JPS61126095A - Novel glucosamine derivative - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I (R<1> and R<2> each represent H or acyl; R<3> represents allyl or benzyl) or its 4,6-o-isopropylidene derivative. EXAMPLE:1-o-Allyl-2-chloroacetylamino-2-deoxy-beta-D-glucopyranose. USE:An intermediate for synthesis of physiologically active lipid A and its analogue existing in a surface layer portion of bacterial cell wall. PREPARATION:For example, using a glucosamine hydrochloride such as 1,3,4,6- tetra-o-acetyl-2-deoxy-2-chloroacetoamino-D-glucopyranose as a starting material, a compound expressed by formula II is derived from said starting raw material by the well-known method, and then the compound is quantitatively deacylated by an action of a base such as ammonia alkali to obtain the compound expressed by formula I, wherein R1 is H.

Description

[Detailed description of the invention] The present invention relates to novel glucosamine derivatives.

Substances that exhibit a variety of physiological activities (immune-enhancing activity, etc.) exist in the surface layer of bacterial cell walls, and it has been reported that lipid A is the active center of these substances [Angew-chem
, 66407 (1954)''], and the compound has been isolated and its structure finally revealed [S et, Lett, 244017 (198
3)).

Up to now, various attempts have been made to synthesize lipid A and its analogs, but the present invention provides novel glucosamine derivatives that are useful synthetic intermediates that can be derived into these compounds. It is something to do.

That is, the present invention is based on the general formula, (wherein t and R2 are each H or an acyl group, and R3 is -CH2-CH=CH2,
A novel glucosamine compound represented by or 4.
．． 6-0-Impropylidene derivatives are provided.

The novel glucosamine derivative according to the present invention can be produced according to the following reaction formula.

(I) ((I) (2)↓ [In the formula, R1 and R2 are each an acyl group, and R3
is an allyl group (-CH, -CH=CH2) or a benzyl group, a new substance according to this reaction formula, (II), (2)),
The manufacturing process will be described in more detail below.

First, using easily available glucosamine sulfate as a starting material, a known method [Ber, 975 (193
1) and CarbOhydr, R13872, C12
-C14 (1979)] to lead to the compound of formula (I), and then the following procedure is carried out based on the methods described in these literatures. That is, the compound of formula (I) is quantitatively acylated by the action of a base, for example, ammonia alkali, leading to the compound of formula ([I). This compound of formula (IT) is dissolved in dimethylformamide, an acidic catalyst,
For example, in the presence of p-toluenesulfonic acid, 2,2-dimethylform is added and the 4.6-position hydroxyl group is improvised/converted to obtain a compound of formula ([IT). Next, the compound of formula (2) can be quantitatively obtained by heating the compound of formula (2) in pyridine and then treating with dilute caustic soda.

Since the compound of formula (1) has a free amine group at the 2-position and a hydroxyl group at the 3-position, various substituents can be introduced into the amino group at the 2-position and/or the hydroxyl group at the 3-position. Ultimately, lipid A or its analogs can be synthesized. Therefore, the above equation ([), (2)
Glucosamine derivatives, represented by decoys, are extremely important intermediates for the synthesis of disaccharide derivatives such as Sudo A or its analogs. For example, an acyl chloride, e.g. (R
> When treated with -3-benzyloxytetradecanoyl chloride and simultaneously esterifying the acyl group of the amino group at the 2-position and the hydroxyl group at the 3-position, the compound of formula (V) shown below can be obtained in high yield. Obtainable.

Next, when compound 2M is hydrolyzed in an acetic acid aqueous solution, preferably at 85 to 90°C, the following formula (Vl
A compound of formula (b) is obtained, and the compound of formula (b) is treated with a basic catalyst,
For example, when reacted with benzyl chloromethyl ether in the presence of diimpropylethylamine, a compound of the following formula (■) is obtained.

Further, by selecting reaction conditions, a substituent can be introduced only to either the amine group at the 2-position or the hydroxyl group at the 3-position. For example, an acyl chloride, e.g.
-dodecanoyloxy 7 is amidated with tetradecanoyl chloride to obtain the compound of the following formula: The compound (ii) is obtained. Furthermore, by treating this with acetic acid, a compound of the following formula (Xll) can be obtained.

By further deriving the compound of formula (■) and the compound of formula (b) obtained by the above-mentioned reactions, useful compounds such as Lib-I-A or its analogs can be obtained. .

The formula for the production route of these compounds as described above is as follows:
It will look like below.

In the following formula, R2 in the general formula is chloroacetyl, and R3 is allyl (al171) When R3 is benzyl, for example, 1,3,4
．． 6-tetra-0-acetyl-2-deoxy-2-chloroacetamino-D-glucobylanose (Ber, ,
975, (1931) and carbO-hydr,
Res 72 C12C14 (1979) is reacted with benzyl alcohol in methylene chloride in the presence of tetramethylurea to give 3.4.6- ) so-0-acetyl-
2-deoxy-2-chloroacetamino-1-〇-benzyl-β-D-glucobylanose (formula I/ below) is obtained. This is subjected to the same reaction treatment as described above ([[l→(2)→■) to form compounds represented by the following formulas (■') and (■'), to obtain compounds of the following formula (■). be able to.

(I') 8H2CH2 CI C1(U')
(W)NH2 (1v) Examples of the present invention are listed below.

Example 1 1-0-aryl-2-chloroacetylamino-2-deoxy-β-D-glucobylanose (■) 3.4.6-
1-ly O-acetyl-2-deoxy=2-chloroacetylamino-1-o-aryl-β-Dr lucopyranose (I) t-28% aqueous ammonia and methanol (1:
Add the mixture of 10) to 76 red and stir at room temperature for 12 hours. Next, the reaction solution is concentrated under reduced pressure. After washing the residue twice with chloroform, dry it to 5.56F (94,04)
The title compound (U) is obtained. m, p, 155-157
°C [α] 22-33.3° (C = 1.00 CH30
H) vKBr(crn-1); 3264 (OH), 1
679.1555 (amide)ax Example 2 1-0-71J-ru-2-chloroacetylamino-2-
Deoxy-4,6-0-inpropylidene-β-D-glucobylanose@) 1-0-aryl-2-chloroacetylamino-2-deoxy-β-D-glucobylanose ([r) 4. 43
Dissolve f in 55 rttl of dry dimethylformamide and add p-)luenesulfone it 0 with stirring at room temperature.
．． 25F and 2,2-dimethquine propane 4.52? Add and stir for 2 hours. Next, the reaction solution was mixed with ion exchange resin I.
It was treated with RA-410 to remove p-toluenesulfonic acid, and then chromatographed on silica gel (CFCl3: CH
30H=10:1) and purified by 4.39f
The title compound (2) of (87,3ti) is obtained. m, p
.

154-155°C, [α]D-54,2' (c =
1.00 cmcts)vKBr(crn-1);
3492.3316 (OH, NH), 1660.

ax 1547 (amide) Elemental analysis value C (@ H (branch)) calculated value 50.
08 6.60 Actual value 49.97 6.58 Example 3 l-o-aryl-2-amino-2-deoxy-4,6
-○-isopropylidene-β-D-glucobylanose-1-0-7'J-/L'-2-chloroacetylamino-
2-deoxy-4,6-〇-impropylidene-β-D
- Glucobylanose ([Ill, pyrun 17 in 68f
mA! Add to the mixture and heat and stir at 90-100°C for 2 hours.

Then, the reaction solution was concentrated under reduced pressure, and 5% caustic soda solution (611LI!) was added to the residue. and 6 rug of methanol, and stirred at room temperature for 1.5 hours. Thereafter, the reaction solution was concentrated to dryness, and the residue was purified by glue gel chromatography (CFCl2:CH30H=
15:1) and purified by 1.279 (98%
) is obtained. Oil [α) D-72,0
(C=1.04 cHct,)-v,, support m (cy-1) 3373 (OH,
NH), 1647 (ALY1), 855
(acetonide) Elemental analysis value C(壬)H(@ Calculated value 55.5 8.16 Actual value 54.9 7.95 Example 4 1-0-aryl-2-[(R)-3-benzyloxytetra Decanoylcoamino-2-deoxy-3-o-[
(R)-3-benzyloxytetradecanoyl] -4
,6-0-improviride/-β-D-glucobylanose (V) 1-0-aryl-2-amino-2-deoxy-4,6
-0-inpropylidene-β-D-glucobylanose (
5) 0゜132.4-dimethylaminopyridine o, oi
Add 0.53r of (R)-3-pene:)ruoxytetradecanoyl chloride and 0.5a of dichloromethane to a solution of sy in 1.0al of pyridine while stirring under ice cooling.
1 solution dropwise. After stirring at room temperature overnight, the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel chromatography (CHCl3:PK=1 (1:1)), 39y (87,
2) The title compound (V) is obtained. m, P, 69-7
1°C [α): 5-14. o (c = t, oo cH
ct3)"4ax ("-1) 3340 (NH),
1739 (ester), 1662 (amide
), 851 (acetonici) Example 5 1-0-aryl-2-((R)-3-be/zyloxytetradecanoylcoamino-2-deoxy-3-〇-
((R1-3-benzyloxytetradecanoyl)-β
-D-glucopyranoside (b)1-0-aryl-2-
[(R) -3-benzyloxytetradecanoylcoamino-2-deoxy-3-o -((R1-3-benzyloxytetradecanoyl) -4,6-0-inpropylidene-β-D- Glucobylanose (V) 0.09o
Dissolve r in 1 at of 90% acetic acid and heat and stir at 85 to 90°C during addition.

This was concentrated under reduced pressure, and the residue was chromatographed on silica gel (CHC).
l3: Acθtono = 5: 1) Well purified, 0.071 1? (83.7%) of the title compound (b) is obtained. m, p, 74-76°C [α) D-34
, 6° (cmo, 22 cHct,) KBr −
1 νmaX(ffi) 3548. 3488(O
H), 3276 (NH), 1729 (ester
), 1647. 1558 (amide) Elemental analysis value C (thi) H (calculated value 71.88 9.58 Actual value 71.65 9.38 Example 6 1-0-aryl-2-((R) -3-benzyloxy Tetradecanoylcoamino-2-deoxy-3-0-
C(R1-3-benzyloxytetradecanoyl)-6
-o-benzyloquinemethyl-β-D-glucobylanose (■) 1-0-aryl-2-[(R)-3-benzyloxytetradecanoylcoamino-2-deoxy-3-〇 -
C(R) -3-benzyloxytetradecanoyl]-
Dissolve 0.1161 of β-D-glucopyranoside (b) and 0.0882 of diimpropylethylamine in 1.5 al of dichloromethane, and while stirring under ice-cooling, add 0.106 f of benzyl chloromethyl ether to 70 g of dichloromethane.
．． Add 5rnl solution dropwise. This is followed by stirring at room temperature for a specified period of time. This reaction solution was concentrated under reduced pressure, and the residue was chromatographed on silica gel (Acetone: IPE = 1
:20) and purified by 0.114? (86.1%
) to obtain the title compound (to).

m, p, 77-79°C [α)22-. 517c
c= 1.3 (CHCl3:CH20H= 1:
1) ') 'max (cm-") 3292 (NH), 1733
(ester), 1650°1549 (amfd
e) Elemental analysis value C(thi) H(thi) Calculated value 72.88 9.23 Actual value 72.79 8.94 Example 7 2-[(R1-3-benzyloxytetradecanoylcoamino-2- Deoxy-3-0-((R1-3-benzyloxytetradecanoyl) -6-,0-benzyloxymethyl-β-D-glucobylanose (■) 1-〇-aryl-2-C(R) - 3-benzyloxytetradecanoylcoamino-2-deoxy-3-o
-[(R1-3-benzyloxytetradecanoyl)-
6-0-penzyloxymethyl-β-D-glucobylanose (■) 0.065 r and [technr (COD)
(PCH3Ph2)2:) PFs O,057?
After dissolving in 10 ml of tetrahydrofuran under a nitrogen atmosphere, the mixture was replaced with hydrogen while stirring vigorously. After further stirring at room temperature for 5 minutes, the mixture was again purged with nitrogen and heated under reflux for 4 hours. The solvent was distilled off under reduced pressure, and the residue was chromatographed on silica gel (
CHCl3: acetone = 2n: l) 0.065 f of the concentrated dry product obtained by purification was dissolved in 1.0 m of tetrahydrofuran-water (10:1), and while stirring at room temperature, dichloromethane of 20.034P was dissolved.
．． 5d solution was added dropwise, and then 0.021 F of pyridine was added. Then, the mixture was stirred at room temperature for 15 minutes, and the reaction solution was concentrated under reduced pressure. The residue was chromatographed on silica gel (Acetone
: pE = t: 20), purified from 0.0371 (60
%) of the title compound (■) is obtained.

m, p, 83-85°C (:α)22-13.5"
(C=0.72 CHCl3)"4a"x ("-
”) 3364 (OH), 3292 (NI(), 1
735 (ester), 1651 (amide)
Example 8 1-0-allyl-2-C(u)-3-dodecanoyloxotetradecanoyl]amino-2-deoxy-4,6-0
-inpropylidene-β-D-glucose QXI 2-amino-2-deoxy-1-o-aryl-4,6
-0-isopropylidene-β-D-glucobylanose■
50■ and 4-dimethylaminopyridine 7■ were dissolved in pyridine 2at, and while stirring under water cooling, (R)-3-dodecanoyloxytetradecanoyl chloride 267~)
A 0.5 d solution of chloromethane was added dropwise. Thereafter, the reaction was allowed to proceed overnight at the same temperature, and the reaction solution was concentrated under reduced pressure. The residue was chromatographed on silica gel (CHCl3: Acetone = 10:
1) and purified by 97! The title compound (74qb) is obtained. m, p, 55-56℃ [α几0-37.65
°(c=1.03 CHCl3)"4X'x 3320
(NH), 1734 (-COOH), 1666 (
arnide) Example 9 1-0-aryl-2-1: (R)-3-dodecanoyloxytetradecanoyl]amino-2-deoquine-3
-O-((R)"-3-tetrazokayloxytetradecanoyl) -4,6-0-inpropylidene-β-D
-Glucobylanose (X) 1-0-aryl-2-((R1-3-dodecanoyloxytetradecanoyl)amino-2-deoxy-4,6-
0-Impropylidene-β-D-glucose■200m
151 ng of pyridine and dimethylaminopyridine were dissolved in 2 pyridine and cooled in a nitrogen stream (R) -3
-Tetrazokairoxytetradecanoyl chloride 2
A solution of 841n9 in dichloromethane is added dropwise. - After stirring overnight, the reaction solution was concentrated and purified by silica gel chromatography (Ko-PE) to obtain 233 to 70% of the title compound (X). m, p, 37-41°C [
α]D-15,6 (C=1.44CHC43) νDingMo3292 (NH), 1741 (C0OH),
1661 (amide) Example 10 1-〇-aryl-2-((R)-3-dodecanoyloxytetradecanoyl]amino-2-deoxy-3-0-
C(R) -3-tetrazokairoxytetradecanoyl]-β-D-glucobylanose (X) 1-o-aryl-2-C(R) -3-todecanoyloxytetradecanoyl Noyl]amino-2-deoxy7-3-
0- C(R1-3-tetrazokairoxytetradecanoyl) -4,6-0-inpropy'J thea-β-
Dissolve 233 mg of raw glucobylanose (X) in 3 ml of 90% acetic acid and stir at 90°C for 100 minutes at zero heat. This is concentrated under reduced pressure and brutalized. 1) Force 0-7
) (CHCl3: Acetone = 10:
1) to obtain 117 ml (52%) of the title compound.

Ill, p, 65-68°C [α]i”-to,
o (C=0.46 cHct, )v” 3456
(OH), 3288 (NH), 1.729 (es
ter), ax 1659 (amide) Elemental analysis value c(@H(%) Calculated value 71.75 11.04 Actual value 71.90 10.90 Example 11 1-o-aryl-2-C(R) - 3-do'decanoyloxotetradecanoyl]amino-2-deoxy7-3-
o -[(R)-3-tetrazokairoxytetradecanoyl]-6-0-trityl-β-D-glucohy 0/
-su(m)], -0-aryl-2-[(R)-3-dodecanoyloxytetradecanoyl]amino-2-deoxy/-3-
〇-C(R) -3-tetradecanoyl/tetradecanoyl]-β-D-glucobylanose H) o7q, 371 ng of trityl chloride, and 2~ dimethylaminopyridine were dissolved in 2 rnl of methylene chloride, and Diisopropylethylamine 17~ is added and reacted overnight. This was reduced to 120%, and then subjected to analytical column chromatography (CHC).
23) Purify to obtain the title compound (Xl[) with 76 m'i (49%).

m, p. 100-10 Cow'C[α]D -14,5(c
=o, tl cHct3) Br νmaz 1738.1723 (eater), 1
651 (amfde), 705 (phenyl
) Elemental analysis value C (chi) H (@ Calculated value 88.33 11.67 Actual value 88.04 11.79 Example 12 3.4.6-1-di-0-acetyl-2-deoxy-2
-Chloracetamino-nee-be/sil-β-D-glucobylanose (1') Calcium sulfate 0.816 F and ferric chloride 0.486
1 was dissolved in 20 mJ of dry methylene chloride and stirred for 10 minutes at room temperature in a nitrogen stream. To this were added 0.8481 1.3,4.6-tetra〇-acetyl-2-deoxy-2-chloroacetamino-D-glucobylanose, 1.08 f of benzyl alcohol, and 0.1 mg of tetramethylurea, and the mixture was stirred overnight. do. Thereafter, a saturated aqueous solution of 17 um of sodium bicarbonate was added and the mixture was separated.

Dry and concentrate. Recrystallized from ethanol and 0.47? (50
%) of the title compound (I') is obtained.

In, p, 186-188℃ [α:]D-41.6
7° (C= 0.24CHCI3) "4'j"x ("-") 3320' (NH), 1
740 (C0OH), 1661 (C0NH) Elemental analysis value C (@H@1 Calculated value 53.38 5.55 Actual value 53,25 5.49 Example 13 ■-0-Benzyru-2-chloroacetamino-2- Deoxy/~β-D-glucobylanose (TT') 3.4.6
- Tory〇-acetyl-2-deoxy-2-chloroacetamino-1-0-benzyl-β-D-g/L/ Copy? / -su(1') 0.472 F, 4% aqueous ammonia, and methanol (1:10) in 5 ml of a mixed solution, and stirred at room temperature for 1 hour. Next, the reaction solution is concentrated under reduced pressure. The residue was washed twice with chloroform and then dried to quantitatively obtain the title compound (U'). m, p, 15
8-160'C [α) fi2-53.0' (C=1.
05 cHct3) ν”nXx (”-”) 3260 (OH), 16
65 (amide) Elemental analysis value C (calculated value 52°05 5.83 Actual value 51.90 5.75 Example 14 1-0-benzyl-2-lyC-acetamino-2-thioquine-4, 6-Itspro e-lidene-β-D~glucobylanose (U') 1-〇-benzyl-2-chloroacetamino-2-deoxy/-β~D-glucobylanose (U') 0゜3461
was dissolved in 5 ytt of dry dimethylformamide and 0.017 ytt of p-)luenesulfonic acid was dissolved while stirring at room temperature.
Add P and 0.32 of 2,2-dimethoxypropane,
Stir for an hour. Next, the reaction solution was treated with ion exchange resin RA.
-410 to remove p-toluenesulfo/acid, and further purified by silica gel chromatography to 0.27f (7
0%) of the title compound is obtained.

m, p, 163-165°C [αEi”-93,0°
(c=0.72 cHc13)νKBr3490 (O
H), 3316 (NH'), 1660 (amide
)ax Elemental analysis value C (correspondence) H (correspondence) Calculated value 55.98 6.27 Actual value 56,11 6.38 Example 15 1-o-benzyl-2-deoxy-4,6-inbropyride - β-D-glucobylanose (IV') 1-〇-
Benzyl-2-chloroacetamino-2-deoxy/-4
, 6-imbropylidene-β-D-glucobylanose (
m') Add 4 ral of pyridine to 0.385 t,
Heat and stir at 90-1o00G for 2 hours. The reaction solution was then concentrated under reduced pressure, and the remaining residue was filled with 5 ml of caustic sorter solution L4rttl.
and methanol (1.6 m/w) were added, and the mixture was stirred at room temperature for 1.5 hours. Thereafter, the reaction solution was concentrated to dryness, and the residue was purified by silica gel chromatography to quantitatively yield the title compound (■').
get. amorphous. [α] 20-74.5° (c=
1.78 cHct3) ν magazine 4In(tM-1) 3
372 (OH, NH), 851 (acetonide
) Elemental analysis value C (Chi I HC Chi) Calculated value 62.06 7.49 Actual value 61.81 7.42

Claims (1)

[Claims] There are general formulas, ▲mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^1 and R^2 are each H or
Or, it is an acyl group, and R^3 is -CH_2-CH
＝CH_2 or ▲Represents mathematical formula, chemical formula, table, etc.▼) Glucosamine compound or its 4,6-O
-isopropylidene derivative