FI62284C - SOM MELLANPRODUKT FOER 1D- (1,3,5 / 2) -1,5-DIAMINO-2,3-CYCLOHEXADIOL ANVAENDBAR 1D- (1,3,5 / 2) -1,5-DIAZIDO-2,3-CYCLOHEXANDIOL OVER FREQUENCY FOR FOUNDATION - Google Patents

Description

I -__.- I fal ADVERTISEMENT ^ n 0 qa V0V M ^ »UTLÄGeNIMOSSKIUFT 62284 c <45> Fa ten Lti issued 10 12 1932 'cSa & U, Patsrnt neddelat λλ_ x * ^ (51) K» .lk? /Tnt.a . C 07 c 117/00 FINLAND — FINLAND (2ij Piwwirtimii-NtiitweiuiiBi 802230 (22) HikmliplM — AnaAknlnpdag 15 · 07 · 80 (FI) (23) Alkupllvt — GIMfhMad ·! 1 ^ .02.75 (41) Tullut tutklMkal - BlWIt of nct1 | 15.07.80

Patents »] · register Managed / 44) Nlhttvikslpanon Ja kuLfulkalaun p» m.— 31.08.82

Patent · och registerstyreleen Ara6kan uttafd oeh utl. »Krlftun pubticurad (32) (33) (31) Pyr» 1 · ** / stueMttus — Begird priori * · * 15.02.7I4

France-France (FR) 7 ^ 05110 (71) Sanofi, Uo, Avenue George V, 75008 Paris, France-France (FR) (72) Andre Cier, Neuilly-sur-Seine, Stephan Gero, Ablon, Alain Olesker, Gif -sur-Yvette, Jean Leboul, Gif-sur-Yvette, France-France (FR) (7U) Oy Borenius & Co Ab (3k) 1D- (1,3,5 / 2) -1,5-diamino-2 1D- (1,3,5 / 2) -1,5-Diazido-2,3-cyclohexanediol useful as an intermediate for 3-cyclohexadiol and process for its preparation - Som mellanprodukt för 1D- (1,3,5 / 2) -1 , 5 ~ -diamino-2,3-cyclohexa diol of the ID- (1,3,5 / 2) -1,5-diazido-2,3-cyclohexanediol and for the preparation of framställ (62) Separated from the application by 750 ^ + This invention relates to a novel 1D- (1,3,5 / 2) -1,5-diazido-2,3-cyclohexanediol and to a process for its preparation.

The cyclohexanediol derivative of the present invention is represented by the general formula:

OH

In this explanation, the nomenclature presented in the magazine Eur. J. Biochem. 5, 1, (1968) "Recommended Rules by the I.U.P.A.C. - I.U.B. Tentative Cyclitol Nomenclature Rules".

2 62284

The compound of formula I may be prepared by heating in a solvent such as N, N-dimethylformamide or hexamethylphosphoric triamide and in the presence of an alkali metal azide, e.g. sodium azide, of formula:

OH

R2N-1 / OH

A compound according to R 3 in which N represents a group when R 2 represents a hydrogen atom or R 1 represents a hydrogen atom in which R 2 represents an alkanesulfonyloxy group such as a methanesulfonyloxy group or an arenesulfonyloxy group such as, for example, p-toluenesulfonyloxy a nyl group such as, for example, a methanesulfonyl group or an arenesulfonyl group such as p-toluenesulfonyl or p-bromobenzenesulfonyl to give the desired diazide of formula I.

Compounds of formula II may be obtained by treatment in a solvent, e.g. pyridine, of formula:

OH

an epoxide of formula wherein R 1 and R 2 are as defined in formula II, with a chloride of formula: R 3 -Cl (IV) wherein R 3 is as defined in formula II to give a formula of formula: R 2 -R 1 / (V) 0 R 3 3 62284, wherein, R 2 and R 2 are as defined in formula II.

The compound of formula V thus obtained is then treated with an acid by heating, e.g. in aqueous sulfuric acid, to give the desired compound of formula II.

Of the compounds of formula III, 1L-2,3-anhydro-SO-tosyl-1,2,3,5 / 0-cyclohexanetetrol and 1L-2,3-anhydro- (1,2,3 / 5) -5 are known. -azido-1,2,3-cyclohexanetriol, which are described in more detail in BE patent 805,949 (published November 4, 1974).

Other compounds of formula III can be prepared by the same method as described in the above-mentioned patents for the preparation of the two derivatives of formula II mentioned above.

The diazide of formula I forms a very useful intermediate which can be used, for example, of the corresponding formula VI

k2n -Γ Y \ <vn

\ _ToH

for the preparation of diaminocyclitol and its salts according to Diaminocyclitol of formula VI is also a very useful intermediate, especially in the preparation of antibacterial compounds. This compound is particularly valuable because it contains in its chemical structure the steric order of amino and hydroxy groups, which is analogous but different from that of the natural diaminocyclitols contained in the molecular structure of the hybrid mucin antibiotics. This use of a compound of formula VI is further described in parent application 750405. However, diaminocyclitol of formula VI is not a very stable compound as it is quite rapidly degraded. It is therefore not easy to store and therefore needs to be prepared just before use.

On the other hand, the diazide of formula I, which can be used for the preparation of diaminocyclitol, is easy to handle, very stable and can be stored for long periods of time, which means that it offers the considerable advantage of being available immediately when needed · 4 62284 manufactures whenever its use is topical. In addition, the two azide groups present in the diazide of the formula I give this molecule a high reactivity and enable subsequent reactions which would otherwise be impossible or at least very difficult.

As stated above, the diazide of formula I can be used to prepare diazocyclitol of formula VI. ..

The production process used for this purpose comprises the catalytic reduction of the diazide of formula I and offers many advantages which make it excellent for use on an industrial scale. The reduction in question can in fact be carried out without the introduction of heat from an external source and can take place at normal atmospheric pressure. These reaction conditions are very advantageous because they make it possible to use energy and work under pressure, which of course improves occupational safety. Furthermore, the diaminocyclitol thus prepared is obtained without impurities, which makes subsequent separation unnecessary, which is always an expensive operation on an industrial scale.

Since the diazide of formula I can be converted to the corresponding diaminocyclitol and its salts without difficulty and in good yield, this diaminocyclitol can be prepared from the diazide of formula I at any time it is needed.

Thus, since the novel diazide of formula I can be easily and rapidly converted to the corresponding diaminocyclitol, it can be considered that the latter compound is almost as readily available as if it could be well preserved before use.

The following examples illustrate the invention:

Example 1 Preparation of 1D- (1,3,5 / 2) -1,5-diazido-2,3-cyclohexanediol a) 1L-2,3-anhydro-1,5-di-O-tosyl-1,2, 3,5 / O-Cyclohexane-tetrol (Formula V) 4 g of tosyl chloride (p-toluenesulfonyl chloride) dissolved in 25 ml of pyridine were added dropwise at 0 ° C to 4 g of 1L-2,3-5,6284 anhydro-5 -O-tosyl-1,2,3,5 / O-cyclohexanetetrol in a solution in 20 ml of pyridine. The reaction mixture was allowed to stand for 20 hours at 0 ° C and then poured onto ice. The mixture was extracted several times with chloroform, and the chloroform extracts were washed with water. After drying over anhydrous sodium sulfate and evaporation of chloroform and pyridine, a white foam separated, which, after crystallization from methanol, * 4.3 g of crystals were obtained. The product obtained was washed three times with 10 ml of methanol.

In this way, recrystallization from ethyl acetate gave analytical grade 1L-2,3-anhydro-1,5-di-O-tosyl-1,2,3,5 / 0-cyclohexane tetrol crystals. Sp. 143.5-145 ° C.

/ five_7p ^ = + 34 ° (c = 1.93, from chloroform)

After crystallization from methanol, the mother liquor was treated at room temperature with 6 ml of sodium methylate solution prepared from 2 g of sodium in 75 ml of methanol. After a few minutes, crystals precipitated. The mixture was allowed to stand for another hour and then filtered.

In this way, a further 1.3 g of the desired ditosylate were obtained, corresponding to a final 5.6 g of 1L-2,3-anhydro-1,5-di-O-tosyl-1,2,3,5 / 0-cyclohexanetetrol.

Total yield: 90%.

b) 1 L-1,5-di-O-tosyl-1,2,5 / 3-cyclohexanetetrol (formula II)

To a flask containing 3.2 g of 1L-2,3-anhydro-1,5-di-O-tosyl-1,2,3,5 / O-cyclohexanetetrol prepared as described above and dissolved in 10 ml 1,2-dimethoxyethane, 50 ml of 1.5 N aqueous sulfuric acid was added.

The reaction mixture was heated to reflux for 150 minutes and cooled to 0 ° C after the immiscible phase formed. The mixture was neutralized with aqueous sodium bicarbonate solution and then extracted with ethyl acetate. The organic phase was washed with water and dried over anhydrous sodium sulfate. Evaporation of the solvents gave a white foam which, after crystallization from chloroform, gave 3.1 g of 1H-1,5-di-O-tosyl-1,2,5 / 3-cyclohexanetetrol (yield 90%). The analytically pure product melted at 121-123 ° C after recrystallization.

2 5 L α_7β = + 10 ° (c = 1, from ethanol) 6 62284 c) 1D- (1,3,5 / 2) -1,5-diazido-2,3-cyclohexanediol (formula I)

To a mixture of 2.6 g of sodium azide in 50 ml of N, N-dimethylformamide was added 4.5 g of 1L-1,5-di-O-tosyl-1,2,5 / 3-cyclohexane-tetrol, prepared as described above.

The resulting black solution was heated under reflux for 2 hours, poured into ice water and then extracted with ethyl acetate. The organic phase was washed with water, dried over anhydrous sodium sulfate and the solvent was evaporated. In this way, 1.92 g of a black oil which was very fluid was separated and decolorized in ethanol with the aid of charcoal.

In this way, 1.2 g of 1D- (1,3,5 / 2) -1,5-diazido-2,3-cyclohexane diol were obtained in the form of beige crystals after two successive recrystallizations from a chloroform / petroleum ether mixture. This corresponds to a yield of 60%. Sp. 62-63.5 ° C.

[α] D = + 2 ° + _ 1 (c = 1, from methanol)

Example 2 Preparation of 1D- (1,3,5 / 2) -1,5-diazido-2,3-cyclohexanediol a) 1L-2,3-anhydro-5-azido-1-O-tosyl-1,2, Preparation of 3/5-cyclohexanetriol (Formula V)

To a pre-cooled solution of 125 mg of 1L-2,3-anhydro- (1,2,3 / 5) -5-azido-1,2,3-cyclohexantriol in 3 ml of pyridine was added 280 mg of tosyl chloride. . The reaction was monitored by thin layer chromatography using 50/50 ethyl acetate / petroleum ether and ultraviolet detection. After 12 hours, the reaction was complete and extracted with chloroform. This gave 192 mg of a very thick clear oil which was then purified by thin layer chromatography.

In this way, 1L-2,3-anhydro-5-azido-1-O-tosyl-1,2,3,5-cyclohexanediol was obtained.

λ p / α7ρ = + 35 ° (c = 1.28, from chloroform)

Analysis: C ^ H ^ O ^ SNg 7 62284 C% H% N% S%

Calculated 50, 4-7 4.89 1 3.58 1 0, 37

Measured 50.26 4.90 13.33 10.39 b) Preparation of 1H-5-azido-1-O-tosyl-1,2,3,5-cyclohexanetriol (Formula II)

To a solution of 150 mg of 1L-2,3-anhydro-5-azido-1-O-tosyl-1,2,3 / 5-cyclohexanetriol prepared as described above in 2 ml of 1,2-dimethoxyethane was added 2 ml of 1.5 N aqueous sulfuric acid solution. The reaction mixture was heated to reflux for 150 minutes and the progress of the reaction was monitored by thin layer chromatography using 7/3 ethyl acetate / petroleum ether as solvent. The mixture was then cooled to 0 ° C and neutralized with aqueous sodium bicarbonate. The mixture was then extracted with ethyl acetate to give 102 g of an oily product, which showed several dirt stains by thin layer chromatography.

In this way, 1H-5-azido-1-O-tosyl-1,2,3,5-cyclohexane triol was prepared in 64% yield.

The presence of two hydroxyl groups was confirmed by the N.M.R spectrum of the product after deuteration.

c) Preparation of 1D- (1,3,5 / 2) -1,5-diazido-2,3-cyclohexanediol (formula I)

To a mixture of 50 mg of sodium azide and 2 ml of N, N-dimethylformamide was added 1L-5-azido-1-O-tosyl-1,2,3,5-cyclohexanetriol prepared as described above. The reaction mixture was heated at reflux for 2 hours and the resulting solution was poured into ice water. The mixture was extracted with ethyl acetate, and the organic phase was washed with water and dried over anhydrous sodium sulfate.

The solvent was evaporated off under reduced pressure to give 30 mg of a brown oil which was decolorized with charcoal and the desired product was obtained by crystallization from chloroform / petroleum ether.

In this way, 23 mg of 1 D- (1,3,5 / 2) -1,5-diazido-2,3-cyclohexanediol were obtained as crystals melting at 61.5-63.5 ° C.

Δ 62284 / -α7ρ5 = + 2 ° + _ 1 (c = 1.36 »from methanol).

Use Example 10 Preparation of 10- (1,3,5 / 2) -1,5-diamino-2,3-cyclohexane diol dihydrochloride

To a solution of 0.49 g of 1 D- (1,3,5 / 2) -1,5-diazido-2,3-cyclohexanediol prepared as described above in 25 ml of ethanol was added 2 ml of Raney nickel (i.e. a fine nickel catalyst obtained by alkali dissolution from an aluminum-nickel-aluminum alloy).

The reaction mixture was reduced with hydrogen for 5 hours. The catalyst was then separated off by filtration through Celite ("Celite" is a registered trademark for a commercial diatomaceous earth product) and washed several times with a mixture of 50 parts of methanol and 50 parts of water.

The hydrogenated solution and washings were combined and evaporated to dryness. In this way, 0.33 g of 1D- (1,3,5 / 2) -1,5-diamino-2,3-cyclohexane diol was obtained as a faint violet foam. This foam remained homogeneous in thin layer chromatographic analysis on cellulose using a mixture of 2 parts pyridine + 1 part ammonia solution + 2 parts ethanol + 1 part water as solvent.

The 0.33 g of diamine thus obtained was taken up in 5 ml of absolute methanol and 3.5 ml of methanol / 10% hydrochloric acid solution.

The solution was allowed to stand for 12 hours at 0 ° C, after which the formed crystals were separated by centrifugation.

In this way, 0.2 g of 1D- (1,3,5 / 2) -1,5-diamino-2,3-cyclohexanediol dihydrochloride was obtained as hygroscopic crystals from a methanol / ether mixture after crystallization. Sp. 230-232 ° C.

/ ~ a_7 * 5 = 3.5 ° + 1 (c = 1.17- from water)

After crystallization of the various mother liquors from methanol / ether mixtures, a further about 0.25 g of the desired dihydrochloride was isolated.

Total yield: 90%.

Claims (4)

9 64484 A cyclohexanediol derivative for use as an intermediate in the preparation of 1D- (1,3,5 / 2) -1,5-diamino-2,3-cyclohexadiol, characterized in that the cyclohexanediol derivative is a 1D- (1,3,5 / 2) -1,5-diazido-2,3-cyclohexanediol. Process for the preparation of a cyclohexanediol derivative according to claim 1, characterized in that a compound of the general formula OH 0 * 2 / 0H or 3 wherein R 1 is an N 2 group when R 2 is a hydrogen atom and R 1 is a hydrogen atom when R 2 is is an alkanesulfonyloxy group or an arenesulfonyloxy group and R 1 is an alkanesulfonyl or arenesulfonyl group, is heated in a solvent in the presence of an alkali metal azide to produce the desired diazide of formula I. A cyclohexane derivative for the preparation of a product containing 1D- (1,3,5 / 2) -1,5-diamino-2,3-cyclohexylate, which can be converted into a cyclohexane derivative from 1P- (1,3,5 (2) -1,5-diazido-2,3-cyclohexanediol with the formula OH N,