JPH0251544B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to the formula The formula obtained by nucleophilically opening the epoxy ring of the compound by the action of azide in a polar solvent, Catalytic hydrolysis of the compound gives the formula, This invention relates to a method for producing a compound of formula (), which is characterized in that the compound is converted into a compound of formula ().

(In the formulas (), (), and (), R represents an alkyl group having 4 or less carbon atoms. Also, the mark * indicates an optically active carbon atom).

The 2-amino-3-hydroxysuccinic acid diester of the above formula () is a useful compound that is recognized to have high utility value as a synthetic intermediate for various physiologically active compounds. In particular, since the epoxy ring carbon of the compound of formula () is an asymmetric carbon, if an optically active form is prepared as the compound of formula (), the compound of formula () can also be obtained as an optically active form. The utility of the compound is greatly increased.

In the present invention, the compound of formula () can be obtained by protecting the hydroxyl group at the 3-position and forming an intramolecular amide bond between the amino group at the 2-position and the ester group at the 4-position.
- It is possible to lead to lactam compounds. Moreover, the compound of formula () can be prepared by 2-
Amino-3,4-0-isopropylidene-3,4
- Can be converted to dihydroxybutanoic acid ester.
Furthermore, since the remaining ester group can be converted into a formyl group, it becomes possible to convert it into an aminoglycoside in a subsequent reaction operation. From these facts, it can be understood how important the compound of formula () and the compound of formula () are as synthetic intermediates.

No advantageous method has been found for the preparation of compounds of formula () disclosed in the past. For example, 2, which is obtained by converting dimethyl 2-acetoxy-3-chlorosuccinate into the compound of formula () using caustic alkali, and then saponifying the ester group,
Open the epoxy ring of 3-epoxysuccinic acid using aqueous ammonia to obtain a 2-amino-3-hydroxysuccinic acid form, and finally diesterize using ethanol under acidic conditions to obtain the compound of formula (). The method for producing hydrochloride is [Bull.Chem.Soc.
Japan, vol. 36, p. 899 (1963)] and T. Kaneko et al., but this method is extremely complicated to prepare the 2,3-epoxysuccinic acid synthesized in the first step; The yield was low (32%), and the yields of the subsequent two steps of ring-opening reaction of the epoxy ring and esterification were also unsatisfactory at 72% and 51%.

The inventors recognize the importance of the above background,
A simple and high-yield method for producing the compound of formula () was intensively investigated. As a result, it was found that when the compound of formula () is reacted with hydrazoic acid or its equivalent in a polar solvent, the epoxide is ring-opened extremely efficiently. Also, the resulting formula ()
When the azide group of the compound is hydrolyzed, the formula ()
The present invention was completed based on the discovery that the compound of the present invention can be obtained in high yield.

A feature of the present invention lies in the discovery that the epoxy moiety of the compound of formula () can be ring-opened very efficiently with hydrazoic acid or its equivalent in a polar solvent. In fact, azides which are generally known to be effective in the ring-opening reaction of epoxides, such as sodium azide, magnesium azide, ammonium azide, etc., are not effective in opening the epoxy ring of the compound of formula (). Direct conversion of a compound of formula () to a compound of formula () using ammonia is also not effective; in this case, only aminolysis of the ester group proceeds, making it impossible to obtain the desired compound ().

Azides that can be used in the present invention include:
Hydroazoic acid or hydrazoic acid equivalents are used. Specific examples of hydrazoic acid equivalents include silyl compounds such as trimethylsilyl azide. When using a silyl compound, it is also possible to use it as is to obtain the 0-trimethylsilyl equivalent of the compound of formula (), or to prepare the silyl compound in advance before mixing it with the compound of formula (). It is also possible to mix it with an equimolar or 1 to 5% excess lower alcohol to convert it into an azide hydric acid before use. Examples of polar solvents used in this reaction include dimethylformamide, dimethylacetamide, N-methylpiperidone, dimethylsulfoxide, hexamethylphosphorictriamide, nitromethane, acetonitrile, and mixed solvents of these with tetrahydrofuran, dichloromethane, chloroform, benzene, etc. be done. The amount of solvent used is usually 5 to 10 times, preferably 5 to 7 times, the weight of the compound of formula (). As a catalyst for hydrogenolysis, palladium supported on activated carbon, which is usually used for hydrogenolysis of azide, is used, but a Lindlar catalyst is also effective. As the solvent used for hydrogenolysis, methanol, ethanol, ethyl acetate, etc. can be used, but ethyl acetate is the best.

The reaction temperature of the present invention is usually 40 to 70°C when converting the compound of formula () to the compound of formula ().
It is preferably carried out at a temperature in the range of 50 to 60°C, and the hydrogenolysis of the compound of formula () is carried out at room temperature. In the conversion of the compound of formula () to the compound of formula (), the reaction time is 10 to 12 hours when the reaction temperature is 50 to 60°C and 1.5 to 2.0 equivalents of hydrazoic acid are used as the azide; When the azide is used as is, the reaction is completed in about 24 hours. Hydrogenolysis of the compound of formula () is usually completed in 6 to 12 hours, although this varies depending on the activity of the catalyst. After the reaction is complete, almost pure compounds of formula () and formula () can be obtained by simply removing the solvent under reduced pressure. If further purification is necessary, column chromatography may be used.

According to the method of the present invention, from a compound of formula (),
The desired compound of formula () can be produced with a simple operation and in a high yield of 90°C or higher. The compound of formula () used in the present invention can be prepared by a known method [K.Mori and H.Imasawa,
Tetrahedron, Vol. 36, 87 (1980)], and thus the compound of formula () can be produced in an optically pure frame.

Example 1 Trimethylsilyl azide was added to a solution of 1.266 g (6.69 mmol) of diethyl (2R,3R)-2,3-epoxysuccinate in dimethylformamide (3.3 ml).
1.79ml (13.5mmol) and 0.54ml methanol
(13.3 mmol) in dimethylformamide (3.3 ml) and stirred at 60°C for 12 hours. The reaction mixture was returned to room temperature, a 5% HCl/methanol solution (1 ml) was added thereto, and after standing for about 1 hour, it was concentrated under reduced pressure. The obtained crude product was single by TLC, and when purified with a small amount of silica gel column, the target diethyl (2S,3R)-2-azido-3-hydroxysuccinate (, = ethyl) was obtained as 1.514 g (97.4%). Yield) obtained. The analytical values for the compound having the structure of formula () (R=ethyl) are shown below.

Optical intensity [α] ¹⁸ _D +16.5° (c, 1.47,
CH ₂ BCH ₂ ); infrared absorption spectrum (Film),
3500 (OH), 2160 (N ₃ ), 1750 (c=o) cm ^-1 ;
¹ H-NMR spectrum (CDCl ₃ ) δ1.32 (6H, t,
OCH ₂ CH ₃ ), 3.45 (1H, d, J=5Hz, -OH ),
4.00−4.50 (5H, m, O CH ₂ CH ₃ , CH N ₃ ), 4.65
(1H, m, CH (OH); 63 mg of activated carbon-supported palladium catalyst (10% Pd) was dispersed in ethyl acetate (6 ml) and heated under a hydrogen atmosphere to approx.
Stir for 30 minutes. A solution of 0.626 g (2.71 mmol) of the compound of formula (R = ethyl) in ethyl acetate (10 ml) is added to this, and hydrogenolysis is carried out at room temperature for 12 hours. After filtering off the catalyst from the reaction mixture and concentrating it, the desired compound of formula () (R=ethyl) is obtained.
Obtain 0.548 g (98.5 yield). The structure of a part of this product was confirmed as an Nt-butoxycarbonyl derivative ().

The analytical values for the compound of formula () are shown below.

Optical intensity [α] ²¹ _D +22.5° (c, 1.91,
CH ₂ Cl ₂ ); infrared absorption spectrum (CH ₂ Cl ₂ );
3540 (OH), 3450 (NH), 1740 (ester c=o),
1719 (NHC=O) cm ^-1 ; ¹ H-NMR spectrum (CDCl ₃ ) δ1.25 (3H, t, J = 7.3 Hz, CH ₂ CH ₃ ),
1.33 (3H, t, J=7.3Hz, CH ₂ CH ₃ ), 1.47 (9H,
s, C(CH3) ₃ ), _3.54 (1H, d, J=4.2Hz,
OH), 4.20 (2H, q, J=7.3Hz, O CH ₂ CH ₃ ),
4.30 (2H, q, J=7.3Hz, O CH ₂ CH ₃ ), 4.50
(1H, dd, J=4.2, 2.2Hz, CH (OH)), 4.83
(1H, dd, 8.3, 2.2Hz, CH (NH)), 5.56 (1H,
d, J = 8.3Hz, NH); ^13C -NMR spectrum ( _CDCl3 ) δ14.04 (q), 14.13 (q), 28.32 (q),
57.02(d), 61.90(t), 62.14(t) 72.18(d),
80.37 (s), 155.67 (s), 168.73 (s), 171.55
(s).

Example 2 Trimethylsilyl azide was added to a dimethylformamide solution (3 ml) containing 1.107 g (5.85 mmol) of diethyl (2S,3S)-2,3-epoxysuccinate.
1.17ml (8.81 mmol) and methanol 0.36ml
(8.89 mmol) in dimethylformamide (3 ml) was added, and the mixture was stirred at 60°C for 12 hours. When post-processing is performed in the same way as in the example, (2R, 3S)-2-
Diethyl azide-3-hydroxysuccinate (.
1.31 g (97.0% yield) of R=ethyl is obtained.
The optical power of this compound is [α] ²⁶ _D −15.4° (c,
1.26, CH ₂ Cl ₂ ), and the data of infrared absorption spectrum and ¹ H-NR spectrum are as shown in Example 1.
It was completely identical to that of the corresponding compound obtained in . Subsequently, this compound was hydrolyzed in the same manner as in Example 1, resulting in a compound of formula () (R = ethyl, [α] ²⁶ _D -15.4° (c, 1.26,
From CH ₂ Cl ₂ ) 0.325 g (1.41 mmol), formula ()
0.287 g (99% yield) of the compound R=ethyl was obtained. A part of this product was converted into an Nt-butoxycarbonyl derivative ()' and its structure was confirmed.

The optical power of the compound of formula (′) is [α] ²⁶ _D −
It was 23.4° (c, 1.13, CH ₂ Cl ₂ ). The data of the infrared absorption spectrum, ¹ H-NMR and ¹³ C-NMR spectra were completely the same as the values for the compound of formula () obtained in Example 1.

Claims (1)

[Claims] 1 formula, (In the formula, R represents an alkyl group having 4 or less carbon atoms. Also, the * mark represents an optically active carbon.) Opening the epoxy ring by reacting an azide in a polar solvent with the optically active compound shown in the formula. According to the formula A formula characterized by obtaining a 2-azido-3-hydroxysuccinic acid diester of (in the formula, R and * have the same meanings as above) and catalytically hydrolyzing the same. A method for producing 2-amino-3-hydroxysuccinic acid diesters (in the formula, R and * have the same meanings as above). 2. The method of item 1, wherein hydrazoic acid or its equivalent is used as the azide. 3. The method according to item 1 or 2, in which palladium supported on activated carbon is used as a catalyst in the catalytic hydrolysis.