Aminopropanol derivatives   

Abstract: wherein R1, R2, n and m are as defined in the specification, processes for their production, their uses and pharmaceutical compositions containing them. Compounds of formula I:

The present invention relates to organic compounds, a process for their production and pharmaceutical compositions containing them.

More particularly the present invention provides a compound of formula I:

wherein each of m and n, independently, is 1, 2 or 3; X is O or a direct bond;

a phenylalkyl wherein alkyl is a straight- or branched (C6-20)carbon chain; or a phenylalkyl wherein alkyl is a straight- or branched (C1-30)carbon chain wherein said phenylalkyl is substituted at the phenyl residue by a straight- or branched (C6-20)carbon chain optionally substituted by halogen, a straight- or branched (C6-20)alkoxy chain optionally substitued by halogen, a straight- or branched (C6-20)alkenyloxy, phenylalkoxy, halophenylalkoxy, phenylalkoxyalkyl, phenoxyalkoxy or phenoxyalkyl, cycloalkylalkyl substituted by C6-20alkyl, heteroarylalkyl substituted by C6-20alkyl, heterocyclic C6-20alkyl or heterocyclic alkyl substituted by C2-20alkyl, and wherein the alkyl moiety may have in the carbon chain, a bond or a heteroatom selected from a double bond, a triple bond, O, S, sulfinyl, sulfonyl, or NR5, wherein R5 is H, alkyl, aralkyl, acyl or alkoxycarbonyl, and as a substituent alkoxy, alkenyloxy, alkynyloxy, aralkyloxy, acyl, alkylamino, alkylthio, acylamino, alkoxycarbonyl, alkoxycarbonylamino, acyloxy, alkylcarbamoyl, nitro, halogen, amino, hydroxy, or carboxy, and

wherein each of R3 and R4, independently, is H or C1-4alkyl, wherein alkyl is optionally substituted by 1, 2 or 3 halogen atoms; in free form or in salt form. Halogen is F, Cl, Br or I. Alkyl or alkoxy may be straight or branched chain. Cycloalkyl is preferably C3-10cycloalkyl, more preferably C3-8cycloalkyl and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Acyl may be a residue Ry—CO— wherein Ry is C1-6alkyl, C3-6cycloalkyl, phenyl or phenyl-C1-4alkyl.

When in the compounds of formula I the carbon chain as R1 is substituted, it is preferably substituted by halogen, nitro, amino, hydroxy or carboxy. When the carbon chain is interrupted by an optionally substituted phenylene, the carbon chain is preferably unsubstituted. When the phenylene moiety is substituted, it is preferably substituted by halogen, nitro, amino, methoxy, hydroxy or carboxy.

In the compounds of the invention, the following significances are preferred individually or in any sub-combination: 1. m and n are each 1 or 2, preferably 1. 2. X is O. 3. R1 is C13-20alkyl, optionally substituted by nitro, halogen, amino, hydroxy or carboxy, and, more preferably those wherein R1 is phenylalkyl substituted by C6-14-alkyl chain optionally substituted by halogen and the alkyl moiety is a C1-6alkyl optionally substituted by hydroxy. More preferably, R1 is phenyl-C1-6alkyl, e.g. phenyl-C1-6alkyl, e.g. phenyl-C2alkyl, substituted on the phenyl by a straight or branched, preferably straight, C6-14alkyl chain. The C6-14alkyl chain may be in ortho, meta or para, preferably in para. 4. each of R3 and R4 is H.

A particularly preferred compound is phosphoric acid mono-[2-hydroxymethyl-4-(4-octyl-phenyl)-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-butyl]ester.

Compounds of formula I may exist in free form or in salt form, e.g. addition salts with e.g. inorganic acids, such as hydrochloride, hydrobromide or sulfate, salts with organic acids, such as acetate, fumarate, maleate, benzoate, citrate, malate, methanesulfonate or benzenesulfonate salts; when R3 or R4 is H, R2 may also be present in salt form, e.g. an ammonium salt or salts with metals such as sodium, potassium, calcium, zinc or magnesium, or a mixture thereof. Compounds of formula I and their salts in hydrate or solvate forms are also part of the invention.

The compounds of formula I have one or more asymmetric centers in the molecule, and thus various optical isomers may be obtained. The present invention also encompasses enantiomers, racemates, diastereoisomers and mixtures thereof. The central asymmetric carbon atom may have the R or S configuration. Moreover, when the compounds of formula I include geometric isomers, the present invention embraces cis-compounds, trans-compounds and mixtures thereof. Similar considerations apply in relation to starting materials exhibiting asymmetric carbon atoms or unsaturated bonds as mentioned above.

A compound of formula I may be prepared by reacting a compound of formula II:

wherein m, n, X, R1 and R2 are as defined in formula I; with an aromatic 1,2-dicarbaldehyde, e.g. benzene-1,2-dicarbaldehyde, and recovering the resulting compound of formula I in free or salt form.

The process may be performed according to methods known in the art, e.g. as described in the examples.

A compound of formula II (e.g. a racemic mixture thereof) may be obtained as described in WO 02/18395 or WO 02/076995.

The present invention also provides a compound of formula I or formula II, wherein greater than 70% by weight of the compound is in the form of the S enantiomer, or greater than 70% by weight of the compound is in the form of the R enantiomer, e.g. greater than 90% is in the form of the R or S enantiomer. More preferably greater than 95% by weight, e.g. greater than 99% by weight of the compound is in the form of the R or S enantiomer. Thus the invention may relate to the substantially pure R or S enantiomer (e.g. the S enantiomer substantially free of the R enantiomer or vice versa), preferably the S enantiomer, of a compound of formula I or formula II. Particularly preferred are the substantially pure (e.g. greater than 99% by weight) R or S enantiomers, especially the S enantiomers, of phosphoric acid mono-[2-amino-2-hydroxymethyl-4-(4-octyl-phenyl)-butyl]ester (FTY720-phosphate) and phosphoric acid mono-[2-hydroxymethyl-4-(4-octyl-phenyl)-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-butyl]ester.

Compounds having the following 3-dimensional configuration are generally preferred:

Enantiomers of the compounds of formula I and II cannot be satisfactorily separated by standard methods. According to the present invention, separation of the enantiomers is achieved by the use of novel separation techniques and synthesis strategies.

A compound of formula I, wherein greater than 70% by weight of the compound is in the form of the R or S enantiomer, e.g. the substantially pure R or S enantiomer, may be obtained by:

a) separation of the S enantiomer from the R enantiomer in a racemic mixture of a compound of formula I, using chromatography on a chiral stationary phase; or b) reacting a compound of formula II, wherein greater than 70% by weight of the compound is in the form of the R or S enantiomer, e.g. the substantially pure R or S enantiomer of a compound of formula II, with an aromatic 1,2-dicarbaldehyde e.g. benzene-1,2-dicarbaldehyde.

According to method a), the chromatographic separation is preferably carried out using a chiral ion-exchange phase based on quinine carbamate or quinidine carbamate as chiral selector, e.g. a quinine carbamate phase (8S,9R) available commercially under the tradename ProntoSIL Chiral AX QN-1:

A compound of formula II, wherein greater than 70% by weight of the compound is in the form of the R or S enantiomer, may be obtained by deprotecting a compound of formula III, wherein greater than 70% by weight of the compound of formula III is in the form of the R or S enantiomer:

wherein m, n, X, R1 and R2 are as defined above and R6 is an amino protecting group, and, where required, converting the compounds of formula I obtained in free form into the desired salt form, or vice versa.

Examples of suitable amino protecting groups as R6 are e.g. as disclosed in “Protective Groups in Organic Synthesis” T. W. Greene, J. Wiley & Sons NY, 2nd ed., chapter 7, 1991, and references therein, e.g. acyl, e.g. tert.-butoxy-carbonyl, benzyloxycarbonyl, 9-fluorenyl methoxy carbonyl, trifluoroacetyl, trimethylsilylethanesulfonyl and the like.

Alternatively and more preferably a compound of formula II, wherein greater than 70% by weight of the compound is in the form of the R or S enantiomer, may be obtained by deprotecting a compound of formula IIIa or IIIb, wherein greater than 70% by weight of the compound of formula IIIa or IIIb is in the form of the R or S enantiomer:

wherein n, m, X, R1 and R2 are as defined above and R6′ is a simultaneous OH and amino protecting group, e.g. such that R6′ together with the O and N atoms to which it is attached, the asymmetric carbon atom and 1 to 3 further carbon atoms forms a cyclic residue, e.g. a 5 to 7-membered heterocyclic ring, e.g oxazolidin-2-one (in IIIa R6′ is —C(O)—) or 2-methyl-4,5-dihydro-oxazole (in IIIb R6′ is —C(CH3)—).

The removal of the R6 or R6′ protecting group in a compound of formula III, IIIa or IIIb may conveniently be performed according to methods known in the art, e.g. by hydrolysis, e.g. in a basic medium, for example using a hydroxide such as barium hydroxide. It may also be performed by hydrogenolysis, e.g. in the presence of Pearlman\'s catalyst, e.g. as disclosed in J. Org. Chem., 1998, 63, 2375-2377.

Thus in a further alternative aspect the present invention provides a compound of formula III, IIIa of IIIb as defined above, in free or salt form. The compounds of formula III, IIIa or IIIb have one or more asymmetric centers in the molecule, and thus various optical isomers may be obtained. The present invention also encompasses enantiomers, racemates, diastereoisomers and mixtures thereof.

The removal of the R6 or R6′ protecting group in a compound of formula III, IIIa or IIIb may conveniently be performed according to methods known in the art, e.g. by hydrolysis, e.g. in a basic medium, for example using a hydroxide such as barium hydroxide. It may also be performed by hydrogenolysis, e.g. in the presence of Pearlman\'s catalyst, e.g. as disclosed in J. Org. Chem., 1998, 63, 2375-2377.

A compound of formula III, IIIa or IIIb comprising greater than 70% by weight of the R or S enantiomer may be obtained by separating the S enantiomer from the R enantiomer in a racemic mixture of a compound of formula III, IIIa or IIIb, using chromatography (MPLC, HPLC, SFC) or simulated moving bed (multi-column) chromatography with a polysaccharide-based chiral stationary phase, preferably an amylose-type phase, e.g. amylose tris[(S)-α-methylbenzyl carbamate coated on silica gel substrate, as available under the tradename CHIRALPAK AS and shown below, or in an immobilized form as prepared according to the processes described in WO 97/04011 and WO 97/49733:

A compound of formula III, IIIa or IIIb comprising greater than 70% by weight of the R or S enantiomer may alternatively be obtained by removing the hydrolysable groups present in R2′ in a compound of formula IV, IVa or IVb comprising greater than 70% by weight of the R or S enantiomer:

wherein m, n, X, R1, R6 and R6′ are as defined above and R2′ is

wherein each of R3′ and R4′ is a hydrolysable group.

Preferably R3′ and R4′ are identical and have the significance of e.g. phenyl or benzyl or form together a cyclic system such as in 1,5-dihydro-2,4,3-benzodioxaphosphepin.

A compound of formula IV, IVa or IVb comprising greater than 70% by weight of the R or S enantiomer may be obtained by separating the S enantiomer from the R enantiomer in a racemic mixture of a compound of formula IV, IVa or IVb, e.g. as described above for the separation of enantiomers of compounds of formula III, IIIa or IIIb.

A compound of formula IV, IVa or IVb, e.g. a racemic mixture thereof, wherein X is O may be obtained by reacting a compound of formula V, Va or Vb:

wherein m, n, R1, R6 and R6′ are as defined above, with a phosphorylating agent, e.g. a phosphorochloridate, e.g. diphenylchlorophosphate or dibenzylchlorophosphate, cyanoethylphosphate, a phosphoramidate such as N-phenyl phosphoramidate, 3-(diethylamino)-1,5-dihydro-2,4,3-benzodioxaphosphepin and the like. The reaction may be carried out according to methods known in the art, e.g. as disclosed in J. Org. Chem. supra. In the compounds of formula IIIa the amino group is preferably in protected form, as R′4 when R4 is other than acyl.

A compound of formula IV, IVa or IVb, e.g. a racemic mixture thereof, wherein X is a direct bond may be obtained by reacting a compound of formula V′, Va′ or Vb′:

wherein m, n, R1, R6 and R6′ are as defined above, and Y is a leaving group, e.g. Br, with a phosphorylating agent, e.g. diethyl phosphite under reducing conditions, e.g. in the presence of NaH. The reaction may be performed in accordance with methods known in the art.

Alternatively the chiral separation may be performed at an earlier stage in the process. Thus a compound of formula IV, IVa or IVb comprising greater than 70% by weight of the R or S enantiomer may be obtained by reacting a compound of formula V, Va, Vb, V′, Va′ or Vb′ comprising greater than 70% by weight of the R or S enantiomer with a phosphorylating agent. A compound of formula V, Va, Vb, V′, Va′ or Vb′ comprising greater than 70% by weight of the R or S enantiomer may be obtained by separating the S enantiomer from the R enantiomer in a racemic mixture of a compound of formula V, Va, Vb, V′, Va′ or Vb′, e.g. using HPLC or simulated moving bed (multi-column) chromatography with a polysaccharide-based chiral stationary phase as described above for separation of the enantiomers of a compound of formula IV, IVa or IVb.

A compound of formula V or V′ may be prepared by reacting a compound of formula VI:

wherein m, n and R1 are as defined above and R9 is OH or a leaving group, e.g. Br, with an amino protecting group donor compound. A compound of formula Va, Va′, Vb or Vb′ may be prepared by reacting a compound of formula VI with an OH and amino protecting compound, e.g the OH and amino protection may be performed simultaneously by reacting the free aminoalcohol or aminodiol of formula VI in order to obtain a cyclic residue, e.g. a 5 to 7-membered heterocyclic ring, e.g oxazolidin-2-one or 2-methyl-4,5-dihydro-oxazole, e.g. by reaction with Cbo-Cl, Boc-anhydride, triethylortho acetate and acetonitrile, or phosgene under basic conditions.

At any stage in the process, R1 in any of the formulae above may optionally be converted to an alternative R1 group using known methods. For example, a compound of formula Vb wherein R1 is (4-benzyloxy-phenyl)-ethyl may be converted to an alternative compound of formula Vb wherein R1 is [4-(6-fluoro-hexyloxy)-phenyl]-ethyl by (a) removal of a benzyl group from R1 by hydrogenation to leave a (4-hydroxy-phenyl)-ethyl residue, followed by (b) reaction with 1-bromo-6-fluorohexane. The alternative compound of formula Vb may then undergo chiral separation or be converted to a compound of formula IVb as described above.

The compounds of formulae III, Lila, IIIb, IV, IVa and IVb comprising greater than 70% by weight of the R or S enantiomer used as starting materials, and salts thereof are also novel and form part of the present invention.

In a further alternative aspect, a compound of formula II wherein greater than 70% by weight of the compound is in the form of the R or S enantiomer, may be obtained by deprotecting and hydrolyzing a compound of formula VII, wherein greater than 70% by weight of the compound is in the form of the R or S enantiomer:

wherein m, n, X and R1 are as defined above, and R2″ is

wherein each of R3′ and R4′ is a hydrolysable group, e.g. tert-butyl, and R7 is an amino protecting group, e.g. benzyloxycarbonyl.

A compound of formula VII, wherein greater than 70% by weight of the compound is in the form of the R or S enantiomer, may be obtained by reacting a compound of formula VIII, wherein greater than 70% by weight of the compound is in the form of the R or S enantiomer,

with a phosphorylating agent, e.g. as described above.

Insofar as the production of the starting materials is not particularly described, the compounds are known or may be prepared analogously to methods known in the art or as disclosed in the Examples hereinafter.

The following Examples are illustrative of the invention.

RT=room temperature CBO=benzyloxycarbonyl FTY720=2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol EDTA=ethylenediaminetetraacetic acid OPA ortho-phthalaldehyde (benzene-1,2-dicarbaldehyde)

Benzyl chloroformate (0.45 ml; 3.2 mmol) is added to a suspension of FTY720.HCl (1.03 g, 3 mmol) in 2N NaOH (20 ml). The reaction is kept at RT over night and in order to complete the reaction further benzyl chloroformate (0.9 ml; 6.4 mmol) is added. After 2 days at RT the reaction is acidified with 1N HCl, extracted with methylenehloride and purified on a silica gel column using methylenehloride/methanol/acetic acid50% (9/1/0.125) as mobile phase.

[M+H]+:334 (ESI-MS)

To a solution of the endproduct of a) (2.4 g; 7.2 mmol) in methylenehloride/THF 1/1 (100 ml) at 0° C. is added tetrazole (recrystallized; 2.52 g; 36 mmol) and 3-(diethylamino)-1,5-dihydro-2,4,3-benzodioxaphosphepintriphenyl-phosphite (5.17 g; 21.6 mmol). After 18 hours at RT, H2O2 (8.2 ml [30% in water]; 72 mmol) is added (cooling) to the solution and kept at RT for additional 90 minutes. After quenching with saturated Na2S2O3 solution (100 ml) the reaction is extracted with ethylacetate (three times). The organic layer is dried over Na2SO4 and the compound is purified on silica gel using cyclohexane/ethylacetate 1/1 as mobile phase.

The endproduct of step b) (1.03 g; 2 mmol) is hydrogenated at normal pressure (Pd/C10%; 50 mg) over a period of 90 minutes. After filtration the reaction is concentrated and used in step d) without further purification.

To a solution of the endproduct of step c) in ethanol (20 ml) LiOH (20 ml; 10% solution in water) is added. After 24 hours at reflux the reaction is neutralized with HCl (1N in water) and concentrated. The residue is treated with glacial acetic acid (5 ml) and precipitation of the endproduct occurs after addition water (50 ml). After filtering, washing (water) and drying pure endproduct is obtained without any further purification.

The endproduct of step d) ((R/S)—FTY720-phosphate) (50 mg; 0.125 mmol) is suspended in a solution of EDTA (0.5 ml; 10 mM in water) and aqueous boric acid (0.5 ml; 3% in water; adjusted to pH 10.5 with aqueous KOH10%). After addition of OPA (33 mg, 0.25 mmol), dissolved in ethanol (0.5 ml), the reaction is kept at RT for 1 hour (ultrasound). After that the pH is adjusted to 3.5 (aqueous HCl; 1N) and extracted with ethylacetate (three times). The organic layer is dried over Na2SO4 and the compound is purified on silica gel using methylenechloride/methanol (95/5→0/100) as mobile phase.

[M−H]−: 502.5 (ESI-MS)

Example 2 is obtained after separation of the final product of step b) by HPLC on CHIRALPAK AS column at a preparative scale (ethanol/n-hexane 40/60 as mobile phase), or by simulated moving bed chromatography on HPLC columns packed with immobilized amylose tris[(S)-α-methylbenzyl carbamate coated on silica gel (n-hexane/ethanol/chloroform 60/20/20 as the mobile phase; feed concentration, 1%) and applying steps c), d) and e) as described for example 1.

Example 3 is obtained after separation of the final product of step b) by HPLC on CHIRALPAK AS column at a preparative scale (ethanol/n-hexane 40/60 as mobile phase), or by simulated moving bed chromatography on HPLC columns packed with immobilized amylose tris[(S)-α-methylbenzyl carbamate coated on silica gel (n-hexane/ethanol/chloroform 60/20/20 as the mobile phase; feed concentration, 1%) and applying steps c), d) and e) as described for example 1.

a) To a solution of 4-(2-hydroxy-ethyl)-phenol (50 g, 0.36 mol) in ethanol (400 ml) is added potassium carbonate (75 g, 0.54 mol, 1.5 eq) and benzyl bromide (47.2 ml, 0.39 mol, 1.1 eq), the reaction mixture is stirred at RT overnight. The reaction mixture is then filtered off through celite and concentrated under vacuum. 2-(4-Benzyloxy-phenyl)-ethanol is isolated after crystallization with diethyl ether. b) To a solution of 2-(4-benzyloxy-phenyl)-ethanol (78.72 g, 0.34 mol) in methylene chloride (400 ml) is added triethylamine (67.3 ml, 0.44 mol, 1.4 eq), then at 0° C. is added mesylchloride (34.8 ml, 0.44 mol, 1.3 eq). The reaction mixture is stirred at 0° C. for 30 minutes and allowed to rise to RT. The reaction mixture is extracted with methylene chloride (2×300 ml), the combined organic layers are then washed with brine (2×300 ml) and concentrated under vacuum. c) To the crude product in solution in ethyl acetate (600 ml) is added sodium iodide (67.2 g, 0.44 mol, 1.3 eq) and the reaction mixture is stirred under reflux for 6 hours. After filtration, the organic layer is washed with brine (3×400 ml), dried with Na2SO4, filtered and concentrated under vacuum. 1-Benzyloxy-4-(2-iodo-ethyl)-benzene is isolated after crystallization with diethyl ether. d) To a solution of acetamidomalonate (59.4 g, 0.27 mol, 2 eq) in dry dimethylformamide (400 ml) is added at 0° C. under inert atmosphere sodium hydride (60% in oil) (9.94 g, 0.49 mol, 1.8 eq), the reaction mixture is stirred for 3 hours at 0° C. 1-Benzyloxy-4-(2-iodo-ethyl)-benzene (46.8 g, 0.13 mol, 1 eq) in solution in dry dimethylformamide (250 ml) is then slowly added at 0° C. and the reaction mixture is stirred at RT overnight. The reaction mixture is quenched with few drops of methanol and concentrated almost to dryness under vacuum, then extracted with ethyl acetate and washed subsequently with 1N HCl (2×500 ml), saturated solution of NaHCO3 (2×500 ml) and brine (2×500 ml), dried with Na2SO4, filtered and concentrated under vacuum. 2-Acetylamino-2-[2-(4-benzyloxy-phenyl)ethyl]-malonic acid diethyl ester is isolated after multiple crystallization using diethyl ether.

e) To a solution of 2-acetylamino-2-[2-(4-benzyloxy-phenyl)-ethyl]-malonic acid diethyl ester (44.1 g, 0.1 mol) in ethanol water (2/1) (285 ml/285 ml) is added CaCl2 (28.5 g, 0.26 mol, 2.5 eq) and NaBH4 by portion (19.4 g, 0.52 mol, 5.0 eq), the reaction mixture is stirred overnight at RT. At 0° C. the reaction mixture is carefully quenched with drop wise methanol (10 ml) and concentrated to almost dryness under vacuum. The crude mixture is extracted with ethyl acetate (4×500 ml) and washed subsequently with 1N HCl (2×300 ml), saturated solution of NaHCO3 (2×300 ml) and brine (2×300 ml). The combined organic layers are then dried with Na2SO4, filtered and concentrated under vacuum. N-[3-(4-Benzyloxy-phenyl)-1,1-bis-hydroxymethyl-propyl]-acetamide is carried on without further purification.

f) To a solution of crude N-[3-(4-benzyloxy-phenyl)-1,1-bis-hydroxymethyl-propyl]-acetamide in a mixture of tetrahydrofuran, methanol, water (1/2/2) (450 ml/900 ml/900 ml) is added at RT lithium hydroxide (32.7 g, 1.36 mol, 8.0 eq). The reaction mixture is stirred at 55° C. for 5 hours, then extracted with ethyl acetate (500 ml) and washed with brine (2×300 ml), the combined organic layers are then dried with Na2SO4, filtered and concentrated under vacuum. 2-Amino-2-[2-(4-benzyloxy-phenyl)-ethyl]-propane-1,3-diol is isolated after crystallization using ethyl acetate. g) To a solution of 2-amino-2-[2-(4-benzyloxy-phenyl)-ethyl]-propane-1,3-diol (31.1 g, 0.10 mol) in acetonitrile (2.381) is added triethylortho acetate (17.1 ml, 0.12 mol, 1.2 eq) and acetic acid (5.48 ml, 0.11 mol, 1.1 eq), the reaction mixture is then stirred at 80° C. for 5 hours.

The reaction mixture is then concentrated under vacuum, {4-[2-(4-benzyloxy-phenyl)-ethyl]-2-methyl-4,5-dihydro-oxazol-4-yl}-methanol is isolated after crystallization with ethyl acetate.

h) To a solution of {4-[2-(4-benzyloxy-phenyl)-ethyl]-2-methyl-4,5-dihydro-oxazol-4-yl}-methanol (26.1 g, 0.08 mol) in methanol (800 ml) is added palladium on charcoal (2.6 g, 10% wt), and the reaction mixture is stirred under hydrogen atmosphere at RT for 5 hours. The reaction mixture is then filtered through celite and concentrated under vacuum. (R/S)-4-[2-(4-Hydroxymethyl-2-methyl-4,5-dihydro-oxazol-4-yl)-ethyl]-phenol is isolated in quantitative yield after crystallization with ethyl acetate and hexanes. i) To a solution of (R/S)-4-[2-(4-hydroxymethyl-2-methyl-4,5-dihydro-oxazol-4-yl)-ethyl]-phenol (500 mg, 2.12 mmol) in dry DMF (8 ml) is added under inert atmosphere Cs2CO3 (901 mg, 2.76 mmol, 1.3 eq.) and 1-bromo-6-fluoro-hexane (464.1 mg, 2.55 mmol, 1.2 eq.). The reaction mixture is stirred under inert atmosphere at 85° C. overnight. A saturated solution of NaHCO3 (20 ml) and ethyl acetate (40 ml) are then added. The organic layer is separated and the aqueous phase is extracted with ethyl acetate (3×40 ml). The combined organic extracts are washed with brine and 1M HCl, dried over MgSO4, and evaporated to dryness. Purification by flash chromatography (cy Hexane/ethyl acetate (9/1) to (1/1) and (0/1)) affords (R/S)-(4-{2-[4-(6-fluoro-hexyloxy)-phenyl]-ethyl}-2-methyl-4,5-dihydro-oxazol-4-yl)-methanol as colorless oil.