JPH0366312B2 - - Google Patents

Description

[Detailed Description of the Invention] The present invention is based on the formula () [In the formula, * indicates an asymmetric carbon. Bzl represents a benzyl group. Positions 4a and 6a are cis-coordinated. ] This relates to a method for producing optically active cis-1,3-dibenzylhexahydro-1H-furo[3,4-d]imidazole-2,4-dione (hereinafter abbreviated as lactone), For more details, please refer to the general formula () [In the formula, * indicates an asymmetric carbon. R represents a lower alkyl group. Bzl represents a benzyl group. 4th place, 5th place
The carboxyl group or lower alkoxycarbonyl group of the optically active cis-imidazolidinedicarboxylic acid derivative (hereinafter abbreviated as half esters) represented by [the cis-coordination] is reduced and the lactone () is ring-closed. The present invention relates to a method for manufacturing.

In the general formula (), lower alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-
It means C _1-6 alkyl such as butyl, t-butyl, n-pentyl, n-hexyl group.

The optically active lactone obtained by the present invention is an important intermediate for biotin and other pharmaceutical products.

Conventionally known methods for producing optically active lactones are the methods described in Japanese Patent Publication No. 49-32551 (Method A) and Japanese Patent Publication No. 53-35076 (Method B).

In method A, (±)-cis-1,3-dibenzyl-5-(3'-cholesteryloxycarbonyl)
An optically active cholesteryl half ester is obtained by a method of optical resolution of a salt of -2-oxoimidazolidine-4-carboxylic acid and triethylamine,
This can be reduced with lithium borohydride to obtain a lactone, or the salt of (±)-cis-1,3-dibenzyl-5-cyclohexyloxycarbonyl-2-oxoimidazolidine-4-carboxylic acid and ehuedrin can be obtained. This method involves optical resolution to obtain an optically active cyclohexyl half ester, which is then reduced with lithium boron hydride to obtain a lactone, but it requires the use of expensive optically active compounds such as ephedrin and cholesterol. And the yield of lactone is low.

In method B, cis-1,3-dibenzyl-2
-Oxoimidazolidine-cis-1,3-dibenzylhexahydropyrrolo[3,4-d]imidazole-2,4 obtained by dehydration from 4,5-dicarboxylic acid and an optically active organic primary amine , 6-trione derivative is asymmetrically reduced with sodium borohydride, etc., and then hydrolyzed to obtain a lactone, but the asymmetric yield is not sufficient and the expensive optically active amine is not used. However, both methods cannot be called economical manufacturing methods.

The present inventors have carried out intensive research to overcome the above-mentioned conventional drawbacks, and as a result, have discovered a method for synthesizing optically active lactones in high yield through economical and industrially easy operations.

That is, by reducing the carboxyl group of optically active half esters (), which are new compounds, with diborane, or by reducing the lower alkoxycarbonyl group with sodium borohydride and ring-closing, optical compounds having the desired coordination are produced. It has been found that active lactone () can be obtained in good yield.

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

A method for selectively reducing the lower alkoxycarbonyl group of optically active half esters () is generally carried out by using a reducing agent that can selectively reduce the lower alkoxycarbonyl group, that is, sodium borohydride. I can do things. The reaction solvent may be any solvent that does not hinder the progress of the reaction, such as ether solvents such as diethyl ether, tetrahydrofuran, dioxane, and ethylene glycol dimethyl ether, halogenated hydrocarbon solvents such as ethylene dichloride and monochlorobenzene, toluene, hexane, etc. Examples include hydrocarbon solvents, alcohol solvents such as ethanol and isopropanol, and mixed solvents of water and alcohol solvents. Preferably, halogenated hydrocarbon solvents, ether solvents, or hydrocarbon solvents are used. A mixture of either of these and an alcoholic solvent may be used. The reaction temperature may be room temperature, but it may be cooled below room temperature or heated to the boiling point of the solvent.

A method for selectively reducing carboxyl groups of optically active half esters () can generally be carried out using a reducing agent capable of selectively reducing carboxyl groups, that is, diborane. The diborane can also be produced, for example, by reacting sodium borohydride with boron trifluoride or its ether complex in an ether solvent such as tetrahydrofuran.

After the reduction reaction is completed, the reaction solution is made neutral or acidic, and then extracted with an organic solvent such as chloroform or ethyl acetate. At this time, the ring is closed, and an optically active lactone () can be obtained. In order to obtain optically active lactone (2) in good yield, it is preferable to make the reaction solution acidic after the reduction reaction.

In the production of an optically active lactone () from an optically active half ester (), there are two methods: reducing and ring-closing the lower alkoxycarbonyl group of the optically active half ester (), and reducing the carboxyl group,
The coordination of the optically active lactone () obtained is opposite to that in the case of ring closure. That is, for example, when the lower alkoxycarbonyl group of an optically active half ester () having 4S, 5R coordination is reduced and ring-closed, the coordination of the optically active lactone () obtained is 4aS, 6aR, and the carboxyl group is When reduced and ring-closed, the resulting optically active lactone () has the coordinations 4aR and 6aS.

The optically active lactone () obtained by the method of the present invention can be converted into optically active biotin. For example, reaction formula (A)
It is as follows.

[In the formula, R and Bzl are as described above, R ¹ represents a lower alkyl group, and X represents a halogen atom of Cl, Br, or I. ] That is, the optically active lactone () obtained by the present invention is induced into the corresponding thiolactone (). Next, the alcohol compound () obtained by introducing a side chain by a Grignard reaction is dehydrated and hydrogenated to obtain a compound (). This compound ()
was made into a thiophanium salt () with hydrogen halide, and reacted with diethyl malonate to form the compound (), which was then hydrolyzed, decarboxylated, and removed the N ¹ , N ³ -dibenzyl groups to form an optically active d- You can get Bichion ().

Therefore, the optically active lactone () obtained by the present invention can be converted into optically active biotin () without going through a special optical resolution step and without being racemized during the process.

Among the optically active lactones () that can be produced by the method of the present invention, if an optically active lactone () with 4aS, 6aR coordination is used as a starting material, the optically active biotin obtained is the natural type (d-biotin). ).

Therefore, the method of the present invention enables an extremely advantageous industrial production method of d-biotin.

The half esters () used in the present invention have, for example, the general formula () [In the formula, R represents a lower alkyl group. Bzl represents a benzyl group. ] Pig Liver esterase (Pig Liver
A method for obtaining optically active half esters (2) is by contacting them with esterase-producing bacteria belonging to the genus Chromobacterium or chromobacterium.

When using Pitugu Liver Esterase, the diesters represented by the general formula () are suspended or dissolved in an aqueous solution or a buffer solution whose pH is adjusted to 2 to 10, preferably 5 to 8, and Pitug Liver Esterase is used. Liver Esterase (Pig
Liver Esterase) is preferably added in a weight ratio of 0.001 to 0.1, and the reaction proceeds by stirring at 0 to 80°C, preferably 10 to 40°C, and the reaction is usually completed in 1 hour to several days.

When using an esterase-producing bacterium belonging to the genus Chromobacterium, the esterase-producing bacterium belonging to the genus Chromobacterium is grown in a medium commonly used for the cultivation of microorganisms, and from the beginning of its growth or The simplest method is to subsequently add diesters () represented by the general formula () above, continue culturing, and perform semi-hydrolysis. In this case, there is no particular restriction on the culture temperature as long as the bacteria can grow, but it is usually 25~25°C.
It is preferable to carry out the culturing at 37° C., the appropriate culture period is usually half a day to 7 days, and the substrate concentration is approximately 0.1 to 10%.

A method of collecting microorganism culture fluid through operations such as centrifugation and performing semi-hydrolysis using the microorganisms and cells, or releasing enzymes by subjecting microorganism cells to ultrasonic treatment, lysozyme treatment, etc., and centrifugation under cooling. Alternatively, an enzyme active product can be obtained by ammonium sulfate fractionation, precipitation dialysis, etc., and then semi-hydrolyzed using this product. In these cases, the diesters represented by the general formula () are suspended or dissolved in an aqueous solution or buffer solution preferably adjusted to a pH of 5 to 8, and microbial cells or enzyme activity is applied to the diesters (). The reaction proceeds by adding preferably 0.001 to 0.1 weight ratio of the compound and stirring preferably at 10 to 40°C, and the reaction is usually completed in 1 hour to several days.

As mentioned above, aqueous solutions include mineral acids such as sulfuric acid, hydrochloric acid, and phosphoric acid, organic acids such as acetic acid and citric acid, inorganic bases such as sodium hydroxide, potassium hydroxide, and sodium carbonate, and organic bases such as triethylamine and pyridine.
It means an aqueous solution to which a salt such as sodium acetate or sodium chloride is added. Buffer solution refers to general buffer solutions such as potassium dihydrogen phosphate-sodium hydroxide, potassium dihydrogen phosphate-sodium dihydrogen phosphate, potassium hydrogen phthalate-hydrochloric acid, glycine-sodium chloride-sodium hydroxide, etc. However, there are no particular restrictions other than those that can prevent reactions.

In any case, alcoholic solvents such as methanol, ethanol, n-propanol, isopropanol, n-butanol, and t-butanol, ether, tetrahydrofuran,
Ether solvents such as dioxane, hydrogen aromatic solvents such as benzene and toluene, ketone solvents such as acetone, methyl ethyl ketone and diethyl ketone, amine solvents such as triethylamine and pyridine, polar solvents such as dimethylformamide and dimethyl sulfoxide, Additionally, surfactants such as sorbitan monopalmitate, sorbitan monolaurate, etc. can also be added.

Diesters () are cis-1,3-dibenzyl-2-oxoimidaridine-4,5-dicarboxylic acid and methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, n-pentanol or The corresponding diesters () can be synthesized by dehydrating lower alkanols such as n-xanol in the presence of sulfuric acid.

The present invention will be explained in more detail with reference to Examples below, but it goes without saying that the present invention is not limited thereto.

Reference Example 1 Method for producing cis-1,3-dibenzyl-2-oxoimidazolidine-4,5-dicarboxylic acid diethyl ester 35.4 g of cis-1,3-dibenzyl-2-oxoimidazolidine-4,5-dicarboxylic acid A reaction solution consisting of 500 ml of benzene, 45 ml of 99.5% ethanol, and 5.0 g of concentrated sulfuric acid was refluxed for 10 hours, cooled, and washed with water, 5% NaOH water, and water in this order.

Thereafter, it was concentrated under reduced pressure, and the resulting residue was recrystallized from 95% ethanol.

mp74-76℃ cis-1,3-dibenzyl-2
-Oxoimidazolidine-4,5-dicarboxylic acid diethyl ester was obtained. Other diesters were similarly synthesized.

Reference Example 2 Cis-1,3-dibenzyl-2-oxoimidazolidine-4,5-dicarboxylic acid dimethyl ester 500ml in 50ml of 0.1M phosphate buffer solution (PH8.0)
10 mg (1600 units, Pig Liver Esterase)
SIGMA product) was added. After stirring this reaction solution at room temperature for 30 hours, 150 ml of chloroform was added.
The pH was adjusted to 2 with dilute sulfuric acid and the liquid was separated. The chloroform layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain 435 mg of (4S,5R)-1,3-dibenzyl-5-methoxycarbonyl-2-oxoimidazolidine-4-carboxylic acid. Ta.

Melting point 141-146℃ [α] ²⁰ _D +2.0゜ (c=1, CHCl ₃ ) [α] ²⁰ ₃₆₅ -21.6゜ (c=1, DMF) In addition, the above half ester was dissolved twice in benzene. Upon recrystallization, it showed a melting point of 149-150°C [α] ²⁰ ₃₆₅ -27.6° (c=1, DMF).

Reference Example 3 Cis-1,3-dibenzyl-2-oxoimidazolidine-4,5-dicarboxylic acid diethyl ester in 50 ml of 0.1M phosphate buffer solution (PH8.0)
Suspend 500mg and add 10mg of Pig Liver Esterase to this.
(1600 units SIGMA product) was added. This was treated in the same manner as in Example 1 (4s, 5R) -
1,3-dibenzyl-5-ethoxycarbonyl-
2-Oxoimidazolidine-4-carboxylic acid 400
I got mg.

Melting point 108-112℃ [α] ²⁰ _D +4.4゜ (c=1, CHCl ₃ ) Reference example 4 Cis-1,3-dibenzyl-2 in 20ml of 0.1M phosphate buffer solution (PH8.0) - Suspend 200 mg of oxoimidazolidine-4,5-dicarboxylic acid di-n-propyl ester, and add Pig Liver Esterase to this suspension.
4 mg (640 units SIGMA product) was added. This was treated in the same manner as in Example 1, and (4S,5R)-1,
164 mg of 3-dibenzyl-5-n-propyloxycarbonyl-2-oxoimidazolidine-4-carboxylic acid was obtained.

Melting point 75-90°C [α] ²⁰ _D +2.1° (c = 1, CHCl ₃ ) Example 3 Using 145 mg of the half ester obtained in Reference Example 4, reduction and ring closure were carried out in the same manner as in Example 1 (4aS ,6aR)−
1,3-dibenzylhexahydro-1H-furo[3,4-d]imidazole-2,4-dione 100
I got mg.

Melting point 107-110℃ [α] ²⁰ _D +38.2゜ (c=1, CHCl ₃ ) Reference example 5 Cis-1 in a solution consisting of 45 ml of 0.1M phosphate buffer (PH 8.0) and 5 ml of methanol. , 3-dibenzyl-2-oxoimidazolidine-4,5-dicarboxylic acid dimethyl ester (500 mg) was suspended in this suspension.
10 mg of Pig Liver Esterase (1600 units, SIGMA product) was added. This was treated in the same manner as in Example 1 to obtain 360 mg of (4S,5R)-1,3-dibenzyl-5-methoxycarbonyl-2-oxoimidazolidine-4-carboxylic acid.

Melting point 142-146℃ [α] ²⁰ _D +2.2゜ (c=1, CHCl ₃ ) Reference example 6 Cis-
1,3-dibenzyl-2-oxoimidazolidine-4,5-dicarboxylic acid di-n-butyl ester
Suspend 500mg and add 10mg of Pig Liver Esterase to this.
(1600 units SIGMA product) was added. This was treated according to Example 1, and (4S,5R)-1,3-dibenzyl-5-n-butyloxycarbonyl-2
-Oxoimidazolidine-4-carboxylic acid was obtained as an oil.

[α] ²⁰ _D +4.1° (c = 1.55, CHCl ₃ ) Example 5 Using 266 mg of the half ester obtained in Reference Example 6, reduction and ring closure were carried out in the same manner as in Example 1. (4aS, 6aR) -
1,3-dibenzylhexahydro-1H-furo[3,4-d]imidazole-2,4-dione 160
I got mg.

Melting point 105-107℃ [α] ²⁰ _D +33.7゜ (c=1, CHCl ₃ ) Reference example 7 Cis-1 in a solution consisting of 900ml of 0.1M phosphate buffer solution (PH8.0) and 100ml of methanol ,3-dibenzyl-2-oxoimidazolidine-4,5-
Suspend 10.0g of carboxylic acid dimethyl ester and add 200mg of Pig Liver Esterase (32000units) to this suspension.
SIGMA product) was added. This was stirred at 30° C. for 42 hours while adjusting the pH to around 8.0 using 1N sodium hydroxide solution. then chloroform
500 ml was added, the pH was adjusted to 2 with dilute sulfuric acid, and the liquid was separated.
The chloroform layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off to give (4S, 5R)-1,3
8.80 g of -dibenzyl-5-methoxycarbonyl-2-oxoimidazolidine-4-carboxylic acid was obtained.

Melting point: 145-147°C [α] ²⁰ ₃₆₅ −25.3° (c=1, CMF) By recrystallizing 8.0 g of this half ester twice in 400 ml of benzene, melting point: 149-150°C [α] ²⁰ ₃₆₅ − 7.07 g of half ester of 27.7° (c=1, DMF) was obtained.

Example 1 A solution prepared by dissolving 2.40 g of the half ester obtained in Reference Example 7 in 30 ml of tetrahydrofuran was added dropwise to a mixed solution of 640 mg of sodium borohydride and 70 ml of isopropyl alcohol at room temperature. Next, add this reaction solution to 60%
Stirred at ~70°C for 7 hours. The reaction solution was cooled, 510 g of concentrated hydrochloric acid was added, and the reaction solution was concentrated under reduced pressure. 500 ml of water was added to the residue and extracted twice with 200 ml of chloroform. The chloroform layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain a residue.
2.07g was obtained.

This was recrystallized from aqueous isopropyl alcohol to give (4aS, 6aR)-1,3-dibenzylhexahydro-1H- with a melting point of 117-118℃ [α] ²⁰ _D + 61.8 degrees (c = 1, CHCl ₃ ) furo[3,4-d]imidazole-2,
1.83 g of 4-dione was obtained.

Reference example 8 Glucose 1.0g, yeast extract (Kyokuto Pharmaceutical Industries)
A solution consisting of 0.5 g of peptone (Mikuni Kagaku Sangyo), 0.5 g of dipotassium hydrogen phosphate, and 100 ml of distilled water was adjusted to pH 7.0 with dilute hydrochloric acid. After steam sterilizing this liquid culture solution at 120°C for 20 minutes, Chromobacterium cocolatum IFO 3758 was contacted.
Shaking culture was performed at 26°C for 48 hours. In this, cis-1,3
-dibenzyl-2-oxoimidazolidine-4,
After adding 400 mg of 5-dicarboxylic acid dimethyl ester, the mixture was further reacted with shaking at 26°C for 72 hours.

100 ml of ethyl acetate was added to this reaction solution, acidified with dilute hydrochloric acid, and then filtered through Celite. The liquid was separated, and the organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in 20 ml of 5% sodium bicarbonate solution, washed with 20 ml of ether, and separated.

The aqueous layer was adjusted to pH 2 with dilute sulfuric acid, and the precipitated white crystals were filtered, washed with water, and then dried.

(4S,5R)-1,3-dibenzyl-5-methoxycarbonyl-2-oxoimidazolidine-4-
340 mg of carboxylic acid was obtained.

Melting point 149-151℃ [α] ²⁰ ₃₆₅ −28.0゜ (c=1, DMF) Reference example 9 Glucose 3.0g, yeast extract (Kyokuto Pharmaceutical Industries)
The pH was adjusted to 7.0 using a solution consisting of 1.5 g, peptone (Mikuni Kagaku Sangyo), 3.0 g, dipotassium hydrogen phosphate, 1.5 g, and 300 ml of distilled water, and dilute hydrochloric acid. This culture solution
After sterilizing by distillation at 120°C for 20 minutes, inoculation with Chromobacterium cocolatum IFO 3758 was carried out at 26°C.
The cells were cultured with shaking for 72 hours. The culture solution was centrifuged at 5000 rpm for 25 minutes under cooling to collect bacteria. The bacterial cells were washed three times with 100 ml of 0.85% saline (by centrifugation) to collect the bacteria. Add 0.1M phosphate buffer solution (PH7.0) to the bacterial cells 50
ml, cis-1,3-dibenzyl-2-oxoimidazolidine-4,5-dicarboxylic acid dimethyl ester (1.50 g) was added, and the mixture was stirred at room temperature for 70 hours while adjusting the pH to around 7 with 1N sodium hydroxide solution. . The reaction solution was filtered through Celite, the pH of the solution was adjusted to 2 with dilute sulfuric acid, the precipitated white crystals were filtered, washed with water, and then dried. 1.40 g of (4S,5R)-1,3-dibenzyl-5-methoxycarbonyl-2-oxoimidazolidine-4-carboxylic acid was obtained.

Melting point 146-148℃ [α] ²⁰ ₃₆₅ -26.0゜ (c=1, DMF) Example 2 Using 1.0g of the half ester obtained in Reference Example 9, reduction and ring closure were carried out in the same manner as in Example 6, and 0.72g (4aS,
6aR)-1,3-dibenzylhexahydro-1H-
Furo[3,4-d]imidazole-2,4-dione was obtained.

Melting point 115-117°C [α] ²⁰ _D +60.1° (c=1, CHCl ₃ ) Example 3 (4S,5R)-1,3-dibenzyl-5-methoxycarbonyl- obtained in Reference Example 7 295 mg of sodium borohydride was added little by little to a solution of 2.40 g of 2-oxoimidazolidine-4-carboxylic acid and 20 ml of tetrahydrofuran at -20°C. 1.38 g of boron trifluoride-ether complex was added dropwise to this, and the mixture was stirred at the same temperature for 1 hour and at room temperature for 3 hours. This reaction solution was poured into 60 ml of ice water, stirred at room temperature for 1 hour, adjusted to pH 9 with an aqueous potassium carbonate solution, and extracted twice with 60 ml of ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give (4aR,6aS)-1,3-dibenzylhexahydro-1H-furo[3,4-d]imidazole-
1.40 g of 2,4-dione was obtained.

Melting point 116-118°C [α] ²⁰ _D -61.3° (c = 1, CHCl ₃ ) Example 4 Using 248 mg of the half ester obtained in Reference Example 3, reduction and ring closure were carried out in the same manner as in Example 1 to obtain 159 mg of half ester. (4aS,
6aR)-1,3-dibenzylhexahydro-1H-
Furo[3,4-d]imidazole-2,4-dione was obtained.

Melting point 108-110°C [α] ²⁰ _D +46.3° (c = 1, CHCl ₃ ) Example 5 In a mixture of 64 mg of sodium borohydride and 7 ml of isopropanol, the sample obtained in Reference Example 2 before recrystallization was added. (4S,5R)-1,3-dibenzyl-5-
240 mg of methoxycarbonyl-2-oxoimidazolidine-4-carboxylic acid was added to 3 mL of tetrahydrofuran.
ml solution was added dropwise at room temperature. After the addition was completed, the mixture was heated to 60 to 70°C, and then stirred at the same temperature for 7 hours. After adding 51 mg of concentrated hydrochloric acid and cooling to room temperature, the solvent was distilled off under reduced pressure. water on the residue
50 ml was added and extracted with chloroform. The chloroform layer was washed with water and then dried over magnesium sulfate. The dried chloroform layer was concentrated under reduced pressure to obtain 207 mg of residue. Recrystallization from water-isopropanol gave (4aS, 6aR)-1,3-dibenzylhexahydro-1H-furo[3,4-d]imidazole-2,4-dione.

Melting point 110-115°C [α] ²⁰ _D +47.9° (c = 1, CHCl ₃ ) Example 6 Using 240 mg of the half ester obtained in Reference Example 5,
And, reduction, ring closure and post-treatment were carried out in the same manner as in Example 5 except that 4 ml of ethylene dichloride was used instead of tetrahydrofuran and 0.7 ml of isopropanol was used to obtain (4aS, 6aR)-1,3-dibenzylhexahydro-1H- Furo[3,4-d]imidazole-2,4-dione was obtained.

Example 7 The half ester obtained in Reference Example 4 was reduced, ring-closed and post-treated according to Example 5 to obtain (4aS, 6aR)-
1,3-dibenzylhexahydro-1H-furo[3,4-d]imidazole-2,4-dione was obtained.

Claims (1)

[Claims] 1. General formula [In the formula, * indicates an asymmetric carbon. R represents a lower alkyl group. Bzl represents a benzyl group. 4th place, 5th place
The position is cis configuration. ] A formula characterized by reducing the carboxyl group of the optically active cis-imidazolidine dicarboxylic acid derivative represented by diborane, or reducing the lower alkoxycarbonyl group with sodium borohydride to achieve ring closure. [In the formula, * and Bzl are the same as above. 4a, 6a
The position is cis configuration. ] A method for producing optically active cis-1,3-dibenzylhexahydro-1H-furo[3,4-d]imidazole-2,4-dione.