Optically active imidazolidin-2-one derivatives

A novel optically active cis-4,5-disubstituted imidazolidin-2-one derivative of the formula: ##STR1## wherein R.sup.1 is a C.sub.1 -C.sub.4 alkyl group or benzyl and R.sup.2 is a chiral aralkyl group optionally having at least one of C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy and hydroxyl groups is produced asymmetrically by the reaction of 1,3-dibenzyl-cis-4,5-dicarboxy-imidazolidin-2-one or its anhydride with an optically active secondary amine of the formula: ##STR2## wherein R.sup.1 and R.sup.2 are each as defined above and is transformed into the lactone of 1,3-dibenzyl-cis-4-carboxy-5-hydroxymethyl-imidazolidin-2-one, which is a key intermediate in the synthesis of d-biotin.

The present invention relates to novel optically active imidazolidin-2-one 
derivatives and their production. 
More particularly, it relates to optically active cis-4,5-disubstituted 
imidazolidin-2-one derivatives of the formula: 
##STR3## 
wherein R.sup.1 is a C.sub.1 -C.sub.4 alkyl group or benzyl and R.sup.2 is 
a chiral aralkyl group optionally having at least one of C.sub.1 -C.sub.4 
alkyl, C.sub.1 -C.sub.4 alkoxy and hydroxyl groups, and their production. 
The said optically active imidazolidin-2-one derivatives (I) are novel and 
useful as intermediates in the synthesis of d-biotin and trimethaphan 
camphorsulfonate. 
d-Biotin is known as Vitamin H and is widely used as a medicine and also as 
a feed additive. The bistin molecule has three asymmetric carbon atoms, 
and there can be eight stereoisomers including optical isomers. Among 
them, however, only d-biotin, whose structure is shown below, is 
biologically active, and otheer isomers are almost inactive. 
##STR4## 
For stereo-specific synthesis of optically active biotin, various methods 
are known. For instance, a method using D-mannose (Tetrahedron Letters, 
page 2765 (1975)) or L-cysteine as the starting material (J.Am.Chem.Soc., 
97, 5936 (1975)) has been reported. In this method, optically active 
starting materials are converted into optically active biotin in a 
stereo-specific manner. This process is advantageous in not including any 
resolution step but is difficult to apply on an industrial scale in 
requiring many reaction sequences and affording optically active biotin 
only in poor yields. 
There is another method using an optically active lactone of the following 
formula (II) as an intermediate. 
##STR5## 
In this method, an optically active intermediate is employed at a 
relatively early stage in the total synthesis of biotin and unnecessary 
antipodes are not produced at a later stage. 
For the production of the optically active lactone (II), many methods are 
available, among which the following two are typical. The first method is 
disclosed in Japanese Patent Publication (examined) No. 32551/1974, U.S. 
Pat. No. 3,700,659, etc., in which the dicarboxylic acid anhydride (III) 
having a cis configuration is reacted with optically active cholesterol or 
cyclohexanol and the resultant diastereomeric half ester (IV) is resolved 
with the aid of triethylamine or l-ephedrine, respectively, to give the 
half ester (IV) in an optically pure form. Reduction of the resolved half 
ester (IV), followed by lactonization gives the optically pure lactone 
(II). The above chemical conversion is represented by the following 
equation: 
##STR6## 
wherein R is cholesteryl or cyclohexyl. However, this method is 
disadvantageous in requiring a resolution step which is complex and 
inefficient. Although the unnecessary diastereomer of the half ester (IV) 
is hydrolyzed and dehydrated to give back the anhydride (III) for repeated 
use, the amount of the desired diastereomer never exceeds that of the 
unnecessary diastereomer separated. 
The second method is disclosed in Japanese Patent Publication (unexamined) 
Nos. 20196/1974, 117,467/1974 and 127,994/1974, U.S. Pat. Nos. 3,876,656 
and 4,014,895. etc., in which the dicarboxylic acid (V) having a cis 
configuration is reacted with an optically active primary amine 
(R'-NH.sub.2), and the resulting imide (VI) is reduced with a metal 
hydride to give an amide-alcohol (VII). Hydrolysis of the amide-alcohol 
(VII), followed by lactonization gives the optically active lactone (II). 
The above chemical conversion is represented by the following equation: 
##STR7## 
In this method, the attack of a metal hydride on the two carbonyl groups 
of the imide molecule (VI) is influenced by the chiral moiety R', and one 
of the diastereomers of the amide-alcohol (VII) is produced much more than 
the other diastereomer. Thus, asymmetric induction is achieved in the 
above process. By the suitable choice of the optically active primary 
amine (R'--NH.sub.2), a maximum optical yield of 75 to 80% has been 
obtained. 
As a result of the extensive study on the asymmetric synthesis of the 
optically active lactone (II), we have accomplished the following 
invention. The reaction of the dicarboxylic acid (V) or the anhydride 
(III) with an optically active secondary amine of the formula: 
##STR8## 
wherein R.sup.1 and R.sup.2 are each as defined above proceeds 
asymmetrically to give the optically active imidazolidin-2-one derivative 
(I) (hereinafter referred to as "amide-carboxylic acid (I)") in a high 
optical yield. It has also been found that the optically active 
amide-carboxylic acid (I) can be converted into the optically active 
lactone (II) in an excellent yield. 
The optically active amide-carboxylic acid (I) obtained in the above 
reaction contains one of the diastereomers (Ia) in a much larger or 
smaller amount than the other diastereomer (Ib). 
##STR9## 
The optical yield (Y) in percent is represented by the following equation: 
EQU Y=[Y(Ia)-Y(Ib)]/[Y(Ia)+(Ib)].times.100 
wherein Y(Ia) and Y(Ib) represent the yields of the diastereomer (Ia) and 
the diastereomer (Ib), respectively. 
This type of asymmetric reaction belongs to asymmetric synthesis starting 
from a meso compound differentiating the enantio-field (Y. Izumi and A. 
Tai: "Stereo-differentiating Reactions", Academic Press, New York, 1977), 
and a high optical yield as much as 90% has not been reported. The high 
optical yield achieved reminds us of a complete selectivity found in the 
biological systems involving microorganisms or enzymes (J. B. Jones et 
al.: "Techniques of Chemistry", published by John Wiley & Sons, Vol. 10, 
1976, pages 107-401). 
For transformation of the optically active amide-carboxylic acid (I) to the 
optically active lactone (II), various procedures are possible. In a 
typical procedure, the optically active amide-carboxylic acid (I) is 
esterified to give the amide-carboxylic ester (IX), which is reduced with 
a metal hydride such as sodium borohydride to an amide-alcohol (X). Acidic 
hydrolysis of the amide-alcohol (X), followed by lactonization gives the 
optically active lactone (II). These chemical conversions are shown by the 
following equation: 
##STR10## 
wherein Z is a lower alkyl group and R.sup.1 and R.sup.2 are each as 
defined above. 
In the above chemical conversions, the racemization at the asymmetric 
carbon atoms is impossible, and all the transformations are carried out to 
completion so that the proportion of (Ia)/(Ib) in the amide-carboxylic 
acid (I) is expected to be equal to that of the enantiomers of the lactone 
(II). Thus, the optical yield of the amide-carboxylic acid (I) is 
considered to be equal to the optical purity of the lactone (II). 
The optically active secondary amine (VIII) used for the production of the 
amide-carboxylic acid (I) is recovered on acidic hydrolysis of the 
amide-aclohol (X) without racemization and can be used again. 
In order to raise the optical purity of the lactone (II), the 
diastereomeric amide-carboxylic acid (I), its salt or amide-ester (IX) can 
be purified by an appropriate operation such as column chromatography on a 
suitable adsorbent or recrystallization from a proper solvent. The 
unnecessary diastereomer separated can be readily hydrolyzed to recover 
the dicarboxylic acid (V) and the optically active secondary amine. 
The recovered dicarboxylic acid (V) may be used again as the starting 
material as itself or the corresponding dicarboxylic anhydride (III). 
Also, the optically active secondary amine (VIII) may be recycled by 
itself. Therefore, the entire amount of the starting material, (III) or 
(V), can be ultimately converted into the desired diastereomer of the 
optically active amide-carboxylic acid (I) or its ester (IX). 
The dicarboxylic acid (V) and the dicarboxylic anhydride (III) are known 
compounds as are disclosed in U.S. Pat. No. 2,489,232. 
With respect to the optically active secondary amine (VII), R.sup.1 is a 
C.sub.1 -C.sub.4 alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl, 
n-butyl, isobutyl) or a benzyl group. The substituent R.sup.1 can be 
introduced into the optically active primary amine of the formula: R.sup.2 
--NH.sub.2 by alkylation or benzylation. 
R.sup.2 is a chiral aralkyl group optionally having at least one of C.sub.1 
-C.sub.4 alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, 
isobutyl), C.sub.1 -C.sub.4 alkoxy (e.g. methoxy, ethoxy, propoxy, 
isopropoxy, butoxy) and hydroxyl groups. The aryl moiety in the aralkyl 
group may be phenyl, naphthyl, etc., and the alkyl moiety may be lower 
alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, etc. 
Specific examples of the said aralkyl group are 1-phenylethyl, 
1-(.alpha.-naphthyl)ethyl, 1-phenyl-2-(p-tolyl)ethyl, etc. 
As R.sup.2, the aralkyl group representable by the following formula is 
particularly preferred: 
##STR11## 
wherein the carbon atom accompanied with an asterisk (*) is an asymmetric 
carbon atom, and R.sup.3 is C.sub.1 -C.sub.4 alkyl (e.g. methyl, ethyl, 
n-propyl, isopropyl, n-butyl, isobutyl, t-butyl), phenyl or benzyl and 
R.sup.4 is benzyl or phenyl optionally bearing at least one of C.sub.1 
-C.sub.4 alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, 
isobutyl, t-butyl) and C.sub.1 -C.sub.4 alkoxy (e.g. methoxy, ethoxy, 
n-propoxy, isopropoxy, n-butoxy, isobutoxy). Thus, specific examples of 
the substituent R.sup.4 are benzyl, phenyl, 2-methoxyphenyl, 
2-isopropoxyphenyl, 2-isopropoxy-5-methylphenyl, etc. 
Accordingly, specific examples of the optically active secondary amine 
(VIII) include the following: 
N-Methyl-1-phenylethylamine; 
N-Benzyl-1-phenylethylamine; 
N-Methyl-1-(.alpha.-naphthyl)ethylamine; 
N-Benzyl-1-(.alpha.-naphthyl)ethylamine; 
N-Methyl-1-phenyl-2-(p-tolyl)ethylamine; 
N-Benzyl-1-phenyl-2-(p-tolyl)ethylamine; 
N-Methyl-2-amino-1,1-diphenyl-1-propanol; 
N-Ethyl-2-amino-1,1-diphenyl-1-propanol; 
N-Benzyl-2-amino-1,1-diphenyl-1-propanol; 
N-Methyl-2-amino-1,1-dibenzyl-1-propanol; 
N-Methyl-2-amino-1,1-diphenyl-4-methyl-1-pentanol; 
N-Methyl-2-amino-1,1-dibenzyl-4-methyl-1-pentanol; 
N-Methyl-2-amino-1,1,2-triphenylethanol; 
N-Methyl-2-amino-1,1-di(2-isopropoxyphenyl)-3-phenyl-1-propanol; 
N-Methyl-2-amino-1,1-di(2-methoxyphenyl)-1-propanol; 
N-Methyl-2-amino-1,1-di(2-isopropoxy-5-methylphenyl)-3-phenyl-1-propanol; 
N-Methyl-2-amino-1,1,3-triphenyl-1-propanol; etc. 
The chiral amine (VIII) having either (R)- or (S)-configuration can be 
employed. 
The reaction of the dicarboxylic acid (V) or the anhydride (III) with the 
optically active secondary amine (VIII) is usually carried out in a 
solvent inert to the said starting materials under the reaction 
conditions. Examples of such a solvent include aromatic hydrocarbons (e.g. 
benzene, toluene, xylene), ethers (e.g. diethyl ether, tetrahydrofuran, 
dioxane, 1,2-dimethoxyethane, diethyleneglycol dimethyl ether), etc. The 
addition of a basic substance such as a tertiary amine (e.g. 
triethylamine, tributylamine) as well as pyridine to the reaction system 
is usually preferred. 
Strict limitation is not present on the reaction temperature. When the 
dicarboxylic anhydride (III) is used as the starting material, the 
reaction is usually effected at a temperature ranging from -20.degree. C. 
to the boiling point of the solvent, preferably at 
-20.degree..about.40.degree. C. When the dicarboxylic acid (V) is employed 
as the starting material, it is advantageous to carry out the reaction 
under continuous removal of water by azeotropic distillation. 
Alternatively, a dehydrating agent such as molecuular sieve or 
dicyclohexylcarbodiimide may be employed. 
The reaction time is influenced by the starting material, the solvent, the 
reaction temperature, etc. When the reaction is carried out using the 
dicarboxylic acid (V) at the boiling temperature of the solvent, it will 
usually take 1 to 20 hours. When the reaction is effected using the 
anhydride (III) at about 25.degree. C., it ordinarily takes 10 to 48 
hours. 
The molar ratio of the dicarboxylic acid (V) or the dicarboxylic anhydride 
(III) to the optically active secondary amine (VIII) is preferred to be 
nearly 1.0, particularly between 0.8 and 1.2. 
Separation and purification of the reaction product from the reaction 
mixture may be accomplished by per se conventional procedures such as 
distillation of the solvent, extraction with a proper solvent, washing, 
chromatography, etc. The progress of the reaction may be traced by the use 
of a thin layer chromatography or a high pressure liquid chromatography. 
The yield is almost quantitative. 
Specific examples of the optically active amide-carboxylic acid (I) as 
prepared by the above method are as follows: 
1,3-Dibenzyl-cis-4-carboxy-5-[N-methyl-N-(1-phenylethyl)carbamoyl]imidazoli 
din-2-one; 
1,3-Dibenzyl-cis-4-carboxy-5-[N-benzyl-N-(1-phenylethyl)carbamoyl]imidazoli 
din-2-one; 
1,3-Dibenzyl-cis-4-carboxy-5-[N-methyl-N-{1-(.alpha.-naphthyl)ethyl}carbamo 
yl]imidazolidin-2-one; 
1,3-Dibenzyl-cis-4-carboxy-5-[N-benzyl-N-{1-(.alpha.-naphthyl)ethyl}carbamo 
yl]imidazolidin-2-one; 
1,3-Dibenzyl-cis-4-carboxy-5-[N-methyl-N-{1-phenyl-2-(p-tolyl)ethyl}carbamo 
yl]imidazolidin-2-one; 
1,3-Dibenzyl-cis-4-carboxy-5-[N-benzyl-N-{1-phenyl-2-(p-tolyl)ethyl}carbamo 
yl]imidazolidin-2-one; 
1,3-Dibenzyl-cis-4-carboxy-5-[N-methyl-N-(1-methyl-2,2-diphenyl-2-hydroxyet 
hyl)carbamoyl]imidazolidin-2-one; 
1,3-Dibenzyl-cis-4-carboxy-5-[N-ethyl-N-(1-methyl-2,2-diphenyl-2-hydroxyeth 
yl)carbamoyl]imidazolidin-2-one; 
1,3-Dibenzyl-cis-4-carboxy-5-[N-benzyl-N-(1-methyl-2,2-diphenyl-2-hydroxyet 
hyl)carbamoyl]imidazolidin-2-one; 
1,3-Dibenzyl-cis-4-carboxy-5-[N-methyl-N-(1-methyl-2,2-dibenzyl-2-hydroxyet 
hyl)carbamoyl]imidazolidin-2-one; 
1,3-Dibenzyl-cis-4-carboxy-5-[N-methyl-N-(1-isobutyl-2,2-diphenyl-2-hydroxy 
ethyl)carbamoyl]imidazolidin-2-one; 
1,3-Dibenzyl-cis-4-carboxy-5-[N-methyl-N-(1-isobutyl-2,2-dibenzyl-2-hydroxy 
ethyl)carbamoyl]imidazolidin-2-one; 
1,3-Dibenzyl-cis-4-carboxy-5-[N-methyl-N-(1,2,2-triphenyl-2-hydroxyethyl)ca 
rbamoyl]imidazolidin-2-one; 
1,3-Dibenzyl-cis-4-carboxy-5-[N-methyl-N-{1-benzyl-2,2-di(2-isopropoxypheny 
l)-2-hydroxyethyl}carbamoyl]imidazolidin-2-one; 
1,3-Dibenzyl-cis-4-carboxy-5-[N-methyl-N-{1-methyl-2,2-di(2-methoxyphenyl)- 
2-hydroxyethyl}carbamoyl]imidazolidin-2-one; 
1,3-Dibenzyl-cis-4-carboxy-5-[N-methyl-N-{1-benzyl-2,2-di(2-isopropoxy-5-me 
thylphenyl)-2-hydroxyethyl}carbamoyl]imidazolidin-2-one; 
1,3-Dibenzyl-cis-4-carboxy-5-[N-methyl-N-(1-benzyl-2,2-diphenyl-2-hydroxyet 
hyl)carbamoyl]imidazolidin-2-one; etc.