GB1595942A - 6-chloro-6-deoxy-mannose - Google Patents

Description

(54) 6-CHLORO-6-DEOXY-MANNOSE (71) We, TATE & LYLE LIMITED, a British Company of Sugar Quay, Lower Thames Street, London EC3R 6DQ, (formerly of 21 Mincing Lane, London EC3R 7QY), 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 6-chloro-6deoxy-mannose. This is a novel compound and possesses male fertility-inhibiting action.

At present, the only available systematic method of fertility control involves the administration of hormones or hormonelike substances to the female, generally to interfere with the normal menstrual or oestrous cycle. Considerable research has been undertaken to find an equivalent systematic method of fertility control in the male, so far without any real success. This research has generally been concerned with hormone-type action, although more recently attention has turned to the use of chemical substances having no hormonal affect, but instead possessing an entirely local action on the sperm.

One particular field of activity which is of considerable interest is intervention in the process of sperm maturation in the epididymis. This is an attractive approach to fertility regulation in the male since methods having this mechanism of action would not depress spermatogenesis or libido. Maturation of the sperm in the epididymis requires several days and the passage of the mature sperm through the epididymis lasts seven to twelve days, during which time the motility of the sperm is promoted. Thus, interference with this process can, in theory, produce immotile sperm which are hence nonfertile.

One substance which has previously been of considerable interest is racemic achlorohydrin. However this compound has recently been reported to have undesirable side effects and hence interest in racemic a-chlorohydrin has waned.

We have discovered that certain 6chlorodeoxysaccharides, when administered orally to the male, have the ability to render the subject infertile. While we do not wish to be bound by theory, we believe this action is due to a depression of the sperm motility. Fertility is subsequently full regained on cessation of the treatment.

In accordance with this discovery, our copending application no. 10694/77 serial no. 1595941 has as its subject male fertilityinhibiting compositions in unit dosage form, containing as an active ingredient certain specified 6-chlorodeoxy monosaccharides or 6-chloro-deoxy disaccharides in association with a physiologically acceptable carrier or excipient.

Many of the compounds of use in compositions according to the invention of our said copending application are known per se, but one, 6-chloro-6-deoxy-mannose, is previously unreported.

The present invention provides the compound 6-chloro-6-deoxy-mannose.

This compound may be prepared by reacting a protected form of mannose with an appropriate chlorinating agent. The mannose is first protected against unwanted chlorination at positions other than the 6-position and then deprotected after the chlorination. In particular, the anomeric centre (the reducing centre) must be protected during chlorination, for example by methylation or by the formation of acetal derivatives such as isopropylidene-bridged derivatives. Various suitable chlorinating agents include methane-sulphonyl chloride in DMF, and triphenylphosphine in carbon tetrachloride.

The following example illustrates the invention further: 6-chloro-6-deoxy-a-D-mannopryanose (6chloro-6-deoxy-mannose) A solution of methyl a-Dmannopryanoside (20 g 0.103 moles) in dry DMF (1 litre) was cooled to 0 C and N-chlorosuccinimide (27.6 g, 0.207 moles) and triphenylphosphine (54 g, 0.206 moles) were added successively in portions. The resulting mixture was heated at 50"C for 2 hours, cooled and partitioned between chloroform (2 litres) and water (2 litres).

The chloroform layer was washed with water and the water layer extracted with chloroform. The water layer and the water washings were combined and evaporated to dryness. The residue was acetylated by treatment with pyridine (200 ml) and acetic anhydride (100 ml). After a conventional work-up in which succinimide was removed in water washings, the syrupy material was de-acetylated by treatment with a catalytic quantity of sodium methoxide in methanol.

Evaporation of the methanol to dryness yielded methyl 6-chloro-6-deoxy-a-Dmanno-pyranoside (15.2 g). This compound was reported by Evans, Long and Parrish, J.

Org Chem 33 (1968) p.1071 but was obtained using a different route.

The residue was then subjected to acetolysis by treatment with glacial acetic acid (450 ml), acetic anhydride (60 ml) and concentrated sulphuric acid (22.5 ml) at 25"C for 70 hours. The mixture was poured into ice/water (2.5 litres) and extracted with chloroform (500 ml). The extract was washed with saturated sodium hydrogen carbonate and then with water and was dried over magnesium sulphate, filtered and evaporated. Thin-layer chromatography (ethyl acetate/petroleum ether, 2:1) on silica gel indicated that the product was homogeneous. The product was confirmed by 'H NMR spectroscopy to be 1,2,3,4 tetra-O-acetyl-6-chloro-6-deoxy-a-D- mannopyranoside. [a]d22+55.5 (c 1.9 chloroform); NMR: 6.32 (lip, H-l. J1.2 = 2Hz); b 5.8-5.5 (3p, H's 2,3 and 4, multiplet); 4.3(1p, H-5, multiplet); 3.75 (2p, H's 6, multiplet); 6 2.05-1.8 (12p, 4 x CH3-).

The tetra-acetate was then de-acetylated by treatment with a catalytic amount of sodium methoxide in methanol to yield 6-chloro-6-deoxy-a-D-mannopyranose.

Analysis: Calc. Cl, 17.85%; Found Cl, 17.41% [a]d8+26.5 (c 0.4 water).

WHAT WE CLAIM IS: 1. 6-chloro-6-deoxy-mannose.

2. A method for preparing 6-chloro-6deoxy-mannose, the method comprising chlorination at the 6-position of mannose protected against chlorination which might occur at other than the 6-position, and deprotection of any protected positions.

3. A method according to Claim 2, wherein the protected mannose is protected at its anomeric centre by methylation or by the formation of an acetal derivative.

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

Claims (3)

**WARNING** start of CLMS field may overlap end of DESC **. centre (the reducing centre) must be protected during chlorination, for example by methylation or by the formation of acetal derivatives such as isopropylidene-bridged derivatives. Various suitable chlorinating agents include methane-sulphonyl chloride in DMF, and triphenylphosphine in carbon tetrachloride. The following example illustrates the invention further: 6-chloro-6-deoxy-a-D-mannopryanose (6chloro-6-deoxy-mannose) A solution of methyl a-Dmannopryanoside (20 g 0.103 moles) in dry DMF (1 litre) was cooled to 0 C and N-chlorosuccinimide (27.6 g, 0.207 moles) and triphenylphosphine (54 g, 0.206 moles) were added successively in portions. The resulting mixture was heated at 50"C for 2 hours, cooled and partitioned between chloroform (2 litres) and water (2 litres). The chloroform layer was washed with water and the water layer extracted with chloroform. The water layer and the water washings were combined and evaporated to dryness. The residue was acetylated by treatment with pyridine (200 ml) and acetic anhydride (100 ml). After a conventional work-up in which succinimide was removed in water washings, the syrupy material was de-acetylated by treatment with a catalytic quantity of sodium methoxide in methanol. Evaporation of the methanol to dryness yielded methyl 6-chloro-6-deoxy-a-Dmanno-pyranoside (15.2 g). This compound was reported by Evans, Long and Parrish, J. Org Chem 33 (1968) p.1071 but was obtained using a different route. The residue was then subjected to acetolysis by treatment with glacial acetic acid (450 ml), acetic anhydride (60 ml) and concentrated sulphuric acid (22.5 ml) at 25"C for 70 hours. The mixture was poured into ice/water (2.5 litres) and extracted with chloroform (500 ml). The extract was washed with saturated sodium hydrogen carbonate and then with water and was dried over magnesium sulphate, filtered and evaporated. Thin-layer chromatography (ethyl acetate/petroleum ether, 2:1) on silica gel indicated that the product was homogeneous. The product was confirmed by 'H NMR spectroscopy to be 1,2,3,4 tetra-O-acetyl-6-chloro-6-deoxy-a-D- mannopyranoside. [a]d22+55.5 (c 1.9 chloroform); NMR: 6.32 (lip, H-l. J1.2 = 2Hz); b 5.8-5.5 (3p, H's 2,3 and 4, multiplet); 4.3(1p, H-5, multiplet); 3.75 (2p, H's 6, multiplet); 6 2.05-1.8 (12p, 4 x CH3-). The tetra-acetate was then de-acetylated by treatment with a catalytic amount of sodium methoxide in methanol to yield 6-chloro-6-deoxy-a-D-mannopyranose. Analysis: Calc. Cl, 17.85%; Found Cl, 17.41% [a]d8+26.5 (c 0.4 water). WHAT WE CLAIM IS:

1. 6-chloro-6-deoxy-mannose.

2. A method for preparing 6-chloro-6deoxy-mannose, the method comprising chlorination at the 6-position of mannose protected against chlorination which might occur at other than the 6-position, and deprotection of any protected positions.

3. A method according to Claim 2, wherein the protected mannose is protected at its anomeric centre by methylation or by the formation of an acetal derivative.