JPS63270682A - Production of (4s,5s)-dihydroxyl-4,5-o-isopropylidene-2-cyclopenten-1-one - Google Patents

Abstract

PURPOSE:To industrially and advantageously obtain the titled compound useful as a synthetic intermediate for prostaglandin, etc., by catalytically reacting O-acetyl-dehydro-deoxy-isopropylidene-beta-D-erythro-pentofuranose with a base. CONSTITUTION:1-O-Acetyl-4, 5-dehydro-5-deoxy-2,3-O-isopropylidene-beta-D-erythro- pentofuranose expressed by formula I is reacted with a base (e.g. sodium methoxide), as necessary, in an organic solvent, preferably at 50-70 deg.C to afford the aimed compound expressed by formula II. The compound expressed by formula I as a starting raw material can be obtained by successively reacting 2,3-O-isopropylidene-5-O-P-toluenesulfonyl-D-ribofuranose expressed by formula III with an acetylating agent, sodium iodide and 1,8-diazabicyclo[5,4-O]undecene.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Application Field) The present invention relates to the use of physiologically active substances such as prostaglandins,
(4S,5S)-4,5-dihydroxy-4 useful as a synthetic intermediate for pentenomycin, nebulanocin, etc.
,5-0-isopropylidene-2-cyclopentene-1
-Relating to a new manufacturing method for on.

More specifically, the present invention provides (4) represented by the following formula (1).
A novel method for the preparation of S,5S)-4,5-dihydroxy-4,5-0-isopropylidene-2-cyclopenten-1-one is presented.

(Prior Art) Conventionally, regarding the synthesis method of the compound of formula (1) above, for example,
The synthesis method shown in the process diagram below is known (J, Am
, Chem, Soc, 108.5655-5656 (
1986).

<a>('D) (
C) [dn(ε)] The synthesis method shown in the reaction process diagram above involves oxidizing cyclopentadiene of formula (a), and then acetylating it with acetic anhydride to form a compound of formula (b), which is expressed by the linear formula ( b) Oxidation of the compound with osminium tetroxide to form the diol and then acetalization to form the compound of formula (C), hydrolysis of the compound of formula (C) in the presence of an alkali, followed by dicyclohexylcarbodiimide. , trifluoroacetic acid to synthesize the racemic compound of formula (d), and linearly convert the compound of formula (d) into (
+)N,S-dimethyl-8-phenylsulfoximine to optically resolve the optically active form (4S
, 5S)-4,5-dihydroxy-4,5-0-isopropylidene-2-cyclopenten-1-one.

(Problems to be solved by the invention) In the above-mentioned conventional proposals, the reaction steps are long, the reaction operations are complicated, the yield is low (total yield 40%), and in addition, it is not suitable for industrial use. Complicated optical resolution means and reagents (
For example, osminium tetroxide) is required.

(Means for Solving the Problems) The present inventors have conducted extensive research in order to avoid the disadvantages and shortcomings of the above-mentioned conventional proposals.

As a result, by using β-D-ribofuranose, which is easily available on the market, as an asymmetric source, (4S) of the above formula (1) of the present invention can be obtained with high optical purity.

It has been discovered that 5S)-4,5-dihydroxy-4,5-0-isopropylidene-2-cyclopenten-1-one can be industrially advantageously synthesized in high yield and with simple operations.

That is, according to the research of the present inventors, it was found that 2,3-0
l-0-acetyl-4 represented by the following formula (2), which can be easily synthesized in 3 steps using -iso4propylidene-5-〇-P-)luenesulfonyl-D-ribofuranose as a starting material ,5-dehydro-5-
It has been discovered that the compound of formula (1) of the present invention can be easily synthesized with high purity by contacting deoxy-2,3-0-isopropylidene-β-D-erythro-bentofuranose with a base.Therefore, the present invention The purpose of is to solve the above equation (
1) (4S,5S)-4,5-dihydroxy-4,5
-0-isopropylidene-2-cyclopenten-1-one is produced with high optical purity using D-ribofuranose as an asymmetric source without racemization during the reaction process.
The purpose is to provide a new method for synthesis.

The above objects and many other objects and advantages of the present invention will become more apparent from the following description.

The process diagram for producing the compound of formula (1) of the present invention can be expressed as follows.

The above formula (1) (7) (4S, 5S)-4,5- of the present invention
The method for producing dihydroxy-4,5-0-isopropylidene-2-cyclopenten-1-one will be explained in detail below according to the above process diagram.

Formula (4) 1-0-acetyl-2,3-0-isopropylidene-5-0-P-)luenesulfonyl-β-D-
Ribofuranose can be easily synthesized by reacting the above formula (5) % toluenesulfonyl-D-ribofuranose with acetic anhydride in pyridine, for example.

This reaction is carried out at a temperature range of, for example, about 0° to about 70°C, preferably about 0° to about 30°C, for example about 1
The reaction can be carried out for about 5 hours.

The amount of acetic anhydride used in the above reaction is, for example, about 0.5 to about 5 mol, more preferably about 1 to about 3 mol, based on the compound of formula (5). be able to. There is no particular restriction on the amount of pyridine used, and it can be used within a wide range.
) It is used in an amount of about 1 to about 30 times the weight of the compound. After the reaction is completed, the reaction product is extracted with a solvent such as ethyl acetate, washed with saturated brine, and then washed with anhydrous chlorine.
After drying with magnesium Jk acid and concentrating, the compound of formula (4) can be obtained as a crystal by purification by means such as column chromatography.

From the compound of formula (4) that can be synthesized as described above, 1-0-acetyl-5-deoxy-5-iodo-2,3-0-isopropylidene-β- of formula (3)
To synthesize D-ribofuranose, a compound of formula (4) is optionally added. 0 reaction, which can be carried out by reacting with sodium iodide in a solvent, e.g.
The reaction is carried out at a temperature range of about 50''C, more preferably about 10'' to about 309C, for about 2 to about 6 hours. The range of sodium iodide used in this reaction is, for example, about 1 to about 5 moles relative to the compound of formula (4).

A more preferable range is about 2 to about 3 moles. Examples of organic solvents include 2-butanone, acetone, 2-butanol, methyl ethyl ketone, and methyl isobutyl ketone. There is no particular restriction on the amount of these 61τd media to be used, and it can be selected as appropriate.
4) A preferable range is about 5 to about 30 M@ times the amount of the compound. After the reaction is complete, for example, a saturated aqueous sodium hydrogen carbonate solution is injected to remove the product, for example.
Extract with an organic solvent such as ethyl acetate, wash with saturated aqueous sodium chloride solution and sodium thiosulfate, and dry over anhydrous sodium sulfate. After condensation, the compound of formula (3) can be obtained as crystals by purification by means such as column chromatography.

Next, from the above formula (3) compound, 1-〇-acetyl-4,5-dehydro-5-deoxy-2,3-0 of the above formula (2)
-Isopropylidene-β-ri-erythrobentofuranose is synthesized using the compound of formula (3) as desired.
It can be easily synthesized by reacting with 1,8-diazabicyclo[5,4,0]undecene in one solvent.

The above reaction is carried out, for example, in the range of about 40° to about 100″C, more preferably about 60″ to 80°C, as the amount of 1,8-diazabicyclo[5,4,0]undecene used in the reaction is For example, for the compound of formula (3), about 1
A range of about 6 mol to about 6 mol, more preferably about 2 mol to about 4 mol, can be exemplified. Also, the nH used
Examples of the medium include solvents such as benzene, toluene, xylene, and tetrahydrofuran. The amount of the organic solvent to be used may be selected as appropriate, but preferably ranges from about 5 to about 30 times the weight of the compound of formula (3).

(4S,5S)-4゜5-dihydroxy-4,5-0-isopropylidene-2-cyclopenten-1-one of the above formula (1) of the present invention can be synthesized as described above. 2) To synthesize from a compound, it can be easily synthesized by contacting the compound of formula (2) with a base in an organic solvent if desired.

The reaction can be carried out, for example, at a temperature in the range of about 30'' to about 1003C, more preferably in the range of about 50'' to about 70''C, and for a reaction time of about 30 minutes to about 3 hours. Preferred examples of the base used in this reaction include sodium methoxide, sodium ethoxide, potassium tert-butanol, etc. The amount of these bases to be used is not particularly limited and may be selected as appropriate. For example, it may be used in an amount of about 1 to about 10 mol, more preferably about 1 to about 3 mol, based on the compound of formula (2).The n-solvent used in the above reaction includes: For example, methanol, ethanol,
Solvents such as tertiary butanol can be mentioned. The amount of these organic solvents to be used may be appropriately selected, and may be, for example, about 5 to about 30 times the weight of the compound of formula (2). After the reaction is complete, a saturated aqueous sodium chloride solution is added, and the product is extracted with a solvent such as ethyl ether, washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, concentrated, and extracted using a means such as column chromatography. The purified compound of formula (1) was obtained as crystals.

Thus, (4S,5S)-4,5-dihydroxy-4,5-0-isopropylidene-2-cyclopenten-1-one of the above formula (1) of the present invention, which can be synthesized as described above, is , is a useful compound that can be easily converted into physiologically active substances such as prostaglandin, pentenomycin, and nebulanocin.

Below, several aspects of the present invention will be described in more detail by giving examples.

(Example) (1) Synthesis of 1-0-acetyl-2,3-0-isopropylidene-5-0-P-)luenesulfonyl-β-D-ribofuranose formula (4).

2.3-0-isopropylidene-5-〇-P-toluenesulfonyl-D-ribofuranose formula (5) 14.7 g
(43 mmol) was dissolved in 100 ml of anhydrous pyridine,
While cooling with ice water, 12.3 ml (129 mmol) of acetic anhydride was added. After stirring at 0°C for 10 minutes, the mixture was returned to room temperature and stirring was continued for 3 hours, and while cooling again with ice water, a saturated aqueous sodium bicarbonate solution containing ice chips was added dropwise to stop the reaction.

The product was extracted with ether, washed with saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated and purified by silica gel column chromatography (benzene: ethyl acetate = 15:1) to obtain compound 1 of formula (4).
5.8 g (yield: 96%) was obtained as syrup.

[(I]D=-13,8' (C=1.3.MeOH
)IR(NaC1)=2980.1720.1590.
1380, 1360.1170cm.

'H-NMR (TMS/CDC13) = 7.76 (2
H, m), 7.36 (2H, m), 6.19 (
IH,s), 4.70 (2H,m)4.47 (I
H, m), 4.04 (2H, m), 2.46 (3
H, s), 2.03 (3H, s), 1.47 (
3H,s), 1.31 (3H,s).

(2) Synthesis of 1-0-acetyl-5-deoxy-5-iodo-2,3-0-isopropylidene-β-〇-ribofuranose formula (3).

9.16 g (23.7 mmol) of formula (4) compound was added to 2
- Sodium iodide dissolved in 70 ml of butanone? -1
g (47.4 mmol) was added and refluxed for 4 hours. The reaction solution was cooled to room temperature, a saturated aqueous sodium bicarbonate solution was added, and the product was extracted with ethyl acetate, washed successively with a saturated aqueous sodium chloride solution and sodium thiosulfate, and then dried over anhydrous magnesium sulfate. After filtration, the filtrate was condensed and subjected to silica gel column chromatography (hexane: ethyl acetate = 10
:1) to give 7.46 g of the compound of formula (3) (yield: 9
2%) was obtained as crystals.

[a]0=-65,8° (C=0.3, M e OH
) Melting point = 38°C0 IR (KBr) = 2950.175o, 138°, 13
70.1240.1200 cm'.

'H-NMR (THS/CDC13) = 6.29, (I
H, s), 4.84 (IH, dd, J=5.86.
0.73H2), 4.73 (IH, d, J=5.8
6H2), 4.52 (IH, ddd, J=0.74
, 5.86. 10.26Hz), 3.28 (IH
, dd, J=5.86, 10.7H2), 3.09
(IH, dd, J=10.6H2), 2.07 (3
H,s), 1.50 (3H,s), 1.35
(3H,s).

(3) Synthesis of 1-0-acetyl-4,5-dehydro-5-deoxy-2,3-0-isopropylidene-β-D-erythrobentofuranose formula (2).

9.71 g (28.4 mol) of the above formula (3) compound was dissolved in 80 ml of benzene, and 6.5 g (42.6 mmol) of 1,8-azabicyclo[5,4,0-oundecene was added thereto for 3 hours. It refluxed. Cool the reaction solution to room temperature,
A saturated aqueous ammonium chloride solution was added, and the product was extracted with diethyl ether. After washing with a saturated aqueous sodium chloride solution,
It was dried with anhydrous magnesium sulfate. After filtration, the filtrate was concentrated and purified by silica gel column chromatography (petroleum ether: ethyl ether = 8:1) to obtain compound S of formula (2).

5 g (yield: 90%) was obtained as a syrup.

[α ko0= + 4 9 , 7 @ (
C = 0, 9, M e OH) I
R(NaC1)=2900.1750,1670.13
70cri'.

'H-NMR (TMS/CDC13) = 6.28 (I
H, s), 5.11 (IH, d, J=5.86H2
), 4.67 (IH, d, J=1.71H2), 4.
63 (IH, d, J=5.85H2), 4.44
(IH, d, J=2.44H2), 2.09 (3H,
s) , 1.48 (3H, s) , 1.17 C3H
,s).

(4) (4S,5S)-4,5-dihydroxy-4,5
Synthesis of -0-isopropylidene-2-cyclopenten-1-one formula (1).

5.0 g (23.3 mmol) of the compound of formula (2) was dissolved in anhydrous methanol, and 1.0 M sodium methoxide 3
5 ml was added and the mixture was refluxed at 57°C for 1 hour. The reaction solution was cooled to room temperature, a saturated aqueous ammonium chloride solution was added, and the product was extracted with diethyl ether, washed with a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate.

After filtration, the filtrate was concentrated and purified by silica gel column chromatography (petroleum ether: ethyl ether = 12:1) to obtain 2.8 g (yield: 80%) of the compound of formula (1) as crystals.

[αko0=+69-9° (C= sail 41.CH
Cl3).

Melting point = 57'C.

IR (KBr) = 1730cm'.

'H-NMR (7MS/CDC13) = 7.61 (I
H, dd, J=5.86.2.44H2), 6°22
(IH, d, J = 5.86H2), 5.27 (IH, d
dd, J=5.37, 2.45, 0°74H2), 4.
47 (IH, d, J=5.37Hz), 1.42 (
6H,S).

17-NMR (7MS/CDC13) = 159.7.1
34.5.78.8.76.7.27.6.26.4° (Effects of the Invention) According to the method of the present invention, useful physiologically active substances such as prostaglandin, pentenomycin, and nebulanocin can be used. (4S, 55)-4,5-dihydroxy-4 represented by the following formula (1) that can be used as a synthetic intermediate
, 5-isopropylidene-2-cyclopenten-1-one, using β-D-ribofuranose as an asymmetric source, can be provided with a manufacturing method that can advantageously produce industrially with high optical purity, at low cost, and with easy operation.

1 other person

Claims (2)

[Claims] (1) The following formula (2) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (2) 1-O-acetyl-4,5-dehydro-5-
The following formula (1) is characterized by the contact reaction of deoxy-2,3-O-isopropylidene-β-D-erythro-pentofuranose with a base ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (1) (4S,5S)-4,5-dihydroxy-4
,5-O-isopropylidene-2-cyclopentene-1
- On's manufacturing method. (2) The compound of formula (2) is 2,3-O-isopropylidene-5-O-P represented by the following formula (5) ▲ Numerical formula, chemical formula, table, etc. ▼ (5)
-Toluenesulfonyl-D-ribofuranose is reacted with an acetylating agent, and 1-O-acetyl-2,3-O is expressed by the following formula (4) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (4) -Isopropylidene-5-O-P-toluenesulfonyl-β-D-ribofuranose is formed, and the compound of formula (4) is reacted with sodium iodide to form the following formula (3) ▲Mathematical formula, chemical formula, table, etc. ▼ (3) 1-O-acetyl-5-deoxy-5-iodo-2,3-O-isopropylidene-β-D-ribofuranose is formed, and the compound of formula (3) is The method according to claim 1, characterized in that it is formed by reacting with 1,8-diazabicyclo[5,4,O]undecene.