GB1587060A

GB1587060A - Oxiranylmethyltetrahydropyran derivative

Info

Publication number: GB1587060A
Application number: GB4152979A
Authority: GB
Original assignee: Beecham Group PLC
Current assignee: Beecham Group PLC
Priority date: 1977-06-15
Filing date: 1977-06-15
Publication date: 1981-03-25

Description

(54) OXI RANYLMETMYLTETRAHYDROPYRAN DERIVATIVE (71) We, BEECHAM GROUP LIMITED, a British Company, of Beecham House, Great West Road, Brentford, Middlesex, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- 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 of a class of antibacterially active esters.

Pseudomonic acid has the structure (I):

and is disclosed as having antibacterial activity in British Patent No. 1,395,907. It has been found that the allylic carboxylic acid moiety of the molecule is useful for preparing other esterified derivatives.

Accordingly the present invention provides a compound of formula (II):

which is a valuable intermediate for the preparation of a compound of formula (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):

(The- numbering is shown for the tetrahydropyran ring).

The salts of compound (III) 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 our copending application No. 24712/76 (Serial No. 1587658).

The esters of the compound of formula (III) are disclosed in our corresponding application No. 23549/77 (Serial No. 1587059). Also disclosed therein are processes for the preparation of esters of a compound of formula (III) directly from the intermediate of formula (it).

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 performed without protecting the hydroxyl groups in psuedomonic acid and is preferably carried out at a low temperature such -500C to -80", suitably -700C to 800.

It will be noted that the triacetate derivative of compound (II) was disclosed in British Patent No. 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).

The following example illustrates the present invention.

Example Preparation of 2S-Acetonyl-3R,4R-dihydroxy-5S- (2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)-2,3,5,6- tetrahydropyran (Compound A)

Ozonised oxygen (ca I /n) was bubbled through a solution of methyl pseudomonate (0.514 g) in methanol (8 ml) and pyridine (2 drops) at -78tC for 0.5 hour (when blue colour developed). The excess ozone was blown off- by dry nitrogen at 780 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-t gave the title compound (0.299 g), m.p. 85--860 (from chloroform), [α]20D -I-11.90(c, 1.0, CHCl3), Vmax (CHCl3) 1708, 1112, 1080, and 1050 cm-'.

WHAT WE CLAIM IS: 1. A compound of formula (II):

**WARNING** end of DESC field may overlap start of CLMS **.

Claims

**WARNING** start of CLMS field may overlap end of DESC **. 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): (The- numbering is shown for the tetrahydropyran ring). The salts of compound (III) 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 our copending application No. 24712/76 (Serial No. 1587658). The esters of the compound of formula (III) are disclosed in our corresponding application No. 23549/77 (Serial No. 1587059). Also disclosed therein are processes for the preparation of esters of a compound of formula (III) directly from the intermediate of formula (it). 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 performed without protecting the hydroxyl groups in psuedomonic acid and is preferably carried out at a low temperature such -500C to -80", suitably -700C to 800. It will be noted that the triacetate derivative of compound (II) was disclosed in British Patent No. 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). The following example illustrates the present invention. Example Preparation of 2S-Acetonyl-3R,4R-dihydroxy-5S- (2S,3S-epoxy-5S-hydroxy-4S-methylhexyl)-2,3,5,6- tetrahydropyran (Compound A) Ozonised oxygen (ca I /n) was bubbled through a solution of methyl pseudomonate (0.514 g) in methanol (8 ml) and pyridine (2 drops) at -78tC for 0.5 hour (when blue colour developed). The excess ozone was blown off- by dry nitrogen at 780 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-t gave the title compound (0.299 g), m.p. 85--860 (from chloroform), [α]20D -I-11.90(c, 1.0, CHCl3), Vmax (CHCl3) 1708, 1112, 1080, and 1050 cm-'. WHAT WE CLAIM IS:

1. A compound of formula (II):

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

or an ester thereof with ozone.