Process for optical resolution of (+)-cis-4-aminocyclopent-2-en-1-carboxylic acid derivative

In optical resolution of an optically inactive (.+-.)-cis-4-aminocyclopent-2-en-1-carboxylic acid derivative into its (+)-derivative and (-)-derivative, the (.+-.)-cis-4-aminocyclopent-2-en-l-carboxylic acid derivative is allowed to react with an optically active cis-2-(arylalkylamino)cyclohexanemethanol or optically active .alpha.-alkylbenzylamine serving as an optically resolving agent, to form diastereomer salts corresponding to the (+)-cis-4-aminocyclopent-2-en-1-carboxylic acid derivative and the (-)-cis-4-aminocyclopent-2-en-1-carboxylic acid derivative.

BACKGROUND OF THE INVENTION 
1. Field of the Invention 
This invention relates to a process for the optical resolution of an 
optically inactive (.+-.)-cis-4-aminocyclopent-2-en-1-carboxylic acid 
represented by Formula (1) (hereinafter abbreviated "(.+-.)ACP acid") into 
its optically active (+)ACP acid derivative and (-)ACP acid derivative. 
##STR1## 
wherein R represents an acyl group. 
2. Description of the Related Art 
In recent years, there is a world-wide problem of an increase in persons 
infected with AIDS (aquired immune deficiency syndrome) viruses, and it 
has been attempted to remedy AIDS infections by various methods. Under 
such circumstances, an optically active isomer of a compound commonly 
called a carbovir, represented by Formula (2): 
##STR2## 
has attracted notice because of its inhibitory action against the 
proliferation of AIDS viruses. 
Thus, it is attempted to synthesize the optically active carbovir of 
Formula (2). For example, it is proposed to use a chiral natural product, 
aristeromycin, as a starting material (C. Willamson, A. M. Exall et al., 
Poster Presentation at SCI Medical Chemistry Symposium, Cambridge, 1989). 
This method, however, has the problem that the chiral natural product as a 
starting material is available with so great a difficulty and is so 
expensive that the carbovir can not be produced in an industrial scale and 
at a low cost. 
For this reason, it is attempted to chemically synthesize the carbovir of 
Formula (2) without using as a starting material the natural product 
available with difficulty (J. Chem. Soc., Chem. Commun., 1120(1990); J. 
Chem. Soc., Perkin Trans., 1, 2479(1990); and J. Chem. Soc., Perkin 
Trans., 1, 589(1992). An important subject in the chemical synthesis of 
such a carbovir is for one thing how an optically active 
(-)-4-hydroxymethyl-2cyclopentenyl group is introduced into the main 
skeleton of the carbovir of Formula (2). 
As one of conventional reliable means for settling this subject, it is 
proposed to use a synthesis method in which optically active 
(-)-4-N-acetylamino-1-hydroxymethyl-2-cyclopentene of Formula (3) which is 
a compound corresponding to the (-)-4-hydroxymethyl-2-cyclopentenyl group 
is allowed to react with 2-amino-4,6-dichloropyridine of Formula (4) to 
produce 
(-)-4-hydroxymethyl-4-[(2'-amino-6'-chloropyrimidin-4'-yl)amino]-2-cyclope 
ntene of Formula (5), as shown below [J. Chem. Soc., Chem. Commun., 
1120(1990)]. 
##STR3## 
In this case, the compound of Formula (3) is synthesized by subjecting 
optically inactive 2-azabicyclo[2.2.1]hept-5-en-3-one to optical 
resolution in the presence of a whole cell catalyst to obtain optically 
active (-)-2-azabicyclo[2.2.1]hept-5-en-3-one, subjecting this isomer to 
hydrolysis to obtain an optically active ACP acid as an intermediate 
material and further subjecting this acid to esterification reaction, 
acetylation reaction and reduction reaction. 
However, the method making use of the whole cell catalyst as mentioned 
above requires a reasonably long time for the optical resolution in order 
to obtain the optically active ACP acid, and has been involved in the 
problem that it is not suited for large-scale treatment and the compound 
can not be produced in an industrial scale and at a low cost. 
SUMMARY OF THE INVENTION 
This invention intends to solve the problems involved in the prior art 
discussed above, and an object thereof is to make it possible to produce 
in a high purity, in a high yield and in an industrial scale, the 
optically active ACP acid useful as a starting material for synthesizing 
the carbovir. 
The present inventors have discovered that the above object can be achieved 
when an optically active cis-2-(arylalkylamino)cyclohexanemethanol or an 
optically active .alpha.-alkylbenzylamine is made to act on an optically 
inactive (.+-.)ACP acid derivative, as an optically resolving agent. They 
have thus accomplished the present invention. 
The present invention provides a process for optically resolving a 
(.+-.)ACP acid derivative represented by Formula (1): 
##STR4## 
wherein R represents an acyl group; into its (+)ACP acid derivative and 
(-)ACP acid derivative, wherein the process comprises the step of allowing 
the (.+-.)ACP acid derivative to react with an optically resolving agent 
comprising an optically active cis-2-(arylalkylamino)cyclohexanemethanol 
or an optically active .alpha.-alkylbenzylamine, to form diastereomer 
salts respectively corresponding to said (+)ACP acid derivative and said 
(-)ACP acid derivative.

DETAILED DESCRIPTION OF THE INVENTION 
The optical resolution process of the present invention will be described 
below in detail. 
In the present invention, a (.+-.)ACP acid derivative is allowed to react 
with an optically active cis-2(arylalkylamino)cyclohexanemethanol, i.e., 
(+)- or (-)-cis-2-(arylalkylamino)cyclohexanemethanol, or an optically 
active .alpha.-alkylbenzylamine, i.e., (+)- or 
(-)-.alpha.-alkylbenzylamine, which is an amine compound serving as an 
optically resolving agent, to form diastereomer salts respectively 
corresponding to the (+)ACP acid derivative and the (-)ACP acid 
derivative. In this case, the diastereomer salts are formed by dissolving, 
with heating, the optically resolving agent in the (.+-.)ACP acid 
derivative preferably in the presence of a solvent. 
The acyl group of the substituent R in the (.+-.)ACP acid derivative of 
Formula (1), used in the present invention can be exemplified by an 
alkanoyl group such as an acetyl group or a propionyl group, an aroyl 
group such as a benzoyl group or a naphthoyl group, and a heteroaroyl 
group such as a franoyl group. These may also be optionally substituted 
with other substituent. 
The (.+-.)ACP acid derivative of Formula (1) can be produced by subjecting 
(.+-.)-2-azabicyclo[2.2.1]hept-5-en-3-one to hydrolysis according to a 
conventional method, for example, by heating it in an aqueous dilute 
hydrochloric acid solution to form (+)ACP acid, followed by acylation of 
the amino group to convert it into an amido group. 
In the present invention, there are no particular limitations on the molar 
ratio of the optically active cis-2-(arylalkylamino)cyclohexanemethanol or 
optically active .alpha.-alkylbenzylamine used as an optically resolving 
agent, to the (.+-.)ACP acid derivative. In order to resolve the (.+-.)ACP 
acid derivative in a good efficiency and a high purity, it is preferable 
to use the optically active resolving agent in an equivalent mole of from 
0.4 to 1.0 based on the (.+-.)ACP acid derivative. 
The arylalkyl group in the optically active 
cis-2-(arylalkylamino)cyclohexanemethanol and the alkyl group in the 
optically active .alpha.-alkylbenzylamine may be selected from various 
groups capable of resolving the (.+-.)ACP acid derivative. The arylalkyl 
group may preferably be a benzyl group, and the alkyl group may preferably 
be a methyl group. 
Such an optically active resolving agent and the (.+-.)ACP acid derivative 
may preferably be allowed to react in the presence of a solvent, as 
previously mentioned. Such a solvent can be exemplified by water; 
C.sub.1-6, preferably C.sub.1-4, alkanols such as methanol, ethanol, 
2-propanol, 1-propanol and 1-butanol; C.sub.3-6 alkyl methyl ketones such 
as acetone and methyl isobutyl ketone; cyclic ethers such as dioxane, 
tetrahydrofuran and tetrahydropyran; mixtures of any of these; benzenes 
unsubstituted or substituted with methyl or the like lower alkyl, such as 
benzene, toluene and xylene; C.sub.6-8 cycloalkanes such as cyclohexane; 
and C.sub.6-10 alkanes such as n-hexane, n-octane and n-decane. In 
particular, in view of the advantage that a highly pure, optically active 
ACP acid derivative can be obtained, it is preferable to use water or 
2-propanol as the solvent. Especially when water is used as the solvent, a 
more highly pure, optically active ACP acid derivative can be obtained by 
neutralizing an excess (.+-.)ACP acid derivative present in the reaction 
mixture after the formation of diastereomer salts, by the use of a base 
such as sodium hydroxide, potassium hydroxide, lithium hydroxide or 
ammonia. 
The amount of the solvent used may vary depending on the type of the 
solvent, dissolving temperature and crystallization temperature. In usual 
instances, the solvent may preferably be used in an amount of from about 
150 to 2,000 ml per mol of the optically active resolving agent used. 
The resulting diastereomer salts are two kinds of ammonium carboxylates 
different from each other, formed of substituted amino groups pertaining 
to the optically resolving agent and carboxyl groups pertaining to the ACP 
acid. When the optically resolving agent used is a (+)-isomer, a [(+)ACP 
acid derivative.(+)optically resolving agent] salt and a [(-)ACP acid 
derivative.(+)optically resolving agent] salt are obtained correspondingly 
to the (+)ACP acid derivative and the (-)ACP acid derivative, 
respectively. When the optically resolving agent used is a (-)-isomer, a 
[(+)ACP acid derivative.(-)optically resolving agent] salt and a [(-)ACP 
acid derivative. (-)optically resolving agent] salt are obtained. 
The diastereomer salts obtained in this way can be mutually optically 
resolved by conventional methods. For example, the diastereomer salts can 
be separated by utilizing a difference in their solubility to solvents. In 
this case, the reaction solution may preferably be cooled to a given 
crystallization temperature into a supersaturated state so that one 
diastereomer salt which is more sparingly soluble can be preferentially 
crystallized from the reaction solution in which the diastereomer salts 
are formed. A preferable crystallization temperature may very depending on 
the amount of the solvent, the type of the solvent and the solvent 
temperature. From an economical viewpoint, it may usually be in the range 
of from -10 to 50.degree. C. 
When one diastereomer salt is crystallized, a very small amount of crystals 
of the diastereomer salt to be crystallized may preferably be added to the 
reaction solution as seed crystals. The diastereomer salt thus deposited 
can be isolated by a commonly available method such as filtration or 
centrifugal separation. 
The diastereomer salts having been optically resolved in this way can be 
formed into optically active ACP acid derivatives by conventional methods. 
For example, the diastereomer salts are each hydrolyzed using an alkali 
hydroxide to convert the carboxyl group of an ACP acid derivative into an 
alkali metal salt, during which the amine compound optically resolving 
agent is released. The released compound is removed by extraction with 
ether and a mineral acid such as hydrochloric acid or sulfuric acid is 
made to act on the aqueous layer, whereby the optically active (+)ACP acid 
derivative or (-)ACP acid derivative can be produced. 
The optically resolving agent recovered by the extraction with ether may be 
reused. 
As described above, in the process for the optical resolution of the 
(.+-.)ACP acid derivative according to the present invention, the 
optically active amino compound cis-2-(arylalkylamino)cyclohexanemethanol 
or optically active .alpha.-alkylbenzylamine and the (.+-.)ACP acid 
derivative are allowed to react to form the diastereomer salts 
corresponding to the (+)ACP acid derivative and the (-)ACP acid 
derivative. Hence, for example, it becomes possible to preferentially 
deposit one diastereomer salt, utilizing a difference in solubility to 
solvents, of the diastereomer salts different from each other. Thus, 
according to the present invention, the (+)- or 
(-)-cis-4-aminocyclopent-2-en-1-carboxylic acid with a high optical 
purity, useful as a starting material for synthesizing the carbovir having 
an inhibitory action against the proliferation of AIDS viruses, can be 
readily separated from a mixture of these. 
EXAMPLES 
In the following, production of the (+)ACP acid derivative to which the 
optical resolution process of the present invention is applied will be 
illustrated as Reference Examples, and the present invention will be 
further described in detail by giving Examples. 
Reference Example 1 
Synthesis of (.+-.)ACP acid {(.+-.)-cis-4-aminocyclopent-2-en-1-carboxylic 
acid} 
To 4.58 g (42 mmol) of (.+-.)-2-azabicyclo[2.2.1]hept-5-en-3-one, 190 ml of 
1N hydrochloric acid was added, and the mixture was refluxed for 2 hours 
with heating. The solvent was evaporated, and the resulting white crystals 
were washed with 30 ml of acetone, followed by drying to give 6.59 g of 
crude crystals of the subject (+)ACP acid. This crude crystals were 
dissolved in ethanol (20 ml) with heating, and thereafter ethyl acetate 
(85 ml) was added to the resulting solution, followed by cooling to room 
temperature. The crystals thus deposited were filtrated to give 4.26 g 
(25.7 mmol; yield: 61.2%) of the subject (+)ACP acid (melting point: 
169-172.degree. C.). 
Reference Example 2 
Synthesis of (.+-.)ACP acid derivative-A 
{(.+-.)-cis-4-benzamidocyclopent-2-en-1-carboxylic acid} 
To 8 ml of water, the (.+-.)ACP acid (1.64 g, 10.0 mmol) obtained in 
Reference Example 1 was added, and an aqueous solution prepared by 
dissolving sodium hydroxide (0.976 g, 24.4 mmol) in water (5 ml) was 
further added under ice cooling, followed by stirring. To the resulting 
reaction solution, a solution prepared by dissolving benzoyl chloride 
(1.83 g, 1.30 mmol) in dioxane (10 ml) and an aqueous solution prepared by 
dissolving sodium hydroxide (0.511 g, 13.8 mmol) in water (5 ml) were 
simultaneously dropwise added over a period of 25 minutes. After the 
addition was completed, stirring was continued at 0.degree. C. for 3 
hours. Thereafter, the reaction solution was washed twice with ethyl 
acetate (30 ml), and then 4N hydrochloric acid (4 ml) was further added to 
make the solution acidic. A white precipitate thereby deposited was 
filtrated, followed by washing with water and then drying to obtain 2.12 g 
of crude crystals of the subject (.+-.)ACP acid derivative A. To this 
crude crystals, acetonitrile (34 ml) was added to dissolve them with 
heating, followed by cooling to room temperature. Crystals deposited were 
filtrated to give 1.91 g (8.20 mmol; yield: 81.9%) of needle crystals of 
the subject (.+-.)ACP acid derivative-A (melting point: 170-172.degree. 
C.). 
Example 1 
Optical resolution (1) of (.+-.)ACP acid derivative-A 
To methanol (110 ml), the (.+-.)ACP acid derivative-A (4.51 g, 19.4 mmol) 
obtained in Reference Example 2 and 
(+)-cis-2-(benzylamino)cyclohexanemethanol (4.25 g, 19.4 mmol) as an 
optically resolving agent were added. While these were heated and reacted, 
the solvent was evaporated. To the resulting yellow oil, 2-propanol (28 
ml) was added to dissolve them with heating, followed by cooling to room 
temperature. Crystals deposited were filtrated, and the resulting crystals 
were further recrystallized four times with 2-propanol. The diastereomer 
salt crystals thus obtained had the properties as shown below. Melting 
point: 133-134.degree. C. [.alpha.].sub.589 -10.7.degree. (c=1.042, 
methanol) 
As a result, the diastereomer salt crystals obtained were found to be a 
[(-)ACP acid derivative-A.(+)optically resolving agent] salt. 
To the crystals obtained, an aqueous 1N sodium hydroxide solution (8 ml) 
was added, and the optically resolving agent released was separated and 
removed by extraction with the addition of diethyl ether (15 ml). To the 
aqueous layer formed, 4N hydrochloric acid was added, and a white 
precipitate thereby deposited was filtrated to give 1.08 g (4.64 mmol) of 
(-)ACP acid derivative-A {(-)-cis-4-benzamidocyclopent-2-en-1-carboxylic 
acid (yield: 47.8% based on (+)ACP acid derivative-A; [.alpha.].sub.589 
-24.0.degree. (c =1.049, methanol); melting point: 150.0-151.1.degree. 
C.). 
The (-)ACP acid derivative-A thus obtained was allowed to react with 
optically active 1-(1naphthyl)ethylamine to derive its amido form, which 
was then analyzed by HPLC to reveal that it had an optical purity of 99% 
or more. 
Conditions for HPLC 
Column: Inertsil SIL (5 .mu.m in diameter) 
Mobile phase: n-Hexane/2-propanol=95/5 
Flow rate: 1.0 ml/min. 
Example 2 
Optical resolution (2) of (.+-.)ACP acid derivative-A 
To water (40 g), the (.+-.)ACP acid derivative-A (10.0 g, 43.3 mmol) 
obtained in Reference Example 2, (+)-.alpha.-methylbenzylamine (2.62 g, 
21.6 mmol)as an optically resolving agent and an aqueous 20% sodium 
hydroxide solution (4.3 g, 21.5 mmol) were added to dissolve them with 
heating. Thereafter, the reaction solution was slowly cooled to 5.degree. 
C. Crystals deposited were filtrated to obtain 3.90 g of crystals of 
diastereomer salts (yield: 51.2% based on (+)ACP acid derivative). 
To 3.00 g of the crystals obtained, 33 ml of an aqueous 1N sodium hydroxide 
solution was added to release the optically resolving agent. The optically 
resolving agent was separated and removed by adding thereto 33 ml of 
diethyl ether. To the remaining aqueous layer, 4N hydrochloric acid was 
added, and a white precipitate thereby deposited was filtrated to give 
1.82 g of (+)ACP acid derivative-A 
{(-)-cis-4-benzamidocyclopent-2-en-1carboxylic acid} (yield: 92.5% based 
on diastereomer salts. The [.alpha.].sub.589 of the (+)ACP acid 
derivative-A obtained was 24.0.degree. (c=1.021, methanol). This value was 
coincident with the absolute value of the specific rotation of the (-)ACP 
acid derivative-A obtained in Example 1. From this fact, the optical 
purity was found to be 99% or more. 
Reference Example 3 
Synthesis of (.+-.)ACP acid derivative-B 
{(.+-.)-cis-4-(N-carbobenzoxy)cyclopent-2-en-1-carboxylic acid} 
To water (10 ml), the (.+-.)ACP acid (2.46 g, 15.0 mmol) obtained in 
Reference Example 2 was added, and an aqueous solution prepared by 
dissolving sodium hydroxide (1.47 g, 36.8 mmol) in water (7 ml) was 
further added under ice cooling, followed by stirring. To the resulting 
solution, a toluene solution containing 30% by weight of 
carbobenzoxychloride and an aqueous solution prepared by dissolving sodium 
hydroxide (0.830 g, 20.8 mmol) in water (7 ml) were simultaneously 
dropwise added over a period of 25 minutes. After the addition was 
completed, stirring was further continued at O.degree. C. for 3 hours. 
Thereafter, the reaction solution was washed twice for extraction with 
diethyl ether (30 ml), and then 2N hydrochloric acid (12 ml) was further 
added to make the solution acidic. A white precipitate thereby deposited 
was filtrated, followed by washing with water and then drying to obtain 
3.56 g of crude crystals of the subject (.+-.)ACP acid derivative-B. To 
this crude crystals, benzene (15 ml) was added to dissolve them with 
heating, followed by cooling to room temperature. Crystals deposited were 
filtrated to give 3.06 g (11.7 mmol; yield: 78.0%) of the subject 
(.+-.)ACP acid derivative-B (melting point: 126-131.degree. C.). 
Example 3 
Optical resolution of (.+-.)ACP acid derivative-B: 
To methanol (60 ml), the (.+-.)ACP acid derivative-B (3.90 g, 14.9 mmol) 
obtained in Reference Example 3 and a solution prepared by dissolving 
(-)-.alpha.-methylbenzylamine (1.80 g, 14.9 mmol) as an optically 
resolving agent in methanol (10 ml) were added. While these were heated 
and reacted, the solvent was evaporated to obtain a white precipitate. 
This white precipitate was further recrystallized eight times with 
2-propanol. The diastereomer salt crystals thus obtained had the 
properties as shown below. 
Melting point: 150-151.degree. C. [.alpha.].sub.589 34.4.degree. (c=1.052, 
methanol) 
As a result, the diastereomer salt crystals obtained were found to be a 
[(+)ACP acid derivative-B.(-)optically resolving agent] salt. 
To the crystals obtained, an aqueous 1N sodium hydroxide solution (5 ml) 
was added, and the optically resolving agent released was separated and 
removed by extraction with the addition of diethyl ether (15 ml). To the 
aqueous layer formed, 4N hydrochloric acid was added, and a white 
precipitate thereby deposited was filtrated to give 0.517 g (1.97 mmol) of 
(+)ACP acid derivative-B 
{(+)-cis-4-(N-carbobenzoxy)cyclopent-2-en-1-carboxylic acid}(yield: 26.6% 
based on (.+-.)ACP acid derivative-B; [.alpha.].sub.589 =34.0.degree. 
(c=1.001, methanol). 
The (+)ACP acid derivative-B thus obtained was allowed to react with 
optically active 1-(1naphthyl)ethylamine to derive its amido form, which 
was then analyzed by HPLC to reveal that it had an optical purity of 99% 
or more. 
Conditions for HPLC 
Column: Inertsil SIL (5 .mu.m in diameter) 
Mobile phase: n-Hexane/2-propanol=96/4 
Flow rate: 1.0 ml/min.