DE1418452C - Tetrasodium kanamycin tetra-N-methanesulfonate, disodium kanamycin di-N-methanesulfonate and its free acid and hexasodium neomycin hexa-Nmethanesulfonate and processes for their preparation - Google Patents

Description

. . _{t M.} . ,. _t,., sulfonate, as is apparent from Example 1 or 3. It

a mi sodium hydroxymethanesulfonate or _{was it established that} ζ _{η control of} the sodium hydroxide

ί _ ^F ° ^rm f ^d . ^eh y ^d " ^nd sodium bisulphite or _methane J _{oaats also the} equimolar mixture of the

c) with sulfur dioxide and then with _{formaldehyde and} Paraform- _Natriumb isulfits aldehyde or formaldehyde solution _{can waßnger> as a 'us} Example 2 can be seen.

a \ , I h ,, cu t υ λ α τ, c ^Dic hydrolysis of the above-mentioned tetra-sodium

d) first with Schwefeld.oxyd and Paraform- kanamydn-tetra-N-methanesulfonate with dilute aldehyde or waßnger formaldehyde solution _ao hydrochloric acid makes formaldehyde in an _{amount such,} and then with _{Natriumhydroxymethansulfonat> frd which proves> that the derivative is a}

implemented in appropriate molar ratios. Is N-methanesulfonate. This can be done through elemental analysis and the determination of the infrared spec-

of the derivative must be confirmed.

35 When kanamycin monosulfate with 2 moles of sodium hydroxymethanesulfonate in aqueous solution for

The invention relates to tetrasodium kanamycin tetra reaction is brought about, a new derivative, namely

N-methanesulfonate, disodium kanamycin-di-N-me-Hch disodium kanamycin-di-N-methanesulfonate sulfate

thanesulfonate and its free acid and hexa-sodium can be obtained according to the following reaction equation:

neoinycin-hexa-N-methanesulfonate and method for 3 « _ru η μ υ cn ι υη ru cn Mo

their manufacture. These antibiotics are against ^^ fg ¹ " ^ MW £ N ^ H SO ΠΠ
M. tuberculosis effective and have a broad anti-Ci ₈ H ₃₈ U _n N ₂ (NH · CH ₂ · 6U ₃ NaJ ₂ · H ₂ ^ u ₄ uu

brokerage spectrum. When studying the structure of the hydrolysis of the compound II with dilute

of kanamycin, which has recently gained practical importance in hydrochloric acid, forms formaldehyde in a form

it was found that this antibiotic was such an amount that proves that the derivative is a

is very stable to chemical treatment. The Stabili- N-Methanesulfonate is. This can be done through elementary

lity put the consideration for modification possible analyzes and the determination of the infrared absorption

Kanamycin and neomycin are close to, in the ionization spectrum of the derivative can be confirmed, as from

Intention to find derivatives that have a lower toxi- Example 2, b) can be seen.

and the same or a higher antibiotic 40 Since the kanamycin monosulphate easily crystallizes

Have effectiveness than these antibiotics. capable and is therefore the most important salt that is used for

The compounds according to the invention now show purification of the kanamycin in the commercially available manner

In fact, a much lower toxicity than can be used in manufacturing is manufacturing

Gang antibiotics with almost the same antibiotic of compound II by the above-mentioned reaction

Effectiveness on. 45 in the commercial manufacture of the Kanamycin

The process according to the invention for the preparation of N-methanesulfonate is particularly advantageous,
of tetrasodium kanamycin tetra-N-methanesulfonate, If an aqueous suspension of the free Kanamycin

Di-natriumkanamycin-di N-methanesulfonate and desamycin base with 2 moles of sulfur dioxide and then with

sen free acid and hexasodium neomycin-hexa-N-me-paraformaldehyde is reacted

thanisulfonat is characterized in that one 50 a new derivative, namely Kanamycin-di-N-methane

Kanamycin or neomycin or their salts with sulfonic acid (III), according to the following reaction scheme

Sulfuric acid or a weak acid such as Koh- are obtained:

oleic acid, in a manner known per se in aqueous solution
_s ° Ci ₈ H ₃₆ N ₄ U _n + 2H ₂ SU ₃ + 2HCHU

χ. _fM . u α> u if λ 55 - + QiH ₁₈ O ₁₁ (NHi) ₁ (NH. CH _1. SOi) ₁ + 2H.O

a) with sodium hydroxymethanesulfonate or ⁵⁵ (IH)

b) with formaldehyde and sodium bisulfite or

c) with sulfur dioxide and then with paraformaldehyde- ^The hydrolysis of compound III with dilute hyd or aqueous formaldehyde solution or hydrochloric acid makes formaldehyde in one

d) first with sulfur dioxide and Paraformalde- ^{such Men} 8 ^{e freely> indicating} that the derivative is a hyd or an aqueous formaldehyde solution and then ^6o N-methanesulfonate. The new derivative is considered to correspond Natriumhydroxymethansulfonat in ^inner complex salt or zwitterion and implements sponding molar ratios. ^{can be divided by the formula ITI} . the

Structure can be determined by determining the infrared

The reactions a) and b) run z. B. can be confirmed according to the absorption spectrum (Example 3). following reaction scheme: 65 By reaction of kanamycin carbonate with 4 mol

Sodium hydroxymethanesulfonate can be tetra-sodium

Kanamycm + η HOCH ₂ SO ₃ Na kanamycin-tetra-N-methanesulforate are obtained,

- * ■ K (NH · CH ₂ · SO ₃ Na) _n + ηH ₂ O (I) where the derivative of the general formula I with η = 4

corresponds, as can be seen from Example 1, c). The procedures inoculated showed that all Reaction of the kanamycin carbonate with the corresponding N-methanesulfonate described above is practical Amounts of formaldehyde and sodium bisulfite give the same bacteriostatic activities as the failure as well Possess tetra-sodium kanamycin-tetra-N-methane sulfate antibiotics, fonat, as described in Example 1, a). S Although the N-methanesulfonates described above

If neomycin is used with sodium hydroxide by the action of acid or heating, the starting methanesulf onate (or with formaldehyde and bisulfite), antibiotic-releasing, was a decomposition within as is hardly observed for the preparation of the tetra-sodium kanamycin from 2 to 3 hours in a buffer solution has been described, to react. Pharmacological studies of the split ion brought, so hexasodium neomycin hexa io tion of the N-methanesulfonate derivatives in the starting N-methanesulfonate won. It was found that post-injection antibiotics were used in rabbits also this neomycin derivative confirmed that during the period of the highest blood ais, much less poisonous the neomycin itself is antibacterial and does not decompose to the original antibiotics is sam, as can be seen from Table 3. took place. Thus it is proven that the N-methanesulfo-

Essentially composed of two neomycin derivatives, neomycin is less toxic and more practical compound, namely neomycin B and C, are reversible, the stereoisomers with the same molecular formula

Cj ₃ H ₄₆ N ₈ Oj ₃ and contain six amino groups. example 1

The structure of neomycin is partly known. Since _ _XT . ,. .., ..

but its overall structure is still unclear ao Tetra-Natnumkanamyan-tetra-N-methanesulfonate prevails, the structure of the N-methanesulfo- a) A mixture of 3.6 g of Kanamycin, 4.0 g of Na-

nation of the neomycin obtained product not triumhydroxymethanesulfonat and 4.0 ecm of water must be specified precisely. By elemental analysis, was on a water bath with stirring for 2 hours Hydrolysis with dilute hydrochloric acid and heated and then cooled to room temperature. Determination of the infrared absorption spectrum 15 300 ecm of methanol were added to the solution, however, it was ensured that the produced worm immediately formed a viscous product which bond the hexasodium hexa-N-methanesulfonate [cf. when rubbed with a glass rod in a crystal example 4, a)], of neomycin. turned into a powder. Yield 4g. The powder

The hydrolysis of the product with dilute chlorine was dissolved in 9 ecm of water and methanol was added to the solution to form hydrochloric acid in such a fractional precipitate. The amount free to ensure that the derivative was a main fraction is a very water-soluble, colorless N-methanesulfonate. Determination of the infrared crystalline powder; Melting point about 202 ° C. The spectrum of the product gives characteristic ab- The product was sorptions of N-methanesulfonate ^{at approximately 105 ° C. in a vacuum.} dried and analyzed. The elemental analysis

The same compound can by reaction of 35 gave that the main fraction is tetra-sodium kanamycin sodium hydroxymethanesulfonate with neomycin tetra-N-methanesulfonate, corresponding to the compound salt of a weak acid, for example with neodification of the general formula I with η = 4. mycincarbonate, as from Example 4, b) Analysis:
can be seen. The reaction of neomycin carbonate

with corresponding amounts of formaldehyde and 40> ._ o2 ^: _in w _ λ At _m _ah c _ η on sodium bisulfite also results in hexasodium neomy- μ = 9490 / · ~ ~ ~

cin-hexa-N-methanesulfonate, as in Example 4, c) ~~ '' ° '

is described. Calculated for C ₂₂ H ₄₀ O ₁₁₃ N ₄ S ₄ Na ₄ :

The N-methanesulfonates described above c = 27.83, H = 4.25, N = 5.95, S = 13.51,

of Kanamycin and Neomycin can be derived from Kan- 45 Na = 9.70%. amycin or neomycin using paper chromatography [ _a ] jo - - (- 65 ° (c = 1, water),

Separate with 0.4% ammonium chloride solution, since the

free kanamycin or neomycin used on b) A mixture of 3.0 g of sodium bisulfite and

The ion exchanger remains sticking (Rf = 0), while the 3.2 g aqueous formaldehyde solution (35%) was good N-methanesulfonate of kanamycin or neomycin 50 stirred. The solution was 5.0 g of kanamycin and eluted by the solvent. 4.5 ecm of water was added as ions, and the solution was dissolved exchanger, the sodium type of cation is heated from a water bath for 1.5 hours and on room exchange resin "Amberlite IRC-50" is used. temperature cooled. The solution was 250 ecm

As mentioned, all N-Me-methanol described above have added to a viscous precipitate thansulfonate of kanamycin and neomycin to obtain a 55, which is strong when rubbed with a glass antibacterial activity, however, are much stab transformed into a crystalline powder; yield less toxic than the parent antibiotics. Tetra-na- 7.0 g. The powder was dissolved in water and poured through triumkanamycin-tetra-N-methanesulfonate eight- adding methanol fractionally precipitated. The major tenth, Di-sodium kanamycin-di-N-methanesulfonate sul- product was tetra-sodium kanamycin-tetra-N-methanefate and kanamycin-di-N-methanesulphonic acid-onlyein three-60 sulfonate, as described in Example 1, a). tenth of the toxicity of kanamycin monosulfate. c) A mixture of 4.5 g of kanamycin monosulfate

Hexasodium neomycin-N-hexa-methanesulfonate exhibits and 3.0 g of carbonate of barium in water became impure Eightieth of the toxicity of neomycin sulfate. Stirred for about 2 hours and at room temperature

Determination of the bacteriostatic activity allowed to precipitate barium sulfate, which is carried out by the above-described N-methanesulfonate derivatives des 65 was removed by filtration. The filtrate, a solution Kanamycins and neomycins, respectively, three hours after their from kanamycin carbonate, became at about 45 ° C Addition to media in the staphylococci after a one-cylinder rapid plate process in a vacuum to a volume of approximately 10 ecm or nephelometri- concentrated, and 4.0 g sodium hydroxymethanesulfonate

were admitted. The resulting mixture was heated on a water bath for 2 hours as the Development of carbon dioxide was observed. The resulting solution became by adding of methanol in the same manner as described in Example 1, a) Tetra-sodium kanamycin-tetra-N-methanesulfonate isolated. The analyzed sample was obtained by fractional precipitation from an aqueous solution of the product obtained by adding methanol. Analysis:

Found:

C = 28.10, H = 4.41, N = 6.15, S = 12.72, Na = 9.60%;

Calculated for C ₁ AgV C = 27.83, H = 4.25, N = 5.95, S = 13.51, Na = 9.70%.

The infrared absorption spectrum of the product was completely identical to that in Example 1, a) described Tetra - natri u mkanamyci η - tetra - D -methanesulfonats.

d) A mixture of 4.5 grams of kanamycin monosulfate and 3.0 grams of carbonate of barium in water was approximately Stirred for 2 hours and left to stand at room temperature to precipitate barium sulfate, which was removed by filtration. The filtrate, a solution of kanamycin carbonate, was at approximately Concentrated to 45 ° C in vacuo to a volume of about 10 ecm, into which a gui stirred solution of 3.0 g of sodium bisulfite and 3.2 g of aqueous formaldehyde solution (35%) were added. The solution was heated on a water bath for 1.3 hours. The solution cooled to room temperature 300 ecm of methanol were added. It imagined

viscous precipitate which turned into a crystalline powder when rubbed with a glass rod; Yield 4.0g. Fractional precipitation from an aqueous solution of the product by adding Methanol gave tetra-sodium kanamycin tetra-N-yne ethanesulfonate

Infrared absorption spectrum:

The absorption maxima of the above-mentioned derivative were 3400 cm- ¹ (wide, OH ", NH), 1650 cm- ¹ ao (- CH ₁ SO, -), 1200 cm- ¹ and 1040 cm- ¹ (- SO ₈ -) ·

Toxicity and antibacterial activities

The toxicity and antibacterial activities of tetra-sodium kanamycin tetra-N-methanesulfonate are compared with those of kanamycin monosulfate in Table 1.

, Table

Toxicity and antibacterial spectrum *) of tetra-sodium-kanamycin-tetra-N-methanesulfonate

and kanamycin monosulfate

Test organisms

Minimum inhibition concentration per ecm

Tctra-sodium kanamycin tetra-N-methanesulfonate

Kanamycin monosulfate

M. pyogenes var. Aureus 209-P

B. anthracis

B. subülis

E. coli

E. coli streptomycin fast

K. pneumoniae

Pr. Vulgaris OX-19

Ps. Aeruginosa

Sh. flexneri

Sh. dysenteriae

Sh. sunny

S. paratyphi A

S. paratyphi B

S. enteritidis

S. typliosa

M. phlci

M. tuberculosis

M.607

M. 607 streptomycin resistant

C. diphteriae

Toxicity in mice by intravenous injection LD ₅₀ • According to the agar plate method.

The kanamycin derivative was also confirmed to be effective against infection of mice with M. pyogcncs and S. typhosa is effective.

Example 2 Disodium kanamycin di-N-methanesulfonate

a) A mixture of 3.6 g (0.0074 mol) of kanamycin, 2.26 g (0.015 mol) of sodium hydroxymethane sulfonal and 4.6 ecm of water w unk · on a water cr-3.13

3.13

1.56

6.25

6.25

3.13
12.5
50

6.25

6.25

6.25

3.13

6.25

6.25

3.13

6.25

3.13

1.56

1.56

1.56
> 5500 mg / kg

0.6

1.25

0.6

5.0

5.0

1.25 10.0 25

5.0

5.0

5.0

5.0

5.0

2.5

2.5

0.5

2.0

2.5

2.5

0.75 313 mg / kg

bath heated for 1.5 hours and then to room temperature cooled down. 300 ecm of methanol were added to the solution in order to precipitate a viscous product, which soon turned into a powdery solid substance; Yield 2.82 g (53%). This stuff was dissolved in 12 ecm W.'isscr and added by Fractional precipitated methanol. All four fractions were liypioscopic powders. The Aiislicute at the / while liaklion was 400mg. The lilcmentaranaIyse revealed that the fraction Di-nalriuinkanamycin-

was di-N-methanesulfonate and the compound of the general formula I with η - 2 corresponded. Analysis:

Found:

C = 32.72, H = 5.41, N = 7.15, S = 9.07, Na = 5.71%.

Calculated for C ₂₀ Hs ₈ O ₁₇ N ₄ SiNa ₈ : C = 33.46, H = 5.34, N = 7.81, S = 8.94, Na = 6.42%.

b) A mixture of 3.0 g of kanamycin monosulphate and 3.04 g of sodium hydroxymethanesulphonate in 4 ecm Water was refluxed on a water bath for 1.3 hours to give a light yellow solution. 180 ecm of methanol were added to the cold solution. A viscous precipitate was obtained which turned into a crystalline powder when rubbed with a glass rod; Yield 5.5g. The product was dissolved in 22 ecm of water and the solution filtered. 25 ecm of methanol were added to the filtrate, and the mixture was left to stand. A viscous precipitate formed which was separated off by decanting and converted into a crystalline powder by rubbing with a glass rod; yield 2.1 g, MT = + 83.0 ° (c = 2, water).

10

15 It melted indistinctly above 206 ^° C. with decomposition.

Analysis:

Found:

C = 28.75, H = 5.11, N = 6.25, S = 11.68,
Na = 5.69%.

Calculated for C ₁₅ H ₃₂ N ₂ O _n (NHCH ₂ SO ₃ Na) ₂
H ₂ SO ₄ :

C = 29.45, H = 4.91, N = 6.87, S = 11.78,
Na = - 5.64%.

Infrared absorption spectrum

Strong absorptions were at 3400 cm- ¹ (wide, OH-, NH), 1630 cm- ¹ (-CH ₄ SO ₃ -), 1200 to 1110 cm- ¹ (SO ₈ -).

Toxicity and antibacterial activity

The disodium kanamycin di-N-methanesulfonate sulfate is much less toxic than kanamycin itself and possesses strong anti-bacterial activity, as evidenced by it Table 2 can be seen. It was also confirmed that the derivative was effective against infection of mice with M. pyogenes and S. typhosa is effective.

table

Antibacterial activity and toxicity of disodium kanamycin di-N-methanesulfonate sulfate

compared to kanamycin monosulfate

Test organisms

Minimum inhibitory concentration Π Yy fm ILIIIJI ....... ...... each ecm anamycinmonosi Disodium kanamycin 0.6 di-N-methanesulfonate sulfate 1.25 0.78 to 1.56 0.6 0.39 to 0.78 5.0 0.39 to 0.78 5.0 6.25 1.25 3.1 to 6.25 5.0 3.1 to 6.25 5.0 6.25 to 12.5 2.5 6.25 to 12.5 5.0 3.1 5.0 3.1 2.5 6.25 to 12.5 2.0 6.25 2.5 1.5 2.5 1.5 300 mg / kg 1.5 > 4000 mg / kg

M. pyogenes var. Aureus 209-P

S. anthracis

B. subtilis

E. coii

E. coli streptomycin fast

K. pneumoniae

Sh. flexneri

Sh. sunny

S. typhosa

S. paratyphi A

S. paratyphi B

S. enteritidis

M. tuberculosis

M. 607

M. 607 streptomycin resistant

Toxicity in mice by intravenous injection LD ₆₀

Example 3 Kanamycin-di-N-methanesulfonic acid ,,

Sulfur dioxide was added to a suspension of 4.85 g (0.01 mol) of kanamycin free base in 5 ml of water until the required amount of sulfur dioxide (1.28 g) had been absorbed. The pH of the resulting viscous solution was 6.0. To the solution, 0.60 g of paraformaldehyde (or 2.0 g of 30% formaldehyde solution) was added, and the solution was allowed to stand at room temperature for 24 hours. The pH of the resulting solution was 7.2 to 7.3. The solution was poured into 40 cc of ethanol, whereupon a viscous product ^s reflected that crystallized by rubbing with a glass rod. The product was redissolved in 10 ecm of water and, after filtration, precipitated by adding 50 ecm of ethanol. The yield of ^{crystalline powder dried at approximately 50 °} C. was 6.32 g (94%). Elemental analysis showed that the product was an inner salt of kanamycin-di-N-methane acid.

Analysis:

Found:
C = 34.90, H =

Calculated for
C ₁₈ H ₂₈ O _n (NHi

6.23, N = 8.06, S = 8.96%;

H ₁ O:

C - 34.78, H - 6.13, N - = 8.11, S- 9.53%.
S ¹ = - λ 103 ° (r = 2, water).

509 686/120

Infrared absorption spectrum:

The absorption maxima of the derivative described above were 3350 cm " ¹ (wide, OH", NH), 1630 cm " ¹ (- CHuSO ₃ -), 1525 cm- ¹ (NH ⁺ ), 1170 cm- ¹ and 1030 cm- ¹ ( - SO ₃ -).

Toxicity and antibacterial activity

The inner salt of kanamycin di-N-methanesulfonic acid had an activity of 710 U / mg, expressed in kanamycin units, against M. pyogenes var. Aureus 209-P, and when injected into mice by the intravenous route, the LD _{50 was} 3500 mg / kg.

Example 4 Hexa-sodium neomycin-N-hexa-methanesulfonate

a) The sulfate of the neomycin sample used in this experiment had an activity of 640 μg / mg on. By paper chromatography with water-saturated, 2% p-toluenesulfonic acid butanol was used found that the sample contained mainly neomycin B and a small amount of neomycin C.

A mixture of 4.3 g (0.007 mol) of neomycin, 6.4 g (0.048 mol) of sodium hydroxymethanesulfonate was dissolved in 6 ecm of water, heated on a water bath with stirring for 2 hours and cooled to room temperature. 60 ecm of methanol were added to the solution, whereupon a viscous product immediately formed which, when rubbed with a glass rod, turned into a crystalline powder; Yield 8.5g. A sample of 7.0 g of the powder was dissolved in 25 ecm of water and fractionally precipitated by adding methanol. The main fractions listed in the following table, F ₂ and F ₃ , are colorless, crystalline powders; F ₃ : [«] £ = \ 28.5 ° (c = 2, water).

Admittedly Factions Weight Methanol of the political groups (ecm) F ₁ (G) 48 F ₂ 1.6 14th F ₃ 2.3 18th F ₄ 1.3 12th F ₅ 0.34 28 F ₈ 0.3 40 0.1

The results of the elemental analysis of the fractions showed that the main product recovered Neomycin was hexasodium hexa-N-methanesulfonate.

Analysis:
Q ₂ : Found:

C = 24.3, H = 4.1, N = 5.7, S = 13.7,
Na - = 10.7%;

Q ₃ : Noted:

C = 25.7, H = 3.9, N = 5.9, S = 13.9,
Na = 10.5%;

Calculated for C ₂₃ H ₄₀ Oi ₃ Nj (CH ₂ SO ₃ Na) ₀ :
_a5 C = 26.6, H = 4.0, N = 6.4, S = 14.7,
Na = 10.5 vol-

Infrared absorption spectrum:
The absorption maxima were 1170 - 1210 cm- ¹ ( ^S ° 5)

Toxicity and antibacterial activity

The sodium neomycin N-melhansulfonate was a lot less toxic than neomycin itself and showed strong antibacterial activity as shown in Table 3 is. The toxicity of the derivative in mice by intravenous injection was approximately one Eightieth! that of neomycin itself.

table

Toxicity and antibacterial activity *) of hexa-sodium-neomycin-hexa-N-methanesulfonate

compared to neomycin sulfate

Experimental organizations

Minimum shirt concentration
each ecm

xasodium neomycin
aN-methanesulfonate Neomycin sulfate 3.13 1.56 1.56 1.56 1.56 1.56 25.0 3.13 25.0 3.13 12.5 3.13 25.0 3.13 > 200 > 200 50 3.13 50 3.13 50 3.13 12.5 3.13 50 3.13 12.5 3.13 12.5 3.13 3.13 1.56 5.0 2.5 3.13 1.56 3.13 1.56 > 3500 rag / kg 50 mg / kg

M. pyogenes var. Aureus 209-P

B. anthracis

B. subtilis

E. coli

E. coli streptomycin fast

K. pneumoniae

Pr. Vulgaris OX-19

Ps. Aeraginosa

Sh. fiexneri

Sh. dysenteriae

Sh. sunny

S. paratyphi A '

S. paratyphi B

S. eniteritidis

S. typhosa

M. p'hlei

M. tuberculosis

M. 607

M. 607 streptomycin resistant

Toxicity in mice by intravenous injection LD ₆₀ * After the agar dilution method.

b) A mixture of 6.4 g neomycin sulfate and 9.0 g carbonate of barium in water became several Stirred for hours and allowed to stand at room temperature to precipitate barium sulfate, which was obtained by filtration was removed. The filtrate, a solution of neomycin carbonate, was im Vacuum reduced to a volume of approximately 10 ecm. 6.4 g of sodium hydroxymethanesulfonate was added. The resulting mixture was on heated in a water bath for 2 hours, during which time the evolution of carbon dioxide was observed. The resulting solution was made by adding methanol in the same manner as in Example 5, a), sodium nitrogen sulfonate isolated.

Analysis:

Q ₂ : Found:

C = 24.25, H = 3.93, N = 5.67, S = 15.58,
Na = 10.70%.

Q ₃ : Found:

C = 24.82, H = 4.09, N = 5.71, S = 14.84,
Na = 10.20%.

Calculated for C ₂₃ H ₃₄ O ₁₃ (NH CH ₈ SO ₃ Na) ₈ :
C = 26.56, H = 3.97, N = 6.41, S = 14.66,
Na = 10.53%.

It was found that the infrared absorption spectrum of the product F ₃ corresponds completely to that of the product described in Example 5, a).

c) A mixture of 6.5 g neomycin sulfate and 9.0 g carbonate of barium in water was

ίο the stirred and left to stand at room temperature, to precipitate barium sulfate, which was removed by filtration. The filtrate, a solution before Neomycin carbonate, was vacuumized at about 45 ° C to a volume of about 10 ecm tight. A well-stirred solution of 4.1 g of aqueous formaldehyde (35%) and 5 g of sodium bisulfite was used added. The solution was heated on a water bath for 2 hours. The one cooled in ice water Approximately 100 ecm of methanol were added to the solution to precipitate a viscous product which was formed Rub into a crystalline powder with a glass rod transformed; Yield 8.2g. Fractionated precipitation from an aqueous solution of the product by adding giving methanol resulted in a product compatible with your in Example 5, a) was identical.

Claims (2)

1 2 Patentaniöruche · in which K represents the residual part resulting from the removal of (NH,) B from the kanamycin molecule; 1. Tetrasodium kanamycin - tetra -N- methane η = 2 or 4. sulfonate, disodium kanamycin - di - N · methane By adjusting the above molar ratio of sulfonate and its free acid and hexa-sodium- 5 sodium hydroxymethanesulfonate to form kanamycin neomycin hexa-N-methanesulfoaate. the above-mentioned, two to four hydroxymethanesul- 2. Process for the preparation of the compounds containing fonatreste as the main pronoun Claim 1, characterized in that products are obtained. If 4 moles or 2 moles one kanamycin or neomycin or their salts sodium hydroxymethanesulfonate with 1 mole of kanamycin with sulfuric acid or a weak acid, such as that which is brought into reaction, is what is obtained Carbonic acid, in a manner known per se in aqueous main product tetra-natriuinkanamycin-tetra-N-meriger Solution of thanesulfonate or disodium kanamycin-di-N-methane