JPS63218693A - 3-demethoxy-1,4-diaminocyclitol antibiotic analog and production thereof - Google Patents

Abstract

NEW MATERIAL:A compound shown by formula I [R<1> is azido or amino; R<2> and R<3> are H or bonded to form diisopropylidene; R<4> is H or benzyl; R<5> is H or (substituted) glycycl]. EXAMPLE:1L-( 1,6/2,3 )-6-Amino-1-O-( 2,6-diamino-2,6-dideoxy-alpha-D-allopyranosyl )-3-glycinamido-3-N-methylcyclohexan-1,2-diol. USE:An antibacterial agent. PREPARATION:A compound shown by formula II (Bn is benzyl; MBn is p- methoxybenzyl) is treated with a dehydrating agent and then with a reducing agent to give a compound shown by formula III.m This compound is treated with hydrogen azide/triphenyl-phosphine/azodicarboxylic acid diethyl ester, the reaction product is catalystically reduced, further successively reacted with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, oxidizing agent, methylamine, benzyl carbonylglycidyloxoysuccinimide and then hydrolyzed with an acid and catalyti cally reduced to give a compound shown by formula IV.

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a novel 3-demethoxy-1,4-diaminocyclitol antibiotic analogue and a method for producing the same.

[Background of the invention]

1.4-Diaminocyclitol antibiotics have strong antibacterial activity against Gram-positive and -negative bacteria, except for phlegmatic bacteria. An example of this group of antibiotics is Istamycin A (Istamycin A).
ycin A) is known.

N.H.

Istamycin Δ It is also known that the amino group at the 1st position and the acylated N-methyl group at the 4th position are essential for the antibacterial properties of this type of antibiotic. Research is being actively conducted to develop derivatives with broader and stronger antibacterial properties and fewer toxicity and side effects (Yomaki et al., "Development of 1,4-diaminocyclitol antibiotics," Organic Synthetic Chemistry, Vol. 40. No. 10 (
1982), 902-911).

The present inventor further enhanced the antibacterial properties of istamycin A,
As a derivative with less toxicity and side effects, we designed a model compound represented by the following formula: %Formula% in which the OCH group at the 3-position, which is considered not to directly contribute to antibacterial properties, was removed, and conducted synthetic research on it. went. The present inventor previously discovered a method for converting methyl maltoside derived from this raw material into a cyclohexane derivative during research on the synthesis of the above-mentioned model compound using 1,6-anhydromaltose as a raw material (Kuzuhara et al. Agricultural Biological Chemistry (＾gric,
Bio1. Chem, ), 45.301-304 (1
981)). However, this series of methods involved complicated operations and poor yields. Therefore, we investigated a method to obtain a glycosylcyclohexane derivative via a thioglycoside using a 1,6-anhytromaltose acetyl derivative as a raw material, and found that 2,6-diacid 2°, which can be a useful intermediate for istamycin A derivatives, was developed. Established a 6-sibuoxyallopyranose derivative and a method for producing the same (see Japanese Patent Application No. 60-277678) [Object of the Invention] An object of the present invention is to provide the above-mentioned model compound and a method for producing the same. .

[Structure of the invention]

The present invention provides a 3-demethoxy-1,4-diaminocyclitol antibiotic analog represented by the following general formula (I).

R'OR' (wherein R' represents an azido group or an amino group, R2
and R3 represent a hydrogen atom or jointly represent a diisopropylidene group, R4 represents a hydrogen atom or a benzyl group, and R5 represents a hydrogen atom, a glycyl group or a substituted glycyl group. ) The above compound is, for example, the compound (1) represented by the formula (1): (wherein, Bn represents a benzyl group and MBn represents a p-methoxybenzyl group) by treating the compound (1) represented by the formula (1) with a dehydrating agent to obtain the formula (2).
Compound (2) represented by : was obtained, and this was treated with a reducing agent to obtain compound (3) represented by formula (3): This was treated with hydrogen azide/triphenylphosphine/diethyl azodicarboxylate. The compound (4) represented by the formula (4) was obtained, and this was catalytically reduced in the presence of a hydrogenation catalyst to obtain the compound (5) represented by the formula (5). The compound (6) represented by the formula (6) is obtained by treatment with dichloro-5,6-dicya-1,4-benzoquinone, and the compound (7) represented by the formula (7) is obtained by treating this with an oxidizing agent. This is reacted with methylamine to obtain a compound (8) represented by formula (8): This is reacted with benzyloxycarbonylglycyloxysuccinimide to obtain a compound represented by formula (9): (9) was obtained, which was acid-hydrolyzed,
It can be further produced by catalytic reduction.

The starting compound (1) of the present invention can be synthesized, for example, as follows.

Maf, 1,6-anhytromaltose acetyl derivative, i.e. 2,3-di-O-acetyl-1゜6-anhydro-4-0-(2,3,4,6-0-tetra-O-acetyl-α -D-glucopyranosyl)-β-D-glucobylanose was deacetylated by treatment with sodium methoxide in methanol, followed by dimethylformamide (DM
In F), p-) is reacted with 2,2-dimethoxypropane in the presence of an acid catalyst such as luenesulfonic acid, camphorsulfonic acid, or methanesulfonic acid to obtain a 4,6-impropylidene compound.

This was dissolved in pyridine at 1,3-dichloro-1,1°3.3
-1,6-anhydro-2,3-di-0-acetyl-4-0-C4, by reaction with tetraisopropyldisiloxane and then acetylation by adding acetic anhydride.
6-〇-isopropylidene-2.3-di0- (1,
1,3,3-tetraisopropyldisiloxanyl)-α
-D-glucopyranosyl]-β-D-glucobylanose is obtained. This was treated with tetrabutylammonium fluoride, potassium fluoride, etc. in acetonitrile, and 1.1
, 3.3-tetraisopropyldisiloxanyl (TIP
S) The group is removed to obtain a compound. This is dissolved in pyridine, and methanesulfonyl chloride, methanesulfonic anhydride, etc. are added to obtain a 2,3-di-O-methanesulfonyl compound. This was treated with sodium methoxide in dichloromethane to produce 1,6-anhydro-4-0-(2,3-anhydro-4,6-0-isopropylidene-α-D-allopyranosyl)-β-D-glucose. get.

This is treated with benzoyl chloride, benzoic anhydride, benzoylimidazole, etc. in a mixed solvent of dichloromethane and pyridine to obtain a 2-0-benzoyl compound. This is dissolved in toluene, tetrabutylammonium hydrogen sulfate, benzyl bromide, benzyl chloride, benzyl triflate, etc. are added, and an aqueous sodium hydroxide solution is added and stirred to obtain the 3-0-benzyl compound. Dissolve this in toluene, add tetrabutylammonium hydrogen sulfate and p-methoxybenzyl chloride or p-
Methoxybenzyl bromide is added, and then an aqueous sodium hydroxide solution is added and stirred to obtain 2-0-p-methoxybenzyl compound. This was dissolved in a mixed solvent of methyl cellosolve and water, and ammonium chloride and a metal azide such as sodium azide, potassium azide, lithium azide, etc. were added, heated and stirred, and 1,6-anhydro-3-0- Benzyl-2-0-p-methoxybenzyl-4-〇-(2-
Azido-2-deoxy-4,6-0-isopropylidene-α-D-altropyranosyl)-β-D-glucobylanose is obtained. This is dissolved in DMSO, acid anhydrides such as acetic anhydride, oxalyl chloride, trifluoroacetic anhydride, and acid halides are added, and after stirring at room temperature overnight, the reaction mixture is poured into ice water and extracted with chloroform. The obtained silica was dissolved in a mixed solvent of methanol and tetrahydrofuran, and added with borohydride while stirring at 0°C. After stirring for 30 minutes, acetone was added and stirring for 20 minutes, and 1,6-anhydrohydride was added. -3-〇-Benzyru 2-
0-p-methoxybenzyl-4-〇-(2-azido-2
-deoxy-4゜6-〇-impropylidene-α-D-
Allopyranosyl)-β-D-glucobylanose is obtained.

This was dissolved in acetone and reacted with 2,2-dimethoxypropane in the presence of an acid catalyst such as camphorsulfonic acid, toluenesulfonic acid, hydrogen chloride, or boron trifluoride.1.
6-Anhydro-3-〇-benzyl-2-0-p-methoxybenzyl-4-〇-(2-azido-2-deoxy-
3,4-0-inpropylidene-α-D-allopyranosyl)-β-D-glucobylanose is obtained. This is reacted with methanesulfonyl chloride or methanesulfonic anhydride in a solvent such as dichloromethane in the presence of a base such as pyridine to yield 6-0-methanesulfonyl compound (A).

At this time, if toluenesulfonyl chloride is used, 6
-0-) luenesulfonyl compound (B) is obtained. When compound (A) or (B) is dissolved in DMF, etc., a metal azide such as sodium azide, potassium azide, lithium azide, etc. is added, and the mixture is stirred at 75 to 80°C for about 4 hours.
-Anhydro-3-〇-benzyl-2-0-p-methoxybenzyl-4-0-(2,6-diacido2,6-sideoxy-3.4-〇-impropyritin-α-D-allopyranosyl)-β -D-glucobylanose is obtained. This was mixed with Zn in a solvent such as 1,2-dichloroethane.
1. . Next, an acetic acid aqueous solution was added, and the mixture was stirred at 60 to 70°C for 2 hours, diluted with water, and extracted with chloroform. The obtained shirabu was mixed with acetone-2
, 2-dimethoxypropane, add an acid catalyst such as camphorsulfonic acid, toluenesulfonic acid, hydrogen chloride or boron trifluoride, and stir overnight at room temperature to obtain phenyl 3-0-benzyl-2-0-p- Methoxybenzyl
4-0-(2゜6-diacido2.6-sideoxy-3
．． 4-0-inpropylidene-α-D-allopyranosyl)-1-thio D-glucopyranoside is obtained. When this is dissolved in dichloromethane-pyridine and reacted with methanesulfonyl chloride by stirring at 0°C for 2 days, 6-0-methanesulfonyl compound is obtained.

Dissolve this in ether etc., LiI, KI, NaI,
A halide salt such as KBr is added and stirred overnight at room temperature under an inert gas atmosphere such as argon. 1. Dissolve the dried sardines in toluene etc. and dissolve 1,8-diazabicyclo(5,4,0)undec-7-ene (DBU), triethylamine, 1,5-diazabicycloC4,3,0E non-5-ene. , a compound (
C) is obtained. Dissolve this in acetone or the like, add an aqueous solution of mercury salts such as mercuric chloride, mercuric acetate, and mercuric sulfate, and stir overnight at room temperature.
,4,5/3)-3-0-benzyl-4-0-p-methoxybenzyl-2-0-(2゜6-diacido2,6-
Sideoxy-3.4-0-inpropylidene-α-D-
Allopyranosyl)-cyclohexanone (I) is obtained.

The reaction of dehydrating compound (1) to obtain compound (2) uses a halogenating reagent such as PBr3, MsCIl,
It is appropriate to use a sulfonating reagent such as TsCII, an esterifying reagent such as acetic anhydride, or a combination of a reagent such as Ph 2 N 2 CO and a base such as triethylamine. The reaction time is suitably 1 to 24 hours, and the temperature is suitably -50°C to 100°C.

The reaction to obtain compound (3) from compound (2) is carried out in a solvent such as tetrahydrofuran (THF) or ethanol in the presence of a reducing agent such as cerium chloride-sodium borohydride, lithium aluminum hydride or its derivatives, or diisobutylaluminum hydride. , -78°C to room temperature, 15 minutes to 2
It is appropriate to do this for 4 hours.

The reaction to obtain compound (4) from compound (3) is performed by adding triphenylphosphine, hydrogen azide benzene solution, diethyl azodicarboxylate, etc. in a solvent such as toluene, and heating at -20°C.
Suitably, it is carried out at a temperature of ~50°C for a period of 1 to 24 hours.

The reaction to obtain compound (5) from compound (4) involves Rh(1!(PPh3)3, Ir(Co)) in a solvent such as benzene.
(PPhs) In the presence of a catalyst such as 3, under a hydrogen atmosphere, 5 to
It is appropriate to carry out the reaction at a temperature of 50°C for 2 to 24 hours.

The reaction to obtain compound (6) from compound (5) is carried out by adding 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) in a solvent such as dichloromethane-water, and
It is appropriate to carry out the reaction at a temperature of 50° C. for 1 to 24 hours.

The reaction to obtain compound (7) from compound (6) is suitably carried out in a solvent such as dichloromethane or DMS○ by adding trifluoroacetic anhydride or the like at a temperature of -78°C to 30°C for 1 to 12 hours. .

The reaction for obtaining compound (8) from compound (7) is carried out using molecular sieves 3A in a solvent such as THF-methanol.

Acetic acid, sodium cyanoborohydride, NaBHl, L
iA17H4, Hz/In the presence of a catalyst such as Pd-C, -78
It is appropriate to carry out the reaction at a temperature of 15 minutes to 24 hours at a temperature of 30 degrees Celsius to 30 degrees Celsius.

The reaction to obtain compound (9) from compound (8) involves using an active ester of glycine with a protected amino group such as N-(N-benzyloxycarbonylglycyloxy)succinimide, triethylamine, and diisopropyl in a solvent such as dioxane. In the presence of a base such as an amine, in an argon cloud, 0
Suitably, the reaction is carried out at a temperature of ~100°C for a period of 1 to 24 hours.

The reaction to obtain compound α1 from compound (9) is carried out by hydrolyzing with 90% trifluoroacetic acid, acetic acid, dilute hydrochloric acid, etc.
It is appropriate to carry out the reaction in a solvent such as hydrochloric acid-ethanol in the presence of a catalyst such as Pd/C under a hydrogen atmosphere at a temperature of 0 to 50° C. for 2 to 72 hours.

Compounds (1), (2), (3), (4) thus obtained
), (5), (6), (7), (8), (9) and α
All of Q are new compounds, and compound σQ exhibits excellent antibacterial properties as described below.

The present invention will be explained in more detail with reference to Examples below. In addition, the elemental analysis value is shown in "%".

Example 1 2L-(2,4/3)-3-benzyloxy-2-(2
,6-diacido2,6-sibuoxy-3,4-0-isopropylidene-α-D-alopyranosyloxy)-4
-(p-methoxybenzyloxy)-cyclohex-5
-enone (2) 2L-(2,4,5/3)-2-(2,
6-diacido2,6-sideoxy-3,4-0-isopropylidene-α-D-alopyranosyloxy)-3-
Benzyloxy-5-hydroxy-4-(p-methoxybenzyloxy)-cyclohexane (1) (170m
g, 0.27 mmol) was dissolved in anhydrous pyridine (3 mI2), and methanesulfonyl chloride (40 μβ
, 0.5 mmol) was added. The reaction mixture was stirred at 0° C. for 4 hours, poured into ice water, and stirred for 3 hours. After extraction with chloroform, the organic layer was washed successively with 1M hydrochloric acid, saturated aqueous sodium chloride, and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting syrup was subjected to flash chromatography (eluent: benzene-acetic acid ethynope).
19:1) and concentrated by adding chloroform-methanol to obtain an amorphous white solid of compound (2) (147 mg, yield 90%).

[Properties of compound (2)] [α]. +114° ([: 0.306. Chloroform) v--X2100 (N3), 1690cm
-' (conjugate C=0)δ□(CDCR3) 3.26 (t, IH,H-2') 3.29 (d
d, LH, Js□, ra 5.6Hz, H-6'a
)3, 36 (dd, IH, Js・, 6□ b
2.7°Jqta* 13.2)+2. H-6'b
)3.74 (s, 3)1. OMe) 3.92 (
dd, LH, Ja・, s・9.7Hz, H-4'
)4.05 (dd, LH, H-3) 4.19 (d, IH, J2.311.OH2,)l
-2>4.33 (dt, IH, J3.48.1゜J
4.5=Ja, s=2.2Hz, H-4) 4.51
(t, IH, J2-.3-=J3-, 4-=4.6
H2゜H-3') 4,62 (s, 2tl, CH2) 4.83 (d
dd, 18. ll-5') 4.88 (d, 1
)1. (1'H2)4.96 (d, IH, Jg
sll 10.5Hz, CH2)5.31 (d
, IH, Jl-, 2-4, H2, H-1')5.
97 (dd, LH, Js, a 10.:llz,
H-6) 6.77 (dd, LH, H-5) Elemental analysis C3+83s [lJg-C as CH3DH, 58,2
9; H, 6, OO; N, 13.15 Measured value C, 58,03; H, 5,90; N, 12.9
3 Example 2 LD-(1,3,4/2)-4-azido-2-〇-benzyl-3-0- (2,6-diacido2゜6-sideoxy-3,4-0-inpropylidene- α-D-Allopyranosyl)-1-0-(p-methoxybenzyl)-cyclohex-5-ene-1゜2.3-)liol (4) Compound (2) (130 mg, 0.24 mmol) Tetra 11:)'07 U7 (1mil-ethanol (1
Cerium chloride (I [I) ・(3
70 mg) was added. This solution was cooled to -78°C, sodium borohydride (37 mg) was added, and the mixture was stirred for 5 hours. Acetone (1 ml7) was added, the mixture was returned to room temperature, and diluted with chloroform. The organic layer was washed with an aqueous ammonium chloride solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
126 mg) was obtained.

Dissolve this silica in toluene, concentrate under reduced pressure to azeotropically remove water, dissolve in toluene (10 mJ), add triphenylphosphine (260 mg), hydrogen azide benzene solution (1.5 ml), and heat to -18°C. Cooled. Diethyl azodicarboxylate (1 mf) was slowly added dropwise to -1
The mixture was stirred at 8°C for 1 hour and then at room temperature for 2 hours. Add 1 ml of methanol, stir for 1 hour, pour into saturated aqueous solution, and extract with benzene. The organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Separation by flash chromatography (eluent benzene-acetic acid ethynope 98:2) yields the compound (
4) (120 mg, yield 79%) was obtained.

[Properties of compound (4)] [α]. +4.7° (CO, 556, chloroform)
δH (CDCR3) 3.33 (dd, LH, JS-, 8-, 7,3°J
9@m 13.2Hz, H-6' a) 3.45 (
t, LH, Jl-, 2-=J2・, 3-=4.6H2
, H-2') 3.51 (dd, E, Js-, e
-b 2.3Hz, H-6't+)3.80 (s,
3H, OMe) 3.92-3.97 (m, 2B, H-3,4'
)4.5Q (dd, ltl, Jl* 27.3
゜J2.310.3H2,H-2) 4.11 (br, d, IH, H-1) 4.19 (
dt, LH, J4-, S-7, 2H2, H-5')
4.25 (t, 1)1. J3.4=J4. S”4
．． 9H2, H4) 4.39 (dd, IH, J3・1
・5.9, H-3')4.58 (d, IH,
J. -11,2, CH2) 4.62 (d, IH,
J,,,, 11.2H2,C'H2)4.87 (d
, LH, Jl--11, OH2, CH2) 4.95
(d, LH, Jq--1,1,OH2,CH2)5
．． 33 (d, IH, H-1')5.80 (d
dd, LH, Jr, s 1.7. Js,s 9
．． 8Hz.

H-5) 5.91 (dd, LH, Jl, [l 2.2H2
, H-6) Elemental analysis C30H3SN90? as C, 56,86; H, 5,57; N, 19.8
9 Measured values C, 57, 19; H, 5, 61; N, 19.4
5 Example 3 ID-(1,3,4/2)-4-azido-2-〇-benzyl-3-〇-(2,6-diacido 2゜6-sideoxy-3.4-0-isopropylidene-α -D-Allopyranosyl)-1-0-(p-methoxybenzyl)cyclohexane-1,2,3-triol (5) Tris(triphenylphosphine)rhodium chloride (50
Compound (4) (42 mg, 0.066 mmol) dissolved in degassed benzea (15 mg) was added and stirred vigorously at room temperature under a hydrogen atmosphere for 5 hours.The reaction mixture was stirred vigorously at room temperature for 5 hours. I) is adsorbed on the column of
Benzene, diethyl ether/lz.

and ethyl acetate were eluted in this order. The ethyl acetate eluate was concentrated under reduced pressure and the resulting silica was subjected to flash chromatography (eluent, benzene-ethyl acetate, 98:2).
When separated with
, yield 71%) was obtained.

[Properties of compound (5)] [α]. +60.2° (CO, 746, chloroform)
δH (CD(J,) 1, 24 (s, 3H, CH3) 1, 38 (s, 3) 1. CH3) 1, 601.7
5 (m, 2H, CH2)1, 82(, 90(m,
2)1. CH2) 3.34-3.46 (m, 3H
, H-2', 6'ab) 3.75 (dd, IH, H
-4') 3.80 (s, 3H, OMe) 3.88-3.91 (m, 3H,H-2,3,4
)4.04 (m, IH, H-1) 4,14 (br, t, , +4-, s・=Js
□, s・=11. QHz, 'H-5') 4.37 (t, IH, J2-.3-=J3-, 4
-=4.6H2゜H-3') 4.53 (d, IH, J9@II 11.OH2
, CH2) 4.61 (d, 1N, CH2)
4.77 (d, LH, Jgall 11.0Hz,
CH2)5.02 (d, IH, C112)5
．． 34 (d, IH, J+□, 2□ 4.9Hz,
H-1') Elemental analysis C3oHs, OJs as C, 56,68; H, 5,87; N, 19.8
3 Measured values C, 56, 42; H, 5, 61; N, 19.6
9 Example 4 ID-(1,3,4/2)-4-azido-2-〇-benzyl-3-0- (2,6-diacido2゜6-sideoxy-3,4-0-inpropylidene- α-D-Allopyranosyl)cyclohexane-1゜2.3-)diol (
6) Compound (5) (42 mg, 0.066 n+mol) was dissolved in dichloromethane (5 ml-water (0.2 ml), 2.
3-Dichloro-5,6-dicyano-1,4-benzoquinone (60 mg) was added and stirred at room temperature for 1 hour. The mixture was diluted with dichloromethane, washed with an aqueous sodium thiosulfate solution, saturated aqueous sodium chloride solution, and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained shirabu was purified by flash chromatography to obtain a shirafu-like compound (6) (25.3 mg, yield 74%).

[Properties of compound (6)] [α]. +67.4" (CO, 184, chloroform)"fiaX 34υ0 (Kano, 2060
cm-' (N3) δH (CDCR3) 1, 37 (s, 3) 1. CH3) 1, 56
(s, 3)1. CI(3) 1.55-1.61
(m, LH, H-5ax) 1.67-1.76
(m, LH, H-6ax) 1.82 (dq, L
H.J. 13J JS@qt6゜.

=JSaXs s*q=J++ 6eq”4.6Hz,
H-6eq) 1.92 (dq, IH, Jq,,
13.9. J4+S@'It=J6'aXy Sa
q"4.5Hz, H-5sq)2.48 (br,
s, if, 0H)3,38 (dd,
LH, Js・, s・-6,8°J91!1m 13.
2Hz, H-6'a) 3.53 (dd, LH, J
s□, rb2.4Hz, H-6'b)3.57 (t
, IH, J+-, z-=J2-, 3-=4.4Hz.

H-2') Approximately 3.6 (m, LH, H-1) 3,74 (t, LH, JI+ 2=J2.3=1.
8Hz, H-2) 3.97 (dd, LH, J3.
42.9H2,H-3) 3.99 (dd, IH,
J3・・・5.6゜Js・、s・9.3Hz,
H-4') 4, 07-4.09 (m, ltl,
J4. s. 3.7Hz, H-4)4.23
(ddd, IH, H-5')4.44 (dd,
IH,H-3')4.76 (d, IH,J,.

11.4H2, CH2) 4.89 (d, IH,
CH2) 5.18 (d, IH, H-1') 31
M3500.1994 [, (M-CH3)”: C2
11426N90. Tojito 500.20041 Example 5 IL-(1,6/2.3)-2-0-(2,6-diacido2,6-dibuoky-3,4-0-inpropylidene-α-D- allopyranosyl)-3-azido-1-0-benzyl-6-(2'-N-benzyloxycarbonylglycinamide)-6-N-methylcyclohexane-1,2
-Diol (9) Dichloromethane (10 mJ') and dimethyl sulfoxide (0.3 ml were cooled to -78°C, trifluoroacetic anhydride (150 μl) was added, and stirred for 30 minutes. Compound (6) (24 mg, 0 .04
A dichloromethane solution (5+nI) of 7 mmol) was added dropwise, stirred for 1 hour, and triethylamine (0
, 3mA7) was added and stirred for 1 hour.

The reaction mixture was allowed to warm to room temperature and diluted with dichloromethane. The mixture was washed with 1M hydrochloric acid, saturated aqueous sodium chloride, and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.

The obtained compound (7) silica was dissolved in THF-methanol (1:4.10 ml), methylamine methanol solution (40%, 1 ml), and molequinylar sieves 3A.
(2g) and further added acetic acid to pH 6.2-6.
I gave it a 5. The mixture was cooled to -15°C, sodium cyanoborohydride (12 mg) was added, stirred for 1 hour, poured into water, and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous potassium carbonate, and concentrated under reduced pressure.

The resulting compound (8) was dissolved in dioxane and N-(N-benzyloxycarbonylglycyloxy)
Succinimide (40 mg) and triethylamine (
0.1 ml) was added thereto, stirred at 60° C. for 8 hours under an argon atmosphere, and concentrated under reduced pressure. Dissolve the residue in chloroform,
The mixture was washed with 1M hydrochloric acid, saturated aqueous sodium chloride, and saturated brine, dried over anhydrous sulfuric acid, and concentrated under reduced pressure. When the obtained silica was separated by flash chromatography (benzene-ethyl acetate, 4:1), compound (9) (1
1 mg, yield 45%) was obtained.

[Properties of compound (9)] [α]o+66.8° ([' 0.564.chloroform)n), 1635cnr' (amide) δo
(CDCj! a) 1, 39 (s, 3H, CH3) 1, 56 (s, 3H, C) Is) 1, 56 (, 79 (m, 2H, CL) 1, 97-2.
17 (m, 2H, CH2) 3.39 (t, LH
, Jl-, 2-=J2-, 3-=4.6H2°H-2'
) 3.46 (dd, IH, Js・, 6・, 6.3°J
q*m 14.2Hz, H-5' a) 3.75
(dd, IH, JCI+1184.2°J9111
116-2)1z, C0C)I,)3.88 (
dd, 1)1. Jc*, x114.2)+2.
C0CH2)4.02-4.05 (m, 3
H, 1(-1,3,4')4.10-4.14 (
m, LH, H-2) 4.38 (d, LH,
CH, Ph) 4.38-4.50 (m, IH,
H-5') 4.58 (d, IHlJq-11,7Hz
, 0CLPh) 4.62 (t, LH, J3-.4
-4.6H2,H-3')4.76 (td,
IH, Js,,1. s 11.7°J,,9. ,=
J,,s=4.0H2,H-6)5.09"5.17(
m, 3N, Ll', C02Ctl-Ph
5.85 (br, t, IN, NH)S
IMS 719.3117(M”:C3384101
319° as 1NIl Example 6 LL-(1,6/2.3)-6-amino-1-0-(2
,6-Diami2,6-sideoxy-α-D-allopyranosyl)-3-glycinamide-3-N-methylcyclohexane-1,2-diol α1 90% trifluoroacetic acid cooled to 0°C (compound (9 ) (11 mg) in THF was added and stirred for 1 hour. The solvent was distilled off under reduced pressure at 0°C, and ethanol was further added and the vacuum concentration was repeated twice. 10% palladium on carbon (8m
g) and 0.01M hydrochloric acid-methanol (1:4.5
A night attack was carried out under a hydrogen atmosphere (mA). The catalyst was filtered off and washed with water (5 mA), the filtrate and the washing liquid were combined, 10% palladium on carbon (7 mg) was added, and a night attack was carried out under a hydrogen atmosphere. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The obtained sillage was dissolved in water (10 ml!) and CM-Sephadex-C25CNH, "" type]
Water (20 mf) was adsorbed onto a column (9 mm x 50 mm).
) and gradient elution (40ml) from OM to 0.5M aqueous ammonia. Fractions of the target product were collected, freeze-dried, dissolved in water, adjusted to pH 4 with 0.01M hydrochloric acid, and further freeze-dried to obtain compound αQ hydrochloride (2.4 mg, yield 43%). Obtained.

[Properties of compound σQ]

[α]. +86.9' (CO, 10?, water) δ, (
020-DCβ, pD2. TMS as external standard) 1.5
8-1.62 (m, IH, H-4eq) 1.81-
1.87 (m, 2H, 5ax, 5eQ) 1,97
(Qd, LH, Js-X, 4-X=J4-X,
a-q=J4. X, 3=11. Hada JS@qs 4a,
44.6H2+H-4ax) 2.85 (S, 3)1. NCH3) 3, 11
(dd, LH, Js・, 6・, 7.1°J, .13.
4) 1z, 11-5' a) 3.32 (dd,
IH, Js-, s-b 3.2H2, H-6'b) approx. 3
．． 52 (m, IH, H-6) 3.55 (dd,
°IH, J3・, 4・3.2°J4・, s・10.0
Hz, H-4')3,69 (t, IH, Jl・
, 2□ = J2・, z□ = 4.0Hz.

H-2') 3.87 (d, LH, J,.-17,2H2,
C0C) 12) 3.89 (d, IH, C0CH
2) 3.91 (ddd, IH, H-5')3.
99 (t, LH, Jl, 2=Jl, 6・3.2
Hz, H-1) 4.15-4.17 (m, 2
H, H-2, 3') 4.26 (td, IH, J2
．． *=J4*q+3=3)12. H-3) 5.33
(d, IH, H-1') SIMS 378 (M
+H)” The compounds of the present invention exhibit excellent antibacterial properties against various bacteria, as shown in the following table.

Claims (1)

[Claims] (1) A 3-demethoxy-1,4-diaminocyclitol antibiotic analog represented by the following general formula (I). ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R^1 represents an azide group or an amino group, and R^
2 and R^3 represent a hydrogen atom or jointly represent a diisopropylidene group, R^4 represents a hydrogen atom or a benzyl group, and R^5 represents a hydrogen atom, a glycyl group or a substituted glycyl group . )(2) Formula (1): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(1) (In the formula, Bn represents a benzyl group and MBn represents a p-methoxybenzyl group.) Dehydrate the compound (1) represented by Formula (2) after treatment with
: ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (2) Obtain the compound (2) represented by and treat it with a reducing agent to obtain formula (3): ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (3) Compound (3) represented by is obtained and treated with hydrogen azide/triphenylphosphine/diethyl azodicarboxylate to obtain compound represented by formula (4): ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (4) (4) was obtained, and this was catalytically reduced in the presence of a hydrogenation catalyst to obtain a compound (5) represented by the formula (5): Compound (6) is obtained by treatment with 3-dichloro-5,6-dicyano-1,4-benzoquinone and is oxidized. A compound (7) represented by formula (7): ▲Mathematical formula, chemical formula, table, etc. is obtained by treatment with a compound (7), and this is reacted with methylamine to form formula (8): ▲Mathematical formula, chemical formula, etc. , tables, etc. ▼ (8) Compound (8) represented by is obtained, and this is reacted with benzyloxycarbonylglycyloxysuccinimide to form formula (9): ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ ( 9) Obtain the compound (9) represented by the formula, acid hydrolyze it,
A method for producing a 3-demethoxy-1,4-diaminocyclitol antibiotic analog represented by formula (10): ▲Mathematical formula, chemical formula, table, etc.▼(10) characterized by further catalytic reduction.