JPS59104396A - Novel antibiotic 2',3'-dideoxykanamycin - Google Patents

Abstract

NEW MATERIAL:2',3'-Dideoxykanamycin A shown by the formula I or its salt. Having the following physical and chemical properties. Appearance: white powder. Specific rotatory power: [alpha]<23>D+114(C 1.0, water). Melting point: 148-162 deg.C. Elementary analysis values (%): C 44.08, H 7.33, N 10.72. Molecular formula: C18H36N4O9.H2O. USE:An antibacterial agent. Effective for remedying infectious diseases especially by Gram-positive and Gram-negative bacteria. PROCESS:For example, a kanamycin A derivative shown by the formula IIwherein hydroxyl groups except hydroxyl groups at the 5- and 2-positions and all the amino groups are protected is obtained from kanamycin A. This compound is chemically reacted at the 2'- and 3'-positions to give a compound shown by the formula III, which is treated with an alkali alcoholate, treated with an aqueous solution of sodium hydroxide, and reduced with hydrogen in the presence of a hydrogenation catalyst.

Description

DETAILED DESCRIPTION OF THE INVENTION This invention relates to a novel compound, 2',3' mono-nodeoxykanamycin A.

The present inventors ingeniously conducted research on the deoxin derivative of kanamycin A, an aminoglycoside antibiotic, and developed 3'-deoxykanamycin A.

We have succeeded in synthesizing 3',4'-sodeoxykanamycin A, 2'-deoxykanamycin A, etc.
8 [Refer to No. 97, specification of Japanese Patent Application No. 1978 6-1 13578].

The present inventors further conducted research on the 2'-1 derivative of kanamycin, and developed the 2', 3/1 derivative as a new derivative.
- Intended to synthesize dideoxykanamycin A. After repeated various studies, we succeeded in synthesizing 2',3'-dideoxykanamycin A, and this new compound was found to be effective against various resistant bacteria. They recognized that it is a synthetic aminoglycoside antibiotic and completed the present invention.

That is, the present inventors used kanamycin A as a starting material whose hydroxyl groups at the 2' and 3' positions were either left free or modified to be convenient for 2',3'-deoxylation. Kanamycin A protected derivatives are prepared in which the hydroxyl groups at the 4'+2+4" and 6" positions and all amino groups are protected except for the relatively unreactive hydroxyl group at the 5-position. The 2' and 3' positions of the protected compound were further subjected to a chemical reaction to form a 2',3'-dideoxy-2' mono-engineered nokanamycin A-protected derivative, which was further subjected to a reduction reaction. and 2'
．． leading to a 3'-zodeoxy-protected derivative of Namycin A,
Next, the target 2', 3' is removed by conventional methods.
-Successfully synthesized dideoxykanamycin A.

Therefore, the present invention provides 2',3'-dideoxykanamycin A represented by the following formula (2',3'-dideoxykanamycin A) or an acid addition ring thereof.

2',3'-dideoxykanamycin A (d
It is a white powdery basic substance with a specific optical rotation of 6 [α) + 114° (Cl, O + water] and a melting point of 148~
+62OC, and the actual value of elemental analysis is C44.0
8%.

H7, 33%, NIo, 72%, its molecular formula (Cl81
■36N40, .H2O).

The 2',3'-dideoxykanamycin A of the present invention is usually obtained as a free base, a hydrate, or a carbonate, but it can be converted into any non-toxic acid salt by a conventional method. As the acid to be added, various acids such as inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and nitric acid, and acetic acid, malic acid, citric acid, ascorbic acid, and methanesulfonic acid are used.

The antibacterial spectrum of 2',3'-dideoxykanamycin A is shown in Table 1 below.
l: Shows high antibacterial activity against p-resistant bacteria.

In all cases of acute toxicity due to intravenous injection in mice, the LD5° value is +ooq/! 9 or higher, and is used to treat various infections caused by Durham-positive and -negative bacteria.

The synthesis of 2',3'-dideoxykanamycin A of the present invention starts from kanamycin A, and can be obtained by a manufacturing method that goes through two main routes.

The first manufacturing method consists of the following steps.

First, kanamycin A (compound I) was treated with Na in water.
In step 1), all the amino groups of kanamycin A are retained with ethoxycarbonyl groups by the action of ethyl chlorocarbonate in the presence of OH, and then benzoyl chloride is reacted in pyridine to bind all amino groups other than the human 90-xyl group at the 5-position. All hydroxyl groups are blocked with benzoyl groups in step 2), and further hydrason hydrate is reacted in pyridine to 2'
Selectively removing the benzoyl group from the hydroxyl group (Step 3)
13578) 0 As a result, as a kanamycin A derivative in which all hydroxide groups and all amino groups other than the 5- and 2-position hydroxyl groups are retained, 3t, 4',
2〃, 4#, 6/l-penta-0-benzoyl-tetra-N-ethoxycarbonylkanamycin A (compound ■) is prepared.

ic (O-protected derivative) The 2'-hydroxyl group is sulfonylated, e.g., mesylated L (Iu4), by reacting with a sulfoninosinating agent, e.g., mesyl chloride, in whole pyridine to obtain hf
l When the 2'-0-mesyl compound (compound ■) is treated with an alkali alcoholade (e.g. sodium methylate) in methanol-dioxane (step 5), the 2'-methylsulfonyloxy group and the 3'-benzoino 1 an epoxide ring is formed by acting on the oxy group (1-meroxylation), and at the same time all 0-benzoyl groups at other positions are eliminated,
This results in 2′.

3'-Anhydro-2'-epi-tetra-N-ethoxycarbonylkanamycin A is formed. This was again reacted with benzoyl chloride in pyridine (cs6), and 5
All hydroxyl groups other than the hydroxyl A group are benzoylated to create 2', 3'-anhydro-4', 2'',
4″, 6″-tetra-0-benzoyl-2′-epi-
This leads to tetra-N-ethoxycarginylkanamycin A (compound ■).

Alkali iodide, *
! For example, when zitorium iodide is reacted with acetone under heating (Engineering, Part 7), the epoxide ring opens to form the 3′
Compounds iodinated at position and 1-, 4', 2", 4",
6〃-Tetra-0-benzoyl-3'-deoxy-2'
, 3''-di-epi-3'-yo to 1-tetra-N-ethoxylic; 1?Nilkanamycin AC compound V) is formed.In contrast to this compound, 4-trimethylaminopyrinone and chloride in pyrinone are formed. When mesyl acts on the presence of triethylamine (step 8), 2'-enolation occurs,
4' + 2I+ 4〃, 6'-7tra-0-benzoyl-2', 3'-nobuoxy-2'-enotetra N
-Ethoxycarbonylkanamycin A (compound ■) is produced. Treatment of the 2'-eno form with an alkali alcoholade such as sodium methylate in methanol (step 9) eliminates the o-benzoyl group. Furthermore, when this debenzoyl compound is treated with an aqueous sodium hydroxide solution (Synthesis 10), the N-ethoxycarbonyl group is de-1
Deprotection is completed at the end of Fusa. and fl, 2', 3
'-dideoxy-2'-enokanamycin A (compound ■
) (this is a new compound) is produced. This was heated in water in the presence of a hydrogenation catalyst such as platinum oxide, Nonoradium, etc.
When reduced with J< element (step 11), the target 2', 3'-
Dideoxykanamycin A (compound ■) is obtained.

The outline of the first manufacturing method described above is illustrated in the chart below. In the diagram, Cbe is ethoxy force/L is a nyl group, IBZ is a benzoyl group, and Ms is a mesyl group (a methylsulfony group). .

7) In the first production method, step 1 of the reaction of adding an etoyashi carbonyl group to protect the group to kanamycin can also be carried out using the protection method for the reaction step of introducing a benzoyl group to the hydroxyl group of the protection group. The details of the implementation method of Step 3 for selectively eliminating 2'-0-benzo for hydrazine-bilino are described in Japanese Patent Application No. 113573.

In Step 4 of sulfonating the 2'-hydroxyl group of compound H, 1ri, sulfonyl 41[[In addition to mesyl chloride, tosylflora sol sulfonyl chloride can be used, and in addition to birinone, triethyl amyl fonylation It is possible to use dichloromethane in an amount of 2 to 10 times the molar amount of the reagent.

The reaction temperature is 110 to 800 G, preferably 15 to 30°C.

In step 5 of converting the 2' and 3' positions of znt,
The alcoholade of lower tetracaf)-al and alkali metal (e.g., lithium or potassium) is used in an amount of 5 to 20 times the molar amount of compound 1H. As a solvent, lower alkanol or lower alkanol and tetrahydrofuran, dioxane ID
MF etc. can be used, and the temperature condition is preferably O-500C. 〇-protection of the deprotected hydroxyl group is carried out again 5
It is used in an amount of ~15 times the molar amount. Pyrinone as a solvent,
Triethylamine/dichloromethane (triethylamine in an amount of 2 to 10 times the mole of the reagent) can be used, and the temperature condition is preferably -10 to 60°C.

In step 7 of iodizing the 3' position of the obtained compound IV, sodium iodide, potassium iodide, etc. can be used as an iodizing reagent in an amount of 4 to 10 times the molar amount of compound (1). At this time, formic acid is used as an acid catalyst.

It is preferable to use a buffer consisting of a lower fatty acid such as H+CH2)n-C02H (n = 1 to 4) or a lower fatty acid and its sodium salt. As a solvent, acetone, tetrahydrofuran, zooxane, dimethylene 1. Formamide can be used, and the temperature conditions are 5° to I2000.
is preferred.

In step 8 of 2'-enation of the obtained compound (4),
-sometenominopyrinone (0.2 to 3 times the mole amount of Compound V), 4-tmethylaminopyridine (012 to 3 times the mole amount of Compound V) and triethylamine (compound V
Mesyl chloride, benzylsulfonyl chloride, tosyl chloride, trifluoromethylsulfonyl chloride 9 (compound V
3 to 7 times the mole of acid chloride such as 9) is reacted.

A base is not necessarily required. Pyridine is used as the solvent, and temperature conditions of 10 to +200G (90 to 120°C when no base is used) are preferred.

In Step 9, which protects the obtained compound (■), a lower alkanol and an alkali gold alcoholade (e.g., sodium or potassium alcoholade (3 to 7 times the molar amount of compound (■)) are used as reactants, and the temperature is Conditions are 0~
50°C is preferred.

Subsequently, in step 1o of N-deprotection, a bath solution containing sodium hydroxide, potassium hydroxide, and barium hydroxide (an amount 30 to 100 times the molar amount of the 〇-hypothetical compound of compound (1)) is reacted. Preferably, the temperature is 80 to IOOOC.

In Step 11 of the reduction of the obtained compound (1), the 2'-eno double bond is added with hydrogen (hydrogen pressure is normal pressure to 3 atm) in the presence of platinum oxide. Implemented.

The temperature condition is preferably 10 to 500c. Hydrogenation saturates the double bond of compound (1) to produce %2',3'-dideoxykanamycin A.

The second method for producing 2',3'-diteoxykanamycin A consists of the following steps.

That is, the amine group at the 6' position of kanamycin A is selectively protected by acting on kanamycin A with benzyloxycarbonyl chloride at a molar ratio of about 1 in water (Carbohydrate Re5).
-search, Vol. 8q, pp. 91-lot (1981)). Next, 4Q et al. treated 6'-N-pencyloxycarbonylkanamycin AK with tosyl chloride in a molar ratio of about 3 in pyridine, thereby protecting all the remaining amino groups with tosyl groups (Step 2). (Car
(see Bohydrate Research) and 6'
-N-Pennoroxycal+J? Nyl-1,3,3"-
Tri-N-tosylkanamycin A (compound flash) can be prepared.

j (D Compound % ((7) In order to simultaneously protect two hydroxy AMs at the 4" and 6" positions, 4" and 6"
- Perform 0-pennolidene formation (Step 3). In this case, the benzylidene group is introduced by known methods such as acting in the presence of penzua/L, dehyde dimethylacetano Lfp-) and enenesulfonic acid, or acting benzaldehyde in the presence of zinc chloride. It can be done. This results in 6
'-N-benzyloxycarbonyl-4〃,6''-0-
pennolidene-1,3,3"-treeN-) 'yyb
-jy Namycin A (compound X) is produced J'.

When this compound
- Generates a rubamate ring, which gives 4', 6'
-0, N-kept pupilization is achieved. At this time, 411.6〃
-Q-benzylidene-6'-N:4'-0-carbonyl-1,3,3''-triN-)zircanamycin A (compound X) is produced.

1,1-dimethoxycyclohexane is applied to compound (Step 5), 2', 3'-0-
Cyclohexylidene is carried out, 4″67′-0-benzylidene-6′-N:4′-0-cals=rni-2′
, 3'-0-cyclohexylidene-1゜3, 3//-
Tri-N-tosylkanamycin A (Compound XIJ)
is generated.

Next, compound x■ is acetylated with acetic anhydride to protect the 2"-hydroxyl group (Step 6)
and 2"-O-acetyl-4", 6"-0-pensolidene-6'-N: 4'-〇-carbonyl-2'.

3'-0-cyclohexylidene-1,3,3'-1-so-N-tosylkanamycin A (compound X[I) is produced.

Furthermore, the occluded 2' position in compound xtr, 3
Hydrolysis with 80% acetic acid aqueous solution (step 7) to liberate the hydroxyl group at position 2', 3'-〇-
The cyclohexylidene group is removed to give 2〃-〇-acetel-4//, 6#-0-benzylidene-6'-N:,
t, /-o-carbonyl-1,3,3'-)soN-
Tosylkanamycin A (compound ■) is produced.

In order to trifluoromethylsulfonylate the hydroxyl groups at the 2' and 3' positions of the cono compound
02) When reacted with 2 (step 8), 2"-〇-acetyl-411.6/7-o-benzylidene-6'
-N: 4'-〇-carbonyl-2', 3'-G0-
Trifluoromethylsulfonyl-1,3,3#-t'J
-N-tosylkanamycin A (compound XV') is produced.

Further treatment of compound XV'i with alkali iodide in DMF in the presence of imidazole results in 2'-enolation (step 9). By this, 2”-〇-acetyl-4
〃,6''-〇-benzylidene-6'-N:4'-〇-carbonyl-2',3'-dideoxy-2'-eno1.
3,3“-triN-)zilcanamycin AC Compound X
VI) is generated. When this compound pool is reduced with hydrogen in the presence of a platinum oxide catalyst (step 10), the 2'-eno double bond is hydrogenated and 2-〇-acetyl-4〃, 6/l-〇- Benzylidene-6'-N: 4'
-0-carbonyl-2', 3'-dideoxy-1,3,
3“-TrieN-) zircanamycin A (compound xvn
) is generated.

When Intercompound I is treated with alkali hydroxide in THF,
4r,,6t-carbamate ring is cleaved and 2〃
-0-acetyl group is also removed (step 11) ・4", 6"
-O-benzylidene-2', 3'-dideoxy-1
,3,3'-)soN-tosylkanamycin A (compound idea) is produced.

In order to remove all the protecting groups from this compound M■, it is treated with an alkali metal in liquid ammonia (Step 12)
Then, the tosyl group and the 4'',6''-0-benzylidene group are removed at once to obtain the desired 2',3'-dideoxykanamycin A.

An outline of the second manufacturing method described above is illustrated in the following chart.

However, in the figure, 2 is a benzyloxycarginyl group -Ts
represents a tosyl group, r Ac represents an acetyl group, and Tef represents a trifluoromethylsulfonyl group.

Second production method chart (Compound M) (Compound X) (Compound X) (Compound XV) (Compound XIV) (Compound Both step 1 of the reaction in which the nyl force is added to the benzyloxycar f and step 2 of the reaction in which a tosyl group is introduced into another amino group can be carried out using known methods.

Fourth, for the 4#,6//g-benzylidene formation in step 3, K(benzaldehyde methyl acetal and p-)luenesulfonic acid, or penzaltehyde and zinc chloride are allowed to react. Solvent and 1-, nomethylphono 1
．． Muamide is used, and the temperature condition is preferably 10 to 300C. For the 4', 6'-carbamate formation in step 4, sodium hydroxide is added to
The reaction is carried out in an amount of 15 times the amount per liter, trimethylformamide is used as the solvent, and the temperature is preferably 10 to 400C. In step 5, 2',3'-0-cyclohexylidene is treated with 1,1-dimethoxycyclohexane, and trifluoroacetic acid, trichloroacetic acid, p
- An acid catalyst such as toluenesulfonic acid and a demethanol agent such as Molecular Sheeps 4A or 5A are present. ll-6, dimethylformamide as a solvent.

A dichloromethane-dimethylformamide mixed solvent is used.

In the 2″-0-acetylation in step 6, acetic anhydride
Acetyl chloride is used, but r+2〃-o-acylation (r+2〃-o-protection can be achieved even when benzoylated 1- is used with benzoic anhydride and benzoyl chloride (2 to 10 times the mole of compound X11)) As a solvent for acetylation, pyridine, triethylamine/dichloromethane (triethylamine is 2 to 10 times the mole of compound X) can be used, and the temperature condition is preferably 10 to 500C.

For 2',3'-0-deprotection in step 7,
50-90 thiacetic acid water, O12-1.0 trifluoroacetic acid or trichloroacetic acid are suitable, and the temperature condition is 20
~50°C is preferred b0 For trifluoromethylsulfonylation of the hydroxyl groups at the 2' and 3' positions in step 8, anhydrous IJ
Fluoromethanesulfonyl, trichloromethanesulfonyl chloride (3 to 10 (pmol) of compound
~30°C is preferred.

For 2'-enolation in step 9, sodium iodide/potassium iodide, sodium iodide or potassium iodide/imidazole, sodium iodide or potassium iodide/zinc (sodium iodide, potassium iodide are 50 to 100 times the mole of Compound Xv and 3 to 10 times the mole of Compound XV) are reacted. Temperature conditions are 80-1, 'OoC.

Step] Reduction reaction in O ([, presence of liquefied platinum.

The process was carried out using hydrogen (hydrogen pressure is normal pressure to 5 atm), and the solvent was 7
-) Hydrofuran, nooxane, methanol, and (yumi) water-containing systems such as i-, etc. can be used.

(2) Sodium hydroxide for deprotection by cleavage of the 4',6'-rubamate ring in Step 11.

Potassium hydroxide 7 Hydrogenated using barium hydroxide u-1
The first one will be raised. At this time, as a solvent, water-containing tetrahydrofuran, dioxane, dimethoxyethane (molten t, Japanese l
I20=2:I water-containing system) is suitable, and the temperature condition is 20~
700C? There is 1′.

In step 12, the compound is treated with an alkali metal such as sodium or potassium in liquid ammonia in a known manner to deprotect the amine and hydroxyl groups. A suitable temperature condition is -70 to -40oC. thus,
The desired 2',3'-nobuoxykanamycin A is produced.

Next, the present invention will be explained by examples. Example 111 shows the synthesis of the target compound of the present invention by the first production method, and Example 2 shows the synthesis of the target compound of the present invention by the second production method.

Example 1 (1) Production of tetra-N-ethoxycarbonycin to kanamycin (Step 1) Kanamycin A sulfate 407 was dissolved in a mixture of 400 d of 2 N -NaOH aqueous solution and 200 ml of methanol, and chlorocarbonate was added to the solution. 69 ml of ethyl was added dropwise, and the mixture was stirred at room temperature for 4 hours. The precipitate was filtered, washed with water, and then dried. Yield 45.7 r (86%) rn, p-26
6-26'/ OC (decomposition) 5 [α) 9 +4L3° (c O, 5, DMF) Elemental analysis Calculated value (C3oH52N401.): C46-6
2, H6, 80, N 7.25% Fire 41 [(Value: C
45-92, H6,79, N 7.05% (2) Hexa-benzoyl-tetra-N=ethoxy Production of carbonyl kanamycin A (Step 2) Tetra-N-ethoxy obtained in Ailtsu 1 (1) Carbonylkanamycin A 7.731 pyridine 200 ml
12.2 ml'7 of benzoyl chloride was added to the solution, and the mixture was left to stand at 5°C overnight to perform O-benzoyl A. water ml
After adding, the bath Jt was reduced and distilled off, and 300 ml of ethyl acetate was added to the residue, washed with water, then with saturated sodium bicarbonate solution, and finally washed with water twice to obtain IL2. The organic layer was dried with sodium sulfate, mixed, and evaporated under pressure to give the title compound + 3.6 r
(97,3zou) Ihii 4pihi.

rrt-p・195-215 cc 5 [αJ o +l OO' 70(co, 9, cH
CA3) Elemental analysis Calculated value (C, 2H76N40.
): C6+, 87. H5,49,N 4.01%
Actual measurements: C61.7g, H5.42, N 3.87
Candy (3) 3', 4', 2〃, 4', 6I!
-Benku O-benzoyl-tetra-N-ethoxy force A yK Formation of nyl-kanamycin A (compound ■) (
Step 3) Replace 427 of the generated ψ in the previous section (2) with birinone 60 rnl
! Hydrazine hydra in a solution dissolved in water) 0.48
rnIV= was added, and the mixture was allowed to stand overnight at room temperature to carry out a reaction in which the 2'-0-benzoyl group was selectively eliminated. After adding 2 ml of acetone, the solvent was distilled off under reduced pressure, and 150 ml of ethyl acetate was added to the residue. After washing with water, IN-KE(
It was washed with an aqueous So4 solution, then with a saturated aqueous sodium bicarbonate solution, and finally twice with water. The organic layer was dried over magnesium sulfate and the temporary solvent was distilled off under reduced pressure to obtain 3.81 of a crude substance. This was purified L7 by silica gel (75y) chromatography, the title substance 2.6 f? Waiting for (67 copies) 1, m-p 19
3~202clc Original yarn analysis calculation 1L1'1 (C6, ■l72N4024
): C60,35, H5,62, N 4.33 Bullet'6 (11 value: C59□41. H5,5+, N 4
．． 32% (4) 3', 4', 2'', 4'', 6〃-penta-〇-pensoyl-2'-〇-methylsulfonyl-
Tetra-N-Shi★Boethoxical TJ? Production of Nilkanamycin A (Compound [II) (Step 3) The chemical compound (3, Og, 2.32 mmol) from page 1 (3) was dissolved in 1'1 horn (30 ml), and mesyl chloride ( 0.63me, 8.08 mmol) and stirred at room temperature for 1 hour. After adding water (0,211174), the solvent was distilled off under reduced pressure and the residue was dissolved in ethyl acetate.
Dissolves in d.

This was washed with water (507xl) and saturated sodium bicarbonate water (50me).

After washing with water (50y, zx2), it is dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. The resulting composite τ1 was purified by full silica chromatography (Wakokel C
-20060P, CI (C7!3: CH3
0I (=50:1) gives the title compound (2,98?,'
73.7chi) is obtained.

m-p・167~+78CC [α'lI24+101-70(c 1.0.CHC
l) 3 NPa (coci3) δ: 2.7 (3H2S, -
8O2CH3)7-2~F3-2 (25H, rn.

CHCO-) 5 Elemental analysis (C66H74N4026S): Calculated value C5
7,79,H5,45,N 4.0? , 82.33%
Actual value C57, 82, H5, 44, N 4.01.3
2.39% (5) 2',3'-anhydro-4'+
2'+4".

6”-tetra-0-benzoyl-2′-epi-tetra-
Formation of N-ethoxylic acid A-bonylkanamycin (compound ■) (Steps 5-6) Preparation of the compound (2J 4 f, 2.07) of the compound (4) in the previous section
mmol), methanol (60 mmol), dioxane (
Sodium methylate (28 methanol solution, 4 m, 20.7 mm/L-
) and stir at room temperature for 18 hours. IN- under water cooling
After neutralization with hydrochloric acid, the solvent is distilled off under reduced pressure. The residue was dissolved in birinone (1004p) and pencey chloride A (2
, 5 ml = 21.5 mmol) and stirred at room temperature.
Worship 4n for 0 minutes. After adding water (0°5d), the solvent is distilled off under reduced pressure and the residue is dissolved in ethyl acetate (70mi). After washing this with water (50rn1.
Dry with magnesium sulfate. The solvent was distilled off, and the resulting residue (2,42y) was subjected to silica gel chromatography (Wakoglu C-20050?).

When separated and purified with CHCl3:CH30H250:l), the title compound PV(+, 98 r, 82
% ) Kai f17'v.

m-p-133~146cC: [α) 20+ 74.5° (c 1.0. CHC7)
3 Elemental analysis (C58■ (S6N4022) 't1 calculation ijH'!, C59,47,H5,69,N
4.78% sharp 1 value C5'? ,66, H5,7
+, N 4.56 section (6) 4', 211.4
n, 6tt-tetra-O-benzoyl-3'-deoxy-2', 3'-di-ebi-37-yotothitra-
Production of N-ethoxycarzdib kanamycin A (compound V) (step 7) Compound Iv of the previous section (5) (1,851i', 1.
58 mmol) in acetone (45d), sodium iodide (+,36t, 9.07 mmol),
Acetic acid (1,26 rrt) was added, and the mixture was allowed to react under stirring and reflux for 8 hours. After cooling, the solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate (70*g). Wash this with water (
50ix2)t, dry with magnesium sulfate. The residue (2,Of) obtained by distilling off the solvent was subjected to silica gel chromatography (Wako Vh C-20050 H).
Separation and purification with CHCl3:CH30H245:I) gave the title compound V (1,541,75%).

m, p, 150-155°C 0 [α:], +33.0° (cO, 8, CHCl3) Original thread analysis (C58H67N40° 2nd process) Calculated value C53,6
1, H5, 2+, N 4.3+, I 9.78 chili 6i11 value C53, 46, f (5, 20, N 4-2
3. I 10.01% (force 4', 2", 4"
, 6-tetra-0-benzoyl-2',3'-nobuoxy-2'-enotetra N-ethoxycart? 2A
7 Production of kanamycin A (compound ■) (Step 8) Compound V (+, Or, 0677 mmol) from the previous section (6) was dissolved in pyrinone (20 mb'), and 4-dimethylaminopyridine (90 my, 0.74 mmol) was dissolved in pyrinone (20 mb'). mmol),
Triethylamine (1rne), mesyl chloride (0,3d
, 3.8 mmol) and stirred at room temperature for 5 hours.

This was poured into ice water (50 mA), and the precipitate was dissolved in ethyl acetate/
Extract with L-(70♂E). The organic layer was washed with IN-potassium hydrogen sulfate solution (50 mlV) and water (50 aJ).

After washing with saturated sodium bicarbonate solution (50 d) and water (50 d×2), drying with magnesium sulfate. The residue (0.85F) obtained by distilling off the solvent was subjected to silica gel/L-chromatography (Wakoglu C-20020f, CHCl3-
Separation and purification using C1 (30) (50:1) gave the title compound (0,65yI 73).

m, p, 151-158oC (dec) [α] 22
+ 77.5 (c O, 8, CHC/ ) 3 Elemental analysis (C58■66N4021) Direct calculation
C60, 30, H5, 77, N 4.85% Actual value C60, +1. T(5,76, N 4.gO%(
Production of 812',3'-dideoxy-2'-enokanamycin A (compound qpl ■) (Steps 9-10) Add (500 kg, 0.43 mmol) of compound ■ of the previous section (7) to methanol (+oy). Dissolve, add sodium methylate (0.3 d of 28% methanol solution, 1.5 mmol), and let stand at room temperature for 30 minutes.

The solvent was distilled off under reduced pressure, and water (5 rne
) + Add sodium hydroxide (1,52). This was stirred at 100°C for 3 hours, left to cool, and water (Ioom
l) and neutralize by adding concentrated hydrochloric acid. This is Amberlite CG-5Q (N'H type 20 m1.0.3 N
-Aqueous ammonia solution) to separate and purify the title compound■
(135 so, 70 fi) was obtained.

m, p, 165-173'e [α] p +l C6' 40 (c 0.7, H2
O) NMR (D20) δ: 6.00 (IH, d,
J = 1OHz, 3'-H).

5.82 (HI, m, 2'-H).

5.43 (IF(, m, , l/-4).

5.00 (IH, d, J=4Hz, l//-H
, ) 3.45 (H(, q, J = 4.” 1O
Hz H-2.

2.96 (IH, t, J = l0Hz, H-3
”) Elemental analysis (C18H34N4o9・H2O) Calculated value C46°+4.) I 7.76, N 11.96
Chu actual measurement i' C46-25, H7, 77, N 11
．． Article 82 (9) Production of 2',3'-dideoxykanamycin A (compound ■) (Step 11) Dissolve (100 to 0.22 mmol) of compound ■ in the preceding paragraph (8) in water (5♂E). Then, platinum oxide (10W) was added and catalytic reduction was carried out at room temperature and under normal pressure for 3 hours.

Insoluble matter - 2 units removed, p liquid removed) eG-50+ (NHfill 3 m1. 0.3 N -77 mo =
7 water)" tl f-1, the title compound (84 rng, 83%) was obtained.

m, p+ 148-1620c 3 [α] D +' l 4 o (c l-0, water) 13
C-NMR (D20, PD Iof measurement):
1"-CIoo, 9 Cpprn) l -C51,
4+'-C9g, 8 3-C50, +6-C88
, 86-C42, 6 4-C86, + 2-C36, 55-C75,
63-C29,3 5-C73,02-C26,8 2"~C724 51/-C72,7 4"-〇 70.2 4-C67,7 6-061,1 3-C55,1 Example (1 ) 6'-N-pennoloxycarbonyl-4"
, 6"-0-benzylidene-1,3,3I'-triN
-) Production of zircanamycin A (compound
3) 6'-N-hensyloxycarbonyl-1,3°3"-
Treat silkanamycin A (compound 仄) with Carbo
Hydrate Re5earch, Volume 89q+ -
lot, n981) from kanamycin A by the method of
was dissolved in 88 g of anhydrous N,N-dimethylformamide (open IF), and 0.8 g of benzaldehyde trimethylacetal was dissolved in 8 g of anhydrous N,N-dimethylformamide (open IF).
27aε (1.2 molar ratio) and 55 m7 of paratoluene/12-phonic acid hydrate were added and reacted at room temperature. After 7 hours, benzaldehyde dimethyl acetal O,I3m
(0.6 molar ratio) was added. After 30 hours, the mixture was poured into 320 rnl of ice-cold saturated sodium bicarbonate water. The resulting scuttling was collected with P, washed with water, and further treated with ethyl ether A.

The resulting material was dried at 1.60 f (7
) i The title compound X was obtained as a yellow solid.

6 [α]-22° (c O = 5. Tetrahydrofuran) Elemental analysis value Calculated value as C54H64N4019S3
C55,47, To I 5.52. N 4.79. S
L23% actual measurement value C55, 30, H5, 49, N 4
．． 84. S 8.28 (2+ 4〃,6〃-0-benzylidene-6'-N:4'-0-carbonyl-1,3
, 3"-tri-N-tosylkanamycin A (compound, N) production (step 4) 4.65 r (3,98 mmol) of compound X from the previous section
was dissolved in 93 dV of anhydrous DMF, 1.72 f of 50% oily sodium hydride (9 times moA) was added under an OOC/nitrogen atmosphere, and the mixture was reacted at 00 G for 1 hour with vigorous stirring, and then further heated at room temperature. The reaction was allowed to proceed overnight.

25 thiacetic acid water under 00C 14. ．． 8ml! (NaH
1.7 times mo/L-) was added thereto, and the mixture was concentrated under reduced pressure. Water was added to the residue, and the formed solid was collected, washed with water, and dried. After further washing with ethyl ether, it was dried to obtain 3.97 r of the title compound X〇〔α〕 -43° (c 1.0. Acetone) Elemental analysis value 047F■56N4o18s3 Toshite calculated value C53
,20,H5,32,N 5.2L S 9.07% Actual law value C52,85,H5,39,N 5.26
．． S 8.81(3) 4〃, 6'-0-benzylidene-6'-N;4'-0-carbonyl-2',
3'-cyclohexylidene-1,3,3''-triN-
Production of tosylkanamycin A (compound XII) (step 5)
) 3.977 (3,74 mmA) f of compound X in the previous section
Dissolve in 20 ml of 7k-free DMF and 400 ml of anhydrous isochloromethane. I, I-dimethoxycyclohexane I O-8r4 (20 times (le)? Add, 10 minutes m
1. After heating to reflux, trifluoroic acid 112. ＋vr
(5 times the amount of A-) was added, and the reflux was continued for 6 hours with a device that inserted molecular sieve 5A during the reflux.

After the reaction, the vacuum was removed, the residue was dissolved in ice-cooled saturated sodium bicarbonate solution '7 A7, and the resulting precipitate was poured into a solution. Wash this precipitate thoroughly with L ether and then water,
Dry the title compound X as a pale yellow solid, 4.
152 profit/and.

[α]-33° (c 0.6.77 tons) Elemental analysis value Calculated value as C63H64N4018S3 C55,
7g, H5,65, N 4.9+, S L43% actual value C55,47, T (5,77, N 4.88.
S g, 3゜(4)2"-〇-acetel-4" 6y-
. -Benzylidene-6'-N;4'-Q-carbonyl-2',3'-0-cyclohexylidene-1,3,
3I'-tri-N-) Production of silkanamaicif A (compound X []) (Step 6) 5.26y (4.6 mmol) of the compound , dissolved in OOC
4.8 d (10 times the mole) of acetic anhydride was added thereto, the temperature was returned to room temperature, and the mixture was allowed to react overnight. The reaction solution was poured into a large amount of saturated aqueous sodium bicarbonate solution, and the resulting white precipitate was separated and dried to obtain a crude product of 5.522. This was subjected to silica del chromatography (Fucoglu C-200, developing system,
Chloroform:acetone-10°7→10:8→10:
9) to give the title compound XJII of 3.51 ii' as a glassy solid. 〇[α]+40° (c 1.0. Acetone) Elemental analysis value C55T (calculated value as 66N4°19S3 C55
, 82, r-I 5.62. N 4.73. S8
．． +3 Chuu j1 Kawabiki:'j C55, 47, H5
,75,N 4.75. S 7.92(5)
2"-〃-acete, -4〃,6/7-Q-benzylidene-6"-N;4'-0-carbonyl-1,3,3"
-) Lee-N-) Zirkanamycin A (Compound XIV)
Production of (Step 7) Compound X [[1 of 1.88fi'(+, 59mi1
80% acetic acid water 38. After stirring the suspension vigorously, the reaction was carried out at 400C for 3.5 hours. The reaction solution was poured into Oma's saturated aqueous solution of hydrogen carbonate, and the resulting precipitate was collected with P and washed with water. , and dried to obtain 1.44 ft' of crude product 3. This was subjected to silica gel chromatography (Wako Kel C-200+ (Ez open group chloroform: acetone - 1:1 → 1:2 → acetone)
The title compound xIV O,'79f was obtained as a glassy solid.

3 [α] -8° (c 1.0. Acetone) Elemental analysis value C49H58N4019 Calculated value as S3 C5
3,35, f-I 5.30. N 5.0g, 88
．． 72% actual value C53, 34, H5, 21, N 5.
13. S 8.66f6) 2"-0-acetel-4", 6"-〇-benzylidene-6'-N;4'-0-
Production of carbonyl-2',3'-di〇-trifluoromethinosulfonyl-1,3,3''-triN-tosylkanamycin A (compound xV) (Step 8) 887■ of compound I7.7
The mixture was dissolved in a nitrogen atmosphere, anhydrous trifluoromethanesulfonyl, 1-13d (8.4 times the mole ratio M 1.i) was added, and the mixture was reacted for 4 hours in OOC. The reaction solution was cooled with water (7 liters of saturated sulfur/lium aqueous solution
ζ Pour in, drain the soaked water, wash with water, dry 1.
The title compound Xv of 01 f was obtained as a pale yellow solid.

[α]-32° (c 1.Q, acetone) Elemental analysis Calculated as C51H56N4023S5F6 C44,80,TI 4.13.
N 4.10. S 11.73%'p
1111J% C4494, H4, 32, N
4.21. S 11.42(7) 2”-0
-acetyl A, -4/l, 6 // -Q-henzylidene-6'-N;4'-0-carbonyl-2',
Production of 3'-dideoxy-2'-dino-1,3,3〃-triN-)zircanamycin A (Compound XVI) (Step 9) 60rrtg of Compound , 9η(7
Double mono Ic nozk DP/TF l, 2 ml
The reaction was carried out for 45 minutes while stirring vigorously at 100°C. (It becomes homogeneous in 1 to 2 minutes.) Add 12 chloroporum to the reaction solution while it is hot, remove the organic layer and concentrate under reduced pressure to obtain a residue. This was extracted with chloroform, and the chloroform layer was sequentially extracted with 0.1M The mixture was washed with an aqueous sodium thiosulfate solution, a saturated aqueous sodium bicarbonate solution, and water, dried with sodium sulfate, and concentrated to dryness to give 47 quartz of the title compound as a glassy solid.

(8) 2〃-0-acetyl-4/J, 6〃-0-
Benzylidene-6'-N;4'-0-calr)? Preparation of Zilkanamycin A (Compound ) 2 m, hydrogen pressure 3 kg / (y
The catalyst was activated by shaking for 30 minutes under n. Add 1009 of the compound xXq from the previous section to this, and reduce the hydrogen pressure to 3.
The reaction mixture was shaken under 5 kg/a'' of water and allowed to react for 45 minutes. The reaction solution was filtered, and the filtrate was concentrated to dryness to obtain 96 mg of the title compound as a glassy solid.

[α]+10° (c 1.0. Acetone) Analyze the original Da'lI! AC4,■58N4017S3W h
Ii+lCc 54.94. H5, 46, N
5.23. S 8.98 %'#'/+riii
7q C54,58,1 (5,54,N 5.
02. S 8.70(9)4"6tt-o-benzylidene-2',3'-dideoxy-1.3.3
”-Production of Kanamycin (Compound X) (Step 11) Add THF-3N to 178 mg of Compound
-NaOH (2: l) 3.6 me was added (2
become layers. ) The reaction was stirred at 5o0C for 2.5 hours while stirring. The reaction solution was concentrated under reduced pressure J2, and the residue was DOWEX 50.
WX2 (IJH type) Lennon l Ome, Tutanoh/
Expand with L-3N ammonia water (2:l)? ] L-,
The eluted active portions of ninhydrin were combined and concentrated to dryness to yield the title compound Xl'l! 166.7~ was obtained.

(Production of 1υ12',3'-nobuoxykanamycin A (compound VnT) (Step 12) Preparation of compound Xv
if ノ166-7 rrq f -500C(7)
Dissolved in 15 g of liquid ammonia and 0.0 g of metallic sodium.
After adding 22 and standing for 1 hour, THF water containing 1% water was added to the reaction solution to remove residual sodium, and the temperature was gradually raised to room temperature to distill off ammonia. The residue was packed into a DOWEX 50WX2 (ten dish type) resin column and eluted with IN aqueous ammonia, and the ninhydrin active portion was collected and concentrated to dryness to obtain 63.4 mg of the title compound.

[α]ゎ+114° (Cl・0.water) Melting point 148~+62oc Elemental analysis value Cl8H36N40.・Calculated value as H2O C44,35, H4,44, N 10.89% Actual value C44,08, H7,33, N 10.72 pages, So-Chromatography (Toyo p paper A50゜Ptanono L-:Viridine: Water: Acetic acid = 6: 4:
Rf kanamycin A2.0 using a 3:1 descending method (64-hour development).

Claims (1)

[Claims] 1.2',3'-dideoxykanamycin A or an acid addition salt thereof.