HU184405B - Process for preparing 3-amino-2,3,6-trideoxy-l-lyxo-hexose/da unosamine/and derivatives thereof - Google Patents

Abstract

The present invention relates to the deunosamine of the formula (I) and its derivatives, wherein R1 is a halogen atom or a methyl group, R2 is a hydrogen atom, a benzyl, acetyl or trifluoroacetyl group, X is an azido, amino, acetamido or trifluoroacetamido group; and when X is an amino acid addition salt thereof, with the proviso that when R 2 is acyl and X is acetamido, R 1 may have a different meaning from the methyl group, which is represented by the formula: in the presence of an inorganic azide in the presence of an inorganic azide in the presence of a solvent with a C 1 -C 4 alkylsulfonyl, unsubstituted or C 1 -C 4 alkyl substituted with C 1-4, followed by an azido compound of formula I wherein R 1 is methyl, R2 is benzyl, and X is azido hydrogenation of 1 mole or 2 moles of hydrogen, followed by hydrolysis or acylation of the amino compound of formula I wherein R 1 is methyl, R 2 is benzyl or hydrogen and X is amino. or converted to an acid addition salt. The compounds of formula (I) according to the invention, coupled to tetracycline aglycones, allow the production of Adriamycin and its analogs known for their extremely strong cytostatic activity. / 1 / / tv / -1-

Description

The present invention relates to a process for the preparation of daunosamine of the formula I and its derivatives and, where applicable, salts thereof, wherein R 1 is hydrogen or methyl,

R2 is hydrogen, benzyl, acetyl or trifluoroacetyl,

And X represents azido, amino, acetamido and trifluoroacetamido. (The daunosamine is represented in formula (I) as a furanose ring, but in the case of free sugars, an aqueous solution is obviously always present in the equilibrium mixture of the pyranose and furanose ring isomers.)

The compounds of formula (I) in which represents R, and R ₂ is hydrogen and X is the amino group (daunosamine; occurs naturally-isolated derivative of piranozidként produced), an important component of known effects of excellent cytostatic adriamycin and daunomycin anthracycline glycoside type antibiotics (see, e.g., F. Arcamone, Lloydia 40, 45 (1977)).

The compounds of formula (I) are those wherein R _2, benzyl, acetyl or trifluoroacetyl group is not known in the literature * These compounds are known per se may be converted into a reactive derivative (see, for example, IF Szabo et al..., Acta Chim Hung 64, 67 (1970)), which, when coupled to an aglycone, allow the synthesis of previously unavailable antibiotic analogs containing daunosamine as furanoside.

Synthesis of aglycones of anthracycline glycosides is known in the art (see, e.g., Wang et al., Can. J. Chem. 51,466 (1973 and 4021457), as well as methods for sugar attachment (see, e.g., EM Acton et al., J. Med. Chem. 17, 659 (1974) and Smith et al., J. Am. Chem. Soc., 98, 1969 (1976).

The compounds of formula (I) of the daunosamine hydrochloride (R, and R ₂ = H, X is NH ₃ Cl) several processes for preparing, but they are either expensive starting materials, for example. Starting from L-rhamnose (JP Marsch et al., Chem. Comm. 973 (1967)) and D-mannose (D. Horton et al., Carbohydr. Res. starting from materials such as D-glucose, many step-up syntheses have poor yields which make the practical use of the process doubtful, such as those described in Japanese Patent No. 79060 and U.S. Pat. U.S. Pat. No. 6,018,600 starts with glucose, but the two processes have in common that the transformations to be performed on glucose (2-OH- + H; 3-OH-> NH ₂ ; 5-OH- + OH and Of -0H- »H), the amino group is first introduced by inversion at the 3-position of the sugar and the reduction of the 2-hydroxyl group is performed as a last step, namely

1 through Compound II. The disadvantage of this method of synthesis is that, except for the compound in which R 1 is methyl, R ₂ is acetyl and X is acetamido (Chem. Bér. 113, 2666-74 (1980)). )).

During the multistep synthesis, care must be taken to ensure that the unsaturated derivative of formula (II) is obtained from the acetohalogen derivative of formula (III) by Zn-powder reduction in very poor yields, mostly in trace amounts, and that the problems with salt concentration.

The present invention is based on the discovery that methyl-xyloxhexofuranosides of the general formula (IV), which can be formed from D-glucose in high yield synthesis steps, wherein R is a (1-4C) alkylsulfonyl or unsubstituted or (1-4C) alkyl substituted phenylsulfinol. group - with sodium azide there was obtained, and then optionally can be converted to high yield of the compound of formula (I) ¹ 5 génezéssel hydrochloride and subsequent acid hydrolysis or by acylation.

Accordingly, the present invention relates to a process for the preparation of compounds of formula I wherein R 1 is hydrogen or methyl,

R ₂ is hydrogen, benzyl, acetyl or trifluoroacetyl and

X is an azido, amino, acetamido or trifluoroacetamido group, and X is an amino25 group, for the preparation of acid addition salts thereof, provided that when R ₂ is acetyl and X is acetamido, R 1 is other than methyl. may.

According to the present invention, compounds of formula I are prepared by reacting a compound of formula IV, wherein R is C 1-4 alkylsulfonyl or unsubstituted or C 1-4 alkyl substituted phenylsulfonyl, in the presence of a solvent. an inorganic azide contacted with, and the azido compound obtained in (I) - wherein R is methyl, R ₂ represents benzyl group and X is azido group is - optionally substituted with 1 mole or 2 hydrogenated at mole hydrogen, followed by the resulting amino compound of formula (I) wherein R 1 is methyl, R ₂ is benzyl or hydrogen and X is amino;

(a) hydrolyzing it in the presence of an aqueous acid and liberating the base, if desired, of the resulting amino compound of formula (I) wherein R 1 is hydrogen and R ₂ is hydrogen or benzyl and X is amino;

(b) acylating with a reactive derivative of acetic acid or trifluoroacetic acid, or

c) converting it into an acid addition salt.

In a preferred embodiment of the process of the invention, the sulfonic acid esters of formula IV are reacted with potassium azides, preferably sodium azide, in an aqueous or anhydrous polar solvent, preferably dimethylformamide, at a temperature between 100 and 200 ° C, preferably at reflux temperature of the solvent. The compound of Formula I, wherein R 1 is methyl, R ₂ is benzyl and X is azide in the presence of a Pd / C catalyst, in an aqueous or anhydrous protic solvent, preferably ethanol, under normal pressure and at room temperature, is reduced to azide reduction. (1 mole of hydrogen.) If a compound of formula (1) is prepared wherein R 1 is methyl, R ₂ is hydrogen and X is amino, then hydrogenation is continued until the benzyl group is removed (2 moles of hydrogen). .

In (I) for the preparation of an acid addition salt of a compound of formula wherein R, and R ₂ is hydrogen, and X is an amino group, according to the invention it may be convenient that an amino compound of formula (I) - wherein R methyl- R _{2 is} hydrogen and X is amino - hydrolyzed with aqueous acid, preferably aqueous hydrochloric acid, at 50-100 ° C. The acid addition salts can be liberated in known manner.

In the preparation of compounds of formula I wherein R 1 is methyl, R _{2 is} benzyl or acetyl or trifluoroacetyl, and X is acetamido or trifluoroacetamido, it is preferred that one of the compounds of formula I an amino compound wherein R 1 is methyl, R _{2 is} benzyl or hydrogen, and X is acylated with acetic anhydride or chloride or trifluoroacetic anhydride in the presence of an amino group, preferably pyridine. The amount of acylating agent used will depend on whether the monoacyl or diacyl compound is desired.

For the preparation of monoacyl compounds (wherein R _t is methyl, R ₂ is benzyl, X is acetamido trifluoroacetamido), 1 to 1.5 equivalents of the reactive acid derivative is preferred; and R ₂ is acetyl or trifluoroacetyl) for the preparation of 2,2,5-reactive equivalents of the acid used.

The compounds of formula (IV) used as starting materials for the process of the invention are novel. Starting from 1,2-O-isopropylidene-D-glucose (V), they can be prepared, for example, by the following two methods:

In Method A, the starting material of formula (V) is benzoylated at the 6-position and then mesylated at the 3 and 5-position (step a) to give the resulting compound of formula (VI) to 5,6-epoxide (VII) (Step 6). Reduction of the latter at low temperature with LiAlIL gives 6-deoxy compound (VIII) (step c), whose free 5-OH group is protected by benzylation (IX) (step d). The mesyl ester is then reductively removed with LiAlEE (X) (step e) and the liberated 3-OH group is benzoylated (XI) (step f). The resulting ester is treated with methanolic hydrochloric acid to give a mixture of alpha-beta-methyl glycosides (XII), from which the alpha anomer is isolated by preparative chromatography (step 9). The latter is tosylated (step h) and the resulting mixed ester (XIII) is treated with sodium methylate to form 2,3-epoxide (XI) (step i). Treatment of the epoxide with LiAlH gives the 2-deoxy compound (XV) (step j) which is converted to the desired phenyl ester by conversion of the 3-OH group to a C 1-4 alkyl or phenyl or C 1-4 alkyl group. For products of formula IV (step k).

The same products can be obtained by Method B by first benzoylation of the isopropylidene derivative (V) followed by conversion of the resulting tribenzoate (XVII) in methanol with hydrochloric acid to the anomeric methyl glycosides (XVIII). When the latter are tosylated, the 2-tosyl ester of beta-methyl glucoside (XIX) can be crystallized (step g), which is treated with the

It can be converted to the 2,3-epoxy compound (XX) (step b). This compound can be converted by partial benzoylation followed by tosylation to a mixed ester of formula XXI (step c) to form sodium methylate diepoxide (XXII) (step d). The terminal epoxy ring of this compound with borohydride is 6-deoxy to a compound (step e) which, upon benzylation, provides the intermediate of formula (XIV) (step f). The latter can be converted to the desired compounds of Formula IV by Method A.

In order to carry out the process of the invention, the following embodiments are set forth. Abbreviations used in the formulas are: Bz = benzoyl; Ms = mesyl; Ts = tosyl; Ph = phenyl, Ac = acetyl. Thin layer chromatography was performed on Kieselgel-G layer.

Example 1

Methyl 3-azido-5-O-benzyl-2,3,6-trideoxy-αL-lixo-hexofuranoside (I, R 1 = CH ₃ , R ₂ = CH ₂ Ph, X = N _} )

12.6 g of methyl 5-O-benzyl-3-O-methanesulfonyl-2,3,6-trideoxy-α-xylhexofuranoside (R = Ms in formula IV) are dissolved in 150 ml of dimethylformamide and 4 g of sodium are added. After the addition of azide, the reaction mixture was heated to 120 ° C with stirring and kept at this temperature for 30 minutes. The reaction mixture was taken up, washed with water and dried over anhydrous sodium sulfate. The filtered chloroform solution was evaporated and the residual syrup was suction-free under vacuum to give the title product (9.8 g, 93%), [α] 25 D = -45.4 ° (c = 1, chloroform) R f = 0.85 ( carbon tetrachloride: ethyl acetate = 3: 1).

Analysis: Calculated for C14H19N3O3 (MW = 277.3): C, 60.63; H = 6.91%; N, 15.15%; Found: C, 60.41; H = 6.75%; N, 14.97%.

For example, the starting compound (IV, R = Ms) can be prepared as follows:

The method:

the step

6-O-Benzoyl-1,2-O-isopropylidene-3,5-di-O-mesia-D-glucofuranos (VI)

146 g of 6-O-benzoyl-1,2-O-isopropylidene-α-D-glucofuranose (V) (H. Ohle: Chem. Ber., 57, 403 (1924)) are dissolved in 900 ml of anhydrous pyridine and 108 ml of mesyl chloride are added dropwise. solution at a temperature below + 10 ° C with stirring. After the addition of mesyl chloride, the reaction mixture was allowed to stand at room temperature for 4 hours and then poured into 10 liters of ice water. The precipitated crystalline material is filtered off, washed with water and dried. This crude product was dissolved in 2 L of acetone and crystallized by addition of 2.5 L of ethanol. 205 g (95%), m.p. 182-183 ° C, [?] D = -17.7 ° (c = 1, chloroform). R _F = 0.65 (carbon tetrachloride: ethyl acetate = 2: 1). .

184 ^ 05

Analysis: Calculated for C 18 H 24 O 11 S 2 (Mw = 480.5): C, 44.99; H = 5.03%; S = 13.35%;

Found: C, 44.02; H = 5.15%; N, 13.12%.

Step b)

5,6-Anhydro-1,2-O-mesyl-β-L-idofuranose (VIII)

192 g of 6-O-benzoyl-1,2-O-isopropylene-3,5-di-O-mesyl-α-D-glucofurazone (VI) are dissolved in 1400 ml of chloroform and 200 ml of a 4N solution of sodium methylate in methanol are added with vigorous stirring. while the temperature rises to 40-44 ° C. The reaction mixture was kept at this temperature for 20 minutes, washed with water to neutral, dried over sodium sulfate and evaporated. The residue was crystallized from 800 ml of ethanol. 86 g (77%), m.p. 100-101 ° C, [α] D = -8.5 ° (c = 1 in chloroform), Rf = 0.5 (carbon tetrachloride: ethyl acetate = 1: 1). (J. Stone and J. Jary, Collektion, 33, 549 (1967), O. p.):

96.5-98.5 °, [α ²⁰ -7.4 °.]

c. step

6-Deoxy-1,2-O-isopropidene-3-O-methyl-α-L-idofuranose (VIII) g of 5,6-anhydro-1,2-isopropylidene-3-O-mesyl-β-L-idofuranose (VIII). VII) dissolved in 800 ml of abs. tetrahydrofuran and 22 g of lithium aluminum hydride were added portionwise to the solution at -20 ° C with stirring. After the addition of lithium aluminum hydride, the reaction mixture was maintained at -10 ° C to -5 ° C for 45 minutes, then the temperature was raised to +10 ° C and the reaction was worked up. Ethyl acetate (80 mL) was added dropwise to the reaction mixture, followed by the addition of water (22 mL), 15% sodium hydroxide solution (22 mL), and water (66 mL). The inorganic salts were filtered off and washed with ethyl acetate. The filtrate was evaporated to dryness and the residue was crystallized from ethyl acetate-petroleum ether. (73.6 g, 94%), m.p. 132-133 °, [α] 25 D = -35.6 ° (c = 1, chloroform), R _F = 0.3 (carbon tetrachloride: ethyl acetate = 1: 1). ).

Analysis: Calculated for C 10 H 20 O 5 S (MW = 282.3): C, 42.54; H = 6.43%; S = 11.36%; Found: C, 42.66; H = 6.52%; S, 11.15%.

Step d)

5-O-Benzyl-6-deoxy-1,2-O-isopropylidene-3-O-methyl-β-L-idofuranose (IX) g 6-deoxy-1,2-O-isopropylidene-3-O-mesyl -? - L-Idofuranose (VIII) is dissolved in 400 ml of dimethylformamide and 36 ml of benzyl chloride and 24 g of powdered potassium hydroxide are added in small portions over 30 minutes. The temperature was maintained at 25-28 ° C for one hour. The reaction mixture was filtered and the filtrate was evaporated. The residue was dissolved in chloroform, washed with water, dried over sodium sulfate and evaporated. The crude product obtained is purified by column chromatography. Eluent carbon tetrachloride = ethyl acetate = 3: 1. R _F = 0.5. The purified product is crystallized from ether petroleum ether. 39.2 g (53%), m.p. 89-91 ° C, [α] D = -39.7 ° (c = 1, chloroform)

Analysis: Calculated for C 11 H 13 O 5 S (MW = 372.5): C, 54.82; H = 6.50%; S = 8.61%; Found: C, 54.95; H, 6.63%; S, 8.52%.

step e)

5-O-Benzyl-6-deoxy-1,2-O-isopropylidene-PL-idofuranose (X) g 5-O-benzyl-6-deoxy-1,2-O-isopropylidene-3-O-mesyl-jf -L-idofuranose (IX) is dissolved in 600 ml of abs. ether and 7 g of lithium aluminum hydride were added to the solution at 0 ° C with stirring. The reaction mixture was then refluxed for 6 hours and then allowed to stand overnight at room temperature. The reaction mixture was worked up at a temperature below + 10 ° C. Ethyl acetate (25 mL) was added dropwise to the reaction mixture followed by 7 mL of water, 7 mL of 15% sodium hydroxide solution and finally 21 mL of water. The precipitated inorganic material was filtered and washed with ethyl acetate. The filtrate was evaporated to dryness and crystallized from ether-hexane. Mp 108-110 ° C, [α] D = -18.4 ° (c = 1, chloroform), Rp = 0.7 (carbon tetrachloride: ethyl acetate = 1: 1).

Analysis: calculated for C ₆ H ₂₂ O ₅ Found (MW = 294.34); C = 65.29%; H, 7.53%; Found: C, 65.35; H, 7.70%.

Step f)

5-O-Benzyl-3-O-benzoyl-6-deoxy-1,2-O-isopropylidene-β-L-idojuranose (XI) g 5-O-benzyl-6-deoxy-1,2-O-isopropylidene -L-idofuranose (X) was dissolved in 60 ml of pyridine and 10 ml of benzoyl chloride was added dropwise at a temperature below + 10 ° C with stirring and the reaction mixture was allowed to stand at room temperature for 3 hours. It was then poured into 600 ml of ice water and extracted with chloroform. The chloroform layer was washed with 5N sulfuric acid, water, 5% sodium bicarbonate solution, dried again with water, sodium sulfate and evaporated to dryness. The product is crystallized from ethanol. 24.9 g (92%), m.p. 91-93 ° C, [α] 20 D = -23.6 ° (c = 1, chloroform), R _F = 0.85 (carbon tetrachloride: ethyl acetate = 3: 1). ).

Analysis: Calculated for C 23 H 26 O 6 (MW 398.44): C 69.33; H = 6.58%; Found: C, 69.10; H, 6.72%.

Step g)

Methyl 5-O-benzyl-3-O-benzoyl-6-deoxy-α-idofuranoside (XII) g 5-O-benzyl-3-O-benzoyl-6-deoxy-1,2-O-isopropylidene / ? -L-idofuranose (XI) is dissolved in 440 ml of O.35N hydrochloric acid in methanol and allowed to stand at room temperature for 16 hours. The reaction mixture was neutralized with solid sodium bicarbonate, filtered, and the filtrate was evaporated. The residue was taken up in chloroform, washed with water, dried over sodium sulfate and evaporated. This crude product contains the α-β-anomeric mixture from which the α-anomer is separated from the β-anomer by column chromatography. (R _F = 0.4 Carbon tetrachloride: ethyl acetate = 3: 1) The title product weighed 10 g (48.5%), [α] _D = -17.1 ° (c = 1, chloroform), R _F = 0.3 (carbon tetrachloride: ethyl acetate = 3: 1).

Analysis; C _2! Calcd for C ₂₄ H _{6 6} (MW = 372.4): C, 67.73; H = 6.50%; Found: C, 67.51; H, 6.85%.

step h)

Methyl 5-O-benzyl-3-O-benzoyl-6-deoxy-2-O-tosyl-α-L-idofuranoside (XIII)

Methyl 5-O-benzyl-3-O-benzoyl-6-deoxy-α-L-idofuranoside (XII) (7.3 g) was dissolved in pyridine (40 ml) and tosyl chloride (5 g) was added. The reaction mixture was stirred for one day

-4184405 at room temperature and then heated on a water bath (80-90 ° C) for 6 hours. The reaction mixture was poured into ice-water (400 mL) which was extracted with chloroform. The chloroform solution was washed with 5N sulfuric acid, water, 5% sodium bicarbonate solution, again water, dried over sodium sulfate and evaporated. The product is crystallized from ethanol-water or methanol. 6.2 g (56.5%), m.p. 95-97 ° C, [α] D20 + 29.7 ° (c = 1, chloroform), R _F = 0.8 (carbon tetrachloride: ethyl acetate = 3: 1).

Analysis: C ₂₈ H 3 ₀ O ₈ S Calcd (MW = 526.59) Calculated: C 63.86%; H = 5.74%; S = 6.09%; Found: C, 63.55; H = 5.85%; S, 5.92%.

step i)

Methyl 5-O-benzyl-2,3-anhydro-α-L-idofuranoside (XIV)

15.4 g of methyl 5-O-benzyl-3-O-benzoyl-6-deoxy-2-O-tosyl-α-idofuranoside (XIII) is dissolved in 100 ml of chloroform and 8 ml of a solution of 4.65 N sodium methylate in methanol are added. solution with vigorous stirring at a temperature of + 5 to 10 ° C. The reaction mixture was stirred at this temperature for another half hour, then washed with water to neutral, dried over sodium sulfate and evaporated. The product obtained is separated from the methyl benzoic acid on a silica gel column. 6.65 g (95%), [α] D = -54.4 ° (c = 1, chloroform), R _F = 0.4 (carbon tetrachloride: ethyl acetate = 3: 1).

Analysis: _{C) 4} H ₈ O ₄ for (MW = 250.28) Calculated: C = 67.18%; H, 7.25; Found: C, 67.03; H, 6.95%.

Step j)

Methyl 5-O-benzyl-2,6-dideoxy-α-L-xyloxhexofuranoside (XV)

6.5 g of methyl 5-O-benzyl-2,3-anhydro-αL-gulofuranoside (XIV) are dissolved in 250 ml of abs. ether and 3 g of lithium aluminum hydride are added with stirring at -20 ° C and the reaction mixture is kept at -15 to 10 ° C for half an hour. The temperature was allowed to rise to 0 ° C over a further half hour and the reaction was worked up. Ethyl acetate (10 mL) was added dropwise to the reaction mixture followed by 3 mL of water, 3 mL of 15% sodium hydroxide solution, and finally 9 mL of water. The precipitated inorganic material is filtered off, washed with ethyl acetate and the filtrate is evaporated and filtered off with suction. 6.4 g (98%), [a] f? = -47.1 ° (c = 1, chloroform), R _F = 0.5 (carbon tetrachloride: ethyl acetate = 2: 1).

Analysis: Calculated for C 14 H ₁₈ O ₄ (Mw = 252.3): C, 66.64; H = 7.99%; Found: C, 66.52; H, 7.63%.

Step k)

Methyl 5-O-benzyl-2,6-dideoxy-3-O-mesyl-a-L-xylo-hexofuranoside (IV, R = MS)

12.4 g of methyl 5-O-benzyl-2,6-dioxy-α-L-xyloxhexofuranoside (XV) is dissolved in 40 ml of pyridine and 6 ml of mesyl chloride are added dropwise at a temperature below + 10 ° C and for 4 hours. allow to stand at room temperature. The reaction mixture was poured into ice-water (400 mL), extracted with chloroform, and the chloroform layer was washed with 5N sulfuric acid, water, 5% sodium bicarbonate solution, again water, dried over sodium sulfate and evaporated. The product obtained is crystallized from ether or petroleum ether. 12.6 g (77.5%), m.p. 69-71 [deg.] C., [.alpha.] D @ 20 = -87.2 DEG (c = 1, chloroform), Rp = 0.4 (carbon tetrachloride: ethyl acetate = 2). : 1).

Analysis: Calculated for C 15 H 22 O 6 S (MW = 330.39): C, 54.53; H = 6.71%; S = 9.71%; Found: C, 54.59; H = 6.80%; S, 9.65%.

Method B.

the step

Methyl 3,5,6-tri-O-benzyl-2-O-tosyl-β-D-glucofuranoside (XIX)

220 g of 3,5,6-Tri-O-benzoyl-1,2-O-isopropylidene-α-D-glucofuranose (H. Olile, Beer 57, 403 (1924)) were dissolved in 600 ml of chloroform and 3.2 liters of 2N HCl in methanol was added. The reaction mixture was kept at 45 ° C for 1.5 hours, then cooled to room temperature and neutralized with solid sodium bicarbonate. The inorganic material was filtered off, washed with methanol and the filtrate evaporated. The residue was dissolved in chloroform, washed twice with water, dried over sodium sulfate and evaporated, then suctioned off. The residue was dissolved in 500 ml of pyridine, 120 g of tosyl chloride were added and the solution was allowed to stand at room temperature for 3 days. The reaction mixture is poured into 4 L of ice water, the crystalline product is filtered off, washed with water and dried. The crude product thus obtained is a 2: 3 mixture of α and β. (R _F = 0.65: 0.75) This crude product is recrystallized from 2.5 L of ethanol and recrystallized twice, 2.5 times and 3 times with ethyl acetate. 109 g (41%) of the title product are obtained. 143-145 ° C, [α] = -105.4 ° (c = 1, chloroform), Rf = 0.75 (carbon tetrachloride: ethyl acetate = 5: 1).

Analysis: Calculated for C 35 H 32 O 11 S (MW = 660.67): C, 63.62; H = 4.88%; S, 4.85; Found: C, 63.75; H = 4.95%; S, 4.68%.

Step b)

Methyl 2,3-anhydro-β-D-mannofuranoside (XX)

Methyl 3,5,6-tri-O-benzoyl-2-O-tosyl -? - D-glucofuranoside (XIX) (64.5 g) was dissolved in chloroform (250 ml) and methanolic solution of 4.4N sodium methylate (30 ml) was added. After stirring at room temperature for 15 minutes, neutralize with solid carbon dioxide, filter the solid, extract the filtrate with water (3 x 50 mL), wash the combined aqueous phase with 2 x 50 mL of carbon tetrachloride and evaporate the aqueous phase. The residue was dissolved in chloroform, dried over sodium sulfate, evaporated and suction filtered. We get a syrup that is clean enough for the next step. If necessary, it can be cleaned on a silica gel column. 16 g (91%), [or] -90 ° (c = 1, chloroform), Rp = 0. 35 (carbon tetrachloride: ethyl acetate = 9: 1).

Analysis: C ₇ H | Calculated Found ₂ O ₅ (MW = 176.17): C, 47.72%; H = 6.87%; Found: C, 47.55; H, 6.98%.

step c)

Methyl 2,3-anhydro-6-O-benzoyl-5-O-tosyl-β-D-mannofuranoside (XXI)

Methyl 2,3-anhydro -? - D-mannofuranoside (XX) (63.5 g) was dissolved in pyridine (250 ml) and benzoyl chloride (58 ml) was added dropwise at -10 ° C with stirring and stirred at room temperature for a further 30 minutes. The reaction mixture was poured into 2.5 liters of ice water, extracted with chloroform, and the chloroform layer was washed with 5N sulfuric acid, water, 5% sodium bicarbonate solution, again water, dried over sodium sulfate and evaporated. The product is crystallized from ether to give 47 g of methyl 2,3-anhydro-6-O-benzoyl -? - D-mannofuranoside. 51 g of the former are dissolved in 150 ml of pyridine, 45 g of tosyl chloride are added and allowed to stand at room temperature for 2 days. The reaction mixture was poured into 1.5 L of ice water, the precipitated crystalline material was filtered off, washed with water and dried. This crude product was recrystallized from 2.5x ethanol to give 66.9 g of pure 6-O-benzoyl-5-O-tosyl derivative (XXI). 98-100 ° C, [α] 20 D = -40.1 ° (c = 1, chloroform),

_Rf = 0.3 (carbon tetrachloride: ethyl acetate = 3: 1).

Analysis: (MW = 434.45) calculated C ₂₂ H 0gS ₂ O: C = 58.05%; H = 5.10%; S = 7.38%; Found: C, 58.15; H = 5.17%; S, 7.06%.

Step d)

Methyl 2,3: 5,6-dianhydro-α-L-gulofuranoside (XXII)

66.5 g of methyl 2,3-anhydro-6-O-benzoyl-5-O-tosyl-γ-5-D-mannofuranoside (XXI) are dissolved in 500 ml of chloroform and 50 ml of 5N sodium methylate in methanol are added with vigorous stirring. . After stirring for 30 minutes at 30-32 ° C, the reaction mixture is washed with water to neutral and the aqueous phase is backwashed with chloroform. The combined chloroform layer was dried over sodium sulfate and evaporated. The product was separated from the methyl benzoate on a silica gel column. 17.5 g (86%), [α] 20 D = -123.6 ° (c = 1, chloroform), R _F = 0.4 (carbon tetrachloride: ethyl acetate = 1: 1).

Analysis: Calculated for C7 H10 O4 (MW = 158.15): C, 53.16; H = 6.37%; Found: C, 53.02; H, 6.52%.

step e)

Methyl 2,3-anhydro-6-deoxy-αL-gulofuranoside (XXIII) Methyl 2,3: 5,6-dianhydro-αL-gulofuranoside (XXII) is dissolved in 50 ml of water and 2 g of sodium borohydride are added. The temperature was maintained at 40 ° C for 4 hours and an additional 1 to 1 g of sodium borohydride per hour was added. The reaction mixture was extracted with chloroform (3 x 50 mL), the chloroform solution was dried over sodium sulfate, evaporated and suction filtered. 2 g (65%), [.alpha.] _D @ 20 = -76 DEG (c = 1, chloroform), R _F = 0. 35 (carbon tetrachloride: ethyl acetate = 1: 2).

Analysis: Calculated for CjHH ^ ChC (MW = 160.17): C, 52.49; H = 7.55%; Found: C, 52.12; H, 7.28%.

Step f)

Methyl 2,3-anhydro-5-O-benzyl-6-deoxy-αL-gulofuranoside (XIV) Methyl 2,3-anhydro-6-deoxy-αL-gulofuranoside (XXIII) is dissolved in 100 ml of dimethylformamide and Benzyl chloride (7 ml) and powdered potassium hydroxide (20 g) were added all at once in small portions over a period of 30 minutes while maintaining the temperature at 25-30 ° C. After stirring at this temperature for an additional hour, the solid was filtered off, washed with a little dimethylformamide and the filtrate was evaporated. The residue was taken up in chloroform, washed twice with water, dried over sodium sulfate and evaporated. The crude product obtained is purified on a silica gel column. Eluent carbon tetrachloride: ethyl acetate = 2: 1. R _F = 0.6. 4 g (64%). The product thus obtained is the same as that obtained according to Method A, which can be converted to IV (R = mesyl) as described in Method A.

Example 2

Methyl 3-azido-5-O-benzyl-2,3, -6-trideoxy-L-lyxhexofuranoside (I, R 1 = CH ₃ , R ₂ = CH ₂ Ph, X = N ₃ )

Methyl 5-O-benzyl-3-O-tosyl-2,3,6-trideoxy-α-L-xylohexofuranoside (R = Ts) (15.5 g) was dissolved in dimethylformamide (150 ml) and, after addition of 4 g of sodium azide, the reaction mixture was stirred. heat to 120 ° C and hold at this temperature for 30 minutes. The reaction mixture was cooled, concentrated in vacuo, the residue taken up in chloroform, washed with water and dried over anhydrous sodium sulfate. The filtered chloroform solution was evaporated and the residual syrup was suction-free under vacuum to give 9.5 g (90%) of the title product as described in Example 1. For example, the starting compound (IV, R = Ts) can be prepared as follows.

Methyl 5-O-benzyl-3-O-tosyl-2,3,6-trideoxy-α-L-xyloxhexofuranoside (IV, R = Ts)

Methyl 5-O-benzyl-2,6-dideoxy-α-L-xylohexofuranoside (XV) (4.2 g) was dissolved in pyridine (15 ml) and tosyl chloride (4 g) was added. After standing for 20 hours, the reaction mixture was poured into 150 ml of ice water. The precipitate was filtered off, washed with water and dried. This crude product was recrystallized from 2.5x ethanol. 4.6 g (68%), m.p. 87-89 [deg.] C., [.alpha.] D @ 20 = -79 DEG (c = 1, chloroform).

Analysis: Calculated for C ₂₁ H ₂₅ O 6 S (MW 406.50): C 62-105%; H = 6.45%; S, 7.89; Found: C, 62.18; H = 6.52%; S, 7.76%.

Example 3

3-A mino-2,3,6-trideoxy-L-Iixo-hexopyranosic hydrochloride salt (daunosamine) (I, X = NH ₂ HCl, R 1 = R ₂ = H)

Dissolve 2.4 g of methyl 3-azido-5-O-benzyl-2,3,6-trideoxy-αL-lixo-hexofuranoside (I, X = N ₃ , R 1 = CH ₃ , R ₂ = CH ₂ Ph). In 50 ml of ethanol, 3 g of Pd / C catalyst are added and the mixture is hydrated for four days. After the hydrogenation is complete, the catalyst is filtered off and the filtrate is evaporated. The residue was dissolved in water (15 ml) and acidified to pH 1 with N hydrochloric acid and kept in a water bath at 90-95 ° C for 1.5 hours. The reaction mixture was evaporated and the product was triturated with ethanol. (Fraction I), the residue was re-evaporated and triturated with a little ethanol and filtered. (Fraction II), overall yield 1.2 g (75%), m.p. 168 ° C dec. [I] f? = -56 ° (c = 1 water). RL Whistler: United States Patent 4181795 (1980). 168-170 ° C dec. [α] D = -65.4 ° (equilibrium c = 1.3 water).

1844C5

Example 4

Methyl 3-acetamido-5-O-benzyl-2,3,6-trideoxy-αL-lxolhexofuranoside (I, X = NHAc, R 1 = CH ₃ , R ₂ = CH ₂ Ph)

2.5 g of methyl 3-azido-5-O-benzyl-2,3,6-trideoxy-η-L-lxo-hexofuranoside (I, X = N ₃ , R 1 = CH ₃ ,

R ₂ = CH ₂ Ph) dissolved in 50 ml of ethanol, add 1 g of Pd / C catalyst and hydrogenate for 1 hour. After hydration was complete, the catalyst was filtered off, the filtrate was concentrated and θ ¹ is drained. The residue was dissolved in pyridine (8 ml) and acetic anhydride (2 ml) was added dropwise. The reaction mixture was poured into 80 ml of ice water, after one-half hour, extracted with chloroform, the kloroformás layer was washed with 5N sulfuric acid, water, 5% nátri- ¹⁵ um dried bicarbonate solution, water, sodium sulphate and concentrated. The product is crystallized from ether. 2 g (76%), m.p. 115-117 ° C. = -56.9 ° (c = 1, chloroform), R _F = 0.5 ethyl acetate. Analysis: Calculated for C ₁₆ H ₂₃ NO ₄ (MW = 283.35): C, 65.50; H = 7.90%; N, 4.76%; Found: C, 65.45; H = 7.93%; N, 4.62%.

Example J ₂₅

Methyl 3-acetamido-5-O-acetyl-2,3,6-trideoxy-αL-lixo-hexofuranoside (I, X = NHAc, R 1 = CH _3> R ₂ = Ac)

2.5 g of methyl 3-azido-5-O-benzyl-2,3,6-trideoxy-αL-30 -xixhexofuranoside (I, X = N ₃ , R 1 = CH ₃ ,

R ₂ = CH ₂ Ph) dissolved in 50 ml of ethanol, 3 g of Pd / C catalyst are added and the mixture is hydrogenated for 4 days. After the hydrogenation is complete, the catalyst is filtered off and the filtrate is evaporated. The residue was dissolved in pyridine (10 mL) and acetic anhydride (2.5 mL) was added dropwise and allowed to stand at room temperature overnight. The reaction mixture was concentrated and the residue was crystallized from ether. The crude product thus obtained is recrystallized from ether. 1.17 g (53%), m.p. _{4 C} 123-125 ° C, [α] 20 D = -106.4 ° (c = 1, chloroform),

R _f = 0.45 (ethyl acetate: ethanol = 9: 1).

Analysis: Calculated for C 11 H 15 NO 5 (MW = 245.27): C, 53.86; H = 7.81%; N, 5.71%; Found: C, 53.73; H, 7.95; N, 5.65%. _4E

Example 6

Methyl 2,3,6-trideoxy-3-trifluoroacelamido-5-O-trifluoroacetyl-αL-lixo-hexofuranoside ςθ (I, X = NHCOCF ₃ , R ₂ = CH 3, R ₂ = COCF ₃ )

4.8 g Methyl-3-azido-5-O-benzyl-2,3,6-trideoxy _: α-L-hexo-hexofuranoside (I, X = N ₃ , R 1 = CH ₃ ,

R ₂ = CH ₂ Ph) in ethanol (100 mL) was added Pd / C (6 g) and hydrated for 4 days. After completion of hydration 55, the catalyst was filtered off and the filtrate was evaporated. The residue was dissolved in pyridine (25 ml) and trifluoroacetic anhydride (8 ml) was added dropwise at a temperature below + 10 ° C for 15 minutes. The reaction mixture was allowed to stand at room temperature for 4 hours and then poured into 250 ml of ice water. The precipitated crystalline material is filtered off, washed with water and dried. The crude product thus obtained is recrystallized from ether. 3 g (49%), m.p. 151-153 ° C, = -92.5 ° (c = 1, chloroform), Rp = 0.9 (dichloroethane: ethyl acetate = 5: 1).

Analysis: Calculated for C 11 H 11 F 5 NO 5 (MW 353.22): C 37.40; H = 3.71%; F = 32.27%; N = 3.97%;

Found: C, 37.54; H = 3.80%; F = 32.18%;

N, 3.95%.

Claims (5)

Patent claims A process for the preparation of daunosamine of the formula I and its derivatives wherein: R 1 is hydrogen or methyl, _R2 is hydrogen, benzyl, acetyl or trifluoroacetyl group, X is azido, amino, acetamido or trifluoroacetamido, and X is an acid addition salt thereof, with the proviso that when R ₂ is acetyl and X is acetamido, other than methyl, characterized in that a compound of formula IV, wherein R is C 1-4 alkylsulfonyl, unsubstituted or C 1-4 alkyl substituted phenylsulfonyl, is reacted with an inorganic azide in the presence of a solvent then hydrogenating the resulting azido compound of formula (I), wherein R 1 is methyl, optionally up to 1 mole or 2 moles of hydrogen, followed by the resulting amino compound of formula (I), wherein R 1 is methyl , R ₂ is benzyl or hydrogen and X is amino - desired optionally hydrolyzing in the presence of an aqueous acid, liberating the base of the resulting amino compound of formula I, wherein R ₁ is hydrogen and R ₂ is hydrogen or benzyl and X is amino, or acetic acid or acylating with a reactive derivative of trifluoroacetic acid or converting it into an acid addition salt. 2. A process according to claim 1, wherein the inorganic azide is an alkali metal amide, preferably sodium azide. 3. The process of claim 1 or 2, wherein the hydrogenation is carried out in a protic solvent in the presence of a Pd / C catalyst at atmospheric pressure. 4. A process according to any one of claims 1 to 3, characterized in that the hydrolysis is carried out at a temperature of 50 to 100 ° C with an aqueous mineral acid, preferably hydrochloric acid. 5. A process according to any one of claims 1 to 4, wherein the acylation is carried out with acetic anhydride or chloride or trifluoroacetic anhydride in the presence of a base, preferably pyridine.