(oxiranylmethoxy)-benzonitriles - Google Patents

Abstract

There is provided a process for the isolation of a compound of formula I, or a solvate thereof, from a mixture comprising a compound of formula I and a compound of formula II, wherein the mixture of compounds of formulae I and II may be prepared by reaction of a compound of formula III, R2-OH III with a compound of formula IV, and wherein R1, R2 and L1 have meanings given in the description.

Description

PROCESS FOR THE ISOLATION OF 4-(OXIRANYLMETHOXY)- BENZONITRILES

Field of the Invention

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.

Background and Prior Art

Oxiranyhnethoxyarene and oxiranylmethoxyheteroarene compounds are useful intermediates in the preparation of biologically active molecules, for example, those containing the 3-aryloxy-2-hydroxypropyl moiety. Indeed, the antiarrhythmic compound tert-butyl 2-{7-[(2<S)-3-(4-cyanophenoxy)-2-hydroxy- propylJ-P-oxa-SjT-diazabicyclop.S.lJnon-S-ylJethylcarbamate, as disclosed in WO 01/28992 and WO 02/83690, is prepared using 4-(oxiranylmethoxy)- benzonitrile, which is exactly such an epoxide intermediate.

An efficient process for the preparation of 4-(oxiranyhnethoxy)benzonitrile is disclosed in both of the above-mentioned documents, which method comprises reaction of cyanophenol with epichlorohydrin. However, the specific embodiment of this process that is disclosed in WO 01/28992 and WO 02/83690 utilises: (i) a solvent (acetonitrile) that, due to its volatility, is undesirable for preparing 4-(oxiranyhnethoxy)benzonitrile on a large scale and to modern health and safety standards; and

(ii) an undesirably large excess of epichlorohydrin. Factor (ii) above presents a particular cost of goods problem if epichlorohydrin is employed in enantiomerically pure (i.e. R- or S-) form (so as to provide enantiomerically pure 4-(oxiranylmethoxy)benzonitrile).

Moreover, it has been found by the applicants that methods disclosed in WO 01/28992 and WO 02/83690 result in the production of significant levels (e.g. about 10%) of a "dimeric" impurity (e.g. a l,l-di(aryloxymethyl)methanol compound) that is difficult to separate from the target epoxide and that can interfere in further reactions of that epoxide. Methods for the separation of the target epoxide from this dimeric impurity are not disclosed in the above- mentioned prior art.

Thus, there remains a need for a process for the production of oxiranylmethoxy- arene and -heteroarene compounds that:

(a) avoids the use of:

(I) large numbers of molar equivalents of epichlorohydrin; and, optionally

(II) volatile organic compounds (VOCs); but yet

(b) still provides the target compound in an acceptable level of purity.

Although a preparation process that employs a toluene/aqueous base solvent system and less than 3 molar equivalents of epichlorohydrin meets requirement (a) above, such reaction conditions have been found by the applicant not to meet condition (b) above (i.e. levels of dimeric impurity were still found to be in the region of 10%).

The applicant has now surprisingly found simple and effective crystallisation methods that effect separation of oxiranylmethoxy-arene and -heteroarene compounds from their "dimeric" analogues and thus allow for the provision of a process that (overall) meets requirements (a) and (b) above. Disclosure of the Invention

According to the invention, there is therefore provided a process for the isolation of a compound of formula I,

or a solvate thereof,

from a mixture comprising a compound of formula I and a compound of formula π,

^{H0 R} wherein, independently at each occurrence:

R¹ represents H or C_1-6 alkyl;

R² 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,

-C(O)OR^4d, -C(O)N(R^4e)R^4f, -N(R^4g)C(O)R^4h, -N(R⁴ⁱ)C(O)N(R^4j)R^4k,

-N(R^4m)S(O)₂R^3b, -S(O)₂N(R⁴ⁿ)(R⁴°), -S(O)₂R^3c, -OS(O)₂R^3d and/or aryl;

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 R⁴° independently represent H or C_1-6 alkyl;

wherein each aryl group, unless otherwise specified, is optionally substituted;

which process comprises:

(a) (1) preparing a solution of the mixture of compounds of formulae I and II in a solvent system comprising an aromatic hydrocarbon; (2) co-crystallising the compounds of formulae I and II from that solution, thereby producing a mixture of crystalline material and mother liquor;

(3) warming the resulting mixture to selectively dissolve crystalline compound of formula I into the mother liquor; (4) separating the resulting solvent phase and crystalline product (i.e. compound of formula II); and

(5) crystallising the compound of formula I contained in the solvent phase; or

(b) (i) preparing a solution of the mixture of compounds of formulae I and II in a solvent system comprising a C_2-6 (e.g. C_3-6) alkyl alcohol; and then (ii) crystallising the compound of formula I from that solution,

which process is hereinafter referred to as "the process of the invention".

The term "selectively 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).

When used herein with respect to compounds of formula I, the term "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.

Further, when used herein, the term "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. Unless otherwise specified, 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. Such 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.

Unless otherwise specified, 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.

The term "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. In this respect, C_6-13 aryl groups that may be mentioned include phenyl, naphthyl, 1,2,3,4-tetrahydronaρhthyl, indanyl, indenyl, fluorenyl and the like. For the avoidance of doubt, the point of attachment of substituents on aryl groups may be via any carbon atom of the ring system.

Unless otherwise specified, 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)₂R^3b, -S(O)₂N(R^4B)(R⁴°), -S(O)₂R³⁰ and/or -OS(O)₂R^3d, (wherein R^3b to R^3d and R^4a to R^4m are as hereinbefore defined). When substituted, aryl groups are preferably substituted by between one and three substituents. The term "halo", when used herein, includes fluoro, chloro, bromo and iodo.

Compounds employed in or produced by the process of the invention may exhibit tautomerism. The process of the invention encompasses the use or production of such compounds in any of their tautomeric forms, or in mixtures of any such forms.

Similarly, 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.

Abbreviations are listed at the end of this specification.

Preferred compounds of formula I and II include those in which: R¹ 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, -NH₂, -C(O)N(R^4e)R^4f, -N(R^4g)C(O)R^4h, and -N(R^4m)S(O)₂R^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: R¹ represents H or methyl; R² represents pyridyl or phenyl, which latter group is optionally substituted by one to three substituents selected from cyano, nitro, C₁^ alkoxy, NH₂ and -N(H)S(O)₂CH₃.

Yet more preferred compounds of formula I and II include those in which: R¹ represents H; R² 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.

It is also preferred that groups R and R take the same definition at each occurrence (i.e. for the compound of formula I and compound of formula II).

As stated above, in a first embodiment of the invention (process (a) above), compounds of formulae I and II are co-crystallised from a solvent system comprising an aromatic hydrocarbon, before compound of formula I is selectively re-dissolved.

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(C₁-₆ 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. When present, 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.

However, in a particularly preferred embodiment of process (a), the solvent system employed in step (1) (i.e. that used to dissolve the compounds of formula I and II) consists essentially of an aromatic hydrocarbon. For step (2) of process (a), it is preferred that the co-crystallisation is effected by cooling the solution obtained from step (1) to any temperature from -10 to 4O⁰C, 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 0⁰C)).

Alternatively, for step (2) of process (a), 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 0⁰C, such as to any temperature from -30 to -1O⁰C (e.g. any temperature from -25 to -15°C, such as about -20⁰C).

The selective dissolution of crystalline compound of formula I (step (3) of process (a)) is preferably effected by warming the mixture of crystalline material and mother liquor to any temperature from 10 to 35⁰C, such as from 15 to 25⁰C (e.g. from 18 to 25°C, such as about 2O⁰C).

In 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).

The crystallisation of 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. In this respect, step (5) of process (a) maybe identical to process (b) above.

With respect to process (a) however, it is preferred that the crystallisation of 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.

To effect the crystallisation of step (5), the solution of the compound of formula I may be cooled to sub-ambient temperature, such as to any temperature from -15 to 2O⁰C (e.g. from -10 to 1O⁰C, such as from -5 to 5°C or, particularly, about 0⁰C).

When performed, 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.

In an alternative embodiment of the present invention, there is provided a process for the isolation of a compound of formula II, or a solvate thereof, from a mixture comprising compounds of formulae I and II, as hereinbefore defined, which process comprises:

(A) preparing a solution of the mixture of compounds of formulae I and II in a solvent system comprising an aromatic hydrocarbon;

(B) co-crystallising the compounds of formula I and II from that solution, thereby producing a mixture of crystalline material and mother liquor;

(C) warming the resulting mixture to selectively dissolve crystalline compound of formula I into the mother liquor; and

(D) isolating the crystalline compound of formula II obtained from step (C). In this embodiment of the invention, preferred compounds of formulae I and II include those indicated hereinbefore in respect of processes (a) and (b). Moreover, as will be appreciated by those skilled in the art, 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). .

As mentioned above, a second embodiment of the present invention (process (b) above) 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. When present, 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.

However, in a preferred embodiment of process (b) 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. In a particularly preferred embodiment, 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.

In 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 35⁰C to reflux, such as from 35 to 80⁰C (e.g. from 35 to 6O⁰C)) 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.

It is preferred that the crystallisation of step (ii) of process (b) is promoted by cooling the solution obtained from step (i). Depending upon the initial temperature of the crystallisation mixture, the crystallisation may be promoted by cooling to any temperature from -10 to 4O⁰C, such as from 10 to 30⁰C (e.g. from 15 to 25°C or, more particularly, from 20 to 25°C (e.g. 23 or 25⁰C)).

When performed, 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.

The 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).

In a further embodiment of the invention, 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,

R²-OH III wherein R² is as hereinbefore defined, with a compound of formula IV,

wherein L¹ represents a leaving group and R¹ 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:

R¹ is as hereinbefore defined in respect of compounds of formulae I and II;

L¹ represents halo (especially chloro); the compound of formula IV is in enantiomerically enriched or enantiomerically pure (e.g. S- or, particularly, R- form).

The 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. For example, 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).

However, it is particularly preferred that the reaction is performed using a biphasic solvent system comprising an aromatic hydrocarbon and aqueous base. In this embodiment of the invention, 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. In this respect, 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).

Unless otherwise stated, when molar equivalents and stoichiometric ratios are quoted herein with respect to acids and bases, these assume the use of 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. Thus, for example, where the acid employed is diprotic, then only half the molar equivalents will be required compared to when a monoprotic acid is employed. Similarly, the use of a dibasic compound (e.g. Na₂CO₃) requires only half the molar quantity of base to be employed compared to what is necessary where a monobasic compound (e.g. NaHCO₃) is used, and so on.

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. 60⁰C) to reflux. When a mixture of toluene and water are employed as the solvent system, the reaction is most preferably performed at about 7O⁰C. 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.

When the reaction between the compounds of formula III and IV is performed in a biphasic solvent system (e.g. an aromatic hydrocarbon/aqueous base system), the phases are separated when the reaction between the compounds of formulae III and IV is substantially complete. As will be appreciated by those skilled in the art, 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. For example, when 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). Similarly, such a solution may be employed in the process for isolating the compound of formula II.

Where isolation of the compound of formula I is initiated in a solvent other than an aromatic hydrocarbon (i.e. process (b) above), the same procedure may still be used for preparing a solution of compounds of formulae I and II in an aromatic hydrocarbon, but this may be followed by exchange of the aromatic hydrocarbon for another solvent. This may be effected by removing aromatic hydrocarbon by reduced pressure distillation and replacing/displacing it with another solvent (e.g. a C_2-6 alkyl alcohol). Mixtures of aromatic hydrocarbons and C_2-6 alkyl alcohols may similarly be obtained by removing only part of the aromatic hydrocarbon solvent.

In addition to the crystallisations mentioned above, 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.

Any of the crystallisations described herein may be further aided by seeding or by other techniques known to those skilled in the art.

It will be appreciated by those skilled in the art that, in the processes described above, the functional groups of intermediate compounds may be, or may need to be, protected by protecting groups.

In any event, functional groups which it is desirable to protect include hydroxy and amino. 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 protection and deprotection of functional groups may take place before or after any of the reaction steps described hereinbefore.

Protecting groups may be removed in accordance with techniques which are well known to those skilled in the art and as described hereinafter.

The use of protecting groups is described in "Protective Groups in Organic Chemistry", edited by J.W.F. McOmie, Plenum Press (1973), and "Protective Groups in Organic Synthesis", 3^rd edition, T. W. Greene & P.G.M. Wutz, Wiley- Interscience (1999).

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. In particular, 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%.

The term "relative volume" (rel. vol.), when used herein, refers to the volume (in millilitres) per gram of reagent employed.

The invention is exemplified, but in no way limited, by the following examples.

Example 1

4-r(25^r)-Oxiranylmethoxy]benzonitrile (via process (V), using n-butanol)

ALTERNATIVE I

(a) Preparation of crude mixture

4-Cyanophenol (20 g, 1 eq) and (i?)-(-)-epichlorohydrin (1.8 eq) were added to a two-phase system of toluene/water (7.5 relative volumes of toluene: 5.7 relative volumes of water). The mixture was heated to an inner temperature of 69-71°C, after which NaOH (30% w/w, 1.12 eq) was continuously added over 6 h. After the addition of NaOH, the conversion was complete (as determined by HPLC analysis). The reaction mixture was then cooled to ambient temperature, after which the layers were separated. 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 60⁰C)) 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).

(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.

¹H NMR (300 MHz, CDCl₃) δ 7.59 (dt, J = 7.8, 3.3 Hz, 2H), 6.99 (dt, J = 7.8, 3.3 Hz, 2H), 4.33 (dd, J = 11.1, 2.7 Hz, IH), 3.97 (dd, J = 11.1, 5.8 Hz, IH), 3.37 (dquintet, J = 4.1, 2.8 Hz, IH), 2.94 (t, J = 4.4 Hz, IH), 2.77 (dd, J = 4.8, 2.7 Hz, IH) ¹H NMR (300 MHz, DMSO-d₆) δ 7.79 (dt, J = 9.0, 2.1 Hz, 2H), 7.14 (dt, J = 9.0, 2.1 Hz, 2H), 4.46 (dd, J - 11.5, 2.7 Hz, IH), 3.94 (dd, J = 11.5, 6.7 Hz, IH), 3.36 (m, IH), 2.87 (dd, J = 5.0, 4.2 Hz, IH), 2.73 (dd, J = 5.0, 2.7 Hz, IH)

ALTERNATIVE II (a) Preparation of crude mixture

4-Cyanophenol (100.0 g 0.8395 mole) was added to a 2-litre reactor. Toluene (650.3 g, 750 mL) and demineralized water (570.0 g, 570 mL) were added and the mixture was stirred at 25°C until the 4-cyanophenol had fully dissolved. (R)- Epichlorohydrin (139.8 g, 118 mL, 1.5109 mole, 1.8 eq.) was added in one portion. The biphasic solution was heated to 7O⁰C ± 3⁰C 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 42⁰C and 45°C and Hie vapour temperature was between 35°C and 4O⁰C. 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 55⁰C and the vapour temperature was between 43⁰C and 52⁰C. After the distillation, the mixture was heated to 60⁰C and rapidly divided into four equal portions (4x166 g) and crystallized with four different time / temperature profiles in the four 250 mL reactors of a MultiMax robot, (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 6O⁰C for 1.5 hours. Then the solution was cooled to 40⁰C 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 26.8 g of a white solid. This solid was dried under vacuum at 50⁰C for 18 hours to yield 21.4 g (58.2 %) of compound.

Reactor N°2:

A portion of the solution generated in step (a) above (166 g) was added to the preheated vessel and stirred at 60⁰C for 1.5 hours. Then the solution was cooled to 40⁰C in 30 minutes, seeded and stirred at this temperature for 30 minutes. Finally, the solution was cooled to 25°C in 2 hours and directly filtered. The collected product was washed three times with of diisopropyl ether (3 x 75 mL) to give 26.4 g of a white solid. This solid was dried under vacuum at 50⁰C for 18 hours to yield 21.3 g (57.9 %) of compound. Reactor N°3:

A portion of the solution generated in step (a) above (166 g) was added to the preheated vessel and stirred at 6O⁰C 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.

Reactor N°4:

A portion of the solution generated in step (a) above (166 g) was added to the preheated vessel and stirred at 6O⁰C for 1.5 hours. Then the solution was cooled to 40⁰C 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 50⁰C for 18 hours to yield 21.6 g (58.7 %) of compound.

Example 2 4-[(2jSVOxiranylmemoxy]benzonitrile (via process (b), using isopropanoD

(a) Preparation of crude mixture

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)).

Reaction 1

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 22.5⁰C ± 2.5°C. (i?)-(-)-Eρichlorhydrin (50.3 kg, 42.7 L, 0.54399 kmole, 1.80 equiv.) was added over approximately 10 minutes at 22.5°C ± 2.5⁰C and the reaction mixture was heated to 7O⁰C ± 2°C. 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. 43.4 kg, which equates to a yield of 81.9%), then the 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.

Reaction 2

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.

(b) Purification Relative weights and volumes mentioned below are determined by reference to the total quantity of 4-cyanophenol utilised in the preparation of the crude material (72.0 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. vol.. The last operation was repeated and the complete removal of (i?)-(-)-epichlorohydrin was confirmed by GC at the end of the second distillation. The oily residue was dissolved in toluene (312.1 kg, 360.0 L, 5.00 rel. vol.), at between 53°C and 58°C. The resulting solution was then cooled to between 6°C and 12°C, seeded with pure, crystalline 4-[(25)-oxiranylmethoxy]benzonitrile, and stirred at between 6°C and 12°C for 1 hour. The resulting suspension was cooled to between -5° and +2°C, and stirred at this temperature for 5 hours to achieve complete crystallization. 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. vol.) and the solvent completely removed in vacuo (at a pressure in the region of 1 to 7 kPa (10 to 70 mbar)) at between 53 and 58°C. The oily residue was dissolved in hot (pre-heated to between 53 and 58°C), pre-filtered isopropanol (452.2 kg, 576.0 L₅ 8.00 rel. vol.), to provide a solution that was then cooled to between 32 and 36°C over approximately 30 minutes. 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.

Example 3

ANALYSIS OF DIMER CONTENT

As detailed in the table below, HPLC or GC analyses of products of Examples 1 and 2 above demonstrate that the purified materials contain very low (less than 0.6%) levels of "dimer" (l,l-di(4-cyanophenoxymethyl)methanol).

4-[(2S)-Oxiranylmethoxy]benzonitrile.

² 1,1 -di(4-cyanophenoxymethyl)methanol.

³ 1 -(4-cyanophenoxy)-2,3-dihydroxypropane.

Abbreviations

Et ethyl eq. equivalents h hour(s)

GC gas chromatography

GLC gas layer chromatography

HCl hydrochloric acid

IPA zsσ-propyl alcohol (isopropanol)

Me methyl

MIBC 4-methyl-2-pentanol min. = minute(s)

Prefixes n-, s-, i-, t- and tert- have their usual meanings: normal, secondary, iso, and tertiary.

Claims

Claims

1. A process for the. isolation of a compound of formula I,

or a solvate thereof, from a mixture comprising a compound of formula I and a compound of formula π,

wherein, independently at each occurrence: R¹ represents H or Ci_-6 alkyl;

R² represents phenyl or pyridyl, both of which groups are optionally substituted by one or more substituents selected from -OH, cyano, halo, nitro, Ci_-6 alkyl (optionally terminated by -N(H)C(O)OR^3a), Ci_-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(R⁴ⁱ)C(O)N(R^4j)R^4k, -N(R^4m)S(O)₂R^3b, -S(O)₂N(R⁴ⁿ)(R⁴°), -S(O)₂R³⁰, -OS(O)₂R^3d and/or aryl; R^3a to R^3d independently represent Ci_-6 alkyl;

R^4a and R^4b independently represent H, Ci_-6 alkyl or together represent C_3-6 alkylene, resulting in a four- to seven-membered nitrogen-containing ring; R^4c to R⁴° independently represent H or Ci_-6 alkyl;

wherein each aryl group, unless otherwise specified, is optionally substituted;

which process comprises:

(a) (1) preparing a solution of the mixture of compounds of formulae I and II in a solvent system comprising an aromatic hydrocarbon; (2) co-crystallising the compounds of formulae I and II from that solution, thereby producing a mixture of crystalline material and mother liquor; (3) warming the resulting mixture to selectively dissolve crystalline compound of formula I into the mother liquor;

(4) separating the resulting solvent phase and crystalline product; and

(5) crystallising the compound of formula I contained in the solvent phase; or

(b) (i) preparing a solution of the mixture of compounds of formulae I and II in a solvent system comprising a C_2-6 alkyl alcohol; and then (ii) crystallising the compound of formula I from that solution.

2. A process as claimed in Claim 1 , wherein R¹ represents H.

3. A process as claimed in Claim 1 or Claim 2, wherein R² represents phenyl substituted by cyano in the pαrø-position relative to the point of attachment to the rest of the molecule.

4. A process as claimed in any one of the preceding claims, wherein the compound of formula I is 4-[(2»S)-oxiranyhnethoxy]benzonitrile.

5. A process as claimed in any one of the preceding claims, wherein the solvent system of step (1) of process (a) of Claim 1 consists essentially of an aromatic hydrocarbon.

6. A process as claimed in any one of the preceding claims, wherein: (A) the crystallisation of step (5) of process (a) of Claim 1 is performed in the presence of a solvent system consisting essentially of a C_2-6 alkyl alcohol and, optionally, up to 25% v/v of an aromatic hydrocarbon; or

(B) the solvent system of step (i) of process (b) of Claim 1 consists essentially of a C_2-6 alkyl alcohol and, optionally, up to 25% v/v of an aromatic hydrocarbon.

7. A process as claimed in Claim 6, wherein the aromatic hydrocarbon is toluene.

8. A process as claimed in Claim 6 or Claim 7, wherein the C_2-6 alkyl alcohol is ra-butanol or isopropanol.

9. A process as claimed in any one of Claims 1 to 8, wherein the mixture of compounds of formulae I and II is prepared by reaction of a compound of formula

HI,

R²-OH III wherein R² is as defined in Claim 1, with a compound of formula IV,

wherein L¹ represents a leaving group and R¹ is as defined in Claim 1.

10. A process as claimed in Claim 9, wherein the reaction between the compounds of formulae III and IV is performed in the presence of a biphasic solvent system comprising an aromatic hydrocarbon and aqueous base.