JPH11189584A - Crystallization of 2-azabicyclo(2.2.1)hept-5-en-3-one - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for preparing, with a simple operation in high recovery rate, the microparticulate crystal of the subject compound which is excellent in fluidity and handleability. SOLUTION: This method of crystallizing the subject compound comprises dissolving 2-azabicyclo[2.2.1]hept-5-en-3-one in an organic solvent consisting mainly of diisopropyl ether and/or methyl-t-butyl ether to prepare an organic solvent solution, and cooling the solution to deposit the aimed crystal of the subject compound.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for crystallizing 2-azabicyclo [2.2.1] hept-5-en-3-one. More specifically, the present invention relates to a method for crystallizing 2-azabicyclo [2.2.1] hept-5-en-3-one into fine-particle crystals having excellent handleability.

[0002]

2. Description of the Related Art Carbocyclic nucleosides have a structure in which an oxygen atom constituting the furanose ring of a nucleoside is substituted with a methylene group, and the structure is very similar to a normal nucleoside having a furanose ring. Can act as substrates and inhibitors for various enzymes. In addition, since carbocyclic nucleosides do not have glycosidic bonds, they are not subject to cleavage by enzymes such as nucleoside phosphorylase and nucleoside hydrolase,
The metabolic pathway is different from that of the nucleoside having a furanose ring, and it shows various biological activities. For example, carbocyclic adenosine, known as Aristeromycin, is a type of carbocyclic nucleoside and a metabolite of Streptomyces citricolor, which, unlike nucleosides having a furanose ring, has a strong cytotoxicity. Has attracted attention. Also, carbocyclic-2,3-dideoxy-2,3-didehydroguanosine, a kind of carbocyclic nucleoside, is being developed as an anti-HIV agent [R. Vince et al., BBR. C., 156, 1046 (1988)].

The carbocyclic moiety of the carbocyclic nucleoside is 2α, 3α-dihydroxy-4β-
Often formed using aminocyclopentanone-1β-methanol or cis-4-aminocyclopent-2-ene-1β-methanol, these 1β-methanol
Methanols are often chemically synthesized from 2-azabicyclo [2.2.1] hept-5-en-3-one [R. Vince et al. J. Org. Chem., 43, 2311 (19
78); L. Kamm. et al. J. Org. Chem., 46,
3268 (1981); C. Faith et al. J. Org. Che
m., 50, 1983 (1985)].

Various methods have been known for producing 2-azabicyclo [2.2.1] hept-5-en-3-one useful as an intermediate for synthesizing carbocyclic nucleosides. ing. However, 2-azabicyclo [2.2.1] obtained by a conventional method.
Hept-5-en-3-one is generally an oily or bulky solid in many cases, and is therefore inferior in handleability when filled in a container, weighed, or used for chemical synthesis. A fine, non-greasy, fine-particle crystal of 2-azabicyclo [2.2.1] hept-5-en-3-one which is excellent in fluidity and handleability has been conventionally required.

[0005]

SUMMARY OF THE INVENTION An object of the present invention is to provide a fine crystal of 2-azabicyclo [2.2.1] hept-5-en-3-one which is not sticky and has excellent fluidity and handleability. It is an object of the present invention to provide a method which can be easily prepared at a high recovery rate with good operability.

[0006]

The present inventors have intensively studied to achieve the above object. As a result, 2-azabicyclo [2. 1... Using a specific organic solvent mainly composed of at least one of diisopropyl ether and methyl tertiary butyl ether as a crystallization solvent.
2.1] Hept-5-en-3-one is dissolved and the resulting solution is cooled, despite the very simple operation, 2-azabicyclo [2.2.1] hept-5. The present invention was completed by finding that fine-particle crystals of -en-3-one were deposited well and at a high recovery rate.

Accordingly, the present invention provides a method for dissolving 2-azabicyclo [2.2.1] hept-5-en-3-one in an organic solvent mainly comprising at least one of diisopropyl ether and methyl tert-butyl ether. An organic solvent solution is prepared, and then the organic solvent solution is cooled to give 2-azabicyclo [2.2.1] hept-5-.
Characterized in that crystals of en-3-one are precipitated,
2-azabicyclo [2.2.1] hept-5-ene-3
-On crystallization method.

[0008]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be described below in detail. In the crystallization method of the present invention, 2-azabicyclo [2.2.1] hept-5-ene-3 used for crystallization is used.
The preparation method, purity, phase morphology, and the like of -one are not particularly limited, and 2-azabicyclo [2.2.
1] It can be applied to any of hept-5-en-3-one.

Although not limited in any way, 2-azabicyclo [2.2.1] which can be used in the crystallization method of the present invention.
Examples of hept-5-en-3-one include (i)
J. C. Jagt et al. J. Org. Chem., 39, 564 (19
74), R.C. Vince et al. J. Org. Chem., 43, 2311
(2-Azabicyclo [2.2.1] hept-5-en-3-one) obtained by a synthesis method as described in (1978) and the like include cyclopentadiene and p-toluenesulfonyl. Cycloaddition reaction of cyanide to 3
-P-toluenesulfonyl-2-azabicyclo [2.
2.1] Hepta-2,5-diene is prepared as an intermediate, and the 3-position toluenesulfonyl group in the intermediate is removed with acetic acid to give 2-azabicyclo [2.2.1].
(Production of hept-5-en-3-one);
-Azabicyclo obtained through a first step of condensing sulfonyl cyanide and cyclopentadiene in a hydrocarbon solvent, followed by a second step of treating with water [2.2.
1) Production of hept-5-en-3-one); (iii) those obtained by the method described in JP-A-5-331140 (sulfonyl cyanide and cyclopentadiene are converted to water or water-hydrocarbon). Reaction in a system mixed solvent 2
-Azabicyclo [2.2.1] hept-5-ene-3-
(Iv) prepared by the method described in JP-A-8-27110 (phenylsulfonyl cyanide and cyclopentadiene are mixed with water and a water-soluble solvent at pH 3 to 4). React under the conditions
(V) azabicyclo [2.2.1] hept-5-en-3-one); (v) a compound obtained by the method described in JP-A-9-165372 (carbonization of sulfonyl cyanide and cyclopentadiene) A first step of reacting in a hydrogen solvent is performed to produce 3-sulfonyl-2-azabicyclo [2.2.1] hepta-2,5-diene (intermediate), and the above solution of the intermediate is dissolved in water and aqueous solution. The mixture is added to a mixed solvent with a neutral solvent under conditions of pH 3 to 7 to hydrolyze the intermediate to give 2-azabicyclo [2.2.1] hept-5.
And (vi) a method obtained by adjusting the pH of the reaction system to a range of more than 4 and 7 or less in the method of (iii) described above.

The 2-azabicyclo [2.2.1] hept-5-en-3-one used in the crystallization method of the present invention may be in any form such as oil, bulk, coarse powder, and solution. There may be. Furthermore, 2 used in the crystallization method of the present invention
-Azabicyclo [2.2.1] hept-5-ene-3-
The ON may be obtained in an intermediate step (for example, before drying, or dissolved in an extraction solvent, even if it is finally obtained by the synthesis method exemplified above or other synthesis methods). In an extracted state, or dissolved in an extraction solvent and concentrated to some extent). Therefore, the crystallization method of the present invention can be carried out independently on 2-azabicyclo [2.2.1] hept-5-en-3-one, which has already been prepared separately, or can be carried out independently on 2-azabicyclo [2.2.1] hept-5-en-3-one. [2.2.1] Hept-5
It may be carried out as a part of the production process in the final step of synthesizing -en-3-one.

In the present invention, the above-mentioned 2-azabicyclo [2.2.1] hept-5-en-3-one is dissolved in an organic solvent mainly composed of at least one of diisopropyl ether and methyl tert-butyl ether. Prepare an organic solvent solution. The organic solvent used in the present invention is preferably an organic solvent containing at least one of diisopropyl ether and methyl tertiary butyl ether in a proportion of 50% by weight or more. Among them, in the present invention, the organic solvent is 100% diisopropyl ether, 50% diisopropyl ether by weight.
Mixed solvent of above and 50% by weight of other organic solvent, 100% of methyl tertiary butyl ether, mixed solvent of arbitrary ratio of methyl tertiary butyl ether and hexane, 50% by weight or more of methyl tertiary butyl ether and 50% by weight of other organic solvent The following mixed solvents are preferably used.

In particular, in the present invention, as an organic solvent, a mixed solvent composed of 100% by weight of diisopropyl ether, 50% by weight or more of diisopropyl ether and 50% by weight or less of methylene chloride and / or isopropanol, particularly, 80% by weight or more of diisopropyl ether Mixed solvent of methylene and / or isopropanol 20% by weight or less, methyl tertiary butyl ether 100%, methyl tertiary butyl ether 50% by weight or more and hexane 5
0% by weight or less of a mixed solvent, particularly 60% by weight or more of methyl tert-butyl ether and 40% by weight of hexane
A mixed solvent comprising the following is preferably used.

In the organic solvent solution used for the crystallization, the concentration of 2-azabicyclo [2.2.1] hept-5-en-3-one is preferably 5 to 30% by weight, and preferably 10 to 30% by weight.
More preferably, it is で 23% by weight. When the concentration of 2-azabicyclo [2.2.1] hept-5-en-3-one in the organic solvent solution exceeds 30% by weight, 2-azabicyclo [2.2.1] hept-5-ene-one is used. The 3-one fine particle crystals are less likely to precipitate, and are more likely to precipitate in an oily form. Further, if this oil is further cooled, it often becomes a blocky solid. On the other hand, when the concentration of 2-azabicyclo [2.2.1] hept-5-en-3-one in the organic solvent solution is less than 5% by weight, 2-azabicyclo [2.2. 1] It takes a very long time to precipitate crystals of hept-5-en-3-one, or crystals of 2-azabicyclo [2.2.1] hept-5-en-3-one are deposited. It is easy to disappear.

In preparing an organic solvent solution used for crystallization, 2-azabicyclo [2.2.1] hept-5-
The dissolution temperature of ene-3-one in an organic solvent is not particularly limited, and 2-azabicyclo [2.2.1] hept-5-ene-
Any temperature may be used as long as it does not cause thermal decomposition or denaturation of 3-one, and can be selected according to the type of the organic solvent. Generally, it is preferable to dissolve 2-azabicyclo [2.2.1] hept-5-en-3-one in the above-mentioned organic solvent at a temperature in the range of 40 to 60 ° C. Also,
If necessary, a seed crystal or the like may be added to an organic solvent solution of 2-azabicyclo [2.2.1] hept-5-en-3-one.

Next, the organic solvent solution of 2-azabicyclo [2.2.1] hept-5-en-3-one prepared above is cooled to give 2-azabicyclo [2.2.1] hept-5. -Ene-3-one is precipitated as fine-grained crystals. The cooling temperature depends on the type of the organic solvent and the 2-azabicyclo [2.2.1] hept-5-ene- in the organic solvent solution.
It can be selected according to the concentration of 3-one, etc.
In general, it is preferable to perform cooling so that the final temperature is 0 to 15 ° C. from the viewpoint of good crystal precipitation. Although the cooling rate at this time is not particularly limited, it is generally preferable to set the cooling rate to 2 ° C./min or less, since fine crystals can be precipitated at a high recovery rate.

The above-mentioned operation of depositing the crystals of 2-azabicyclo [2.2.1] hept-5-en-3-one may be carried out while standing, but is preferably carried out with gentle stirring. By stirring, fine-grained crystals without aggregation can be more smoothly precipitated.

The 2-azabicyclo [2.
2.1] The crystals of hept-5-en-3-one are collected by filtration or other separation means, and dried if necessary. The 2-azabicyclo [2.2.
1] Crystals of hept-5-en-3-one are in the form of fine particles, are not sticky, and have excellent fluidity and handleability, so that they can be well filled and weighed in containers and the like, and furthermore, racemic. It can be used very smoothly in the separation of 2-azabicyclo [2.2.1] hept-5-en-3-one into D- and L-forms, synthesis of carbocyclic nucleosides and other compounds. .

[0018]

EXAMPLES The present invention will be described below in more detail with reference to examples, but the present invention is not limited thereto.

<< Synthesis Example 1 >> Four-necked flask (capacity 500
ml), 276.5 g of a toluene solution of p-toluenesulfonyl cyanide (concentration: 61.5% by weight, 0.940 m
ol) and 31.75 g of toluene, and 89.5 g (1.35 mol) of cyclopentadiene were added. 20
After reacting at ３０30 ° C. for 45 minutes, the reaction solution was cooled to 5 ° C., 261.5 g of water was added, and the mixture was stirred at 30 ° C. or lower for 30 minutes. This reaction solution was filtered to remove a by-product sulfinyl sulfone compound, and separated into an aqueous layer and a toluene layer using a separating funnel. The aqueous layer was neutralized to pH 8 with aqueous sodium hydroxide. The toluene layer was extracted with 125 g of water, and the extracted aqueous layer was neutralized to pH 8 with an aqueous sodium hydroxide solution. Combine the two aqueous layers and add 3 g with 400 g of methylene chloride.
Extracted times. The methylene chloride extract was concentrated under reduced pressure to obtain 89.0 g of a crude product. The crude product is distilled to a boiling point of 85-90 ° C./1 mmHg, mp 55.0-57.0.
67.5 g of 2-azabicyclo [2.2.1] hept-5-en-3-one at <RTIgt; The 2-azabicyclo [2.2.1] hept-5-en-3-one obtained here was a white massive solid.

Example 1 (1) 10 g of 2-azabicyclo [2.2.1] hept-5-en-3-one obtained in Synthesis Example 1 above was
In a 0 ml three-neck flask, 20 g of diisopropyl ether was added, and the mixture was heated to 50 ° C. to dissolve 2-azabicyclo [2.2.1] hept-5-en-3-one. [2.2.1] Hept-5
A 20% by weight solution of -en-3-one in diisopropyl ether was prepared. (2) 2-Azabicyclo [2.
2.1] A 20% by weight solution of hept-5-en-3-one in diisopropyl ether was stirred (150 rpm).
The mixture was gradually cooled to 10 ° C over 30 minutes and stirred at 10 ° C for another 30 minutes. As a result, a large amount of fine particles of 2-azabicyclo [2.2.1] hept-5-en-3-one crystals were formed. During this time, no precipitation of oily 2-azabicyclo [2.2.1] hept-5-en-3-one and no attachment of crystals to the wall of the beaker occurred. (3) The crystals obtained above were placed at 45 ° C. (100 mmH
g) and its weight was measured to be 4.5 g. The recovery of 2-azabicyclo [2.2.1] hept-5-en-3-one was 90%. The crystals of 2-azabicyclo [2.2.1] hept-5-en-3-one thus obtained were uniform in particle size, were not sticky, and were extremely excellent in fluidity and handleability.

Example 2 (1) In Example 1, (1), 2-azabicyclo [2.2.1] hept-5 to diisopropyl ether was used.
The concentration of 2-azabicyclo [2.2.1] hept-5-en-3-one was changed to 1 by changing the amount of -en-3-one dissolved.
0% and 30% by weight diisopropyl ether solutions were prepared, respectively. (2) 2-Azabicyclo [2.
2.1] Using a diisopropyl ether solution of hept-5-en-3-one, a crystallization operation was carried out under cooling in the same manner as in (2) of Example 1. As a result, in a diisopropyl ether solution in which the concentration of 2-azabicyclo [2.2.1] hept-5-en-3-one is 10% by weight,
Fine particles of 2-azabicyclo [2.2.1] composed of azabicyclo [2.2.1] hept-5-en-3-one.
Hept-5-en-3-one crystals formed smoothly with a recovery of 78%. Also, 2-azabicyclo [2.2.1]
In a diisopropyl ether solution in which the concentration of hept-5-en-3-one is 30% by weight, oily 2-azabicyclo [2.2.1] hept-5-en-3-one is formed and crystals on the wall of the flask are formed. Is slightly observed, and fine particles of 2-azabicyclo [2.2.1] hept-5-ene-
The 3-one recovery was 93%.

Example 3 Instead of 20 g of diisopropyl ether, 20 g of a mixed solvent consisting of 20 parts by weight of diisopropyl ether and 1 part by weight of isopropanol was used as the crystallization solvent, and the final cooling temperature during crystallization was 3 ° C. Except as described above, 2-azabicyclo [2.2.1] hept-5 was prepared in the same manner as in (1) and (2) of Example 1.
Crystallization of -en-3-one was performed. As a result, fine particle crystals of 2-azabicyclo [2.2.1] hept-5-en-3-one were obtained with a recovery of 74%. The crystals of 2-azabicyclo [2.2.1] hept-5-en-3-one thus obtained were uniform in particle size, were not sticky, and were extremely excellent in fluidity and handleability. In Example 3, oily 2-azabicyclo [2.2.
1] No precipitation of hept-5-en-3-one and no attachment of crystals to the beaker wall surface occurred.

Example 4 The procedure of Example 1 was repeated except that 15 g of methyl tert-butyl ether was used instead of 20 g of diisopropyl ether as the crystallization solvent, and the final cooling temperature during crystallization was 3 ° C. ) And (2)
2-azabicyclo [2.2.1] hept-
Fine particles of 5-en-3-one were obtained with a recovery of 78%. The 2-azabicyclo [2.2.
1] The crystals of hept-5-en-3-one had a uniform particle size, were not sticky, and were extremely excellent in fluidity and handleability. In addition, in Example 4, precipitation of oily 2-azabicyclo [2.2.1] hept-5-en-3-one and attachment of crystals to the wall surface of the flask did not occur.

Example 5 Example 1 (1) was repeated except that 20 g of a mixed solvent consisting of 60 parts by weight of methyl tert-butyl ether and 40 parts by weight of hexane was used instead of 20 g of diisopropyl ether as a crystallization solvent.
2-Azabicyclo [2.2.
1] A fine particle crystal of hept-5-en-3-one was converted to 88
% Recovery. The crystals of 2-azabicyclo [2.2.1] hept-5-en-3-one thus obtained were uniform in particle size, were not sticky, and were extremely excellent in fluidity and handleability. In Example 5, oily 2-azabicyclo [2.2.1] hept-5-ene-
No precipitation of 3-one and attachment of crystals to the wall of the flask occurred.

Example 6 (1) Cyclopentadiene 5 was placed in a four-necked flask (capacity: 500 ml) equipped with a nitrogen flow tube and a thermometer.
2.9 g (0.80 mol), 10 g of toluene and 130 g of water were charged, and the internal temperature was adjusted to 10 ° C. to this,
Benzenesulfonyl cyanide (purity 9
103.2 g (0.58 mol) was added dropwise over about 3 hours while maintaining the internal temperature of the four-necked flask at 8 to 15 ° C. When the benzenesulfonyl cyanide is dropped, the pH of the contents in the flask is continuously measured at the same time, and a 25% aqueous sodium hydroxide solution is dropped to keep the pH of the reaction system in the range of 4.4 to 4.7. Continued. Under the same pH, the reaction was carried out by stirring for further 30 minutes while maintaining the internal temperature at 8 to 15 ° C. (2) Next, the pH of the reaction system was adjusted to 7.5 by dropwise addition of a 25% aqueous sodium hydroxide solution, and then the reaction solution in the flask was transferred to a separating funnel to separate an aqueous layer. (3) The aqueous layer separated in the above (2) is mixed with methylene chloride 4
The operation of extracting with 0 g was repeated 5 times (total use of methylene chloride: 200 g), and then a part of methylene chloride was distilled off under reduced pressure to give 2-azabicyclo [2.
2.1] 50 g of a concentrated solution containing hept-5-en-3-one dissolved therein was obtained. (4) 2-Azabicyclo [2.
2.1] Concentrate 50 containing hept-5-en-3-one
After adding 133 g of diisopropyl ether to the resulting mixture and heating to 50 ° C. to dissolve, the mixture was gradually cooled to 10 ° C. over 30 minutes with stirring, and further kept at 10 ° C. with stirring for 30 minutes to obtain 2-azabicyclo [ 2.2.1] Hept-5-
Fine particle crystals of en-3-one were precipitated. The crystals thus obtained were dried at 45 ° C. (100 mmHg) and found to be uniform in particle size, not sticky, and extremely excellent in fluidity and handleability (2-azabicyclo [based on the amount of benzenesulfonyl cyanide used). 2.2.1] Hept-5-en-3-one yield 65% by weight).

Comparative Example 1 2-azabicyclo [2.2] was prepared in the same manner as in (1) and (2) of Example 1 except that 20 g of toluene was used instead of 20 g of diisopropyl ether as a crystallization solvent. .1] Hept-5-ene-
The 3-one was crystallized, but no crystals were precipitated and no oily substance was precipitated.

Comparative Example 2 Instead of 20 g of diisopropyl ether, 20 g of a mixed solvent consisting of 5 parts by weight of hexane and 1 part by weight of ethyl acetate was used as a crystallization solvent, and the final cooling temperature during crystallization was 4 ° C. Except that the crystallization operation of 2-azabicyclo [2.2.1] hept-5-en-3-one was performed in the same manner as (1) and (2) of Example 1, but no crystals were obtained. Without precipitation, 2-azabicyclo [2.2.1] hept-5-en-3-one as an oil was precipitated.

<< Comparative Examples 3 and 4 >> As crystallization solvents,
Hexane 2 instead of 20 g of diisopropyl ether
20 g of a mixed solvent consisting of 1 part by weight of toluene and 1 part by weight of toluene (Comparative Example 3) or 20 g of a mixed solvent consisting of 2 parts by weight of hexane and 1 part by weight of acetone (Comparative Example 4) were used. A crystallization operation of 2-azabicyclo [2.2.1] hept-5-en-3-one was performed in the same manner as (1) and (2) of Example 1 except that the temperature was changed to 4 ° C. In both Comparative Example 3 and Comparative Example 4, no crystals were precipitated, the layers were separated into two layers, and 2-azabicyclo [2.
2.1] An oil layer consisting of hept-5-en-3-one settled in the lower layer.

[0029]

According to the method of the present invention, 2-azabicyclo [2.2.1] hept-5-en-3-one, which is not sticky, has excellent fluidity and handleability, has a uniform particle size. Crystals can be obtained with a very simple operation at a high recovery rate. The crystals of 2-azabicyclo [2.2.1] hept-5-en-3-one obtained by the method of the present invention are filled or weighed into containers or the like due to their excellent fineness, fluidity, and handleability. Can be performed smoothly,
Further, when used for chemical synthesis or when 2-azabicyclo [2.
2.1] It can be used very conveniently and smoothly, for example, when separating the racemic form of hept-5-en-3-one into D-form and L-form.

Claims (1)

[Claims] 1. An organic solvent solution comprising: dissolving 2-azabicyclo [2.2.1] hept-5-en-3-one in an organic solvent mainly composed of at least one of diisopropyl ether and methyl tert-butyl ether; And then cooling the organic solvent solution to precipitate crystals of 2-azabicyclo [2.2.1] hept-5-en-3-one. 1] A method for crystallizing hept-5-en-3-one.