JPH041167A - 1-aceamidoinositols and production thereof - Google Patents

Abstract

NEW MATERIAL:Optically active 1L-1-acetamido-3,4,5,6-tetra-O-acetyl-1-deoxy-2- O-methyl-chiro-inositol shown by formula l. USE:Useful as a starting substance for synthesizing aminocyclotols usable as a synthetic raw material for drugs such as antibiotics and anti-cancer drugs and agricultural chemicals. PREPARATION:A compound shown by formula I is obtained by using L- quebrachitol as a starting raw material, subjecting the 1-position thereof to azide formation, reducing the azide group and acetylating to give an acetylamino group and a process of converting the 3,4,5 and 6-orders of L-quebrachitol into Oacetyl groups. A compound shown by formula II is obtained by using L- quebrachitol as a starting raw material and the compound is also a new compound.

Description

Detailed Description of the Invention <Industrial Application Field> The present invention is a novel aminocyclitol, an optically active 1L-1-acetamido-3゜4.5.6-tetra-0-acetyl-1 -deoxy-2-0-methyl-tyro-inositol and optically active 1L-1-acetamido-24,5,6-tetra-0-acetyl-1-deoxy-3-O-methyl-styro-inositol, - A method for obtaining the novel aminocyclitol using quebratitol as a starting material without going through the step of optical resolution.

Aminocyclitols are useful as synthetic raw materials for medicines such as antibiotics and anticancer agents, and agricultural chemicals.

<Conventional technology> Aminocyclitol (amino sugar) is a constituent sugar of glycoconsugates that widely exist in nature as a structural polysaccharide and plays an important role in sustaining life, and is also a constituent of important antibiotics. There have been attempts to synthesize it using various methods.

To give an example, furan and acrylic acid are subjected to a Diels-Alder reaction to obtain a 111,4-androcyclohexane compound, which is decomposed with hydrochloric acid to cleave the anhydro ring, and then subjected to azidation, reduction, etc. A method for obtaining amino sugars using the naturally occurring salt ebrachitol as a starting material was proposed by Paulsen et al.
Method for obtaining optically active valienamine through 21 steps 2+
Method 31 using benzene glycol as a starting material
Inositol disulfonate or cis-1,
There is a method 41 in which hydrazine is made to act on 4-diepoxide.

References 1) S, Ogawa and Y, 5
Hibata, Chem, Letter.

1985, p, 1518 2) H, Paulsen and F, R,) Ie
iker, LiebigsAnn, Chem,
1981. pp, 2180-22033) M, N
akajima, N, urihara, et a
l.

Liebigs Ann, Chem, 1965.
Vol, 689°p, 243 4) F, W, Lichtenthaler
, “Newer Methods of Prepa
rative Organic Chemistry
y, 196B.

Vol, IV, p, 155 S, Ogawa, Journal of Organic Synthesis, 1969° Vol, 27. p, 731 <Problems to be Solved by the Invention> As mentioned above, methods for synthesizing aminocyclitols are known. However, all of these known methods
There have been problems in that the synthesis process is complicated and that an optical separation process must be performed. As a result, both methods have the problem of low yields.

The present invention has been made in view of the above facts, and 2.
A variety of new optically active aminocyclitols and L-
The object of the present invention is to provide a method for producing the two optically active novel aminocyclitols using quebratitol as a starting material and not requiring an optical resolution step.

<Means for Solving the Problems> The present invention provides optically active 1L-1 represented by the following formula (1).
-acetamido-3,4,5,6-chitler O-acetyl-1-deoxy-2-0-methyl-thyro-inositol and an optically active 'I represented by the following formula (II)
L-1-acetamido-2,4,5,6-tetra-0
-acetyl-1-deoxy-3-O-methyl-styro-
Provides inositol.

The present invention also provides an optically active 1L-1-acetamido-3,4,5,6-chitler〇-acetyl-1-deoxy-2-〇- characterized in that L-quebratitol is used as a starting material. Methyl-thyroinositol (I) and optically active 1L-1-acetamide-2,4,5゜6-
A method for producing tetra-0-acetyl-1-deoxy-3-〇-methyl-styroinositol (n) is provided.

The present invention will be explained in detail below.

The compound of the present invention is an optically active 1L-1-acetamido-3,45,6-tetra-0- represented by the above formula (I).
Acetyl-1-deoxy-2-o-methyl-thyro-inositol and optically active 1L-1-acetamido-2,4,5,6-chitler O represented by the above formula (II)
-acetyl-1-deoxy-3-〇-methyl-stylo-inositol.

1L-1-acetamido-3,4,5,6-tetra-0
-Acetyl-1-deoxy-2-0-methyl-thyro-inositol (I) has a melting point of 183 to 184°C, a specific optical rotation ([α]) of -10.5°, and is insoluble in hydrocarbon solvents.
It is a white solid that is soluble in alcohols, halogenated hydrocarbons, dimethylformamide, etc.

In addition, 1L-1-acetamido-2,4゜5.6-tetra-0-acetyl-1-deoxy-3-O-methyl-styro-inositol (II) has a melting point of 206 to 208
℃, specific optical rotation ([α],) is -3.4° It is a white solid that is insoluble in hydrocarbon solvents and soluble in alcohols, halogenated hydrocarbons, dimethylformamide, etc.

The above compound of the present invention (1-acetamidoinositols) is a compound belonging to aminocyclitols,
Preferably, it is synthesized using ebrachitol, which has no optical activity, as a starting material. Since ebrachitol, which is a starting material, is an optically active compound, only the optically active compound can be obtained. In addition, the compound can be further converted into other aminocyclitols or derivatives thereof, and thus serves as a raw material for pharmaceuticals, agricultural chemicals, and the like.

Ebrachitol (L-(-)-2-0-Methyl-
Chiro-1 nositol is a monomethyl ether of inositol and is widely found in the bark of Hevea brasiliensis, the sap of Hevea brasiliensis, and other plants. Therefore, ebrachitol derived from these plants may be used as a starting material.

A method for collecting L-quebratitol from such plants is described, for example, in Japanese Patent Application No. 168562/1983 and Japanese Patent Application No. 161922/1999, in which ebrachitol is collected from Hevea rubra.

According to the latter, L-quebratitol is produced by dissolving the concentrate or dry product of natural rubber serum (the remaining aqueous solution after removing the coagulated rubber in the natural rubber manufacturing process) in methanol, and concentrating the solution. However, it can be easily collected by crystallizing L-quebratitol. All of the quebratitol thus collected is of the optically active L type.

As mentioned above, the production method of the present invention uses L- as a starting material.
It is characterized by the use of quebratitol, but the optically active 1L-1-acetamido-3,4,5,6-tetra-0-acetyl-1-deoxy-2-0-methyl-thyro-inositol (I ), the method includes the steps of azidating the 1-position of L-quebratitol and then reducing and acetylating the azide group to form an acetylamino group;
- 3rd, 4th, 5th and 6th positions of Quebratitol are 0
- A production method that involves a step of forming an acetyl group, and an optically active 1L-1-acetamido-2,4,5,6-tetra-0-acetyl-1-deoxy-3-O-methyl-styro-inositol ( In the case of the manufacturing method II), L-
A process of azidating the 6-position of quebratitol and then reducing and acetylating the azide group to form an acetylamino group; and 1-, 3-, 4-, and 5-positions of L-quebratitol.
A manufacturing method that involves a step of changing the position to an 〇-acetyl group is preferred.

An example of a preferred manufacturing method will be explained below based on FIG. 1.

optically active 1L-1-acetamide-34,5,6-
Tetra-0-acetyl-1-deoxy-2-0-methyl-thyro-inositol (I) and optically active 1L-1
Synthesis of -acetamido-2,4,5,6-chitler ○-acetyl-1-deoxy-3-O-methyl-styro-inositol (II)> Since it is a group, two adjacent hydroxyl groups (the hydroxyl group at the 3 and 4 positions and the hydroxyl group at the 5 and 6 positions) can be protected with a bridge type protecting group. Examples of such protecting groups include isopropylidene, cyclohexylidene, and benzylidene groups. and,
In the reaction for introducing a protecting group, 2,2-dimethoxypropane, acetone, cyclohexanone, or benzaldehyde is used, respectively.

When L-quebratitol 1 is treated with a compound (2,2-dimethoxypropane in the example shown in Figure 1) for introducing the above-mentioned bridge-type protecting group, only the hydroxyl group at position 5.6 undergoes bridge-type protection. A mixture of compound 2 protected with a group (isopropylidene group in the example shown in FIG. 1) and compound 3 protected with the hydroxyl groups at the 3.4- and 5.6-positions is obtained.

Therefore, using water and an organic solvent such as ethyl acetate, compound 1 is extracted into the aqueous phase and compound 3 into the organic phase.

Preferably, after crystallizing Compound 3, when Compound 3 is reacted with an organic sulfonyl halide such as alkylene sulfonyl halide, P-toluene sulfonyl halide, naphthylsulfonyl halide, etc. in the presence of pyridine, a protecting group (the example shown in FIG. 1) is formed. In this case, the methanesulfonyl group) is 1
bond to the oxygen atom at

Next, when hydrochloric acid or the like is applied, the bridge-type protecting groups at the 3.4-position and 5.6-position are removed and the hydroxyl group is regenerated.

Subsequently, when acetic anhydride is reacted in the presence of pyridine,
The hydroxyl groups at the 3rd, 4th, 5th, and 6th positions are acetylated to give Compound 4.

When this compound 4 is reacted with an azidating agent such as sodium azide, ammonium azide, potassium azide, barium azide, etc., and simultaneously reacted with 2-methoxyethanol, a compound 5 in which the 1-position is substituted with an azide group is produced. and a compound in which the 6-position is substituted with an azide group are obtained as a mixture. In addition, in a compound in which the 6-position is substituted with an azide group, the 1-position and the 6-position are simultaneously reversed. The introduction position of the azide group and the inversion of the substituents here are inevitably determined by the electron bias in the transition state of compound 4 before undergoing the nucleophilic substitution reaction with the azidating agent and the steric hindrance by the methanesulfonyl group. Ru.

Subsequently, when acetic anhydride is reacted in the presence of pyridine,
The methanesulfonyl group bonded to the oxygen atom at the 1st position of a compound in which the 6th position is substituted with an azide group is substituted with an acetyl group, resulting in Compound 6.

At this stage, the compound sample and the compound sample are a mixture, so Compound 5 and Compound 6 are each isolated from this mixture by means such as silica gel column chromatography.

Note that at the same time as reacting compound 4 with the azidating agent, 2-
When methoxyethanol is reacted to obtain a mixture of compound 2 in which the 1st position is substituted with an azide group and a compound in which the 6th position is substituted with an azide group, each compound is immediately isolated, and then the 6th position is an azide group. The methanesulfonyl group bonded to the 1st-position oxygen atom of the substituted compound may be substituted with an acetyl group.

Next, when this compound 5 is subjected to a reduction reaction in the presence of acetic anhydride, the azide group is reduced and acetylated to form an acetylamino group, resulting in compound 7 (1L-1-acetamide ~ 34.5. 6-tetra-0-acetyl-1
-Deoxy-2-0-methyl-thyro-inositol is obtained. Note that a nickel-based catalyst is usually used in this step.

Similarly, when Compound 6 is subjected to a reduction reaction in the presence of acetic anhydride, the azide group is reduced and acetylated to form an acetylamino group, Compound 8 (1L-1-acetamide-2°4.5. 6-tetra-0-acetyl-1
-Deoxy-3-O-methyl-styro-inositol is obtained. Note that a nickel-based catalyst is usually used in this step.

The above is a preferred example of the production method of the present invention, and in each step, operations such as extraction, concentration, desalting, purification, etc. are usually performed as necessary.

<Example> EXAMPLES The present invention will be specifically explained below with reference to Examples.

(Example) 1L-1-acetamide-3,4゜5.6-
Tetra-0-acetyl-1-deoxy-2-0-methyl-thyro-inositol (compound 7) (1) and 1L-
Synthesis of 1-acetamido-2,4,5,6-tetra-0-acetyl-1-deoxy-3-〇-methyl-styroinositol (compound 8) (II) Compound starting from L-quebrachitol The synthesis steps of No. 7 and No. 8 will be explained based on FIG. 1.

■ L-quebratitol (compound 1) 10.0 g (51.5 mmof) and DMF 100
mjl, 2,2-dimethoxypropane 31mj! (25
0 mmof) and 0.5 g of p-toluenesulfonyl chloride were added (the reaction solution had a pH of about 4), and the mixture was stirred at room temperature for 16 hours. After neutralizing by adding sodium hydrogen carbonate, 300 mA of ethyl acetate and 300 ml of water were added and shaken, and 1 L of 5,6-0-isopropylidene-2-〇-methyl-thyroinositol (compound 2)
, 1L-1,2:3,4-di-0-isopropylidene-5-0-methyl-thyro-inositol (compound 3) was extracted into the organic phase.

(2) After drying the organic phase over anhydrous sodium sulfate, the sodium sulfate was filtered off, and the filtrate was concentrated under reduced pressure to obtain 36.9 g of the compound as a pale yellow syrup. Compound 3 was then crystallized from this syrup using petroleum ether.

To 325 mg (1,18 mmof) of compound 3, 2 mjl of pyridine and 1 ml of methanesulfonyl chloride
83 μfl (2,36 anofL) was added and stirred at room temperature for 15 hours. The reaction solution was diluted with 30 mJ2 of ethyl acetate, washed with 10 mJ2 of water, dried over anhydrous sodium sulfate, and the sodium sulfate was filtered off to obtain a pale yellow syrupy residue.

1 ml of ethanol and IMHCjlj4m12 were added thereto, and the mixture was stirred in an oil bath at 50°C for 1 hour.

Toluene was added to the reaction solution, and the mixture was azeotroped with the toluene, and the reaction solution was concentrated under reduced pressure. 5 mJZ of pyridine and 5 ml of acetic anhydride were added to 0.35 g of the residue after concentration under reduced pressure, and the mixture was stirred at room temperature for 3 hours. Toluene was added to the reaction solution, and the mixture was azeotroped with the toluene, and the reaction solution was concentrated under reduced pressure. Obtained residue 0.57g
Silica gel column chromatography (toluene:
Purified with MEK=4:1), 1L-3,4,5
, 6-tetra-0-acetyl-1-〇-methylsulfonyl-2-0-methyl-thyro-inositol (compound 4
) 467 mg (yield*: 90%) was obtained.

Compound 4 Rf=0.37 (Tolyne:MEK=3:1 (V+V)) Melting point Syrup IR, (neat) 1750 cm-' (OAc),
1175cm-'(SO2)' H-NMR(90MHz, CD C
fl 3 ) δ = 5, 63~5. 50 (m, IH, H-6)
, 5, 45-5, 20 (m, 3H, H-3, 4, 5), 5, 08 (dd, IH% J Engineering 3.5
Hz, J=5. 0Hz, H-1), 3,
76-3. 54 (m, IH, H-2),
3, 48 (s, 3H, OMe), 3,
20 (s, 3H, 0M5), 2, 17
, 2 , 08 , 2 , 02 , 1 , 98 (4s
, each 3 H, 4x OA c
) Elemental analysis theoretical value (CI6H240125) C: 43.63%, H: 5.49% Actual value C: 43. 33%, H:5.15% [α)
D-27.

(C1,35, CHCjZs) ■To 485 mg (1°10 mmoj2) of Compound 4, 354 mg (5,45 mmon) of sodium azide and 5 mJ2 of 90% 2-methoxyethanol aqueous solution were added, and the mixture was heated under reflux for 13 hours in an oil bath at 120°C. did. Toluene was added to the reaction solution, and the mixture was azeotroped with toluene, and the reaction solution was concentrated under reduced pressure to obtain a brown solid residue.

To this were added 5 mu of pyridine and 5 mρ of acetic anhydride, and the mixture was stirred at room temperature for 3 hours. Toluene was added to the reaction solution, the mixture was azeotroped with toluene, the reaction solution was concentrated under reduced pressure, diluted with ethyl acetate, and insoluble materials were filtered off. The filtrate was concentrated under reduced pressure to obtain 0.45 g of a brown syrupy residue. This was purified by silica gel column chromatography (toluene:ethyl acetate = 6:1), and 1L-3゜4.5.6-tetra-0-acetyl-1-azido-1-deoxy-2-0-
Methyl-thyro-inositol (compound 5) 290mg
(Yield: 68%) and 1L-2,4,5,6-tetra-
0-acetyl-1-azido-1-deoxy-3-〇-methyl-styloinositol (compound 6) 16 mg (
Yield: 4%) was obtained.

Compound 5 Rf=0.33 (Toluene:Ethyl acetate=5:1 (V:V)) Melting point Syrup IR (neat) 2100 cm (N3), 175
0cm-'(OAc)' H-NMR(90MHZ, CD CA
3) δ = 5.55 ~ 5.00 (m, 4H, H-3, 4, 5, 6), 4.12 (t, IH, J,, = J,, ~4.0
Hz, H-1), 3.61 (dd, IH, J2 to 9, OHz, H-2), 3.49 (s, 3H%OMe), 2.16.2.07.2.02.1 .97 (4s%ea
ch 3H, 4xOAc) Elemental analysis δ = Theoretical value (CISH21N30s) C: 46.51%, H: 5 46%, N: 10.84% Actual value C: 46. 73%, H:5.45%, N:
10.47% [α)o 14.4° (c O,44, CHCll5) Compound 6 Rf = 0.34 (Toluene: Ethyl acetate = 5: t (V:V)) Melting point 144-145°C (ethanol) IR(neat)
2100cm (N3), 1750cm-' (OA
c) 'HNMR (90MHz, CD C42s
)5, 23-4, 93 (m, 4H, H-2, 4, 5, 6), 3, 73-3. 30 (m, IH% H-3
) , 3, 42 (s, 3H, OMe)
, 2 , 17 , 2 , 08 , 2 , 06 , 2 0
0 (4s, each 3H, 4x OA
c) Elemental analysis theoretical value (CIlH21N3011) C: 46.51%,) i: 5.46%, N: 10.84
% Actual value C: 46.73%, H: 5.45%, N: 10.47% [α] D −9° (c O, 78, CHCA!) ■ Compound 5 1
57 mg (o, 405 mmon) and 0.0 mg of acetic anhydride.
2mj2 and Lane Nickel-74. (Catalyst) One small spatula was added, and the mixture was stirred under a hydrogen atmosphere (1 atm) for 6 hours. After filtering off the catalyst, 1L-1-acetamido-3,4°5.6-tetra-
0-acetyl-1-deoxy-2-〇-methyl-thyroinositol (compound 7) (I) 152 mg (yield:
93%). Compound 7 was a white solid.

Compound 7(I) Rf=0.47 (Toluene:ethanol=5:1 (V:V)) Melting point 1
83-184℃ (chloroform) IR (neat)
3300cm-'(NH), 1750cm-'(OA
c), 1650 cm-' (NHAc), 1550 Cm-' (NH) 'H-NMR (90 MHz1 CDCIIs) δ = 6, 09 (d, IH% Jl, NH-4, OHz, NH), 5
, 65-5. 50 (m, IH, H-6)
, 5, 38-5, 06 (m, 3H, H-3, 4, 5), 4, 73-4. 48 (yn, IH, H-1
), 3.80-3. 60 (m, IH, H
-1) , 3, 47 (s, 3H, OMe)
, 2, 12, 2. 10. 2. 04, 2.03 (
4s, 3H, 3H, 3H, 6H5 4XOAc, NHAc) Elemental analysis theoretical value (CI7H25N Oto) C: 50.62%, H: 6.25%, N: 3.47% Actual value C: 50.40%, H: 5.93%, N: 3.48% [α) o -1o, 5° (c 1.04, CHCus) ■ Compound observation 12 mg (31 μmou), acetic anhydride 0.2 mf, Raney nickel-74 (catalyst) One small spatula was added, and the mixture was stirred under a hydrogen atmosphere (1 atm) for 10 hours. After filtering off the catalyst, it was purified by silica gel column chromatography (toluene:ethanol=5:1) to obtain 1L-1-acetamido-2,4,5,6-tetra-0-acetyl-1-deoxy-3. 8 mg (yield: 64%) of -O-methyl-styro-inositol (compound view) (II) was obtained.

Compound 8 was a white solid.

Compound 8 (II) Rf=0.39 (Toluene:ethanol=5:1 (V:V)) Melting point 2
06-208℃ (chloroform) IR (neat)
3260cm (NH), 3230cm-
'(NH), 1750cm-'(○ Ac), 1660cm-'(NHAc), 1570cm-
'(NH) 'H-NMR (90 MHz, CDCl2) δ = 5, 6 6 (d, I H, Jl, NH = 1
0, 0Hz, NH), 5, 25-4, 83 (m, 4H, H-2, 4, 5, 6), 4, 31 (q, IH, J 1. = J+
, =10, 0Hz, H-1), 3, 62~3. 46 (m, IH, H-3)
, 3, 45 (S, 3H, OMri, 2
, 09, 2.07, 2 , 01 , 2.00.1, 8
8 (5s % each 3H,4XOAc
, NHAc) Elemental analysis theoretical value (C+tH2sN Oto) C: 50.62%, H: 6.25%, N: 3.47% Actual value C: 50.84%, H: 6.25%, N: 3 .46
% [α)o 3.4° (co, 26, CHCJIs) <Effects of the invention> The present invention provides novel aminocyclitols, optically active 1L-1-acetamido-3,4,5,6- Tetra-0-acetyl-1-deoxy-2-〇-methyl-thyroinositol and 1L-1-acetamide-2
,4゜5.6-tetra-0-acetyl-1-deoxy-
3-0-methyl-styro-inositol and methods for producing the same starting from L-quebratitol are provided.

The novel aminocyclitols of the present invention can be further converted into other aminocyclitols or derivatives thereof, and can be used as raw materials for antibiotics, medicines such as anticancer drugs, agricultural chemicals, etc. Therefore, it is a very useful compound.

Since the production method of the present invention uses ebrachitol as a starting material, which has no optical activity, there is no need to perform optical resolution.
In addition, compared to the conventional production method of aminocyclitol,
The number of steps is small and consists of simple steps.
Therefore, aminocyclitols can be provided at low cost and in high yield.

[Brief explanation of drawings]

FIG. 1 shows the graph from L-quebratitol to 1L-1-acetamido-3,4,5,6-tetra-0-acetyl-1-
Deoxy-2-0-methyl-thyro-inositol and 1L-1-acetamido-2,4,5,6-tetra-0
-acetyl-1-deoxy-3-O-methyl-styro-
It is a reaction route diagram leading to inositol. 1G. 502 CHI

Claims (6)

[Claims] (1) Optically active 1_L-1-acetamido-3,4,5,6-tetra- represented by the following formula (I)
O-acetyl-1-deoxy-2-O-methyl-thylo-
Inositol. ▲There are mathematical formulas, chemical formulas, tables, etc.▼……(I) (2) Optically active 1_L-1-acetamido-2,4,5,6-tetra- represented by the following formula (II)
O-acetyl-1-deoxy-3-O-methyl-styro-inositol. ▲There are mathematical formulas, chemical formulas, tables, etc.▼……(II) (3) Optically active 1_L-1-acetamide-3,4 characterized by using L-quebratitol as a starting material
,5,6-tetra-O-acetyl-1-deoxy-2-
A method for producing O-methyl-thyro-inositol. (4) A step of azidating the 1st position of L-quebratitol and then reducing and acetylating the azide group to form an acetylamino group; and 3rd, 4th, and 5th positions of L-quebratitol.
Optically active 1_L-1-acetamide-3, which is characterized by passing through a step of making O-acetyl groups at the 6- and 6-positions,
4,5,6-tetra-O-acetyl-1-deoxy-2
- Method for producing O-methyl-thyro-inositol. (5) Optically active 1_L-1-acetamide-2,4 characterized by using L-quebratitol as a starting material
,5,6-tetra-O-acetyl-1-deoxy-3-
A method for producing O-methyl-styro-inositol. (6) A step of azidating the 6-position of L-quebratitol and then reducing and acetylating the azide group to form an acetylamino group;
Optically active 1_L-1-acetamide-2, which is characterized by passing through a step of making O-acetyl groups at the 5- and 5-positions,
4,5,6-tetra-O-acetyl-1-deoxy-3
- Method for producing O-methyl-styro-inositol.