JPH05331140A - Method for producing 2-azabicyclo [2.2.1 hept-5-en-3-one - Google Patents

Abstract

(57) [Abstract] [Objective] 2-azabicyclo [2.2.1] hept-5-en-3-one is synthesized by condensation reaction of sulfonyl cyanide and cyclopentadiene, which is one of the conventional techniques. In order to improve the drawbacks sometimes found, 2-azabicyclo [2.2.1] hept-5-en-3-one can be economically and safely produced with high purity and high yield by using cyclopentadiene as a starting material. It is intended to provide a method for manufacturing. [Structure] 2-azabicyclo [2.2.1] hept-5-en-3-one is obtained by reacting a specific substituted sulfonyl cyanide and cyclopentadiene in water or a water-hydrocarbon mixed solvent. It is a manufacturing method.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to 2-azabicyclo [2.2.1] which is an intermediate for synthesizing carbocyclic nucleosides useful as medicines such as antiviral agents.
It relates to a method for producing hept-5-en-3-one.

[0002]

[Industrial application] Carbocyclic nucleosides have a structure in which the oxygen atom that constitutes the furanose ring of the nucleoside is replaced with a methylene group, and its structure is similar to that of natural nucleosides. Can act as a substrate or inhibitor of

Further, since it has no glycosidic bond, it is not cleaved by nucleoside phosphorylase or hydrolase, and its metabolic pathway is different from that of natural nucleosides, thus showing various physiological activities. Alisteromycin
It is known as "thermycin" and is noted for its strong cytotoxicity.

Recently, carbocyclic-2,
3-Dideoxy-2,3-didehydroguanosine is anti-H
It is being developed as an IV agent [R. Vince et al.
B. B. R. C. 156, 1046 (1988)].

2-azabicyclo [2.2.1] hept-
5-en-3-one is the carbocyclic moiety of these carbocyclic nucleosides, 2α, 3α.
-Dihydroxy-4β-aminocyclopentane-1β-
Methanol or cis-4-aminocyclopent-2
It is the most used compound as an intermediate for the pure chemical synthesis of -ene-1β-methanol and the like [R. V
ince et al. Org. Chem. , 43, 2311
(1978); L. Kamm et al., J. Am. Org. Ch
em. 46, 3268 (1981); C. Fai
th et al. Org. Chem. , 50, 1983 (1
985); C. Cermak et al., Tetrahed
ron Letters 1981, 2331; V
ince, J. Med. Chem. , 33, 17 (19
90); Vince et al., Tetrahedron
Letters 1976, 3005; D. Enn
is, Nucleosides & Nucleoti
des 9,875 (1990)].

[0006]

2. Description of the Related Art There are two known methods for synthesizing 2-azabicyclo [2.2.1] hept-5-en-3-one.

The first method involves cycloadding cyclopentadiene and p-toluenesulfonyl cyanide to give 3-tosyl-
2-Azabicyclo [2.2.1] hepta-2,5-diene, and a method of removing the tosyl group at the 3-position using acetic acid [J. C. Jagt et al. Org. Chem. , 3
9,564 (1974); Vince et al. Or
g. Chem. 2311 (1978); L. Ka
mm et al. Org. Chem. , 46, 3268 (1
981)], and the second method is a method of cycloadding cyclopentadiene and chlorosulfonyl isocyanate to remove the chlorosulfonyl group using sodium sulfite (J. Malpass et al., J. Chem. So.
c. , Perkin I, 1977, 874).

The first method requires that cyclopentadiene, which is stoichiometrically equimolar to p-toluenesulfonylcyanide, must be used in a large excess of 15 to 35 times by mole. A step of concentrating and extracting 3-tosyl-2-azabicyclo [2.2.1] hepta-2,5-diene, which is a body, and pulverizing it into a powder is required. The p-toluenesulfonyl cyanide used to remove the tosyl group at the 3-position of the resulting intermediate was
Acetic acid is used in a large excess of 5 to 23 times and must be added all at once. Furthermore, the rapid exothermic reaction at that time is controlled, and the heat removal efficiency is particularly good in order to react at a predetermined temperature or lower. When a heat exchanger is required and the exothermic reaction can be controlled, 2-azabicyclo [2.2.1] hept-5-en-3-one can be synthesized with a yield of about 60 to 70%. If the exothermic reaction cannot be controlled, the product cannot be isolated at all or can be obtained in very low yields. Further, in order to isolate 2-azabicyclo [2.2.1] hept-5-en-3-one, a large amount of an alkaline substance is required to neutralize acetic acid used in a large excess, and in that case, There are many problems such as the need to control the exothermic reaction and the reaction below a predetermined temperature, and further, the quality of the obtained crystals is inadequate, which is economically and safely industrially satisfactory. It cannot be said to be an uru manufacturing method.

The second method is a method suitable for synthesizing 6-azabicyclo [3.2.0] hept-3-en-7-one, which is a by-product originally, and 2-azabicyclo [2.2.
1] Hept-5-en-3-one needs to be repeatedly purified by column chromatography or the like in order to isolate it, and crystalline 2-azabicyclo [2.2] can be obtained with an isolated yield of up to 27.5%. 1] It has only been reported that hept-5-en-3-one can be synthesized, and the quality of the obtained crystals is insufficient, which is not very satisfactory as an industrial production method. ..

[0010]

The object of the present invention is 2-azabicyclo [2.2.1] hept-5 by the condensation reaction of sulfonyl cyanide and cyclopentadiene, which is one of the conventional techniques. The drawbacks found in the synthesis of -en-3-one were improved, and 2-azabicyclo [2.2.1] hept- was used starting from cyclopentadiene.
It is intended to provide a method for economically and safely producing 5-en-3-one with high purity and high yield.

[0011]

This object is characterized in that a substituted sulfonyl cyanide represented by the following general formula (1) and cyclopentadiene are reacted in water or a water-hydrocarbon mixed solvent. 2-Azabicyclo [2.2.
1] It is achieved by the method for producing hept-5-en-3-one.

[0012]

[Chemical 2] (However, R ₁ and R ₂ are a hydrogen atom, an alkyl group, and a halogen atom.) Hereinafter, the method of the present invention will be described in more detail.

The substituted sulfonyl cyanide represented by the following general formula (1) used in the present invention is preferably phenyl, p-methylphenyl (p-tolyl, p-toluene), m-methylphenyl, The case of o-methylphenyl, 3,4-dimethylphenyl, m-chlorophenyl, p-chlorophenyl derivative and 3,4-dichlorophenyl, particularly preferably phenyl, p-methylphenyl or p-chlorophenyl derivative.

[0014]

[Chemical 3] (However, R ₁ and R ₂ are a hydrogen atom, an alkyl group, and a halogen atom.) The substituted sulfonyl cyanide used in the present invention is as described in M. S. A. Vrijland's method [Organic Syntheses 57, 88].
Can be used to cyanate the corresponding substituted sulfinic acid metal salt with cyanogen chloride or cyanogen bromide, and the product immediately after the synthesis can be dried and isolated as a liquid or crystal, or It is preferably used as a solution or slurry liquid of a hydrocarbon solvent used in the method.

The cyclopentadiene used in the present invention is preferably used immediately after the dicyclopentadiene is depolymerized and subjected to fractional distillation under the condition that the receiver is cooled with a refrigerant or a cryogen.

When the previously stored cyclopentadiene is used in the method of the present invention, cyclopentadiene is rapidly dimerized to dicyclopentadiene at room temperature. It is desirable to use the one kept in at least -20 ° C or lower.

The amount of cyclopentadiene used is at least 1 time mol, preferably 1 mol, based on the substituted sulfonyl cyanide.
~ 2 times the molar amount. That is, the reaction may be carried out in an amount of more than 2 times the molar amount, but it is necessary to prepare equipment for recovering the clopentadiene used in excess, or to dimerize cyclopentadiene generated by using it in excess. Due to the multimerization reaction, the amount of by-products is increased and the yield and the purity decrease.

The greatest feature of the present invention is that the reaction is carried out in water which is a solvent capable of easily promoting the hydrolysis reaction of the substituted sulfonyl cyanide.

The cyclocondensation reaction between cyclopentadiene and the substituted sulfonyl cyanide is faster than the hydrolysis reaction rate of the substituted sulfonyl cyanide, and 3-tosyl-2-azabicyclo [2. 2.1] It is considered that the decomposition reaction of the 3-position substituent of hepta-2,5-diene occurs promptly to allow the reaction in water to proceed.

When the condensation reaction of cyclopentadiene and the substituted sulfonyl cyanide is carried out, the amount of water used is 5 to 30 times mol, preferably 10 to 2 times the molar amount of the substituted sulfonyl cyanide.
It is desirable to use it in a 0-fold molar range.

In the present invention, it is possible to coexist with a hydrocarbon solvent. Suitable hydrocarbon solvents in that case are acyclic, cycloaliphatic hydrocarbons and / or aromatic hydrocarbons having 5 to 10 carbon atoms, preferably hexane, heptane, cyclohexane, benzene, toluene, It is xylene.

The use of a hydrocarbon-based solvent shows solubility which is convenient for separating the raw material intermediate, the product and the by-product from each other, and further, the sulfinyl sulfone compound which is a by-product precipitated after hydrolysis is used. Since it has a function of making it difficult to adhere to the vessel wall of the reactor, it may be convenient depending on the type of the substituted sulfonyl cyanide used.

When a hydrocarbon solvent coexists, it is preferably used in a range of 0.5 to 20 times mol, preferably 1 to 3 times mol, of the substituted sulfonyl cyanide.

The condensation reaction proceeds by mixing the substituted sulfonyl cyanide and cyclopentadiene in water. First, the substituted sulfonyl cyanide is added to water or a water-hydrocarbon solvent and stirred. The method of dropping cyclopentadiene is preferable.

The temperature at the time of dropping cyclopentadiene is 0 to
It is 50 ° C., preferably 0 to 25 ° C.

Cyclopentadiene dropping time is 10 to 6
It is desirable to do it for 0 minutes.

After the dropwise addition of cyclopentadiene, the temperature of the reaction system is 0 to 50 ° C, preferably 0 to 25 ° C. 0.5 ~
After stirring for 2 hours, the by-product sulfinyl sulfone compound is separated by a usual organic chemical method such as filtration and liquid separation.

If the reaction system is left to stand for a long time, the decomposition reaction of the by-product sulfinyl sulfone compound may cause the decomposition reaction of the product. Therefore, it is desirable to separate the by-product within 24 hours.

2-azabicyclo [2.2.1] hept-
When the isolation of 5-en-3-one is carried out in a water-hydrocarbon solvent, the filtered reaction liquid is a two-phase system, and thus the aqueous solution is first separated. If performed in water, perform the following operations as they are.

Since the obtained aqueous solution is acidic due to a small amount of by-product sulfinic acid, if it is left in an acidic state for a long period of time, the decomposition reaction of the product is likely to occur, and the yield and the purity are lowered. It is desirable to adjust the pH to 7-8. Inorganic alkaline substance for pH adjustment,
Alkali metal hydroxides and alkali metal carbonates are particularly preferable.

In the case of carrying out the reaction with a water-hydrocarbon solvent, some products are dissolved in the separated organic solution when the hydrocarbon solvent used is an aromatic solvent. It is desirable to extract the product with water, adjust the pH of the aqueous solution to 7 to 8 in the same manner as described above, and then mix with the pH adjusted aqueous solution after liquid separation. The pH-adjusted aqueous solution is salted out by adding sodium chloride, if necessary, to obtain a saturated sodium chloride solution, and then extracted with a chlorine-based hydrocarbon solvent, preferably methylene chloride or dichloroethane.

The product can be isolated by concentrating the extract thus obtained.

The product after concentration obtained by the method of the present invention has a purity that can be sufficiently utilized for the synthesis of an antiviral intermediate in the next step, but if necessary, distillation, treatment with activated carbon, It can be further purified by a usual organic chemical method such as recrystallization or sublimation.

[0034]

【Example】

Synthesis Example 1 Synthesis of benzenesulfonyl cyanide In a 1000 ml flask equipped with a thermometer, a condenser, a stirrer and a cyanogen chloride inlet tube, 268.0 g of sodium benzenesulfinate dihydrate (1.34 mo)
1) and 470 g of water were added. Keeping the temperature of the reaction system at 10 ° C., 90.6 g of cyanogen chloride (purity 95.5%, 1.4
(1 mol) was introduced into the flask over 100 minutes with nitrogen. After the completion of the introduction of cyanogen chloride, 3 more at 5 ℃
Stir for 0 minutes. The lower layer was separated to obtain 212.5 g of crude benzenesulfonyl cyanide (purity 97.9%). This is distilled to obtain a fraction of 86 to 88 ° C./2.5 mmHg,
198.3 g of benzenesulfonyl cyanide was obtained. Synthesis Example 2 Synthesis of p-toluenesulfonyl cyanide In a 300 ml flask equipped with a thermometer, a condenser, a stirrer and a cyanogen chloride inlet tube, 54.8 g (0.215 mo of sodium p-toluenesulfinate tetrahydrate) was added.
1), 200 g of water and 30 ml of toluene were charged.
After adjusting the reaction solution to 10 ° C with a water bath,
2 ml (purity 95.5%, 0.225 mol) were introduced into the reactor over 60 minutes with nitrogen entrainment. After the introduction of cyanogen chloride, the mixture was further stirred at 10 ° C. for 60 minutes. After separation by filtration,
Toluene solution of p-toluenesulfonyl cyanide 56.
1 g was obtained. The concentration of p-toluenesulfonyl cyanide was 61.5% and the yield was 88.6%. Synthesis Example 3 Synthesis of cyclopentadiene 504.7 g of dicyclopentadiene was placed in a 1000 ml distillation flask equipped with a distillation column kept at 50 ° C and a receiver cooled at -20 ° C, and heated to 160 to 180 ° C. , Pyrolysis of dicyclopentadiene for 8 hours, 40-5
307.5 g of cyclopentadiene was obtained as a fraction at 0 ° C. The yield based on dicyclopentadiene was 60.9%. Example 1 89.6 g (0.536 mol) of benzenesulfonyl cyanide and 111 of toluene in a 500 ml four-necked flask.
g, 150 g of water were charged, and CPD of 46.9 g (0.70
(2 mol) was added dropwise over 12 minutes while maintaining the reaction temperature at 9 to 11 ° C. After reacting for 1.5 hours after dropping, the reaction solution was filtered and the filtered product was washed with 30 ml of toluene. The filtrate was separated into a toluene layer and an aqueous layer, and the aqueous layer was neutralized with a 25% aqueous sodium hydroxide solution at a temperature of 15 ° C. or lower until pH = 8.2. The toluene layer was extracted with 75 g of water, and this aqueous layer was also neutralized with 25% aqueous sodium hydroxide solution to pH = 8.2. The two aqueous layers were mixed, saturated with sodium chloride, extracted three times with 250 g of methylene chloride and then distilled under reduced pressure to give a melting point of 5
38.7 g (yield 66%) of 2-azabicyclo [2.2.1] hept-5-en-3-one showing 5 to 57 ° C was obtained. Example 2 20.1 g of benzenesulfonyl cyanide (0.120 m
ol) and 50 ml of water were placed in a 100 ml four-necked flask and adjusted to 15 ° C., and then cyclopentadiene 10.2
g (0.155 mol) was added dropwise over 19 minutes. 1
The reaction was carried out at 5 ° C for 20 minutes and then cooled to 3 ° C. The reaction solution was filtered, and the precipitate separated by filtration was washed with 10 g of water. To the filtrate was added 25% aqueous sodium hydroxide solution to neutralize the pH to 7.9, and then salt was added to saturate the mixture with methylene chloride 6
Extracted twice with 5 g. The methylene chloride solution was distilled under reduced pressure to give 2-azabicyclo [2.
2.1] hept-5-en-3-one 9.3 g (yield 7
1%) was obtained. Example 3 Into a 500 ml four-necked flask, 110.6 g (0.66 mol) of benzenesulfonyl cyanide and 150 g of water were put and, with stirring, 53.3 g (0.80) of cyclopentadiene.
7 mol) was added. After reacting at 5 to 15 ° C for 45 minutes, the reaction solution was filtered while being cooled to 5 ° C to remove a by-product sulfinylsulfone compound. The aqueous layer was neutralized to pH 8 with aqueous sodium hydroxide solution. 10 g of powdered activated carbon was added to the neutralized solution and filtered, and the filtrate was extracted 3 times with 220 g of methylene chloride. The extract is concentrated under reduced pressure, melting point 5
2-azabicyclo [2.2.
1] hept-5-en-3-one 60.3 g (yield 84
%) Was obtained. Example 4 In a 100 ml four-necked flask, 55.3 g of a toluene solution of p-toluenesulfonyl cyanide (concentration: 61.5%,
0.188 mol), toluene 6.35 g, and water 5
2.3 g of cyclopentadiene was added and 17.9 g (0.
27 mol) was added. After reacting at 10 to 20 ° C. for 45 minutes, the reaction solution was cooled to 5 ° C., and the reaction solution was filtered to remove a by-product sulfinyl sulfone compound,
The filtrate was separated into a toluene layer and an aqueous layer. The aqueous layer was neutralized with a 25% aqueous sodium hydroxide solution to pH = 8 under the condition of 15 ° C. or lower. The toluene layer was extracted with 75 g of water, and this aqueous layer was also neutralized to pH = 8 with a 25% aqueous sodium hydroxide solution.
After mixing the two aqueous layers and saturating with sodium chloride, 5 g of powdered activated carbon was added to the neutralized solution and filtered, and the filtrate was 90 g of methylene chloride.
It was extracted 3 times with. The methylene chloride extract was concentrated under reduced pressure to give 2-azabicyclo [2.2.
1] hept-5-en-3-one 17.5 g (yield 85
%) Was obtained. Example 5 108.4 g (0.538 mol) of p-toluenesulfonyl cyanide and 150 g of water were placed in a 500 ml four-necked flask.
, And cyclopentadiene 46.7g (0.70mo
1) was added and reacted at 10 to 15 ° C. for 45 minutes. The reaction solution was filtered to remove the by-product sulfinylsulfone compound, and the filtrate was adjusted to pH = with sodium hydroxide aqueous solution.
Neutralized to 7.9. The neutralized solution was saturated with sodium chloride, extracted three times with 230 g of methylene chloride, added with 6 g of powdered activated carbon and filtered, and the filtrate was concentrated under reduced pressure to give a melting point of 55.0 to 57.
41.3 g (yield 70%) of 2-azabicyclo [2.2.1] hept-5-en-3-one at 0 ° C was obtained. Example 6 m-Methylphenylsulfonyl cyanide 120 g (0.66 mol) and water 150 g in a 500 ml four-necked flask.
, Cyclopentadiene 46.70 g (0.70 m
ol) was added and the mixture was stirred at 10 to 25 ° C. for 30 minutes. The reaction solution was filtered, and the filtered product was washed with 30 ml of water. The filtrate and the washing solution were combined and neutralized to pH = 8 with an aqueous sodium hydroxide solution while keeping the temperature at 15 ° C. or lower. The neutralized solution was saturated with sodium chloride, extracted three times with 300 g of methylene chloride, added with 8 g of powdered activated carbon and filtered, and the filtrate was concentrated under reduced pressure to a melting point of 55.
54.6 g (yield 76%) of 2-azabicyclo [2.2.1] hept-5-en-3-one at 0-57.0 ° C was obtained. Example 7 Benzenesulfonyl cyanide 75.0 g (0.449 mol), hexane 50 g, in a 500 ml four-necked flask,
Add 200 g of water, 45.6 g of cyclopentadiene
(0.690 mol) was added and reacted at 15 to 25 ° C for 45 minutes. The reaction solution was cooled to 5 ° C., filtered to remove the sulfinylsulfone compound as a by-product, and separated into an aqueous layer and a hexane layer. The aqueous layer was neutralized to pH = 8 with an aqueous sodium hydroxide solution, 80 g of sodium chloride was added to the aqueous layer, and the mixture was extracted 6 times with 131 g of methylene chloride. Powdered activated carbon (5 g) was added to the methylene chloride extract and the mixture was filtered. The filtrate was concentrated under reduced pressure and the 2-azabicyclo [2.
2.1] Hept-5-en-3-one (40.2 g, yield 82%) was obtained. Comparative Example 1 60 g (0.33 mol) of crushed p-toluenesulfonyl cyanide was placed in a 500 m four-necked flask, and -1
336 g (5.1 mol) of cyclopentadiene at 8 ° C was added. After stirring at 9 to 24 ° C for 40 minutes, the reaction solution was concentrated under reduced pressure without heating at 20 ° C or lower. 105 ml of glacial acetic acid (1.
(77 mol) was quickly added and stirred. During this time, the temperature of the reaction system was cooled to 20 ° C. or lower. The reaction solution was poured into 430 ml of ice water, and after stirring, Celite was added and filtered. The filtered product was washed with 50 ml of water, the filtrate and the washing liquid were cooled to 20 ° C. or lower, and an aqueous sodium hydroxide solution was added to the mixture to neutralize the pH to 8 with stirring. The solution was saturated with sodium chloride and extracted three times with 450 ml of methylene chloride. The extract was dried over magnesium sulfate and concentrated to give a brown oil (28 g).
After distillation, 2-azabicyclo [2.2.1] hept-5-
18.8 g of en-3-one (shrinkage 52%) was obtained. The melting point of the isolate was 50 to 52 ° C. Comparative Example 2 12 g of p-toluenesulfonyl cyanide (0.066 m
ol) into a 200 ml four-necked flask, and after the temperature in the flask under ice cooling reached 6 ° C, 70.8 g (1.063 mol) of cyclopentadiene at -20 ° C was added, and
Stir for 0 minutes. The reaction solution was concentrated under reduced pressure to give a pale yellow solid 1
7.48 g was obtained. This solid was crushed, and 21.89 g (0.365 mol) of glacial acetic acid at 13 ° C. was added under ice cooling to give 1
Stir for hours. The reaction solution was poured into ice water (86 g), stirred for 30 minutes, and then decanted to obtain a supernatant (110.3 g).
Got After cooling to 20 ° C. and stirring, 12N aqueous sodium hydroxide solution was added until the pH = 7.4. To the aqueous layer was added 21.2 g of sodium chloride to saturate, and 90 ml of methylene chloride was added.
Extract 3 times with ml. The extract was dried over magnesium sulfate and concentrated to obtain 2.91 g of a brown oily substance. After standing, the precipitate was filtered to obtain 1.25 g of 2-azabicyclo [2.2.1] hept-5-en-3-one (yield 17%). The melting point of the isolated product was 48 to 51 ° C.

[0035]

EFFECTS OF THE INVENTION According to the present invention, the condensation reaction of 3-substituted sulfonyl-2-azabicyclo [2.2.1] hepta-2,5-diene and the sulfonyl group can be carried out without using a large excess of cyclopentadiene. The removal reaction of 2-azabicyclo [2.2.
1] It has the advantages that the productivity of hept-5-en-3-one can be significantly improved, and that it can be obtained with high purity and high yield, and by an industrially extremely simple method.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Rengo Igarashi No. 28 Kurashiki-cho, Nakajo-cho, Kitakanbara-gun, Niigata Prefecture Kuraray Co., Ltd. (72) Inventor Akira Nakamura 2-28 Kurashiki-cho, Nakajo-cho, Kitakanbara-gun, Niigata Prefecture Kuraray Co., Ltd.

Claims (2)

[Claims] 1. A substituted sulfonyl cyanide represented by the following general formula (1) and cyclopentadiene are mixed with water or water-
Characterized by reacting in a hydrocarbon mixed solvent 2
-Azabicyclo [2.2.1] hept-5-ene-3-
On manufacturing method. [Chemical 1] (However, R ₁ and R ₂ are a hydrogen atom, an alkyl group, and a halogen atom.) 2. The substituted sulfonylcyanide is benzenesulfonylcyanide, p-toluenesulfonylcyanide, p
The method for producing 2-azabicyclo [2.2.1] hept-5-en-3-one according to claim 1, which is -chlorophenylsulfonyl cyanide.