JPH0827110A - Method for producing 2-azabicyclo [2.2.1] hept-5-en-3-one - Google Patents

Abstract

(57) [Summary] [Purpose] 2-Azabicyclo [2.2.1] hept-5-en-3-one is highly purified from cyclopentadiene as a starting material.
A method for producing in high yield is provided. [Constitution] 2-azabicyclo [2.2.1] hept-5 by reacting phenylsulfonyl cyanide with cyclopentadiene
In the method for producing an ene-3-one, 2-azabicyclo [reacted by reacting phenylsulfonyl cyanide and cyclopentadiene in a mixed solvent of water and a water-soluble solvent under the condition that the pH of the reaction system is 3 to 4 2.2.1] Hept-5-en-3
-On manufacturing method.

Description

Detailed Description of the Invention

[0001]

The present invention relates to 2-azabicyclo [2.2.1] hept which is an intermediate for synthesizing carbocyclic nucleosides useful as medicines such as antiviral agents.
-5-En-3-one manufacturing method.

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 very similar to that of natural nucleosides. Can act as an inhibitor. In addition, since it does not have a glycoside bond, it is not cleaved by nucleoside phosphorylase or hydrolase, etc., and its metabolic pathway is different from natural nucleosides, thus showing various physiological activities.For example, carbocyclic adenosine which is a bacterial metabolite is alisteromycin. (Ari
It is known as steromycin) and has attracted attention due to its strong cytotoxicity.

More recently, carbocyclic-2,3
-Dideoxy-2,3-didehydroguanosine is being developed as an anti-HIV agent [R. Vince et al. BBRC
156, 1046 (1988)].

2-Azabicyclo [2.2.1] hept-5-ene-3
-One is the carbocyclic moiety of these carbocyclic nucleosides 2 α, 3 α-dihydroxy-4-β-aminocyclopentane-1β-methanol or cis-4-aminocyclopent-2-ene-1β -The most used compound as an intermediate for the pure chemical synthesis of methanol etc. [R. Vince et al. J. Org.
Chem., 43, 2311 (1978); BL Kamm et al. J. Org.
Chem., 46, 3268 (1981); WC Faith et al. J. Org. C
hem., 50, 1983 (1985); RC Cermak et al. Tetrahe
dron Letters1981, 2331; R. Vince J. Med. Chem., 3
3, 17 (1990); R. Vince et al. Tetrahedron Letters
1976, 3005; MD Ennis Nucleosides & Nucleotides
9, 875 (1990)].

[0005]

2. Description of the Related Art Conventionally, 2-azabicyclo [2.2.1] hept-5
-There are two known synthetic routes for en-3-one. The first route is the cycloaddition of cyclopentadiene and p-toluenesulfonyl cyanide to give 3-tosyl-2-azabicyclo
[2.2.1] Method to remove tosyl group at 3-position using acetic acid with hepta-2,5-diene [JC Jagt et al. J. Org. C
hem., 39,564 (1974); R. Vince et al. J. Org. Che
m., 2311 (1978); L. Kamm et al. J. Org. Chem., 4
6, 3268 (1981)], and the second route is a method of cycloadding cyclopentadiene and chlorosulfonyl isocyanate to remove the chlorosulfonyl group using sodium sulfite (JR Malpass et al. J. Chem. . Soc., P
erkin I, 1977, 874).

However, in the first route, cyclopentadiene, which is stoichiometrically equimolar to p-toluenesulfonylcyanide, must be used in a large excess of 15 to 35-fold. The intermediate, 3-tosyl-2-azabicyclo [2.2.1] hepta-2.5-diene, needs to be concentrated and taken out and pulverized into a powder. The tosyl group at the 3-position of the obtained intermediate is required. In order to remove the p-toluenesulfonyl cyanide used, it is necessary to add acetic acid in a large excess of 5 to 23 times the molar amount of p-toluenesulfonyl cyanide and to add it all at once, and control the rapid exothermic reaction at that time, 2-Azabicyclo [2.2.1] is required in a yield of about 60 to 70% when a heat exchanger with high heat removal efficiency is required to react at a temperature below a predetermined temperature and when the exothermic reaction can be controlled. Hept-5-d -3-turned on can be synthesized, if it can not control an exothermic reaction, the product or not be isolated at all, or very fact obtained only in low yield, and 2-azabicyclo
[2.2.1] In order to isolate hept-5-en-3-one, a large amount of alkaline substance is needed to neutralize the acetic acid used in a large excess, and the exothermic reaction at that time is controlled to control the reaction. There are many problems such as the need to react below the temperature of 1), and it is hard to say that the manufacturing method is industrially satisfactory from the economical and safety viewpoints.

On the other hand, the second route is originally a by-product.
A suitable method for the synthesis of 6-azabicyclo [3.2.0] hept-3-en-7-one, 2-azabicyclo [2.2.1] hept-5
-Repeating purification by column chromatography etc. is required to isolate en-3-one, and the maximum of 2
It only reports that crystalline 2-azabicyclo [2.2.1] hept-5-en-3-one can be synthesized with an isolated yield of 7.5%, and also the quality of the obtained crystals. Is insufficient, and it is not satisfactory as an industrial manufacturing method.

[0008]

Therefore, the object of the present invention is to obtain 2-azabicyclo [2.2.1] hept-5-ene- by the condensation reaction of sulfonyl cyanide and cyclopentadiene, which is the prior art. The above problems found in the synthesis of 3-one were improved, and 2-azabicyclo [2.2.1] hept-5-ene-3 was prepared using cyclopentadiene as a starting material.
(EN) It is intended to provide a method for economically and safely producing ION with high purity and high yield.

[0009]

According to the present invention, the above object is achieved by reacting phenylsulfonyl cyanide with cyclopentadiene to give 2-azabicyclo [2.2.1] hept-5-ene.
In the method for producing -3-one, 2-azabicyclo [2.2. Is prepared by reacting phenylsulfonyl cyanide and cyclopentadiene in a mixed solvent of water and a water-soluble solvent under conditions such that the pH of the reaction system is 3 to 4. 1] It is achieved by the method for producing hept-5-en-3-one.

The method of the present invention will be described in more detail below.

The phenylsulfonyl cyanide used in the method of the present invention is obtained by the method of MSA Vrijland [Organ.
ic Synthesis 57, 88]], it can be synthesized by cyanating a metal salt of phenylsulfinic acid with cyanogen chloride or cyanogen bromide, and it is preferable to dry and use the product immediately after the synthesis.

The cyclopentadiene used in the present invention is preferably used immediately after the dicyclopentadiene is depolymerized and subjected to fractional distillation with the receiver cooled with a refrigerant or a cryogen. When the stored cyclopentadiene is used for the method of the present invention, the cyclopentadiene dimerizes rapidly to dicyclopentadiene at room temperature, and therefore, within 24 hours after the adjustment, at least until immediately before the reaction. It is desirable to use the one kept at 20 ° C or less.

The amount of cyclopentadiene used is 1-fold or more moles, preferably 1- to 3-fold moles, with respect to the phenylsulfonyl cyanide. That is, it may be used in an amount exceeding 3 times the molar amount, but it is necessary to prepare equipment for recovering the excessively used cyclopentadiene, or to dimerize cyclopentadiene generated by excessive use. Due to the multimerization reaction, the formation of by-products increases, and the yield and purity may decrease.

The method of the present invention is characterized in that the ring-fusing reaction of cyclopentadiene and phenylsulfonyl cyanide is carried out in a mixed solvent of water and a water-soluble solvent, and the water-soluble organic solvent at that time is acetone. , Acetonitrile is preferably used.

The amount of water used in the condensation reaction of cyclopentadiene and phenylsulfonyl cyanide is in the range of 1 to 10 times by weight, preferably 1.2 to 3 times by weight, relative to phenylsulfonyl cyanide. Desirably, the amount of the water-soluble solvent used is in the range of 0.3 to 6 times by weight, preferably 0.4 to 2 times by weight, based on phenylsulfonyl cyanide.

In the condensation reaction, cyclopentadiene is put in a water-water-soluble solvent, and the mixture is stirred with phenylsulfonyl cyanide and an inorganic alkaline substance for adjusting the pH of the reaction system, particularly an alkali metal hydroxide or an alkali metal carbonate. It is necessary to add the respective aqueous solutions separately to each other and mix them while adjusting the pH of the reaction system within the range of 3 to 4. Usually, the temperature at the time of dropping is 0 to 50 ° C., preferably 1
The temperature is 0 to 25 ° C., and the dropping time is preferably 10 to 60 minutes. If the pH of the reaction system cannot be controlled within the range of 3 to 4, the reaction will run out or precipitates will be deposited, and the desired product cannot be obtained.

After completion of the dropping, the temperature of the reaction system is about 0 to 50 ° C., preferably 10 to 25 ° C., but the mixture is stirred for 0.5 to 2 hours and separated to give 2-azabicyclo [2.2.1]. ]
An aqueous solution containing hept-5-en-3-one can be obtained.

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

Since some of the product is dissolved in the separated organic solution, if necessary, the product may be extracted with water,
It is desirable to 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 separation. If necessary, sodium chloride is added to the pH adjusted aqueous solution for salting out to obtain a saturated sodium chloride solution, which is then extracted with a chlorinated hydrocarbon solvent, preferably methylene chloride or dichloroethane.

The product can be isolated by concentrating the extract thus obtained. A product obtained by concentrating the product obtained by the method of the present invention has a purity sufficiently usable for the synthesis of an antiviral intermediate in the next step, but if necessary, distillation, treatment with activated carbon, recrystallization is carried out. Further, it can be further purified by a usual organic chemical method such as sublimation.

[0021]

The present invention will be described in detail below with reference to examples, but the present invention is not limited to these examples. Reference Example 1 (Synthesis of benzenesulfonyl cyanide) 268.0 g (1.34 mol) of sodium benzenesulfinate dihydrate and 470 g of water were placed in a 1000 ml flask equipped with a thermometer, a condenser, a stirrer and a cyan chloride inlet tube. It was
Keeping the temperature of the reaction system at 10 ° C, 90.6 g of cyanogen chloride (purity
(95.5% 1.41 mol) was introduced into the flask over 100 minutes with nitrogen. After the introduction of cyanogen chloride, at 5 ° C
It was stirred for 30 minutes. The lower layer was separated to obtain 212.5 g of crude benzenesulfonyl cyanide (purity 97.9%). Distill this, 86 ~
198.3 g of benzenesulfonyl cyanide was obtained as a fraction at 88 ° C / 2.5 mmHg. Reference Example 2 (Synthesis of cyclopentadiene) Dicyclopentadiene 504. was added to a 1000 ml distillation flask equipped with a distillation column kept at 50 ° C and a receiver cooled at -20 ° C.
7 g was put and heated to 160 to 180 ° C. to thermally decompose dicyclopentadiene for 8 hours to obtain 307.5 g of cyclopentadiene as a fraction at 40 to 50 ° C. The yield based on dicyclopentadiene was 60.9%. Example 1 A 500 ml reactor equipped with a PH meter, a thermometer, a condenser, a stirrer and two dropping funnels was charged with 110 g of water and 38 g of acetone.
Cooled to ° C. 85 g (0.488 mol) of benzenesulfonyl cyanide was placed in the dropping funnel, and 85 g of 25% aqueous NaOH solution was placed in the other dropping funnel. Cyclopentadiene 43g (0.
(631 mol), benzenesulfonyl cyanide was added dropwise over 1 hour while maintaining the reaction temperature of 15 ° C. Since the pH of the reaction solution gradually decreased from 7 with the addition of benzenesulfonyl cyanide, a 25% NaOH aqueous solution was simultaneously added dropwise while adjusting the pH to a range of 3.5 to 4. After dropping, 10
It was cooled to ℃ and aged for 30 minutes. Further, a 25% NaOH aqueous solution was added dropwise to adjust the PH to 8. Transfer the reaction mixture to a separatory funnel 30
The solution was allowed to stand for a minute and then separated to obtain 335.7 g of a lower layer aqueous solution. 2-
The concentration of azabicyclo [2.2.1] hept-5-en-3-one is
The yield was 10.5% and the yield was 66%. Example 2 The same 500 ml reactor as in Example 1 was charged with 110 g of water and 38 g of acetonitrile and cooled to 15 ° C. 85 g (0.488 mol) of benzenesulfonyl cyanide was placed in the dropping funnel, and 85 g of 25% aqueous NaOH solution was placed in the other dropping funnel. After charging 43 g (0.631 mol) of cyclopentadiene into the reactor, the reaction temperature was 15 ° C.
While maintaining the temperature, benzenesulfonyl cyanide was added dropwise over 1 hour. Since the pH of the reaction solution gradually decreased from 7 with the addition of benzenesulfonyl cyanide, a 25% NaOH aqueous solution was simultaneously added dropwise while adjusting the pH to the range of 3 to 4.
After completion of dropping, the mixture was cooled to 10 ° C and aged for 30 minutes. 2 more
5% NaOH aqueous solution was added dropwise to adjust the pH to 8. Transfer the reaction solution to a separatory funnel and leave it for 30 minutes, then separate the solution into the lower aqueous solution 33
0.4 g was obtained. 2-Azabicyclo [2.2.1] hept-5-ene-3
-The concentration of on was 10.3% and the yield was 64%. Example 3 The same 500 ml reactor as in Example 1 was charged with 110 g of water and 38 g of acetonitrile and cooled to 15 ° C. 85 g (0.488 mol) of benzenesulfonyl cyanide was placed in the dropping funnel, and 85 g of 25% aqueous NaOH solution was placed in the other dropping funnel. After charging 66.5 g (0.976 mol) of cyclopentadiene into the reactor, reaction temperature 15
Benzenesulfonyl cyanide was added dropwise over 1 hour while maintaining the temperature. The pH of the reaction solution gradually decreased from 7 with the addition of benzenesulfonyl cyanide.
A 25% NaOH aqueous solution was added dropwise at the same time while adjusting the range. After completion of dropping, the mixture was cooled to 10 ° C and aged for 30 minutes. Further, a 25% NaOH aqueous solution was added dropwise to adjust the PH to 8. The reaction solution was transferred to a separating funnel and allowed to stand for 30 minutes, and then separated to obtain 330.5 g of a lower layer aqueous solution. The concentration of 2-azabicyclo [2.2.1] hept-5-en-3-one was 10.9% and the yield was 68%. Comparative Example 1 The same 500 ml reactor as in Example 1 was charged with 110 g of water and 38 g of acetonitrile and cooled to 8 ° C. 85 g (0.488 mol) of benzenesulfonyl cyanide was placed in the dropping funnel, and 85 g of 25% NaOH aqueous solution was placed in the other dropping funnel. After charging 43 g (0.631 mol) of cyclopentadiene into the reactor, the reaction temperature was 8
Benzenesulfonyl cyanide was added dropwise over 1 hour while maintaining the temperature. A 25% NaOH aqueous solution was added at the same time while adjusting the pH of the reaction solution along with the addition of benzenesulfonyl cyanide, but the pH could not be controlled within the range of 3 to 4, and a large amount of precipitate was deposited 40 minutes after the start of the reaction. The target product could not be obtained. Comparative Example 2 The same 500 ml reactor as in Example 1 was charged with 110 g of water, 38 g of acetonitrile and cooled to 15 ° C. 85 g (0.488 mol) of benzenesulfonyl cyanide was placed in the dropping funnel, and 85 g of 25% NaOH aqueous solution was placed in the other dropping funnel. After charging 43 g (0.631 mol) of cyclopentadiene into the reactor, the reaction temperature was 15
Benzenesulfonyl cyanide was added dropwise over 1 hour while maintaining the temperature. A 25% NaOH aqueous solution was added at the same time while adjusting the pH of the reaction solution to 6 to 7 with the addition of benzenesulfonyl cyanide, but the temperature of the reaction system suddenly increased, the reaction went out of control, and the target product was obtained. I couldn't. Comparative Example 3 The same 500 ml reactor as in Example 1 was charged with 110 g of water and methylene chloride.
40 g was charged and cooled to 15 ° C. 85 g (0.488 mol) of benzenesulfonyl cyanide was placed in the dropping funnel, and 85 g of 25% NaOH aqueous solution was placed in the other dropping funnel. After charging 43 g (0.631 mol) of cyclopentadiene to the reactor, benzenesulfonyl cyanide was added dropwise over 1 hour while maintaining the reaction temperature of 15 ° C. A 25% NaOH aqueous solution was added at the same time while adjusting the pH of the reaction solution with the addition of benzenesulfonyl cyanide, but the pH could not be controlled within the range of 3 to 4, and a large amount of precipitate was deposited 20 minutes after the start of the reaction. The target product could not be obtained. Comparative Example 4 110 g of water and 20 g of acetone were placed in the same 500 ml reactor as in Example 1.
Was charged and cooled to 15 ° C. 85 g (0.488 mol) of benzenesulfonyl cyanide in the dropping funnel, and in the other dropping funnel.
85 g of 25% NaOH aqueous solution was added. After charging 43 g (0.631 mol) of cyclopentadiene to the reactor, benzenesulfonyl cyanide was added dropwise over 1 hour while maintaining the reaction temperature of 15 ° C. The pH of the reaction solution gradually decreased from 7, but the pH of 3 to
It could not be controlled within the range of 4, and after 30 minutes from the start of the reaction, a large amount of precipitate was deposited and the target product could not be obtained.

[0022]

As described above, according to the method of the present invention, 2-azabicyclo [2.2.1] hept-5-ene is obtained by reacting phenylsulfonyl cyanide with cyclopentadiene.
In the method for producing -3-one, 2-azabicyclo [2.2. Is prepared by reacting phenylsulfonyl cyanide and cyclopentadiene in a mixed solvent of water and a water-soluble solvent under conditions such that the pH of the reaction system is 3 to 4. 1] A method for producing hept-5-en-3-one, and according to the method of the present invention, an unstable crystal that is a by-product produced by a conventional method without using a large excess of cyclopentadiene The productivity of 2-azabicyclo [2.2.1] hept-5-en-3-one can be significantly improved without precipitating a phenylsulfinyl sulfone compound having high properties into the reaction system, with high purity and high yield. Moreover, there is an advantage that it can be obtained industrially by a very simple method.

Claims (5)

[Claims] 1. A method for producing 2-azabicyclo [2.2.1] hept-5-en-3-one by reacting phenylsulfonyl cyanide with cyclopentadiene, wherein the method is performed in a mixed solvent of water and a water-soluble solvent. 2-azabicyclo [2., Characterized in that phenylsulfonyl cyanide and cyclopentadiene are reacted under the condition that the pH of the reaction system is 3-4.
2.1] Method for producing hept-5-en-3-one. 2. The production method according to claim 1, wherein the water-soluble solvent is acetonitrile or acetone. 3. The production method according to claim 1, wherein the reaction is carried out at a temperature of 10 to 25 ° C. 4. The method according to claim 1, wherein an aqueous solution of alkali metal hydroxide or alkali metal carbonate is used for adjusting the pH of the reaction system. 5. The amount of water used in the condensation reaction of cyclopentadiene and phenylsulfonyl cyanide is in the range of 1 to 10 parts by weight relative to phenylsulfonyl cyanide.
Further, the amount of the water-soluble solvent used is in the range of 0.3 to 6 parts by weight relative to phenylsulfonyl cyanide, and the production method according to any one of claims 1 to 4.