JPS59172498A - Novel method for producing 1-n-(alpha-substituted-omega- aminoacyl)-3'-deoxy-5-o-pentofuranosylneamine derivative - Google Patents

Abstract

NEW MATERIAL:A compound of formula I [R7 is OH, NH2 or NHR8 (R8 is acyl); n is an integer 1-4]. EXAMPLE:1-N-[(S)-4-Amino-2-hydroxybutyryl]-5-O-(5-amino-5-deoxy-beta-D -xylofuranosyl)-3'-deoxyneamine. USE:An antibiotic substance effective against germs resistant to chemicals, particularly ''Kanamycin''. PREPARATION:A compound of formula II [Y is a group of formula III (R1 and R2 are H, alkyl or aryl), cycloalkylidene, etc.; Z is alkoxycarbonyl, acyl, etc.] is reacted with a compound of formula IV [R3 is acyl, aroyl, etc.; X is halogen, acyl or aroyl; W is OSO2R' (R' is alkyl, etc.)], etc., and the resultant reaction product is then hydrolyzed, sulfonated and converted into an azide to cleave the carbamate ring. The resultant compound is reacted with an amino acid compound to form a compound of formula V, which is then reduced.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides /-N-(α-substituted-ω-
The present invention relates to a novel method for producing 7-lanosylneamine derivatives (aminoacyl)-3'-deoxy-j-〇-bento.

The present inventors have investigated whether WFC drug-resistant Durham-negative bacteria, resistant Staphylococcus aeruginosa, and Pseudomonas aeruginosa isolated from patients have a hydroxyl group at the 3' position of kanamycin. It was discovered that the phosphorylating enzyme is fully produced, and that this enzyme has a resistance mechanism that inactivates kanamycin and kanamycin Bi (Science/J7, Vol.
/J,! ; Y page/re 27 years).

Based on this resistance mechanism, we began the synthesis of an antibiotic that is effective against kanamycin-resistant bacteria.
(Tokukosho!/-3310 de); 3','I'-dideoxykanamycin B (hereinafter referred to as DKB) (Tokukosho!
0-7. ! ;9. No. S), 3'-deoxykanamycin B and 8'-deoxylidestamycin (Special Publication Sho S7-
was synthesized.

These deoxy derivatives exhibit strong antibacterial effects against the above-mentioned resistant bacteria, and the clinical effects of DKBK have already been confirmed. Furthermore, they found that a small number of resistant Durham-negative bacteria (R factor E. coli) isolated from patients produce an enzyme that inactivates kanamycin and DKB by nucleotidylating the 2'-hydroxyl group (Journal Op.・
Antipiotics, vol. +23, p.2 Geta, /97.2). Therefore, the present inventors considered the molecular model of kanamycin and decided to create a derivative that does not undergo this enzymatic reaction by modifying the amine group at position 7 of kanamycin group antibiotics to create a steric barrier. Are you researching yuzu derivatives that you think can be made? went. And /-N-(Q-aminocohydroxybutyryl)-DKB (Tokukosho, f
2-. 3.3A2Y), /-N-(4t-aminocohydroxybutyryl)-kanamycin (JP-A-Sho Q9-
91764'za No.), /-N-inseryl-kanamycin (Special Publication Showa SS-1, 2031 No.), sequence fc/-N-
Isoseryl-kanamycin B and/-N-inseryl-DKB [Tokukosho, t, No. S-3/79♂] etc.? Synthesized.

Furthermore, the present inventors found that both the 7- and co'-position amine groups of kanamycin B or DKB have the general formula H2I(-(OH2)n
Kanamycin B derivative acylated with α-hydroxy amino acid represented by -0H(OH)-000H has antibacterial properties that are strong against not only kanamycin-susceptible bacteria but also various resistant bacteria including Pseudomonas aeruginosa. It was confirmed that the substance has low toxicity. These derivatives are chemically derived substances based on the elucidation of the resistance mechanism of aminoglycoside antibiotics and the study of the relationship between activity and structure, as described above.

Furthermore, the present inventors have previously synthesized /-N-(α-substituted-ω-aminoacyl)-31-deoxylidestamycin! rA;-33A; No. 7 and JP-A-Sho J/-/,
No. 2704t). The present invention differs from these inventions in that /-N-(α-substituted-ω-aminoacyl)-! −
New compounds in the form of deoxy, S -O-hentofuranone reneamine derivatives? The present invention provides a method for manufacturing. That is, in the present invention, it was discovered that the amino group at the 7-position and the hydroxyl group at the 2-position of 8'-deoxyparomamine or 3'-deoxyneamine combine with each other to form a j-carnomate ring. Furthermore, the hydroxyl group at tel, 61 or these hydroxyl groups and the amino group easily react with a protecting reagent to form a protected and occluded form, and only the hydroxyl group at position 9.3 can be selectively liberated. , by reacting pentose halide or its active form at the / position, the 8'-
A bond occurs between the 5-position of the deoxyparomamine or al-theoxyneamine moiety and the 77-position of the pentose, s, i'
- discovered that the bond is generated 0 Furthermore, the above /,
When a z-carbamate compound is hydrolyzed under alkaline conditions, the -carnomate ring specifically decomposes and the amino group at position 7 is released, and at this time, other protective a, the protecting group is not removed from the amino group that has been
In addition, when the free amino group at the 7-position is reacted with an amino acid compound represented by the general formula (Vl) or a functional derivative of its cardixyl group, the amino group at the 7-position is converted to /-N in high yield.
-(α-substituted-ω-aminoacyl). The present invention was completed based on these discoveries.

That is, the gist of the first invention is as follows: or a hydroxyl protecting group representing a cycloalkylidene group, a tetrahydropyranyl group, a caracyl group or a phenyloxyl group; basis,
An 8'-deoxynoglomamine/6-carbamate derivative compound represented by an amino-protecting group representing an alkylsulfonyl group, an arylsulfonyl group, or an aralkylsulfonyl group (4) is combined with the following general formula [wherein is an acyl group or an aroyl group]. , alkoxycaracyl group or acylkoxycarbonyllii! I! :? X represents a hydroxyl protecting group, X represents a halogen atom, an acyl group or an aroyl group, W represents a group -oso2a'(
However, is R' an alkyl group, an aryl group, or an aralkyl group?
) or a pento-7-sinosyl compound represented by a sulfonyloxy group represented by the following general formula [wherein R3 and W have the same meanings as above, and where R4 is an alkyl group or an aryl group? In the expression, 穐 is an alkyl group t
By reacting the bentofuranosyl-orne ester compound tasted in the following general formula [in the formula R3, R4,
Y, Z and W have the same meaning as above]
A part of the hydroxyl protecting group is generated by generating a compound sound and then subjecting the compound to water splitting. After elimination, the following general formula or [where R+3. R4, Z and W have the same meanings as above] to produce a compound represented by the general formula %() [wherein represents an alkyl group, an aryl group or an aralkyl group] , T represents a halogen atom, particularly chlorine or bromine, or a group of 108O2R6 (provided that ~ has the above meaning)] to form 2.
′ position hydroxyl group? Selective sulfonation and further azide compounds? The sulfonyl ester group at the 2'-position is azidated and converted into an I-azido group, and at this time, the sulfonyl ester group (5) at the position is also azidated with the azide compound, and further under basic conditions. Hydrolyzed with /, 2-carnomate ring? The 7-position amine group and the 2-position hydroxyl group are released by cleavage, and this
At the same time, part or all of the remaining human tetraxyl protecting group is removed, and the resulting product has the following general formula % () [wherein R7 is -OH, -NH2 or -NHRg (
provided that R8 is an acyl group), and n is /, 2.
3 or Da, A represents a hydrogen atom or a known monovalent amine group-protecting group, B represents a hydrogen atom or a known monovalent 7-mino group protecting group, or A and B represent an integer of 3 or All in all, a known divalent amino group-protecting group can be used to form an amino acid compound or a reactive rust conductor on the carboxyl group of this n to form the following general formula % formula. % [In the formula, A, B, R7, Z and n have all the same meanings as above, and R3' is a hydrogen atom or 3 (R3 has the same meaning as above!)? Display] and clothe /
-N-acylated compound is formed, and then a 2'-azido group! The following general formula [wherein, R7 and n have the same meanings as above] n/-N-(α-substituted-ω-aminoacyl)-3
A method for producing a '-deoxy-j-0-bento7lanosylneamine derivative is provided.

In the present invention, 7.
For the 1-carnomate compound, the group Y is shame, ■(2
Suitable examples where is an alkyl group are alkyl groups having a carbon number of 1 to 100, such as methyl, ethyl, propyl, isopropyl, butyl.

Suitable examples of R1 and It2 being aryl groups include phenyl group, methylphenyl group, and methoxyphenyl group. Y
A suitable example where represents a cycloalkylidene group is a group having 5 carbon atoms.
-7 cycloalkylidene groups, such as cyclopentylidene groups, cyclohexylidene groups, and cycloalkylidene groups. Further, Y can also represent a tetrahydropyranyl group (0σx), a carzenyl group, or a phenylboronyl group. In addition, Z is an alkoxycartanyl group, especially carbon number/~t
Examples of alkoxycarbonyl groups include methoxycarbonyl group, ethylsulfonyl group, propoxycarbonyl group, inzolopoxycarbonyl group, butoxycarbyl group, and t-butoxycarbonyl group.
Examples of aryloxyrudenyl groups include phenoxycarbonyl group, nononoranitrophenoxycarbonyl group,
When z is an aralkoxycarbonyl group, examples include penzyloxycardinyl group, noξramethoxypenzyloxycarbonyl group, nograethoxybenzyloxycarzenyl group, noξrachloropenzyloxy Carzenyl group, paranitrobenzyloxycarbonyl group are open n1
When Z is an acyl group, examples include an alkanoyl group having from 1 to S carbon atoms, particularly an acetyl group, a propionyl group, a butyryl group, and a valeryl group.When Z is an aroyl group, examples include a benzoyl group, IIFIL when n and Z are an alkylsulfonyl group; In the case of , examples of nomiladolenesulfonyl group,
Examples include an orthonitrobenzenesulfonyl group, a halanidobenzenesulfonyl group, a corner 7-talenesulfonyl group, and an example of the aralkylsulfonyl group is a benzylsulfonyl group.

Examples of pentofuranosyl compounds represented by general formula (n) or (H') include β-D-lyse 7lanosyl derivatives,
β-D-xylofuranosyl conductor, α-L-arabinofuranosyl conductor, s-7 minnow 5-deoxy-β-D
-xylofuranosyl conductors, ie generally pentofuranosyl derivatives.

When 1t3 in the pentofuranosyl compound of general formula (11) or (■') is an acyl group, specific examples include an alkaroyl group having 2 to S carbon atoms, such as an acetyl group, a propionyl group, and a butyryl group. Examples of when R3 is an aroyl group include a benzoyl group, a pacyclobe/zoyl group, and a noranitropenzoyl group. Examples of when OR3 is a phenoxycarbonyl group are an ethoxytridinyl group, Examples of aralkoxycarbonyl groups include t-butoxycarbonyl group and t-amyloxycarminyl group, and examples of aralkoxycarbonyl groups include penzyloxybenzylzenyl group, paramethoxybenzyloxycarzenyl group, and ethoxypenzyloxy. Compounds such as carinyl group and nogurachlorobenzyloxycarbonyl group? I can give it to you.

Examples of W include alkylsulfonyl groups such as methylsulfonyloxy groups, ethylsulfonyloxy groups, benzenesulfonyloxy groups, toluenesulfonyloxy groups, and benzylsulfonyloxy groups, arylsulfonyl groups, and aralkyl-sulfonyloxy groups. Ru.

In addition, as the group X, in particular, a substituent selected from a halogen atom, ie, bromine, iodine, chlorine, and fluorine can be mentioned. Specific examples of R4 in the compound represented by the general formula Examples include n-butyl group and t-butyl group. In this case, the compound of formula (It') is in the form of a /2.2-cis orthoester.

In the method of the present invention, the reaction solvent used when condensing the compound of formula (■) with the compound of (10 or (■)) includes dichlorotetramethane, chloroform, tetrahydrofuran, dioxane, dimethylformamide, dimethylacetamide, acetonitrile, Any solvent inert to the reaction can be used, such as nitromethane, benzene, toluene, ether, etc., mercuric cyanide, mercuric bromide, silver carbonate, oxidation to accelerate the reaction. It is appropriate to carry out the reaction by adding silver, pyridine, etc. The reaction is carried out at a temperature in the range of Q to 10°C, and the reaction time is 0.2 to at hours.

The thus obtained compound of formula (]!D or (1') is
For example, when hydrolyzed under acidic conditions using a hydrous aliphatic cardinic acid such as dilute hydrochloric acid, hydrous acetic acid, or hydrous propionic acid, or under basic conditions using gold such as a limited amount of aqueous sodium chloride hydroxide solution, this hydration Due to the decomposition reaction, MY is removed as part of the human tetraxyl protecting group, resulting in (F) or (
A compound of formula lV'1 is produced.

Next, the compound of formula (IV) or (ff3) is treated with a sulfonic compound (R, aSO2T) of formula (9) to selectively sulfonate the hydroxyl group at the 6I position.

In this case, examples of when the R,,802 group of the compound of formula 9 is an alkylsulfonyl group include a methylsulfonyl group, an ethylsulfonyl group, a flobylsulfonyl group, a butylsulfonyl group, and an arylsulfonyl group. Examples of aralkylsulfonyl groups include gradruenesulfonyl group, orthonitrobenzenesulfonyl group, nocranitrobenzenesulfonyl group, Examples include sulfonyl groups. Also T
10802B, ie, when the closed-type sulfonating agent is in the form of nulponic anhydride, methylsulfonic anhydride and toluenesulfonic anhydride can be used. As the reaction solvent used in this sulfonation reaction, any solvent inert to the reaction such as pyridine, dioxane, methylene chloride, etc. can be used. The sulfonation reaction is generally carried out at −JO°C.

It is carried out in the range of °C. The 6'-sulfonated product thus obtained is reacted with an azide compound to perform 6'-azilation.

Examples of the azidizing agent that can be used at this time include alkali metal azides such as sodium azide and potassium azide, and compounds such as ammonium azide. Solvents that can be used in this azation reaction include dimethylformamide, acetonitrile, dioxane, pyridine, dichlorotetramethane, and the like. At this time, since the sulfonyl ester group (6) is already present at the j″′ position of the above 6′ monoazide, this also undergoes azation, so in the end, the 6′ monoazide
',! #-diazidation main product is obtained.

Thus obtained 41. The 4-carbamate ring is cleaved by hydrolysis of the Jl-diazide product under basic conditions using a basic reagent such as sodium hydroxide, chlorium hydroxide, carbonate, etc. In this way, the amino group at the 1st position and the hydroxyl group at the 6th position are released. During this hydrolysis,

The protecting group B13 at the 3'' and 5N positions may be simultaneously eliminated by hydrolysis depending on the type thereof.

Then, the following general formula (7) HOOO-OH-(OH2)n NAB
(vDl R・7 [wherein R17 is -OH, -NH2 or -NHRs (
However, R and 8 represent an acyl group, particularly a lower alkanoyl group], n represents an integer of l, co, 3, or hiro, and A
represents a hydrogen atom or a known monovalent amino group-protecting group,
B represents a hydrogen atom or a known monovalent amine group-protecting group, or A and B together represent one known divalent amino group-protecting group; When reacted with reactive derivatives such as acid halides, acid anhydrides or N-hydroxysuccinimide esters at the carbonyl group of general formula (2), / -
All N-acylated compounds are produced. Here, general formula (9)
Examples of the α-substituent R17 of the amino acid compound (acylating agent) represented by include a hydroxyl group, an amino group, or an acyl-substituted amino group, such as an acetylamino group.

In the amino acid compound of formula (2), both A and B can be hydrogen, but when each of A and B is a monovalent amino protecting group, it can be an acyl group, an alkoxycarzenyl group, an aralkyloxycarbunyl group, or an aralkyl group. A sulfonyl group or a sulfonyl group is preferred. When A and B together represent one known divalent amine protecting group, it is preferably an alkylidene group or an alkylidene group. Specific examples of the -valent amino group protecting group B include acyl groups such as acetyl, benzoyl and orthonitrophenyl groups; alkoxycarzenyl groups such as tertiary buteroxycarzenyl and tertiary aralkyloxycarcinyl group; examples of the aralkylsulfonyl group include penzyloxycarzenyl group and nozoranitropenzyloxycarzenyl group;
15 methoxybenzyloxycarbonyl group; examples of aralkylsulfonyl group include phenoxycarbonyl group,
Examples of the lower alkylsulfonyl group include a methylsulfonyl group; examples of the arylsulfonyl group include a nozoradolenesulfonyl group; examples of the aralkylsulfonyl group include substituents such as a benzylsulfonyl group.

When the groups A and B are together a divalent amine protecting group, this has the formula < g g > D or -0 HD
(where D is an alkyl group or an aryl group), in the former case, for example, the entire group is a phthaloyl group, and in the latter case, the alkyl group is a methyl group, an ethyl group, Propyl group, butyl group; Examples of the aryl group include substituents such as a phenyl group, a nogramethoxyphenyl group, a nograchlorophenyl group, and a nogranitrophenyl group.

The solvent for this /-N-acylation reaction is water.

Tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, dimethylformamide, dimethylacetamide, propylene glycol dimethyl ether, or a mixed solvent thereof can be used, and a mixed solvent of water and tetrahydrofuran is particularly preferred.

The optimum temperature for the /-N-acylation reaction is below 0.degree. C., preferably below -25.degree. Further, reactive derivatives of amino acids that can be used at this time include acid halides, acid azides, active esters, and mixed acid anhydrides.

Further, the acylating agent compound represented by the general formula (Vl) used in the present invention, that is, the α-substituted-ω-amino acid compound, may be a racemic form or an optically active form, but for example, α
In the case of -hydroxy-γ-aminobutyric acid (when n = 2) and α-hydroxy-J-7 minovaleric acid, 5 is preferred in view of the antibacterial properties of the target product. The obtained /-N-acyl compound vi-1 of the general formula (to) is then treated with hydrogen in the presence of a catalyst selected from iR radium, platinum, Ranetian nickel, rhodium, ruthenium and nickel, or By treating with metallic lithium, metallic sodium, etc. in liquid ammonia, the 31-position azide group of the /-N-acylated compound and! Both '-azido groups are simultaneously reduced to amine groups.

At this time, in the case of hydrogen reduction, at the same time, the amine protecting group Z at the 3°21 position and protecting groups A and B are decomposed by hydrolysis depending on the type (for example, aralkoxycarcinyl group). be separated. As the solvent used in the above-mentioned catalytic hydrogen reduction reaction, a water-water miscible solvent selected from water, dioxane, tetrahydro Z-ran, ethylene glycol dimethyl ether, and propylene glycol dimethyl ether can be used. The conditions for the catalytic hydrogen reduction reaction at this time are hydrogen pressure/-j atmospheric pressure, reaction temperature o-1oooC, reaction time o,
It is time for s-p.

Note that if any amine protecting groups remain in the 2'-7 minated product produced in this step, these remaining amino protecting groups A, B, and Zi are removed, but for example, if the amine protecting group is an acyl In the case of a group, an alkoxycardiinyl group, or a trityl group, it can be eliminated by a conventional method by hydrolysis with a base or an acid. In addition, when the aralkyloxycardinyl group (including the ben-JL-group) still remains as an amine protecting group, a catalyst selected from radium, platinum, Raney nickel, rhodium, ruthenium and nickel is used. It is then reduced and eliminated with hydrogen under the conditions described above.
Radium-carbon is preferred. Furthermore, when the amino protecting group is an alkylsulfonyl group, a 17-ralkylsulfonyl group, or an arylsulfonyl group, it can be treated using conventional methods such as photochemical decomposition, radical decomposition, or alkali metal ('C, for example, sodium) in liquid ammonia. It is removed by treatment, preferably with sodium in liquid ammonia.

The target substance (5) thus obtained can be purified by a chromatographic purification method using CM-Sephadex etc. As an example of the target compound of the method of the present invention, 1-N-(
(8)-F-aminocohydroxybutyl)-!
-o-Cj-amino-deoxy-β-D-xylofuranosyl)-! '-Theoxyneamine is a compound that has antibacterial activity against a wide range of bacteria, including Durham-negative and positive bacteria, and the antibacterial spectra of these compounds are shown in Table 1 below. Minimum inhibitory concentration (M, 1.O,
) (mcf/rILl) was measured at a culture temperature of 37° C. and a culture time of 7 hours; however, in the case of Myco/macterium and Smegmatis, the culture time was at waiting time.

Also, general formula (I) which is a starting material used in the present invention
, [), (XIT) and (XV) are all new substances, and examples of their production methods are shown later as reference examples.

Next, Example 1-λ showing the implementation of the first invention, Examples ≠ to 6 showing the implementation of the third invention, Example 7 showing the implementation of the fourth invention, and Example 7 showing the implementation of the fifth invention. Example 1 showing implementation. −／
2, the present invention will be explained in more detail. In addition, examples of preparation of starting materials used in each example are shown in Reference Examples.

Example 1 (a) 39.2'-di-N-penzyloxycarzenyl-<11.41 Q-cyclohexylitine-3'-theoxyparomamine/, 4-carumate 1.36V (
Refer to Reference Example 1) was suspended in anhydrous dichloromethane, 2jtnt, and 2.62 f of anhydrous calcium sulfate and 2.6 f of mercuric cyanide were added, and then 2,3-di-acetel-j-0-(p- ) luenesulfonyl) -D-xylofuranosyl, promitoko, rit (see reference example λ) 1-
In addition, the condensation reaction was carried out by stirring vigorously overnight. After removing insoluble matter in an oven, the filtrate was thoroughly washed with dichloromethane, the filtrate and the washings were combined, washed with water, dried over anhydrous sulfuric acid, and the solvent was distilled off. The residue was subjected to silica gel column chromatography using dichloroform-ethanol (30:
l) Purified as a fully developed system, j-Q-(2,j-di-O-acetyl-j-O-(p-
) luenesulfonyl)-β-D-xylofuranosyl)-
J, 2'-)-N-penzyloxycarbunyl-
4</, 6/-0-cyclohexylidene-37-zooxyparomamine /, A-force A, pZ me-) /,
2 I t f Obtain 7' IC0 [α] 0 to D+ (CI
, chloroform) Analysis values: OjI, /J, H! , 3? ,N3JJ,
Calculated value (Os > Hst N3019 S): 0
! 1.22. ．． H, tJ4', N 3. Tata, S3.0! Steamed rice (b) Nine substances obtained in the previous section/, Oj? 'i 70%
Dissolve in acetic acid, 6! Heated at ℃ for 2≠ hours. After distilling off the solvent under reduced pressure, the residue was dissolved in chloroform, the solution was washed with water, and then dried over anhydrous sodium sulfate.

The solvent was distilled off, and j-Q-(-2,j-di-0-acetel-j-Q-(p-)luenesulfonyl)-β-D-xylofuranosyl)-3,λI-di-N-penzyloxycal -Nyl-3'-deoxyparomamine/6-carpamate 20 µm was obtained.

[α]F+13° (C/ , chloroform) (C)
The substance obtained in the previous section /,0/f was added to pyridine-20rnl
Dissolve p-)luenesulfonyl and cool to -io°C.
Chloride 6Qη was added and left at the same temperature overnight.

A small amount of water was added and the after-dissolution*i was concentrated to obtain a syrup. This was dissolved in chloroform, and the solution was washed successively with a normal potassium hydrogen sulfate solution, a saturated sodium hydrogen carbonate solution, and water, dried over anhydrous sodium sulfate, and then concentrated to obtain a solid. The resulting material was purified by a silica gel column using chloroform-ethanol (JQ:/) as a developing agent.

j-0-(,2,j-di0-acetyl-j expressed by the following formula
-Q-p-)luenesulfonyl-β-D-xylofuranosyl)-3,a'-diN-)undiloki7carzenyl-3'-deoxy-47-0-p-)luenesulfonylnoξromaminet,tr-cal / mate 7ri got 1 wg next.

[α]■+5°(c' rchloroform) Analysis value: a
5s) t, Hs, 3i, N 3. rti.

5 j, 71% Calculated value (as 0szHs+9Na02tSz): Q
jj, Hiroshi 4. ) l S, 21. NJ, 73°S
Section 5.67 (d) Dissolve the obtained substance j6Jmp'i in anhydrous dimethylformamide//ml in the previous section and add 21 ml of sodium azide.
0■ was added and stirred at 60°C for 6 hours. The reaction solution was filtered, and the p-liquid was distilled off under reduced pressure. The residue was thoroughly washed with water, dried, further dissolved in dioxane, the solution was filtered, and the solvent was distilled off from the furnace solution, yielding the following formula (% ry-deo*cy β-D-xylov 7/sil) -6/
-Azide-3,27-di-N-penzyloxycarynyl-"+"-siteoxynozromamine/, local mate ≠17■ were ipped.

[α]D+1O0 (cl, chloroform) analysis value: 0
! Ko, 30. H! , 22. N/41.66% calculated value (as 03sH<gNsO+s): 0 12) ri,) l j,, 23. N/Hiroshi! 3% (e) 260η of the substance obtained in the previous section was dissolved in 1 volume of dioxane, the solution was heated to 2°C, and 0% was added to the solution. 1 s7I of I N hydroxide solution was gradually added over 2 hours. Carbon dioxide gas was bubbled through the ridge, the precipitate precipitated was filtered, and the filtrate was concentrated to dryness. The resulting solid was dissolved in dioxane, the solution was filtered, and the filtrate was concentrated. The obtained residual liquid is j-Q-(,2,J-di-O-acetyl-j
-azido-yo-deoxy-β-D-xylofuranosyl)
-6'-azido-3,,21-di-N-benzyloxycarbonyl-3t,6t) deoxynoglomamine.

The entire residue was dissolved in 3-tetrahydrofuran, 5olIv of triethylamine was added thereto, and N-hydroxysuccinimide ester of (S)-≠-penzyloxycarzenylamino-λ-hydroxybutyric acid/j7■ was added under ice-cooling.
I let it react over time. After performing the /-N-acylation in this manner, the reaction solution was filtered, the filtrate was concentrated to dryness, the residue was dissolved in chloroform, and the solution was dissolved at 0.0%. Washed with normal potassium hydrogen sulfate solution, then saturated sodium hydrogen carbonate, and dried over anhydrous sulfuric acid.

After filtration, the P solution was concentrated to dryness, and this residue was developed by silica gel column chromatography using dichloroform-methanol (l(7:/)' as a developing system. The desired portion was collected and concentrated to dryness. .

j-0-(j-azido-j-deoxy-β-
D-xylofuranosyl) 6t-azido-/-N-(
(81-≠-benzyloxycarnylamino-2-hydroxybutyryl)-3,,21-di-N-benzyloxycarbonyl-3161-dideoxyparomamine 1
16 mg was obtained. [α]98+/ /” (c/, chloroform) Analysis value: Qj4', jri, Hs, sa, N ia, r0
% calculated value (04sHssNxoC)+s):
c sa, as, Hs, 6i, N ia, 1i4(r
) The friend substance Tata (2) obtained in the previous section was dissolved in dioxanco, 0.1 mtf of water and 2 drops of acetic acid were added, and the mixture was reduced with hydrogen using palladium black as a catalyst. The reaction solution was filtered, and the filtrate was concentrated to dryness to obtain a powder. Dissolve this in water and OM
- Develop cyanmonia water (increasing concentration sequentially to 0, / -0, l/- standard) as a developing agent through a column of Sephadex C-, 2J, and as the final target product.
.

311nff of /-N-((81-guamino-λ-hydroxybutyryl)-j-0-('-amino-j-thioxy-β-D-xylofuranosyl>-Jl-deoxyneamine), which is represented by the following formula, was obtained 1ζ.

[α]π+−2゜(C7, Water) Reference Example 1 (a) / 131-” -) Preparation of Li N-penzyloxycarzenyl J / -theoxyparomamine 3'-deoxyparomamine!, 3 u r 'i was dissolved in water, sodium carbonate was added, and methanol fj, 12 was added with stirring.Benzyl chloride formate (C1000CH20
sH, )"y, ore was added dropwise. After 2 hours, the reaction mixture was filtered, and the filtered solid was washed with water and ether and then dried. ,s
, dioxane).

Analysis value: 0 60.70. HA, 06. N, f,
jp3% calculated value (as CagH<sNaolg):
0 60, ri2. Ht, //, N j, ri+2cI
b(b) l, 31.2'-tri-N-penzyloxycarzenyl-Hiroshi/,6'-0-cyclohexyl-7
Preparation of 1J, +17-3'-deoxynoglomamine Dissolve the tri-N-penzyloxycalse obtained in the previous section (a) in the -7'oxynozoromamine θ-. p-) Luenesulfonic acid 100, /, /-dimethoxycyclohexane Hiroshi-
was added and heated at SO°C for 1 hour.

Most of the solution was concentrated under reduced pressure, and after fc, 60% of the solution was added to this concentrated solution.
After adding jOdf acetic acid and heating the mixture to 3°C for 1 hour, 200q of sodium hydrogen carbonate was added and the mixed solution was concentrated to dryness. Dissolve the residue in chloroform,
After washing this solution with water, drying it with sulfuric acid and concentrating it under reduced pressure to dryness, the following formula 〇H2C'
N) (OOOB ZNHOOOBz
2.79 f of the title compound represented by OH (Bz is a benzyl group) was obtained. [α) ”D +
J i ' (Ctl chloroform).

(C)j,,2'-di-N-penzyloxycarzenyl-F/,4/-o-cyclohexylitine-3'
- Preparation of deoxynoglomamine/6-carbamate The substance obtained in the previous section (b)! -29 was dissolved in 2ml of anhydrous dimethylformamide and added to the oil-based sodium hydride solution.
- Omyf-2jOmyf was added, and the mixture was stirred for 3 hours under ice cooling. The reaction mixture was concentrated by adding Hiromi acetate, and the concentrated solution was poured into ice water. The deposited precipitate was collected, washed with water, and dried. The entire culm of the title substance i and ori was prepared.

[α) +5.2° (cl, chloroform).

Analysis value: OA! , 31. HAJ/, N 6.01%
Calculated value (as 035H411N3011): 0 6
/, 66, HA, 3 Otsu, -N 6. /A% Reference example Coλ, Preparation of 3-diO-acetel-0-(p-toluenesulfonyl)-D-xylofuranosyl bromide/, 2-Q-inpropylidene-j-0-(p -toluenesulfonyl)-α-D-xylofuranose (R,,
A, Le'jene and A, L, R, ayman
d, ``Journal of Biological and Chemistry'' Volume 102, Page 317 (according to the method of 1733) 3.1 → of acetic acid! 37! Dissolved in acetic anhydride 6-
The mixture was cooled on ice, and 2.1 tons of concentrated sulfuric acid was added while ensuring that the liquid temperature did not rise above 75°C. After being left at room temperature overnight, it was poured into about 30 ornl of ice water, and the aqueous mixture was extracted three times with jO-chloroform.

Combine the chloroform solution and the sodium bicarbonate solution.

Subsequently, it was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off. Obtained/, 2. J-)! J-0-acetyl-5-o-(p-toluenesulfonyl)-D-xylofuranose≠, 22 was dissolved in 75 liters of dichloromethane, heated to 0°C, and saturated with hydrogen bromide gas. After standing at 0°C for 3 hours, it was concentrated to dryness to obtain the title bromide compound,
It was obtained as a syrup.

Claims (1)

[Scope of Claims] The following general formula [wherein Y represents the following formula (1 and R2 represent -n-'r:n hydrogen atoms, alkyl groups, or aryl groups] or cycloalkylidene 2 is a hydroxyl protecting group representing a group, a tetrahydropyranyl group, a carbonyl group, or a phenyl/I/boron group, and 2 is an alkylsulfonyl group, an aryloxycarbonyl group, an aralkoxycarbonyl group, an acyl group, an aroyl group, an alkylsulfonyl group , an arylsulfonyl group or an aralki A. It is represented by an amine protecting group representing a sulfonyl group! -deoxyparomamine/, J-carnomate derivative compound has the following general formula) [wherein is an acyl group, an aroyl group, an alkoxyl group, or an aralkoxycarbonyl group], which is a hydroxyl protecting group; X represents a norogen atom, an acyl group, or an aroyl group, and W represents a group -0802B' (however, R
'represents an alkyl group, aryl group or aralkyl group) represents a sulfonyloxy group]
A pentofuranosyl compound or a pentofuranosyl compound of the following general formula [wherein R3 and W have the same meanings as above, skin represents an alkyl group or an aryl group, and horse represents an alkyl group? The bentofucinosyl e-ortho ester compound represented by the following general formula [in the formula 1t3. )14. Y
. A compound which is eliminated and represented by the following general formula [wherein R3, R4, Z and W have the same meanings as above]? This is then converted into the following general formula % formula % () [wherein is an alkyl group, an aryl group, or an aralkyl group 7
In the expression, T is a halogen atom, especially chlorine or bromine, or a group of 10802 (however, R6 has the meaning of iσ)?
A sulfo/coating agent compound? The reaction selectively sulfonates the 2'-position hydroxyl group, and further forms an azide compound? The sulfonyl ester group at the t1 position is converted into a t'-azido group by azidation, and at this time! The sulfonyl ester group (5) at position 7 was also converted into azide with the azide compound, and further under basic conditions 7
1[]Water split/fucarnomate ring? By cleavage, the amino group at position 97 and the hydroxyl group at position 3 are liberated, and at the same time, part or all of the remaining hydroxyl protecting group is released. The product is treated with the following general 2H
OOO-CH(OR2)n NAB (VD [wherein R7 represents -OH, -NR2 or -NHR++ (however, horse is an acyl group)?, n represents an integer of /, 2°3 or more, A represents a hydrogen atom or a known monovalent amino group-protecting group, B represents a hydrogen atom or a known monovalent amino group-protecting group, or A and B are both V
C is coated with one known divalent amino group-protecting group]
The following general formula [wherein A+ Bt k t Z and n represent the same meanings as above, and presently represents a hydrogen atom or Rs ( R3 has the same meaning as above) /-N-acylated compound? and then a 2'-azido group! - reduction of the azide group to convert it into an amine group, and at the same time or after that, the remaining protecting group must be eliminated? The following general formula [wherein and n have the same meaning as above] /-N-(α-substituted-ω-aminoacyl)-! -Deoxy-j-0-bentonolanosylneamine derivative manufacturing method.