IE57750B1 - Aromatic diols - Google Patents

Description

GLAXO GROUP LIMITED, a British Company, of Clarges House, 6-12 Clarges Street, London WlY SDH, England. 7 7 5 0 This invention relates to aromatic diols. More soecifically this invention relates to benzodioxindiols useful as intermediates in the preparation of therapeutically useful benzodioxinopyrrole derivatives.

The present invention accordingly provides compounds of general formula (ill) W I // \ / (III) w / \ /:-\ - CHoOH H 2 wherein Rl is a haloqen atom or a qroup selected from alkyl. alkoxy, hyaroxyl, cyano, nitro and -NR3R*4 where R3 and R*4 is each a hydroqen atom or a alkyl group; and R2 is a hydrogen atom or a substituent as defined above for R3.

In general formula (III), the alkyl groups represented by R 3 and R may be straight or branched chain groups.

The haloqen atoms represented by R3 and R2 may be fluorine, chlorine, bromine or iodine atoms. Examples of alkyl and alkoxy groups representea oy R 3 and R2 are methyl, ethyl, methoxy and ethoxy groups. The group -NR3R1+ may oe, for example, an amino, methylamino, ethylamino, dimetnylamino or diethylamino qroup.

It will be appreciated that each compound of general formula (III) is a trans isomer and exists as two enantiomers. The structural formulae herein are to oe understood to depict either enantiomer of each compound as well as mixtures of the enantiomers, including racemates, even though the precise structure as set out only relates to one enantiomer.

A preferred group of compounds Of formula (III) is that in which R3 is a haloqen atom or a alkyl or Cy_^ alkoxy qroup, in particular a chlorine or fluorine atom or a methyl or methoxy group2 5 A further preferred group of compounds of formula (ϊίϊ) is that in «hich ft2 i® a hydrogen or fluorine atom, particularly s hydrogen atom.

Particularly inportant compounds of fortnuia (III) are those in which R* is a chlorine or fluorine atom or a methyl or methoxy orouo, particularly a chlorine or fluorine atom and especially a fluorine atom; and R2 is a hydroqen or fluorine atom, especially a hydrogen atom., Important compounds are:(±)~(trans)-5-methy1-2„3-dihydro-H,4-Penzodioxin-2,3-dimethanol; (±)-(trans)-5-chloro-2,3-dihydro-1„4-benzoaioxin-2,3-dimethanol; and (t) -(trans)-5,8-difluoro-2,3-dihydro-l,4-oenzodioxin-2,3-dimethanol.

Particularly preferred compounds include:-. (±)-(trans)-5-fluoro-2,3-dihydro-1,4-oenzodioxin-2 s3-dimethanol.

The compounds of formula (III) are useful as intermediates in the preparation of benzodioxinopyrrole derivatives for example as described in Patent Specification No. /OS 2/8/ which describes and claims compounds of the oeneral formula (I) / \\ / \T/ ι ί ί λ //\ /Ξ\ Ο Ξ · ί Η I) <ι.' 5- ;··? ι ί ι Ρ is a hydroqen atom or a qroup selected from C j . sJkyl (optionally substituted by C 3_ 7 cycloalkyl), C3_0 alkenyl, C3_6 alkynyl (wherein the -C=C- or -C=C- linkage rs not directly attached to the N-atom) , c37 cycloalkyl, aralkyl (in which the alkyl moiety contains 1-5 carbon atoms) and —CHO; ' and R2 are as defined for compounds of formula (III) above and the physiologically acceptable salts and hydrates thereof.

The compounds of formula (1) may oe prepared from compounds of formula (III) Dy the methods disclosed in Patent Specification No. IQ53/V' The compounds of formula (III) may be prepared by reduction of a correspondinq dibenzyl ether of formula (IV): Λ\ AT/ch2°Bz \ // \ /Ξ\ 7 0 5 CH,08z I . H 2 (IV) (where Bz represents oenzyl) using hydrogen and palladium on charcoal with a solvent e.g. ethanol.

Alternatively, an ether of formula (IV) may oe treated with a Lewis acid, such as aluminium chloride, in a solvent such as toluene to yield a diol of formula (III).

A compound of formula (IV) may oe prepared oy heating the oistosylate (V): TsO —-r-— CH208z TsO —-a'—CH9OBz IJ (V) (where Ts represents CH3-*^ /®-S02-) with a catechol of formula (VI) / \\ / « I OB \ // \ OH OH R· (VI) in acetonitrile or dimethylformamide containing cesium fluoride or cesium carbonate.

The intermediates of formula (VI) are known compounds and may be prepared by standard methods of benzene rinq substitution (cf. for example Barton, Linnell & Senior. Quat.3.Pharmacy & Pharmac. , 1945. 18, 41-47 and Ladd 4 Weinstock. J.Orq.Chem. 1981. 46, 203-206).

The bis-tosylate of formula (V) may be prepared by reaction of the known dibenzyl threitol of formula (VII) HO ----CH20Bz HO.

-CH 20Bz (VII) witn 4-toiuenesulphonyl chloride in pyridine.

To ootain a specific enantiomer of the compounds formula (I), a dioi of formula (III) havinq the reauired chirality is desiraole. Tne required enantiomeric dioi of formula (III) startinq material can be prepared from the appropriate dibenzyi threitol of formula (VII) or (VIII) HO' * —CHjOBz HO ——CH90Bz H 2 as described above.

A specific enantiomer of aeneral formula (III) may also be prepared by resolution of a mixture of enantiomers of formula (III) by conventional methods. Alternatively, resolution may be effected at any suitable intermediate staae.

It may be desirable to protect various reactive substituents in the startinq materials for a particular reaction or seauence of reactions and suoseauently to remove the protectinq qroup after ι completion of the reaction or sequence. Such protection and subsequent, deprotection may oe particularly pertinent when Ry and/or when Rj is a s hydroxy or amino suostxtuent, Conventional protection and deprotection procedures can De employed cf. Protective Groups in Organic Chemistry Ed. Oy J F W McOmie (Plenum Press. 1973). Thus, For example., a primary amine may tie protected by formation of a phthalimide group which may subsequently be cleaved by treatment with a hydrazine, e.g. hydrazine hydrate or a primary amine, for example methylamine. and a phenolic hydroxyl qroup may be protected as an ether e.q. a 2-tetrahydropyranyi or methyl ether, which may subsequently be cleaved by a Lewis acid such as boron tribromide or IO aqueous hydroqen bromide.

It will be appreciated that certain of the reactions described above are capable of affectinq other aroups in the startinq material (e.q. nitro, cyano) which are desired in the end product; care must therefore be taken in accordance with conventional practice, either to use reaction conditions under which such aroups remain substantially inert, or to perform the reaction as part of a sequence which avoids its use when such groups are present in the startinq material.

The foliowinq examples illustrate the invention. All temperatures are in °C. In the foliowinq, ER represents ether, IMS 2q represents industrial methylated spirits, MeOH represents methanol, EtOH represents ethanol and liqht petroleum refers to the fraction boilinq at 60-80°. Dried refers to dryina over maqnesium sulphate unless otherwise stated.

Intermediate 1 2β (i)-(trans)-5-Fluoro-2,3-dihydro-2,3-0 is[(phenylmethoxy)methyl ]-1,4benzodioxin A mixture of 3-fluorobenzene-1,2-diol (5.12a) and (R*,R*)-( ±)-1,4-bis (phenylmethoxy)-2.3-butanediol, bis(4-methylbenzenesulphonate) (24.4a) was stirred with dimethylformamide (D.M.F.) (160mi) under a nitroqen stream for 45 rain. Anhydrous cesium carbonate (13.0a) was added and the mixture was heated to 150° under reflux for 18 hours. The dark brown mixture was cooled to 30° and diluted with di-isopropyl ether (370mi) and water (320mi). The layers were separated and the aqueous layer was re-extracted with di-isopropyl ether (150mi then 100ml).

The extracts were sequentially washed with M hydrochloric acid (300ml), 30% aqueous sodium chloride (100ml) and were comoined and evaporated in vacuo to a dark brown oil (12.6q) which was dissolved in liqht petroieum-dichloromethane (3:1) (40ml) and chromatoqraphed over Sorbsil (I26q) usinq liqht petroieum-dichloromethane mixtures of qradually increasinq polarity. Combination of appropriate fractions and evaporation of the solvents qave the title compound as a yellow oil (7.0q), NMR τ (CDC13) 2.6-2.8 (10H, ra, Ph). 5.18-3.38 (3H. m. 6-H, 7-H, 8-H), 5.32-5.58 (AH, m, CH? Ph), 5.64 (2H, m, 2-H, 3-H), O 6.06-6.32 (4H, m, CH9O).

Intermediates 2-8 (shown in Table 1) were prepared in a similar manner from the appropriate catechol and (R*,R*)-( ±)-1,4-t>is(phenylmethoxy)2,3-butanediol, bis(4-methylbenzenesulphonate).

TABLE 1 rl R2 Reaction Solvent NMR τ (CDC13) Ph Ph CH ? OCH 2 2-H, 3-H Aromatic Me OMe ch3 (2) H ch3cn 2.68 5.41 6.21 5.6-5.8 3.29 7.78 CH3O (3) H CH 3CN 2.7 5.2-5.8 5.8-6.5 5.2-5.8 3.0-3.6 - 6.13 Cl (4) H ch3cn 2.66 5.3-5.55 6.0-6.3 5.55-5.7 3.0-3.3 - — · NO? (5) H D.M.F. 2.6-2.8 5.3-5.54 6.05-6.27 5.6 2.51.2.85 3.12 - CH3 (6) ch3 CH 3CN 2.6-2.8 5.38-5.44 6.1-6.3 5.67. 3.39 7.82 Cl p). Cl ch3cn 2.73 5.43 6.18 5.6 3.17 F (8) F O.M.F. 2.5-2.8 5.37,5.48 6.1 ,6.2 5.58 3.39 Example 1 (::)-(0rans)-5-Cnloro-2,3"diriydro-1 >6-benzodioxin-2 ,3-dimethanol A solution of (trans)-( ±)-5-chioro-2,3-ois[(phenyimethoxy) methyl ]»2»3-dihydro-1,6-t>enzodioxin (2.2q) (Intermediate 26) in trifluoroacetic acid (T.F.A.) (50mls) was hydroqenated over 10% palladium on carbon (0.22q). The solid was filtered off. washed with chloroform and the solution was evaporated to dryness to qive the diol as a colourless liquid 1.2q, NMR τ (CDC13) 2.9-3.3 (3H, m, aromatic), 7.72 (2H, s, OH), 5.7-6.2 (6H, m, 2-H, 3-H, CHJ3).

Examples 2-6 (shown in Table 2) were prepared in a similar manner.

Example 2 (±)-(trans)-5-Methy1-2,3-dihydro-I,6-benzodioxin-2,3dimethanol (from Intermediate 2) Example 3 ( ±)-(trans)-5-Methoxy-2,3-dihydro-1,6-benzodioxin-2,3dimethanol (from Intermediate 3) Example 6 (±)-(trans)-5,8-Dimethyl-2,3-dihydro-1,6-benzodioxin-2,3dimethanol (from Intermediate 6) Example 5 (±)-(trans)-5,8-Dichloro-2,3-dihydro-1,6-oenzodioxin-2,3dimethanol (from Intermediate 7) Example 6 (±)-(trans)-5,8-Difluoro-2,3-dinydro-1,6-oenzodioxin-2,3dimethanol (from Intermediate 8).

Example 7 (ί)-(trans)-5-F luoro-2,3-dihyoro-1 ,6-benzodioxw-2 ,3-dime thanol Intermediate 1 (7.0q) was dissolved in a mixture of toluene (70mi) and anisole (7.8ml) and the solution was stirred and cooled to -5° under a qentie stream of nitroqen. Anhydrous aluminium chloride (2.6q) was added and the temperature was maintained at 0-5° for 20 min. More anhydrous aluminium chloride (2.6a) was added and after 20 min. at 0-5° the mixture was allowed to warm to 20° with continued stirrinq. After 20 min. at 20°, it was cooled back to 0°, water (25ml) was added and after 5 min. stirrinq at 20°, the mixture wa3 diluted with ethyl acetate (75ml) and the layers were separated. The aqueous (lower) layer was re-extracted with ethyl acetate (2x50ml) and Qi the orqanic solutions were washed with 50* aqueous sodium chloride (25ml) and were combined and concentrated in vacuo to 56q, qivinq a thick slurry of sliqhtly purple crystals. After 30 min. at 20°, the crystals were harvested, washed with toluene (10mi)? light petroleum (20ml) and di-isopropyl ether (20mi) and dried to qive the title compound (2.93q) m.p. 122-124°. Concentration of tne mother liquor qgve a crude second crop of title compound (0.32q) which after chromatographic purification afforded a further quantity of pure title compound (0.24q) m.p. 121-123θ. NMR τ (DMSO-dg) 3.1-3.3 (3H. m, . aromatic), 4.85-5.0 (2H, m, OH) 5.8-5.9 (2H, m, 2-H,3H) 6.1-6.4 (4H. m, CH^O) · Example 8 ( ±)-( trans)-5-Nitro-2 .3-dihydro-l,4-benzodioxin-2.3dimethanol (shown in table 2) was prepared in a similar manner from intermediate 5. .15 TASLE 2 rl R2 Reaction So lvent NMR (τ) M.pt Solvent Aromatic ch2oh 2-H,3-H OH Me ch3 (2) H EtOH COCI 3 3.3 5.8-6.1 5.8-6.1 7.59 7.8 - CH30 (3) H EtOH compour id unstao .e, used vithout cf iarac ;eris< ation ch3 (4) ch3 MeOH DMS0-d6 3.42 6.3 5.9 5,04 7.89 77-9° Cl (5) Cl TFA DMSO-dg 3.02 6.0-6.4 5.75 4.8- 5.5 - 172-5° F (6) F EtOH DMSO-dg 3.2 6.08- 6.32 5.8 . 4.89 - 128130 ° NO 2 (8) H Toluene used without c 1 S-- :haracter; sation ί 0

Claims (7)

CLAIMS :

1. A compound of formula (Hi) R 1 φ « (III) φ ® Λ) \\ / \ /-\ I ο ΐ ch 2 oh R 2 H wherein R 1 is a haloqen atom or a qroup selected from C|_^ alkyl, Calkoxy, hydroxyl, cyano, nitro and -NR 3 R l+ where R 3 and R* 4 is each a hydroqen atom or a Cj_i, alkyl qroup; and R 2 is a hydroqen atom or a suostituent as defined aoove for R^. 2. A compound accordina to Claim 1 wherein R 1 is a haloqen atom or a C^-14 alkyl or C^^ alkoxy qroup. 3. A compound accordinq to Claim 1 or Claim 2 wherein R 2 is a hydroqen or fluorine atom. 4. A compound accordina to any one of Claims 1 to 3 wherein R 1 is a chlorine or fluorine atom or a methyl or methoxy oroup and.R 2 is a hydroqen or fluorine atom. 5. A compound accordina to any one of Claims 1 to 4 wherein R 1 represents a fluorine atom ar id R reo resents a h ydrooen atom.

2. 6. A compound selected from (+)-(trans)-5-methvl-2,3-dihydro-1,4penzodioxin-2,3-dimethanol; · (+)-(trans)-5-chloro-2,3-dihydro-1 ,4penzodioxin-2 ,3-dimethanol; and (+)-(trans)-5,8-di f1uoro-2,3-dihydrΟΙ ,4-oenzodioxin-2,3-dimethanol.

3. 7. ( + )-(trans)-5-F1uoro-2,3-dihydro-1,4-oenzodioxin-2,3-dimethanol. ϊ 1

4. 8. A process for the preparation of a compound of formula (HI) ss defined in Claim 1 which comprises debenzylation of a compound of formal a (IV):R 1 /A /°\?/ CHi ° Bz OD φ φ I « I (iv) \\ Λ /Λ • 0 ; CHjOBz R 2 H wherein R 1 and R 2 are as defined in Claim 1 and 8z represents a benzyl g roup.

5. 9. A compound of formula (ill) given and defined in Claim 1, substantially as hereinbefore described and exemplified.

6. 10. A process for the preparation of a compound of formula (III) given and defined in Claim 1, substantially as hereinbefore described and exemplified.

7. 11. A compound of formula (III) given and defined in Claim 1, whenever prepared by a process claimed in a preceding claim.