HU180208B - Process for producing 1-deoxy-nojirimycine and n-substituted derivatives - Google Patents

Description

(54)

Process for the preparation of N-substituted derivatives of 1-deoxy-nojirimycin and its compound

The present invention relates to a novel process for the preparation of compounds of formula (I) wherein:

R is hydrogen, C 1-4 alkyl, or phenyl.

The compound of formula (I) wherein R is hydrogen is known as 1-deoxynojirimycin. This compound is prepared from plant species by extraction (German Patent Publication No. 2,656,602).

The compound can also be produced post microbiologically. Strains of the Bacillaceae family, preferably strain EQM 7, can be used for this operation (German Patent Publication No. 2,658,563).

The compounds of formula (I) of the present invention are useful in the treatment of diabetes, hyperlipaemia and adiposity. In addition, it is known that deoxyynojirimycin can be prepared from unstable free bases of formula Γ / 111 by hydrogenation H. and Ohki, Chem. Pharm. Bull. 16, 2477-2481 (1968); Pau '

H., Sangster, I. and Heyns, H., Chem. 100, 802-815 / _

The starting compound (11) is prepared by treating 5-amino-5-deoxy-1,2-O-isopropylidene-O-D-glucofuranose (5U) with sulfur dioxide. During this operation, the sulfur dioxide gas is introduced into the solution containing the starting material for 60 hours. In this way, a stable bisulfite adduct of formula (V) is formed and treated with barium hydroxide to give compound (11). The procedure is illustrated in Scheme A. A / 11 / starting compound can be prepared in such a way that the / IV / Formula vegyülevagy ^> who sen ^ _w 967 / f.

-1180208 is converted to the trifluoroacetyl derivative of the formula (VI) and the compound is converted to the trifluoroacetyl derivative of the formula (VII) by treatment with dilute hydrochloric acid. The resulting compound is passed through an anion exchange column to give compound (11).

The compound of the formula JYI can be prepared microbiologically (U.S. Pat. No. 3,998,698).

Compound (111) is prepared from 6-amino-2,3-O-isopropylidene-6-deoxy-d-L-sorbofuranose (VIII).

The compound of formula VIII is treated with hydrochloric acid to give the hydrochloride salt fTL. Passing this compound through an anion exchange column gives compound (11). The reaction is illustrated in Scheme C.

The above-described processes for the preparation of 1-deoxy-nojirimycin are carried out in time-consuming steps, whereby the unstable compound (TL / and / 111) produces several by-products.

A further disadvantage of the prior art is that expensive purification steps, such as extraction, column chromatography or ion exchange column treatment, are always required to prepare the compound of formula I where R is hydrogen. hydration of the free base does not occur stereospecifically.

Surprisingly, it has been found that the compounds of formula (I) can be obtained in very favorable yields when treated with an acid of formula (X) or (XI), wherein R is as defined above. During the acid treatment, the ammonium salts of the formulas (XII) and (XIII) are formed.

The resulting compounds are then either isolated or hydrogenated with a suitable hydrogen donor. Alternatively, the compounds of formula (X) and (XI) may be first deprotected by treatment with acid and then directly hydrogenated by addition of a base. Hydrogenation of salts of formula (XIII) occurs in a stereospecific manner to yield the desired gluco derivative.

Most surprisingly, it has been found that the compounds of formula (I) can be prepared in excellent yield and stereospecifically by the process of the invention. Based on the state of the art, this result was not expected. It was expected in the prior art that deprotection of compounds of general formula (X) with mineral acid could lead to only pyridine derivatives, and hydrogenation of free bases obtained by deprotection of compound of general formula (XI) only to a mixture of glucose and time compounds. can be obtained / see Paulsen 's communication above.

Suitably, the compounds of formula (I) of the present invention are those wherein R is hydrogen, (C1-C4) -alkyl, or phenyl.

The starting compounds (X) and (XI) can be prepared in a known manner, for example by 3-O-benzyl-6-O-triphenylmethyl-1,2-O-iso-propylidene-JL-D-xylo- hexofuranos-5-ulose is subjected to reductive amination and then trityl and benzyl groups are removed from the resulting compound in liquid ammonia with sodium. The procedure is illustrated in Scheme D.

The above starting material may also be prepared by reacting furanose 2,3-O-isopropylidene-6-O-p-toluenesulfonyl-QC-L-sorbose-2180208 with sodium azide and then optionally reductively alkylating it to give the starting material. is directly reacted with amines. The operation is illustrated in Scheme E.

When starting material is 6-amino-2,3-O-isopropylidene-6-deoxy-o-C-L-sorbofuranose and the acid is hydrochloric acid, the reaction proceeds according to Scheme F.

When starting from 1,2-O-isopropylidene-5-methylamine-5-deoxy-δ-C-D-glucofuranose, the reaction proceeds according to Scheme G.

The salts prepared as described above can be liberated after addition of the appropriate inorganic or organic base or neutralization of the mixture on an anion exchange column.

Among the acids used in the process of the invention are mineral acids such as hydrochloric acid, sulfuric acid; of organic acids, acetic acid, formic acid. Hydrochloric acid is preferably used. When removing the isopropylidene group, the concentration of the hydrochloric acid solution may vary within wide limits, preferably 2-6N hydrochloric acid solution.

An important aspect of the present invention is that the acid concentration must be reduced prior to hydrogenation. The acid concentration can be reduced by the addition of inorganic or organic bases, preferably triethylamine or pyridine.

The compounds of formula (I) are obtained in high purity and particularly high yields when 1 to 1.2 molar equivalents of acid are used per mole of hydrogenated compound.

Diluents include water, lower alcohols or other protic solvents. The most advantageous is the use of water.

In the process of the invention, the hydrogenation is carried out in the presence of a catalyst or other suitable hydrogen donor. Among the catalysts commonly used for hydrogenation are Raney nickel, platinum dioxide, palladium / carbon, etc. mentioned; hydrogen donors include, for example, sodium borohydride or sodium ethane borohydride,

The reaction temperature for each reaction step can be varied within _a wide range. In general, the reaction is carried out at a temperature of 0 to 150 ° C, preferably 20 to 100 ° C.

The reaction proceeds at normal pressure or at elevated pressure for both reaction steps. Usually we operate at a pressure of 1-5 bar.

Example 1 5 g of 5-anino-5-deoxy-1,2O-isopropylidene-O-C-D-glucofuranose was dissolved in 8 ml of 2N hydrochloric acid. After stirring for 24 hours, the solution was diluted with 5 ml of water and then hydrogenated at 3 x 5 bar after addition of 0.69 g of triethylamine and 0.3 g of Raney nickel. The catalyst is then removed by filtration, the solution is concentrated in vacuo, and after the addition of ethanol, the concentration is repeated twice when crystallization occurs. The resulting crystals were triturated with ethanol, filtered and washed with ethanol. 1.45 g of 79% (7% by weight) of 1-deoxynoyloimycline hydrochloride are obtained. M.p. 209-210 ° (dec).

-3180208

Example 2

A / 100 g of 6-amino-6-deoxy-1,2-o-isopropylidene-L-sorbofuranose is dissolved in 120 ml of 8N hydrochloric acid solution with gentle cooling. The reaction mixture was stirred for 2 hours, then inoculated and stirred for an additional 1 hour. To the resulting reaction mixture was added 600 mL of ethanol. The resulting reaction mixture was allowed to stand in an ice bath for 3 hours, filtered off with suction and washed with ethanol. 73.4 S of 6-amino-6-deoxy-L-sorbofuranos hydrochloride monohydrate is obtained, m.p.

B / 2 g of 6-amino-6-deoxy-L-sorbofuranose hydrochloride monohydrate was dissolved in 10 ml of water and hydrogenated with 0.2 g of penta-oxide for 2 hours at 3.5 bar. The catalyst was removed by filtration, the solution was concentrated and the methanol was added twice more after the addition of methanol.

The resulting crystals were triturated with methanol and suction filtered. This gave 1.3 g (76% yield) of 1-deoxy-noojirimycin hydrochloride. 210 DEG C. (dec.).

3 «example

500 mg / 2.5 mol / l-deoxynojirimycin hydrochloride is suspended in 2 ml of dimethylformamide. Subsequently, 0.7 ml / 5 mmol / triethylamine and 5 ml of ethanol were added to the suspension with stirring. After 30 minutes, the mixture was filtered and the resulting material was washed well with ethanol. 385 mg (95%) of chloride-free 1-deoxynojirimycin are obtained.

4 »example

6 mg of 6-phenylamino-2,3-O-isopropylidene-6-deoxy-06-L-sorbofuranose (250 mg) was dissolved in 1.0 ml of 6N hydrochloric acid and allowed to stand at 0 ° C for 18 hours. The mixture was diluted with water (3 mL) and triethylamine (0.755 mL) was added and hydrogenated for 3 hours at 3 bar. Raney nickel was used as a catalyst for the operation. On completion of hydrogenation, the catalyst is filtered off, the catalyst is rinsed with water, the solution is treated with an anion exchanger (OH form), filtered and concentrated. The resulting residue was subjected to mass spectrometry. N-phenyl-l-deoxynojirimycin spectrum obtained during operation with the following characteristics: m / e 239 / molekulacsucs /, m / e 208 / M-CH ₂ 0H / m / e 148 / M-CH ₂ 0H - 2 CHOH /

Example 5 "A mixture of 5-methylamino-5 'deoxy-l _and 2-0-isopropylidene-.alpha.-D-glucofuranose / mp. : 127 ° C / 4 ml in 6 N hydrochloric acid and the solution was allowed to stand at 0 ^o C for 18 hours, then the mixture was diluted with about 10 ml of water to 2.76 ml of triethylamine and 0.2 g of in the presence of platinum oxide, the mixture is hydrogenated at 3.5 bar for 3 hours. After completion of the reaction, the mixture was filtered and the catalyst was washed with water. The aqueous solution was loaded onto a cation exchange column (H-form) and eluted with 1% aqueous ammonia. Evaporate the eluate _? the residue is taken up twice in ethanol and concentrated again. Upon cooling, a crystalline compound is obtained. The resulting material was triturated with methanol, filtered and rinsed with methanol. 420 mg of N-methyl-1-deoxy-nojirimine are obtained.

Mp: 152 ° C.

Claims (4)

Patent claims Γ. The process is 1-deoxyiminojirimycin of formula (1) -4180208 and N-substituted derivatives of this compound, wherein R is hydrogen, C 1-4 alkyl or phenyl. characterized in that the compound of formula (X) or (XI), wherein R is as defined above, is treated with a strong mineral acid, and the intermediate is isolated in the form of a salt and is preferably hydrogenated using a complex metal hydride or catalytically hydrogenated or the starting compounds of formula (b) a (X) and (XI), wherein R is as defined above, are treated with an acid and then directly hydrogenated after addition of the base. 2. Method of seeding a tooth according to claim 1, characterized in that the mineral acid is hydrochloric acid. 3. A process according to claim 1, wherein the acid is 2-10 N hydrochloric acid. 4. A process according to claim 1, wherein the hydrogenation is carried out at a pressure of 0 to 150 ° C at a pressure of 1 to 5 bar. F. F .: Zoltán Himar Onzágo Invention Office 70- ΟΤΗ- 83.158 -5180.208 International Classification: C 07 D 211/40 4/1