JPS5967272A - Optically active half ester - Google Patents

Abstract

NEW MATERIAL:(4S, 5R)-1,3-Dibenzyl-5-carboxy-4-alkoxy(or alkenyloxy)carbonyl- imidazolidin-2-one derivative of formula I (R1 is 1-5C alkyl or 1-5C alkenyl; the configuration of 4- and 5-sites is 4S, 5R). USE:An intermediate of pharmaceuticals. It can be converted to an important intermediate of biotin by reducing with diborane. PROCESS:The optically active ester can be prepared e.g. by (1) reacting 1,3-dibenzyl-4,5-dicarboxyimidazolin-2-one with corresponding alcohol under heating to obtain a mixture of optically active half esters of formula I and formula II, (2) adding a solent and an optically active d- or l-amine of formula III (R2 and R3 are H, halogen or methyl) (e.g. alpha-phenyl-beta-phenylethylamine) to the mixture to form an amine salt, (3) cooling the reaction mixture slowly to precipitate one of the salts of the optically active compound, and (4) decomposing the remaining salt with an acid.

Description

Detailed Description of the Invention The present invention is based on the general formula [I] (1) (In the above formula, k□ represents an alkyl group or an alkenyl group having 1 to 5 carbon atoms. Coordination of the 4th and 5th positions) is a 4S, 5R coordination.) An optically active (4S, 5R)-1,3-dibenzyl-5-carboxy-4-alkoxy or alkenyloxycarbonylimidazolidin-2-one derivative (
(hereinafter referred to as the Hafestel class).

(1:1) of the optically active hafestales represented by the general formula CI) and the optically active hafesters represented by the general formula (I[) (in the above formula, k□ has the same meaning as above). ) have been known for a long time, and optically active halfesters represented by the general formula (I []) have been obtained, but the compound of the general formula CD is a novel compound isolated for the first time by the present inventors For example, by reducing diborane, it is an important intermediate for biotin (3S).

4R)-(1,3-dibenzyl-2-keto-imidazolide)-2-keto-tetrahydrofuran, and is an important compound as a pharmaceutical intermediate.

The optically active hafestels represented by the general formula [l] of the present invention are added to a mixture of the optically active hafesters represented by the general formula [■] and the general formula (II), and the optically active hafestels represented by the general formula [I[[
) (3) (In the above formula, R2 and R3 are hydrogen, halogen,
Indicates a methyl group. ) can be produced by reacting with

The optically active halfesters represented by the general formula [■] and the general formula [II"l, which are the raw material compounds of the compounds of the present invention, are, for example, 1,3-dibenzyl-4,5-dicarboximidacillin-2-one (Japanese Patent Application No. 57-71777) A method for producing optically active halfesters represented by the general formula CI) is obtained by heating the corresponding alcohol. A predetermined amount of a solvent and an optically active d- or l-
An amine is added to form a salt of the optically active halfester represented by the general formulas [I) and (II] and the optically active d- or l-amine represented by the general formula (III), and this is dissolved in a solvent. let

The optically active amines represented by the general formula (4) (I ) lyl)ethylamine, α-phenyl-β-(p-chlorophenyl)ethylamine, α-(P
-tolyl)-β-phenylethylamine and the like are exemplified.

The amount of optically active d- or l-amine to be used is determined by the general formula [
The amount is usually about 0.7 to 1.2 times by mole, preferably 0.8 to 1.1 times by mole, relative to the mixture of optically active Hafester represented by [2] and (II).

The solvents used include a mixed solvent of water and a water-soluble organic solvent such as methanol, ethanol, and isoprobanonopear, benzene, toluene, chloroform,
An example is ethyl acetate.

The amount of solvent to be used is determined between the optically active halfesters represented by the generated general formulas [I] and [■] and the general formula (I[[]
This value is suitable for fractional crystallization of a salt with an optically active d- or l-amine represented by (5) from its solution.

The reaction temperature is arbitrary within the range of 0° C. to the boiling point of the solvent used (however, it is not below the melting point of the solvent used), but it is preferably at least the temperature at which the produced salt precipitates.

After producing the optically active amine salts represented by the general formulas CI) and (II) of the optically active Hafester general formula (I []) by the above reaction, the reaction mixture is slowly cooled, and one of the optically active forms is precipitates salt.

At this time, it is more preferable to inoculate the mixed system with seed crystals of the same type as the salt so as to precipitate it.

The crystals thus obtained are separated, dried and decomposed with acid. The acid used here is hydrochloric acid,
These are sulfuric acid, phosphoric acid, etc., and the amount thereof is arbitrary, at least 1 mole based on the filtered crystals, but is usually about 1 mol to 1.1 mol. The decomposition solution is mixed with an organic solvent (e.g. toluene,
Extraction (6) is carried out using a solvent such as chloroform, ether, ethyl acetate, etc. alone or a mixture thereof. After washing the oil layer with water as necessary, the solvent is distilled off to obtain one of the optically active halfesters. I can do it.

In addition, the water obtained by washing the aqueous layer and extracted oil layer obtained by the extraction process is neutralized with an alkali (for example, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, etc.), and then mixed with an organic solvent (tatoehatoluene, After washing the extracted oil layer with water and distilling off the solvent, the optically active d- or l-amine represented by the general formula [■] used as a resolving agent is highly purified. It can be recovered in high yield. The fact that this resolving agent can be recovered in high yield is a major advantage in industrial implementation.

On the other hand, the furnace liquor after separating the precipitated crystals is concentrated, the obtained solid is decomposed with acid, the decomposed liquid is extracted, and the extraction solvent is removed from the extracted oil layer. A mixture of optically active halfesters represented by general formulas (I) and (II) containing an excess of noofesters is obtained, and in the next step (7), this is dissolved in a suitable solvent such as benzene, toluene, xylene, etc. By slow cooling, the other optically active halfester is precipitated (preferential crystallization), and this is separated and dried to obtain the other optically active halfester. At this time, it is more preferable to inoculate the mixed system with seed crystals of the same type as the other optically active halfester before it precipitates.

The acid and extraction solvent used for decomposition are the same as those described above. The amount of benzene used for preferential crystallization is an amount suitable for separately crystallizing the other optically active halfester from its solution.

Hereinafter, the present invention will be specifically explained with reference to Examples.

Example 1 (48,5R)-1,3-dibenzyl-4-carboxy-5-methoxycarbonylimidazolidin-2-one and (48,5R)-1,3-dibenzyl-5-carboxy-4(8) Monomethoxycarbonylimidazolidin-2-one (1:
368.49 (total 1 mol) of the mixture of 1), 1.51 mol of Improper Tool and 1.51 ml of water were placed in a flask and heated to 50°C. This tL is d-α-phenyl-β-phenylethylamine 197°3f! (1 mol) was added dropwise. (4S, 5R)-1 was slowly cooled and separately adjusted at 35°C.
, 3-dibenzyl-5-carboxy-4-methoxycarbonylimidazolidin-2-one and d-α-phenyl-
A small amount of β-phenylethylamine salt crystals were added as seed crystals, and the mixture was further slowly cooled to 20°C, kept at 20°C for 2 hours, and the precipitated crystals were separated. After acid decomposition by adding 500 cm of water and 46.5 F of concentrated hydrochloric acid to the oven-dried crystals, ethyl acetate aoo oc was added (4S, 5
R) -1,3-Dibenzyl-5-carboxy-4-methoxycarbonylimidazolidin-2-one is extracted and separated. After washing the extract twice with 100 cr of water, ethyl acetate was distilled off to give (4S,5R)-1,3-dibe(
9) Fujiru 5-carboxy-4-methoxycarbonylimidazolidin-2-one 155.1 f (yield 42.1%
) was obtained.

0 [α) = + 27.8° (c = l, D
MF) 66 m, P, 148-149.5°C Example 2 (4S,5R)-1,3-dibenzyl-4-carboxy-5-ethoxycarbonylimidazolidin-2-one and (4S,5R)-1 ,3-dibenzyl-5-carboxy-4-ethoxycarbonylimidazolidine-2
- mixture (1:1) of 382°42 (total 1 mol)
, Improper Tools 2゜5I! A flask was charged with 2.5 liters of water and heated to 50°C.

To this, 211.39 (1 mol) of d-α-phenyl-β-(p-tolyl)ethylamine was added dropwise.

It was slowly cooled and adjusted separately at 30-31°C (4S.

5R)-1,3-dibenzyl-4-carboxy-5-ethoxycarbonylimidazolidin-2-one and d-α-
A small amount of phenyl-β-(p-(10)tolyl)ethylamine salt crystals were added as seed crystals, and the mixture was further slowly cooled to 10°C and kept at 10°C for 2 hours, after which the precipitated crystals were separated by furnace. After concentrating the obtained r liquid, 600 heads of water and 62 f of concentrated hydrochloric acid were added for acid decomposition, and further 400 [of ethyl acetate was added to give (45,5R)-
Contains an excess of 1,3-dibenzyl-5-carboxy-4-ethoxycarbonylimidazolidin-2-one (
4St 5 R) -s t3-dibenzyl-5-carboxy-4-ethoxycarbonylimidazolidine-2
-one and (48,5K)-1,3-dibenzyl-4
The mixture of -carboxy-5-ethoxycarbonylimidazolidin-2-ones is extracted and separated. Add the extract to 100% water
After washing twice with CC, ethyl acetate is distilled off. The obtained solid was mixed with toluene 11! Dissolve in. Thereafter, it was slowly cooled and (4S, 5R)-1,3-dibenzyl-5-carboxy-4-ethoxycarbonylimidazolidine-2-
After inoculating seed crystals of 4S.

(11) 5R)-1,3-dibenzyl-5-carboxy-4-ethoxycarbonylimidazolidin-2-one is preferentially precipitated. After slowly cooling to 10°C and keeping warm at 10°C for 2 hours, the precipitated crystals were dried by t-P (48,5R)-1,
3-dibenzyl-5-carboxy-4-ethoxycarbonylimidazolidin-2-one 165.61 (yield 43
゜3chi) was obtained.

[α] +18°8° (c=1tDMF) 66 m, P, 113-115°C Example 3 (4S, SR) -1,3-dibenzyl-4-carboxy-5-isopropoxycarbonylimidazolidine-2
-on and (4S.

5R)-1,3-dibenzyl-5-carboxy-4-isopropoxycarbonylimidazolidin-2-one (1
:1) mixture 396.42 (total 1 mol), Impropatool 2.51! and water 2.51! into a flask and warm to 50°C. To this, d-α-phenyl-β
-(12) (P-tolyl)ethylamine 211.3f! (1 mole)
drip. Slowly cooled and separately adjusted at 31-32°C (
4S, 5R) -1,3-dibenzyl-4-carboxy-5-isopropoxycarbonylimidazolidine-2-
A small amount of salt crystals of 1 and d-α-phenyl-β-(P-)IJl)ethylamine were added, and the mixture was further slowly cooled to 10°C. After being kept at 10°C for 2 hours, the precipitated crystals were separated by furnace. After concentrating the obtained furnace liquid, 600 liters of water and 63 liters of concentrated hydrochloric acid were added for acid decomposition, and then 400 liters of ethyl acetate was added.
Add ω to (4S, 5K)-1,3-dibenzyl-5-
(4S, 5R)-1, containing an excess of carboxy-4-inpropoxycarbonylimidazolidin-2-one,
3-dibenzyl-5-carboxy-4-isopropoxycarbonylimidazolidin-2-one and (4S.

The mixture of 5R)-1,3-dibenzyl-4-carboxy-5-isopropoxycarbonylimidazolidin-2-ones is extracted and separated.

(13) After washing the extract twice with 100 cm of water, ethyl acetate is distilled off. The obtained solid is dissolved in 11 toluene. After that, it was slowly cooled (4S).

After inoculating seed crystals of (5R)-1,3-dibenzyl-5-carboxy-4-isopropoxycarbonylimidazolidin-2-one, (45,5R)-1,3-dibenzyl-5-carboxy-4- Isopropoxycarbonylimidazolidin-2-one is preferentially precipitated.

After slowly cooling to 10°C and keeping at 10°C for 2 hours, the precipitated crystals were separately dried to give 4S, 5R)-1,3-dibenzyl-5-carboxy-4-isopropoxycarbonylimidazolidin-2-one 167 .7 El (yield 42.
3%).

[α] 365=+26.7° (c=l, DMF
) m, p, 140-142°C Example 4 (48,5R)-1,3-dibenzyl-4-carboxy-5-methoxycarbonylimidazolidin-2-one and (45,5R) (14) -1 , 3-dibenzyl-5-carboxy-4-methoxycarbonylimidazolidin-2-one (1:1) 368.49 (total 1 mol), acetone 3I! and water 31 are placed in a flask and heated to 60°C. This is l-α-phenyl-3-(p-)! 211.32 (1 mol) of ethylamine are added dropwise. Cool slowly, 34-3
(4S,5R)-1゜3-dibenzyl-4-carboxy-5-methoxycarbonylimidacillin-2-one and 1-a-phenyl-β-(P-
A small amount of salt crystals of tolyl)ethylamine were added as seed crystals, and the mixture was further slowly cooled to 15°C, kept at 15°C for 2 hours, and the precipitated crystals were separated by furnace.

The furnace liquid was concentrated, and 600 oc of water and 64 ml of concentrated hydrochloric acid were added to the resulting solid, and after dilution with acid, ethyl acetate/L/3
QQ CC is added (48,5R)-1°3-dibenzyl-5-carboxy-4-methoxycarbonylimidazolidin-2-one is contained in excess (4S,5R)-1
, 3-dibenzyl-4-carboxy-5-methoxycarbonylimidazolidin-2-one and (4S, 5R)
The mixture of -1,3-dibenzyl-5-carboxy-4-methoxycarbonylimidazolidin-2-ones is extracted and separated.

After washing the extract twice with water ioo oc, ethyl acetate is distilled off. The obtained solid is dissolved in benzene 61. After that, it was slowly cooled (4S).

After inoculating with seed crystals of (48,5R)-1,3-dibenzyl-5-carboxy-4-methoxycarbonylimidazolidin-2-one, (48,5R)-1,3-dibenzyl-5-
Carboxy-4-methoxycarbonylimidazolidine-
2-one is preferentially precipitated. Slowly cool to 15℃ and
After incubating at 5℃ for 2 hours, the precipitated crystals were dried from house to house.
175.07 (yield: 47.5%) of 3-dibenzyl-5-carboxy-4-methoxycarbonylimidazolidin-2-one was obtained.

0 [α) = +27.4° (c = l, DMF
)66 m, p, 148-149℃

Claims (1)

[Claims] (1) Optical formula represented by the general formula (in the above formula, k represents an alkyl group or alkenyl group having 1 to 5 carbon atoms. The coordination at the 4th and 5th positions is a 48,5R coordination.) Active (4St5R)1 t3-dibenzyl-5-carboxy-4-alkoxy or alkenyloxycarbonylimidazolidin-2-one derivative.