GB2188626A - New 1,3-dioxane derivatives useful in the synthesis of leukotrienes - Google Patents

Abstract

Compounds of the formula <IMAGE> in which R<1> is optionally substituted phenyl and R<2> is -CHO, -CH=CHCO2H, -CH2CH2COOH, -CH=CHCH2COOH, -CH2-CH=CHCOOH or -CH2CH2CH2COOH; are new. The compounds are useful intermediates in the preparation of leukotrienes via compounds of formula <IMAGE> in which n is 1 or 2 and COOR is an ester group.

Description

SPECIFICATION Novel compounds and their preparation This invention relates to novel compounds, their preparation and use.

Recent years have seen the discovery of an important group of compounds known as leukotrienes with importance in a variety of biological functions. Samuelsson et al. proposed nomenclature for such compounds in, for example, Prostaglandins Vol. 19 No. 5 pages 645 to 647 (1980). The different types of naturally-occurring leukotriene are derived from leukotriene A4 (LTA4), namely, 5(S),6(S)-oxidd-7,9-trans- 1 1,1 4-cis-eicosatetraenoic acid and have a specific (S),(R) chirality at the 5 and 6 carbon atoms of the molecule It is of interest to devise synthetic routes for such leukotrienes because of their importance in research and because of the development of related compounds which have valuable properties in their own right, for instance nor-leukotrienes, isomers with one fewer carbon atoms in the functionalised alkyl side chain.

Accordingly the invention relates to useful intermediates, processes for preparing them and methods for the preparation of chiral leukotriene products employing the intermediates.

The compounds of the invention are of the general formula

in which R1 is optionally substituted phenyl and R2 is-CHO,-CH=CHCO2H,-CH2CH2COOH, -CH=CHCH2COOH,-CH2CH=CHCOOH or-CH2CH2CH2COOH; and salts and esters thereof.

When compounds of formula (I) contain a carboxyl group an opportunity exists of forming base addition salts, and furthermore esters can be prepared from compounds which bear a carboxyl group. Such salts and esters are included as part of the present invention. Examples of salts are those derived from alkali and alkaline earth metal hydroxides, carbonates and bicarbonates, ammonium hydroxide and aliphatic an aromatic amines, aliphatic diamines and hydroxy alkylamines. The potassium and sodium salt forms are particularly preferred salts. Esters include alkyl esters, for example, those prepared from C14 alkanols, the methyl and ethyl esters being most preferred. Free acids can, of course, be prepared from the corresponding salts and esters when these are produced directly by the synthetic routes described herein.

When R' is optionally substituted phenyl it is preferably phenyl or phenyl substituted by C14 alkyl, C14 alkoxy, hydroxyl, trihalomethyl, halogen, nitro, -NR3R4 where R3 and R4 are hydrogen or C14 alkyl, or -COR5where R5 is-OH or NR3R4. R1 is most preferably phenyl.

Compounds of formula (I) in which RZ is-CH=CHCH2COOH or-CH=CHCOOR where-COOR is an ester group, are prepared from those in which R2 is -CHO by Wittig reactions described below. Reduction of the compound in which R2 is -CH=CHCH2COOH gives the saturated compound in which R2 is -CH2CH2CH2COOH and reduction of the compound in which R2 is -CH=CHCOOR gives the compound in which R2 is -CH2CH2COOR. These compounds are important intermediates since they are the starting point for sequences of reactions which give, in high yield, epoxy intermediates having the appropriate chirality for preparing the leukotriene derivatives described above.

The novel compounds of formula (I) having the following structure

where R1 is as defined above can readily be prepared in good yield from D(+)glucose by reaction firstly with the appropriate acetol and then by oxidation, for example, in the following reaction scheme:

Thus, a further aspect of the invention is a process for preparing a compound of formula (II) which comprises oxidising a compound of the formula:

in which R7 is as defined above. This process is preferably carried out under basic conditions at a temperature of from 0 C to 100"C and in an inert organic solvent such as for example dichloromethane. The oxidising agents which may be employed include for example aqueous sodium periodate and sodium bicarbonate.

The compounds of formula (I) in which R2 is -CH2H=CHCOOR where -COOR is an ester group can be prepared from 2-deoxy-D-ribose by a Wittig reaction with Ph3P=CHCOOMe, followed by reaction with R1CHO and trifluoroacetic acid in dichloromethane.

As mentioned above, corn pounds of formula (II) may be converted to those compounds of formula (I) in which R2 isCH=CHCH2COOH by a Wittig reaction, using well known Wittig reagents of the formula Ph3P+CH2CH2COOH CI-. Preferably a temperature of from -80 C to 250C is employed and the reaction is performed in an inert organic solvent such as for example tetrahydrofuran. When it is desired to prepare compounds of formula (I) in which R2 is -CH2CH2CH2COOH, the product of the Wittig reaction is subjected to reduction by reaction with a reducing agent such as hydrogen an palladium on charcoal at a temperature of from 00C to 1 000C in an inert organic solvent such as tetrahydrofuran.

As described above, the compounds of formula (I) can be converted to key intermediates of use in the synthesis of leukotriene compounds. Thus the invention includes a process for preparing a compound of the formula

in which n is 1 or 2 and -COOR is an ester group, by reacting a compound of the formula

where R1 is as defined above and R7 is a leaving group such as methanesulphonyl, with acid and reacting the product thus formed with base.The acid employed is preferably mineral acid such as hydrogen chloride in an organic solvent such as methanol, and the product formed having the formula

can be reacted in situ with a base, such as for example potassium carbonate, to yield the compound of formula (Ill). Alternatively the unsaturated compounds of formula

in which R2 is -CH=CH-COOR or -CH2CH=CHCOOR can be reduced with Pearlmond's catalyst to give the compound of formula (IV).

Compounds of formula (III) can be converted to leukotriene derivatives by the synthetic routes described in, for example, Cohen petal J.Am.Chem.Soc. 1983,105,3661-3672.

The invention is illustrated by the following Examples.

EXAMPLE 1 4,6-0-Benzylidene-D-glucose D-(+)-Glucose (270 g) was heated at 65-700C in dry DMF (850 ml) in a two litre Florentine flask whilst rotating on a rotary evaporator. After 10 minutes, when most solid had dissolved, benzaldehyde dimethyl acetal (130 ml) and p-toluenesulphonic acid monohydrate (1.0 g) were added and the mixture heated at 65-80"C under vacuum for ca 1 hour during which time most solvent and volatiles had distilled over to leave a colourless syrup. The crude product was quenched with cooling into a solution of sodium hydrogen carbonate (10 g) in water (750 ml). After stirring for ca 15 minutes at 5-10"C, the product that had precipitated was removed by filtration, washed with cold water (50 ml) and dried to constant weight at 40"C in vacuo to give 4,6-O-benzylidene-D-glucose, as a slightly off-white solid, m.p. 178181'C.

EXAMPLE 2 Preparation of Z4-O-Benzylidene-D-erythrose 4,6-O-Benzylidene-D-glucopyranose (13.41 g) and sodium hydrogen carbonate (12.6 g) were added together to a magnetically stirred two phase solution of sodium periodate (21.39 g) in water (260 ml) and dichloromethane (520 ml). Stirring was continued for 0.5 hours at room temperature until carbon dioxide evolution had ceased. The layers were separated and the aqueous layer (pH ca 6.5) was extracted with dichloromethane (250 ml) (emulsions) and the organic layers bulked, dried (Na2SO4) and evaporated to dryness to give a clear oil which slowly crystallised, m.p.134-136 C.IR (KBr disc) 3600-3300 (OH) 1725 cm-l (C=O).1HNMR: (CDC1) 9.85 (s,1H, C-CHO), 7.53 (m, 5H, Ar), 5.6 1H, PhCH), 5.40 (m, 1H, CHOH),3.35-4.5 (m, 3H, CH2O+CHCHO).

EXAMPLE 3 Preparation of 5(S),7-0-Benzylidene-6(R)-hydroxyhept-3-enoic acid Triphenyl (2-carboxyethyl)phosphonium chloride (35.94 g) was added with magnetic stirring to dry THF (380 ml) and dry DMSO (95 ml) in a flame dried one litre round bottomed 3 neck flask under nitrogen. The solution which contained a little undissolved solid was cooled to - 1 O > C and n-butyl lithium (1.6 molar n-hexane) (114 ml) was added via a syringe and septum over ca 10 minutes maintaining the temperature at -10 to-5 C to give a blood red fine suspension of the ylid. To this mixture was added from a pressure equalised funnel, over 10 minutes at -100C to --5"C a solution of 2,4-O-benzylidene-D-erythrose (10.41 g) in dry THF (120 ml).During this addition, the red colouration was discharged and a precipitate formed which was separate from the supernatant by decantation and stirred with ether (500 ml) and water (50 ml) containing glacial acetic acid (7.6 g) (pH of aqueous was 5). The layers were separated and the aqueous phase was extracted with two further 500 ml portions of ether.The combined extracts were dried over Na2SO4 and evaporated to give an amber oil which proved intractable to crystallisation from a variety of solvents and was therefore chromatographed on silica gel (300 g) with ethyl acetate:acetic acid (99:1) as eluantto give, after trituration with ether-hexane, 5(S),7-O-benzylidene-6(R)-hydroxyhept-3-enoic acid, m.p. 1161 170C. IR: (KBr disc) 3500,2900-3300, 1720, 1660 cm-1.1HNMR: (CDC13) 7.4(s, 5H, Ar), 5.92 (dt, 1 H, J= 15 Hz) (Ch2CH)=, 5.55 (dd, 1 H, J= 15 Hz, CHCH=), 5.55(s,1 H, pHCH), 5.0 (s,1H, CH-OH EX), 4.1 54A (m, 2H, CHOH, CH.CH-),3.55 (d, 2H, CH2O), 3.35 (d, 2H, CH2CO2H) 13C NMR Anal. calcd. for C14H1605: C, 63.63; H, 6.10; 0,30.27.

Found: C, 63.36; H, 5.90; 0.30.44 EXAMPLE 4 Preparation of 5(S),7-O-Benzylidene-6(R)-hydroxyheptanoic acid 5(S),7-O.Benzylidene-6(R)-hydroxyhept-3-enoic acid (5.3 g) was dissolved in THF (100 ml) and hydrogenated at 60 psi in the present of 10% Pd/C (0.5 g) for 1 hour. The catalyst was removed by filtration through Celite and the filtrate evaporated to give 5.32 g of 5(S) g of 5(S),7-O-benzylidene-6(R)-hydroxyheptanoic acid as a colourless oil which solidified on standing, m.p. 110-111 C. IR: (KBr disc) 3500,2800-3200, 1725 cm-1.

1HNMR (CDCl3) 7.4 (s, 5H, Ar), 5.45 (s, 1 H, PhCH), 4.2 (m, 1 H, CHOH), 3.55 (m, 3H, CH2O, CHO), 2.35 (t, 2H, CH2CO2H),1.4-1.9 (m,4H, (CH2)2). 13C NMR Anal. calcd. for C14H18Os: C, 63.15; H, 6.81; 0,30.04; Found: C, 62.94: H, 6.60; 0,30.24.

EXAMPLE 5 Preparation of Methyl-S(S), 7-O-Benzylidene-6(R)-h ydroxyheptanoate To an ice cold solution of 5(S),7-O-benzylidene-6(R)-hydroxyheptanoic acid (1.46 g) in dry ether (20 ml) was added dropwise ethereal diazomethane until the yellow colouration no longer discharged. The pale yellow solution was evaporated to dryness to give 1.54 g of methyl 5(S),7-O-benzylidene-6(R)-hydroxyheptanoate as a pale yellow viscous oil. IR (thin film) 3400-3500,1724,1600 cm1. 1HNMR: (CDCl3) 7.4 (S 5H, Ar), 5.5 (s, 1H, phCH), 3.72 (s, 3H, CO2CH3), 2.35 (t, 2H, CH2CO2CH3), 1.3-1.9 (m, 4H (CH2)2).

EXAMPLE 6 Preparation ofMethyl-5(S), 7-O-benzylidene-6(R)-mesyloxyheptanoate To a solution of methyl-5(S),7-O-benzylidene-6(R)-hydroxyheptanoate (0.89 g) in dry methylene chloride (10 ml) at 0 C was added under a nitrogen atmospheretriethylamine (0.67 g) then methane sulphonyl chloride (0.64 g). The mixture was allowed to warm to room temperature over ca 2 hours then quenched into saturated aqueous sodium hydrogen carbonate solution (50 ml). The layers were separated and the aqueous phase extracted with methylene chloride (20 ml).The combined extracts were washed with water, dried over Na2SO4 and evaporated to give an amber oil which was dissolved in hot methanol (5 ml) and reprecipitated on cooling to 0 C to give after filtration and drying 0.74 g of methyl-5(S),-7-O-benzylidene-6(R)-mesyloxyheptanoate as pale yellow fibrous crystals, m.p. 89-90 C. IR: (KBr disc) 1735, 1340, 1180 cm-. HNMR: (CDCI3) 7.4 5H, Ar), 5.49, (s, 1 H, PhCH), 3.67 (s, 3H, CO3CH3), 3.1 (s, 3H, SO2CH3), 2.37 (t, 2H, CH2CO2CH3),1.4-1.9 (m, 4H (CH2)2, Anal. calcd. for C16H2207St C, 53.62; H, 6.19; 0,31.25; S,8.95 Found:C, 53.70; H, 6.05; Q,30.99; S, 8.85 EXAMPLE 7 Preparation of Methyl-5(S),7-dihydroxy-6(R)-mesyloxyheptanoate and Methyl-S(S), 6(S)-epoxy- 7- hydroxyheptanoate To a stirred suspension of methyl-5(S),7-O-benzylidene-6(R)-mesyloxyheptanoate (0.6 g) in dry methanol (3 ml) was added dry methanol (3 ml) containing 3% hydrogen chloride. The solid passed into solution on stirring at room temperature for 2 hours and TLC indicated that reaction was complete. Potassium carbonate (0.8 g) was added to the mixture without isolation of the intermediate diol mesylate.The slurry which thickened as the reaction proceeded was stirred at room temperature for 15 minutes at which point. TCC indicated that reaction was complete. The mixture was quenched into methylene chloride 170 ml) and washed with water. The latter was back washed with methylene chloride (50 ml) and the combined organic extracts dried over Na2SO4 and evaporated to give 0.34 g of a pale yellow liquid consisting of epoxy alcohol alqng with benzaldehyde and benzaldehye dimethylacetal. The oil was chromatographed on silica gel (10 g) with toluene-ethyl acetate (1 :3) as eluant to give methyl-5(S),6(S)-epoxy-7-hydroxyheptanoate as a pale yellow oil.

IR: (thin film) 3500, 1730 cm-1.

EXAMPLE 8 Preparation of Methyl 5(S61RJ, 7-trihydroxyhepta-2E-enoate 2-Deoxy-D-ribose (123 g) and (carbomethoxymethylene)triphenylphosphorane (328 9) were heated at reflux in DME (900 ml) for 6 hours. The solvent was evaporated to leave a colourless oil which was stirred with water (900 ml) and filtered to remove Ph3PO. The filtrate was evaporated to dryness to give 174.4 g of methyl 5(S),6(R),7-trihydroxyhepta-2E-enoate as a colourless oil which was stirred with water (900 ml) and filtered to remove Ph3PO. The filtrate was evaporated to dryness to give 174.4 g of methyl 5(S),6(R),7-trihydroxyhepta- 2E-enoate as a colourless oil which slowly solidified mp 55-57 C.

EXAMPLE 9 Preparation of Methyl 5(5), 7-O-benzylidene-6(R)-h ydroxyhepta-2E-enoate Methyl 5(S),6(R),7-trihydroxyhepta-2E-enoate (174.4 g) and fresh benzaldehyde (131 ml) were heated at reflux, under nitrogen, in methylene chloride (3 litres) containing trifluoroacetic acid (10 ml) for 6 hours. The mixture was extracted with saturated aqueous potassium bicarbonate (1 litre), saturated aqueous sodium metabisulphite (1 litre) and water (1 litre) and dried over Na2SO4. Filtration and evaporation gave a yellow oil (207.5 g).

EXAMPLE 10 Preparation of Methyl 5(S), 7-O-benzylidene-6(R)-mesyloxyhepta-2E-enoate Methyl 5(S),7-O-benzylidene-6(R)-hydroxyhepta-2E-enoate (207.5 g) was dissolved in dry methylene chloride (1.5 litres) and the solution cooled to OOC. To the stirred cold solution under nitrogen was added methylamine (217 ml) in one lot followed by methanesulphonyl chloride (102 ml) over about 30 minutes at about -5 C. The mixture was allowed to warm with stirring to room temperature and washed with saturated aqueous sodium bicarbonate (2x 1.5 litres). The bulked aqueous washings were back-washed with methylene chloride (450 ml) and the combined organics dried over Na2SO4.Filtration and evaporation gave an amber oil 257 g (96%) of crude Methyl 5(S),7-O-benzylidene-6(R)-mesyl-oxyhepta-2E-enoate. This material vyas dissolved in hot methanol (1.3 litres) and cooled with stirring to about -20 C to give a white solid precipitate which was isolated byfiltration and washed with ether (2x75 ml) to give pure methyl S(S),7-0-ibenzylidene- 6(R)-mesyl-oxyhepta-2E-enoate, m.p. 109"C.

EXAMPLE 11 Preparation of Methyl 5(5), 7-dihydroxy, 6(R)-mesyloxyheptanoate Methyl 5(S),7-O-benzylidene-6(R)-mesyl-oxyhepta-2E-enoate (10 g) was dissolved in ethyl acetate (100 ml) and hydrogenated at 50-60 psi in the presence of Pearl many catalyst Pd (OH)2-(Aldrich) 3.4 g for 2 hours py which time uptake had ceased. The catalyst was filtered off (fibre glass paper) and thqfiltrate evaporated to give a colourless gum 8.7 g.

EXAMPLE 12 Preparation of 5(S),6(S)-Epoxy-7-hydroxyheptanoate Methyl 5(S),7-dihydroxy,6(R)-mesyloxyheptanoate (8.7'9) was dissolved in dry methanol (130 ml) and stirred, under nitrogen, for 2 hours with anhydrous powdered K2CO3 (4.5 g). The mixture was evaporated to a thick slurry under vacuum ( < 35 C) and diluted with methylene chloride (120 ml) and water (17 ml) (NB on agitation all solid dissolves in the aqueous layer). The aqueous layer was separated, saturated with ipaCI, and back washed with methylene chloride (45 ml). The combined organic phases were dried over Na2$O2 and evaporated to give a pale yellow oil; pure 5(S),6(S)-epoxyb7-hydroxyheptanoate one enantiomer only,

Claims (5)

1. Acompound of the formula

in which R1 is optionally substituted phenyl and R2 isCHO,CH=CHCO2H,CH2CH2COOH, -CH =CHCH2COOH, -CH2-CH =CHCOOH or -CH2CH2COOH; and salts and esters thereof.

2. A compound according to claim 1 in which R1 is phenyl.

3. A process for preparing a compound according to either of claims 1 and 2 in which R2 is -CHO, which comprises oxidising a compound of the formula:

in which R1 is optionally substituted phenyl.

4. A process for preparing a compound of the formula:

in which n is 1 or 2 and -COOR is an ester group, by reacting a compound of the formula

where R1 is optionally substituted phenyl and R7 is a leaving group with acid and reacting the product thus formed with base.

5. A process for preparing a compound of the formula:

in which n is 1 or 2 and -COOR is an ester group, by reacting a compound of the formula

in which R1 is optionally substituted phenyl, R7 is a leaving group and R2 iS -CH=CH-COOR or -CH2CH=CHCOOR with Pearlmond's catalyst, and reacting the product with base.