CH615197A5 - Process for the preparation of antibiotic compounds - Google Patents

Description

615197

2nd

Claim for a process for the preparation of a compound of formula I.

wherein Ri and R2 stand for the radical -COCHa, and Rs stands for hydrogen, and their non-toxic, pharmaceutically acceptable acid addition salts, characterized in that tetra- (Nl, N-3, N-2 "', N-6 "') -acetyl-octa-0-acetyl-paromo-mycin reacted with nitrous acid at room temperature.

The present invention relates to a process for the preparation of new antibiotic aminoglucoside derivatives which contain the 2-deoxystreptamine residue. These derivatives correspond to the general formula:

ch2or2

nhr] _

ch2nhr1

(I)

wherein Ri and R2 each represent a -COCH3 radical, and wherein R3 represents a hydrogen atom.

These compounds are new and have antibiotic activity and can be used for the synthesis of other glucosidic antibiotics, namely by condensation, for example with the dimeric form of a compound of the general formula IV

ch2x

(iv)

in which A, B, C and D each represent a hydrogen atom or a hydroxy group or in which one of the groups A and B and / or one of the groups C and D is an O-acetyl

45

50

represents grappe, X represents an O-acetyl or O-tosyl group and Y represents a nitroso group.

The process according to the invention for the preparation of a compound of the above formula I and its non-toxic pharmaceutically acceptable acid addition salts is characterized in that tetra- (Nl, N-3, N-2 "', N-6"') - acetyl-octa-0 -Acetyl-paromomycin is reacted with nitrous acid at room temperature.

The starting product tetra- (N-1, N-3, N-2 '", N-6'") - acetylparomomycin is described in DE-OS 2 515 629 by the same applicant. It corresponds to the above general formula I, in which Ri represents COCH3, R2 represents a hydrogen atom and R3 represents group IV, in which B, D and Y each represent a hydrogen atom and A, C and X each represent a hydroxyl group. The production is expediently carried out according to the method described below.

60

65

The product produced according to the invention can be used as such as an antibiotic or can be used for the synthesis of other antibiotics. A compound of formula I in which R 1 and R 2 are COCHs can be reacted with a compound containing a group of formula IV as defined above at room temperature for 40 to 60 hours to give derivatives in which Rs is a group IV represents.

3rd

615 197

Production of the starting material

Tetra- (Nl, N-3, N-2 "', N-6"') - acetyl-octa-0-acetyl-paromo-mycin chloride (I; Ri = R2 = Ac, Rs = IV; A = C = X = OAe, B = D = H, Y = NH2 or NH2 • HCl)

460 ml of acetone and 217 g of sodium bicarbonate are added to a solution of 14.5 g of tetra- (Nl, N-3, N-2 "', N-6"') acetylparomomycin in 550 ml of water and then added with cooling Ice a solution of 4.6 ml carbobenzoxychloride in 90 ml acetone while shaking. After the addition has ended, the mixture is stirred for a further 4 hours and then left in the refrigerator for 3 days. The solvent is evaporated, the residue is taken up in methanol and the product is precipitated with ether. 16 g of tetra- (N-1, N-3, N-2 "', N-6"') acetyl-N-2'-carbobenzoxyparomomy-cin are obtained, which melts at 198 to 200 ° C. (decomposition).

[a] jj °° = + 57 ° (c = 1, MeOH), Rt = 0.47 (TLC on

Silica gel, solvent CHCls: Et0H: H20 = 4: 7: 2), Rf = 0.57 (CHCls: MeOH = 1: 1).

16 g of this compound, which is dried in vacuo over P2O5, are dissolved in 160 ml of anhydrous pyridine and treated slowly with shaking with 12 ml of acetic anhydride. The mixture is kept at room temperature for 96 hours and then the reaction mixture is decomposed with water and ice, acidified to pH 5 with aqueous acetic acid and concentrated to 200 ml. From this solution, 13.2 white crystals of tetra- ( Nl, N-3, N-2 "', N-6"') - acetyl-N-2'-carbobenzoxy-octa-O-acetylparomomycin. A further 2.24 g of product are obtained from the mother liquor. Melting point = 269 to 271 ° C,

lai g> ° = + 56 ° (c = 1, MeOH).

A solution of 14.5 g of this product in 1000 ml of methanol containing 11.1 ml of hydrochloric acid is hydrogenated at room temperature and atmospheric pressure using 10% palladium on activated carbon as a catalyst. During the reaction, the pH is kept neutral by adding hydrochloric acid in methanol. The catalyst is then filtered off, the solution is concentrated in vacuo and 13.5 g of the desired compound having a melting point of 200 to 205 ° C. are obtained by precipitation with ether.

[«]

20 ° _

D

= + 62 ° (c = 1, MeOH).

Compound prepared in accordance with the invention for the preparation of derivatives in which R3 represents a group IV.

5 Example 2

l, 3,6-N, N, 0-triacetyl-4,0- (3,4-di-0-acetyl-2-oximino-6-0-tosyl-aD-arabinosopyranosyl) -5-0- [2,5-di-0-acetyl-3-0- (2,6-diacetamido-3,4-0-diacetyl-2,6-dideoxy-aL-idopyranosyl) -10 ^ -D-ribofuranosyl] -2 -deoxystreptamine

(I; Ri = R2 = Ac, Rs = IV, A = C = OAc, B = D = H, X = OTs, Y = NOH)

A solution of 9.4 g of the compound obtained in Example 1 in 31 ml of anhydrous dimethylformamide is mixed with 7.1 g of the dimer of 3,4-di-0-acetyl-2-deoxy-2-nitroso-6-15 O- tosyl-aD-glucopyranosyl chloride (II; A = C = COCH3, B = D = H, X = Ts - prepared according to TL Negabhushen, Canad. J. Chem 48, 257 [1970]) and the mixture is added for 50 hours Room temperature stirred. When 600 ml of ether are added, a solid is obtained which is treated with methylene chloride and precipitated with excess ether. 13.5 g of this material is chromatographed on a column with salicylic acid (500 g) using chloroform and methanol as the eluent. The fractions containing 7% methanol are collected and the solvent is evaporated. 7.34 g of product are obtained, which melts at 152 to 153 ° Celsius (decomposition).

[a]

20 ° D

+ 18 ° (c = 0.5, CHCI3).

30th

35

example 1

l, 3,6-N, N, 0-triacetyl-5-0- [2,5-di-0-acetyl-3-0- (2,6-diacetamido-3,4-di-0-acetyl- 2,6-dideoxy-aL-ido-pyranosyl) - /? - p-ribofuranosyl] -2-deoxystreptamine (I; Ri = Ra = COCHs, Ra = H)

A solution of 12.5 g of the compound obtained as described in the previous example in 85 ml of water, which is cooled at 0 ° C., is treated with 47.5 ml of 10% aqueous acetic acid and 2.70 g of sodium nitrite with shaking, whereby keeping the pH between 3 and 4. The reaction mixture is stirred for 1 hour at 0 ° C., subjected to a stream of nitrogen to remove the nitrous vapors and then lyophilized. The solid is dissolved in a mixture of chloroform: methanol: water (150: 42: 6) and chromatographed on a silica gel column, using the above mixture as the eluent. The presence of the end product is determined by TLC: Rf = 0.45. The solvent is evaporated to give 4.85 g of compound I (Ri = R2 = COCHs), which melts at 157 to 160 ° C (decomposition).

Example 3

l, 3,6-N, N, 0-triacetyl-4-0- (2,3,4-tri-0-acetyl-6-0-tosyl-aD-glucopyranosyl) -5-0- [2.5 -di-0-acetyl-3-0-2,6-diacetamido-3,4-di-0-acetyl-2,6-dideoxy-aL-idopyranosyl) - / 5-D-ribo-furanosyl] -2- deoxystreptamine (I; Ri = R2 = Ac, Rs = IV, A = C = Y = OAc, B = D = H, X = OTs)

A solution of 3 g of the compound according to Example 2 in 18.4 ml of acetonitrile is mixed with 1.84 ml of an aqueous 40 hydrochloric acid and 3.7 ml of acetaldehyde. After shaking for 5 hours at room temperature, the excess acetaldehyde is removed in vacuo, the mixture is diluted with 50 ml of methylene chloride and extracted with an aqueous solution of sodium bicarbonate. The organic phase is separated off, dried over sodium sulfate and evaporated in vacuo.

2.75 g of the residue are poured into a mixture of 42 ml of dioxane and 8.5 ml of water and treated with 690 mg of sodium borohydride while shaking and cooling at 0 ° C. The solution is neutralized with a sulfonic acid exchange resin (acid form), the resin is filtered off and the solution is evaporated to dryness. 1.8 g of the residue are dissolved in 30 ml of anhydrous pyridine, treated with 20 ml of acetic anhydride and kept at room temperature for 16 hours. The excess of acetic anhydride is mixed with water and ice, and 1.9 g of compound is obtained by lyophilization, which melts at 171 to 172 ° C.

60

65

M

20 °

= + 17 ° (c = 1, CHCls).

The following examples show the use of the invented

Example 4

4-0- (6-amino-6-deoxy-aD-glucopyranosyl) -5-0- [3-0-2,6-diamino-2,6-dideoxy-aL-idopyranosyl) - /? ID-ribofuranosyl] -2-deoxy-streptamine (I; Ri = R2 = H; R3 = IV, B = D = H, A = C = Y = OH, X = NH2)

A solution of 1 g of the compound obtained in Example 3 in 30 ml of anhydrous dimethylformamide is mixed with 1.1 g of sodium azide and with shaking at 100 ° for 7 hours

615197

4th

Celsius heated. The solution is then cooled, filtered and evaporated in vacuo. The residue dissolved in 100 ml of methanol is mixed with 1.25 ml of hydrochloric acid and hydrogenated at room temperature and atmospheric pressure with 10 percent palladium-on-activated carbon as a catalyst. When the reaction has ended, the catalyst is filtered off, the solution is neutralized with sodium hydroxide, the methanol is evaporated, 2.5 ml of 50 percent sodium hydroxide are added and the mixture is heated at 135 ° C. for 6 hours. After cooling, the pH is brought to 6N with water

The sulfuric acid is adjusted to 10.5 and the solution is extracted twice with 20 ml of n-butyl alcohol containing 2.5 ml of benzaldehyde. The desired product is obtained from the extracts with dilute sulfuric acid. The acid phase is separated off and the sulfuric acid is removed with an ammonium exchange resin (base form). Lyophilization gives 0.22 g of product, which melts at 190 ° C. (decomposition).

[a] g> ° = + 46 ° (c = 0.5, H20).

M