IE45004B1 - Oxiranylmethyltetrahydropyran derivative - Google Patents

Description

This invention relates to a chemical intermediate, which is) useful, for the preparation of a class of acids which are themselves useful for the preparation ox a.class of antibacterially active esters.

. Pseudomonic acid has the structure (1): and is disclosed as having antibacterial activity in British Eatfflit, Sgncificatioa-No. 1,395,907. It.has bssn found that ths allylic carboxylic acid moiety of the molecule is useful for preparing other esterified derivatives.

Accordingly the present invention provides a compound of formula (II): - 2 which is a a compound valuable intermediate of formula (III); for the preparation of CH.

I 3 C = CH.CO2H (III) or a salt thereof.

The compound of formula (III) wherein the double bond is in the E configuration, we have designated monic acid and it. will be referred to as such in this specification. The corresponding Z-isomer is termed isomonic acid. It is believed that monic acid has the absolute sterochemistry as shown in formula (IIIA): OH (IIIA) - 3 (The numbering is shown for the tetrahydropyran ring).

The salts of compound (XII) may be pharmaceutically acceptable, but need not be, as the utility of compound (III) is as chemical intermediate.

The compounds of formula (III) form the subject of Patent Specification No. 45003.

The esters of the compound of formula (III) are disclosed in Patent Specification No. 450S3 s if available Also disclosed therein are processes for the preparation of esters of a compound of formula (III) directly from the Intermediate of formula (II).

The compound (II) may be produced by a process -which comprises treating pseudomonic acid of formula (I) above, or an ester thereof, with ozone.

This reaction, may be par formed without protecting the hydroxyl groups in psuedomonic acid and is preferably carried out at a low temperature such as -5O°C to -80°, suitably -70°C to -80°.

It will be noted that the triacetate derivative 20 of compound (II) was disclosed in British Patent Specification Ko. 1,395,907 during the structure elucidation of pseudomonic acid. However, the compound (II) is not disclosed therein and there is no suggestion of a method of removing the acetate groups in order to prepare compound (II). 25 The following examples illustrate the present invention.

Example 1 Preparation of 2S-Acetonvl-3R,4R-dihydroxv-5S-(2S.3Sepoxyr5S-hvdroxv-4S-methvlhexvl)-2,3,5,6-tetrahydropyran (Compound A) Ozonised oxygen (ca 1%) was bubbled through a solution of methyl pseudomonate (0.514 g) in methanol (8 ml) arid pyridine (2 drops) at -78°C for 0.5 hour (when blue colour developed). The excess ozone was blown off by dry nitrogen at -78°C. Triethyl phosphite (80%, 0.3 ml) was then added and the reaction mixture was allowed to come to room temperature. The solvent was removed at room temperature in vacuo and the residue was chromatographed over silica gel (20 g), Elution of the column with chloroform-methanol (93:7) at the rate of 2 ml min"''· gave the title compound (0.299 g), m.p. 85-86° (from chloroform), + 11.9° (c, 1.0, CHCIa), V a (CHC1_) 1708, 1112, 1080, and 1050 cm . - 5 Example 2 Preparation of monic acid from ketone fA) by Wittiq condensation (i) Diethyl carboxvmethylenephosphonate.

Triethyl phosphonoacetate (44.8 g, 0,2 M) was dissolved in IN sodium hydroxide solution (200 ml; 0.2M) and stirred at room temperature overnight. The pH was adjusted from 9.0 to 1.0 with dilute hydrochloric acid. The solution was saturated with sodium chloride and extracted with ethyl acetate (3 x 100 ml)0 The latter was washed with saturated brine, dried over magnesium sulphate, filtered and evaporated to dryness in vacuo to give a viscous, colourless oil, ivhdch crystallized to a white solid when kept below room temperature (37.4 g; 96%). Thin layer chromatography revealed one component in chloroform at Rf = 0.02 as no visualised with iodine vapour. nD = 1,3900» δ (CDCl^) 9.33 (IH, s, C02H), 4.07 (4H, octet, Me-CHg-O-P, = 6 Hz, = 8 Hz), 2.88 (2H, d, P-CHg-COgH, JHp = 22 Hz) and 9.25 (6H, t, CH -CH„, J = 6 Hz), Irradiation at 3 £ δ 9.25 produces a doublet at 4.07 with JHp = 8 Hz, V max(filra) 1730 (C = 0 Str.), 1230 (P = 0 str.), 1170 (P - 0 vib.), 1050 (P - 0 vib.) cm-1. (Found: C, 37.10; H, 7.07; P, 15.66%; CgH-^PO^ requires:.

C, 36.74; H, 6.69; P, 15.79%). - 6 4300] ( ii) Monic Acid Ν,Ο-Bistrimethylsilylacetamide (1.52 ml; 6mM) was added to a solution of 2-acetonyl-3,4-dihydroxy-5~ (5-hydroxy-2,3-epoxy-4-methylhexyl)-2,3,5,ό-tetrahydropyran (302 mg; ImM) in dry acetonitrile (6 ml). The solution was stirred at room temperature for 1 hour followed hy evaporation tp dryness in vacuo at 40°C. The oily residue was dissolved in dry dimethylformamide (6 ml) for use in the next stage.

Sodium hydride (114 mg; 80% pure; 3.8 mM) was 10 added portionwise over hour to a solution of diethyl carboxymethylene phqsphonate (392 mg; 2mM) in dry dimethylformamdie (5 ml) at 0° under dry nitrogen. The inixture was stirred for a further 2 hours.

The solution of the silylated ketone above was added 15 dropwise to this mixf uie at 0°C under nitrogen and the resulting reaction mixture stirred overnight at room temperature. The latter was evaporated to dryness and the dark residue dissolved in water (10 ml) and ethanol (10 ml) and the pH adjusted to 1.8. After 5 min., at room temperature the solution was diluted witli water (15 ml) saturated with sodium chloride and extracted with ethyl acetate (4 x 10 ml), The latter was washed with brine, dried over magnesium sulphate, filtered and evaporated to dryness in vacuo to give monic acid.

A sample of the resulting oil mixture was dissolved in ethyl acetate and treated with diazomethane, thus converting the monic acid present into methyl monate. The presence of the latter was confirmed by 4 analytical h.p.l.c. compcirisons with authentic pure methyl monate.

Claims (2)

1. CLAIM S:1. A compound, of formula (II): (II)

2. A process for the preparation of a compound as claimed in claim 1, which process comprises reacting a compound of formula (I): (I) or an ester thereof with ozone.