JPS6332062B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing 3-aminoglutaric acid dialkyl ester.

3-Aminoglutaric acid is an important dibasic amino acid that is a type of β-amino acid and is an important intermediate for the synthesis of physiologically active substances. As a physiologically active substance, it is particularly important as a synthetic element for a series of carbapenem β-lantum antibiotics represented by the β-amino acid moiety of negamycin and thienamycin, which is known to be effective against Gram-negative bacteria. Although these physiologically active substances are known as antibiotics, the productivity of their fermentative production method is extremely poor, and an approach using an organic synthetic production method is strongly desired.

3-Aminoglutaric acid is also useful as a nutrient source in the culture medium of bacteria producing the antibiotic negamycin.

An object of the present invention is to easily and efficiently produce 3-aminoglutarate dialkyl ester as an important intermediate that enables easy synthetic approaches to the above-mentioned difficult-to-obtain physiologically active substances.

A conventional method for producing 3-aminoglutarate dialkyl ester is a method in which ammonia is added to the condensation reaction product of malonic acid ester and chloroform in a Michael type (JACS, 77.5427
(1955), H. Feuer and WA Swarts). However, this method is a multi-step reaction and cannot be called an economical method.
Therefore, the present inventors have conducted intensive studies on a simpler method for producing 3-aminoglutaric acid, which is particularly important as an intermediate for producing physiologically active substances, and have arrived at the present invention.

The present invention is based on the following formula The 3-ketoglutaric acid dialkyl ester [wherein R represents an alkyl group] is reacted with an ammonium salt or ammonia to form the following formula: or The following formula is characterized by producing an unsaturated amine compound of [wherein R has the same meaning as above] and further reducing this with an alkali of cyanoborohydride. The gist of the present invention is a method for producing a 3-aminoglutaric acid dialkyl ester, [wherein R has the same meaning as above].

The 3-ketoglutarate dialkyl ester used as the starting compound (I) in the method of the present invention may be an alkyl ester having 1 to 4 carbon atoms such as methyl or ethyl. The ammonium salt of the reactant may be an ammonium salt of an inorganic acid, such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, or an ammonium salt of an organic acid, such as a lower alkanoic acid, especially formic acid, acetic acid, propionic acid or benzoic acid. Ammonia may be used instead of ammonium salt. The reaction is conveniently carried out in lower alkanols such as methanol and ethanol, as well as in solvents such as acetone and tetrahydrofuran.

The amount of ammonium salt may be equimolar to the starting material compound (I), but it is used in large excess in consideration of the reaction rate and equilibrium point. The ammonium salt may be an inorganic acid salt, but an organic acid salt is usually used in an amount of 5 to 30 times the molar amount, preferably about 10 times the molar amount. The reaction proceeds sufficiently quickly even when the reaction temperature is around room temperature, but if necessary, it can be carried out at a temperature other than room temperature, for example from 0°C to 130°C, by heating or cooling.

In the present invention, ammonium formate, ammonium acetate, etc. are dissolved in methanol, and the solution is diluted with acetic acid.
Adjust the pH to 8.0 or less, preferably 3.0 to 6.0, and
This is conveniently carried out by adding -ketoglutarate dimethyl ester, ie acetonedicarboxylic acid dimethyl ester.

Thus, from the 3-ketoglutarate dialkyl ester the unsaturated amine compound () or (')
is produced as an intermediate.

To the reaction solution containing this intermediate compound () or (') (which is tautomeric) is added an alkali cyanoborhydride of the following formula MBH ₃ CN (wherein M represents an alkali metal) to carry out reduction. This reduction reaction proceeds at room temperature and can also be heated or cooled to 0°C.
It can also be carried out at temperatures in the range ~100°C. This reaction is conveniently carried out by adding sodium cyanoborohydride or lithium cyanoborohydride to the above reaction solution at room temperature. The amount of alkali cyanoborhydride used is equal to or more than the equivalent molar amount, usually 1.5 to 2.0 molar equivalents. The reaction time depends on the time required for the addition of the alkali cyanoborhydride.
~5 hours. It takes 10 to 30 hours at room temperature.

The end point of the reaction can be determined by taking out a portion and performing thin layer chromatography, but it is preferable to treat it for a longer time than usual in order to complete the reaction. After the reaction, the reaction solution is concentrated at below 30°C, adjusted to pH 9.0 with saturated potassium carbonate, and extracted with an organic solvent such as methylene chloride. Further, the aqueous layer is adjusted to pH 10 and extracted completely. After drying the organic layer, the resulting oily substance is separated and purified by column chromatography to obtain the desired 3-aminoglutaric acid alkyl ester () in high yield.

To further elaborate on the advantages of the method of the present invention:
While the above-mentioned known method obtains 3-aminoglutaric acid ester by a multi-step synthesis method, the method of the present invention obtains 3-aminoglutaric acid ester directly from the alkyl ester of 3-ketoglutaric acid, that is, acetonedicarboxylic acid, which is easily obtained from citric acid. It is a more economical and simple method because 3-aminoglutarate can be synthesized, and treatment with an ammonium salt or ammonia and subsequent reduction can be performed in one reaction tank. In addition, in the step of converting the raw material compound (I) into the unsaturated amine compound () or ('), ammonia may be used, but it is preferable to use an ammonium salt of an inexpensive organic acid such as formic acid or acetic acid in terms of yield. One of the advantages is that it can be obtained.

The present invention will be described below with reference to Examples.

Example 1 400ml of 38.6g (500mmol) ammonium acetate
of methanol and adjust the pH of the solution to 6.0 with acetic acid. Furthermore, 8.7 g (50 mmol) of 3-ketoglutarate dimethyl ester is added.

Add 2.5 g (40 mmol) of NaBH ₃ CN to this solution.
Add slowly over time. After stirring at room temperature for 22 hours, the pH was adjusted to 5.5 with acetic acid, 0.63 g of sodium cyanoborohydride was further added, and the mixture was stirred at room temperature for 9 hours.

The reaction solution is concentrated below 30°C, adjusted to pH 9.0 with saturated potassium carbonate, and extracted twice with methylene chloride.
Further, the aqueous layer is brought to pH 10, extracted twice with methylene chloride, the methylene chloride solution is washed once with saturated brine, and dried over anhydrous sodium sulfate. 8.9 g of the oily substance obtained by concentration is separated and purified by silica gel column chromatography to obtain 7.9 g of oily 3-aminoglutarate dimethyl ester. IR and ^1H
-The structural formula was confirmed by NMR and elemental analysis values.
IR (cm ^-1 ); 3400 (amino group), 1740 (ester group),
^1H -NMR ( _CDCl3 ); δ1.92 (s, 2H, _NH2 ),
δ2.24~2.64 (dd×2, 4H, −CH ₂ −), δ3.54 (dd,
1H, -C ¹ H-), δ3.68 (s, 6H, CO ₂ Me) Elemental analysis value: Calculated value (C ₇ H ₁₃ O ₄ N) C, 47.99; H, 7.48; N, 8.00 Actual value C , 47.79; H, 7.47; N, 7.74 Example 2 31.5 g (500 mmol) of ammonium formate in 400 ml
of methanol and adjust the pH of the solution to 6.0 with acetic acid. Furthermore, 8.7 g (50 mmol) of 3-ketoglutarate dimethyl ester is added.

Add 2.5g of sodium cyanoborohydride to this solution.
(40 mmol) was slowly added over 5 hours.
After stirring at room temperature for 22 hours, the pH was adjusted to 5.5 with acetic acid, and 0.63 g of sodium cyanoborohydride was further added.
Stir at room temperature for 9 hours.

The reaction solution is concentrated below 30°C, adjusted to pH 9.0 with saturated potassium carbonate, and extracted twice with methylene chloride.
Further, the aqueous layer is brought to pH 10, extracted twice with methylene chloride, the methylene chloride solution is washed once with saturated brine, and dried over anhydrous sodium sulfate. 7.5 g of the oily substance obtained by concentration is separated and purified by silica gel column chromatography to obtain 5.6 g of oily 3-aminoglutarate dimethyl ester. ¹³ C and
The structural formula was confirmed by ¹ H-NMR and elemental analysis.

Example 3 38.6 g (500 mmol) of ammonium acetate in 400 ml
of methanol and adjust the pH of the solution to 6.0 with acetic acid. Furthermore, 8.7 g (50 mmol) of 3-ketoglutarate dimethyl ester is added.

2.4 g of lithium cyanoborohydride was slowly added to this solution over a period of 5 hours. After stirring at room temperature for 20 hours, the pH was adjusted to 5.5 with acetic acid, 0.60 g of lithium cyanoborohydride was further added, and the mixture was stirred at room temperature for 8 hours.

The reaction solution is concentrated below 30°C, adjusted to pH 9.0 with saturated potassium carbonate, and extracted twice with methylene chloride.
Further, the aqueous layer is adjusted to pH 10, extracted twice with methylene chloride, the methylene chloride solution is washed once with saturated saline, and dried over anhydrous sodium sulfate. 8.20 g of the oily substance obtained by concentration is separated and purified by silica gel column chromatography to obtain 6.0g of oily 3-aminoglutarate dimethyl ester. The structural formula was confirmed by ¹³ C and ¹ H-NMR and elemental analysis.

Example 4 Example 1 was repeated using 10 g of 3-ketoglutarate diethyl ester. 8.0 g of oily 3-aminoglutaric acid diethyl ester was obtained. IR (cm ^-1 ):
3400 (amino group), 1742 (ester group).

Claims (1)

[Claims] Linear formula The 3-ketoglutaric acid dialkyl ester [wherein R represents an alkyl group] is reacted with an ammonium salt or ammonia to form the following formula: or The following formula is characterized by producing an unsaturated amine compound [in the formula, R has the same meaning as above], and further reducing this with an alkali cyanoborohydride. A method for producing a 3-aminoglutaric acid dialkyl ester, [wherein R has the same meaning as above].