JPS61246176A - Preparation of aminolactone - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed Description of the Invention] [Industrial Application Field] The present invention provides a novel aminolactone represented by the following formula (■): ■. Regarding Ml 與 method.

[Prior art]

The compound of formula (1) is an intermediate in the total synthesis of the known antibiotic teninamycin and related compounds. The total synthesis and the method for preparing aminolactone are described in European Patent No. 32
No. 400. This process is based on ethyl (E)-2-7cetyl-3-benzylamino-2-
Starting from the pentenedioate, which is treated first with cyanoborohydride and then with concentrated hydrochloric acid, and after further reductive demurandilation, the aminolactone is obtained as an oil in an overall yield of 20-25%.

C Invention A The purpose of the present invention is to find a better synthetic method for the preparation of aminolactones.

[Structure and effects of the invention]

The following contents were found. That is, the isoxazole derivative represented by formula III: (in the formula, R represents a C4-6 alkyl group) is subjected to reductive cleavage to form the following formula... A compound represented by the group ) is obtained, which is treated with a complex hydride and then with concentrated hydrochloric acid to obtain a crystalline aminolactone in a total yield of 40%. This synthetic route eliminates the introduction and removal of a protected benzyl group, two essential steps of conventional methods.

The starting material of the general formula (III) and the method for its preparation are disclosed in the applicant's earlier Hungarian patent application No. 661/83 (=BE89900).
7) and 939/84. but,
Methods for their preparation are also described herein.

Thus, the present invention relates to a method for preparing an aminolactone of the formula (1), which method comprises: al) reducing a compound of the formula (1) (in which R is a C1-6 alkyl group); , R is the meaning defined above), the obtained compound is treated with a complex hydride in the presence of an alkane carboxylic acid having a lower alkyl chain in the alkane moiety, and then treated with concentrated hydrochloric acid to obtain the compound of the above formula. (C2) The compound of formula (1) (wherein R has the same meaning as defined above) is added to the compound of formula (2) in the presence of an alkane carboxylic acid having a lower alkyl chain in the alkane moiety, It is characterized in that it is treated with a complex hydride and then treated with concentrated hydrochloric acid to obtain the compound of formula I.

According to variant IL1, the synthesis is carried out by the above formula (1) (wherein R is C
Starting from isoxazole derivatives having 1 to 6 alkyl groups, in particular 6≠nityl or n-butyl groups. To convert the compound of general formula ■ into the corresponding compound of formula ■,
The starting material is subjected to reduction, preferably catalytic hydrogenation. Hydrogenation is accomplished in the presence of a platinum metal catalyst, preferably parazoom supported on charcoal, in a suitable organic solvent, ie, a lower alkanol or alkane carboxylic acid, at atmospheric pressure.

The compound of formula (II) is then reacted with a complex hydride, in particular sodium borohydride or cyanosodium borohydride, in the presence of a lower alkane carboxylic acid, such as glacial acetic acid or propionic acid, followed by concentrated hydrochloric acid in the same solvent. Process with. Treatment with nucleic acids is carried out at elevated temperatures, preferably at the boiling point of the reaction mixture.

According to a particularly preferred embodiment of the invention, the three reaction steps are carried out without recovery of intermediates, i.e. obtaining the target compound directly in a one-pot synthesis, for example in glacial acetic acid;
This is collected after evaporation and then crystallized.

The invention is illustrated in a non-limiting manner by the following examples.

〔Example〕

Example 1゜Diptyl (E)-2-acetyl-3-amino-2-pentenedioate 2010.067 mo/L/) of n-butyl 5-methyl-
4-n-Butoxycarbonyl isoxazol-N-3-yl-acetate is dissolved in 130 rILl of methanol and hydrogenated at room temperature under atmospheric pressure in the presence of 2 g of 4-radium on charcoal. After the hydrogenation is complete, the reaction mixture is filtered and then evaporated. Triturate the residue with pentane to obtain 17.8P (88%) of the crystalline title compound.

Melting point: 45-46℃ (pentane) 'H-NMR (CDC23): δ0.93t (3H)
:0.95t(3H) ;1.15-1.9m(8H
); 2.29s (3H): 3.6g (2H): 4.15
t(2H): 4.18t(2H).

Two methods for preparing the starting materials are described below as Method A and Method B.

Method A A,) A solution of 2,29 g (10 mmol) of ethyl trans-5-methyl-4-methoxycaryl-4,5-dihydroisoxazol-3-yl-acetate dissolved in 7.5 a/ml of tetrahydrofuran. 25-
A solution of 5.68 g (34 mmol) of potassium iodide and 2.68 g (10.5 mmol) of iodine dissolved in water is added and the reaction mixture is refluxed for 6 hours with stirring. The excess iodine is decomposed with hydrogen sulfite and the reaction mixture is extracted five times with 10 rnl portions of dichloromethane. The organic phases are combined, washed twice with 10 rnl portions of saturated aqueous sodium chloride solution and finally the organic phases are dried over magnesium sulfate, filtered and the limbs are concentrated. The residue was triturated with ether to give crystalline 5-methyl-4-methoxycarnylisoxazole-3-
1.56.9 (79%) of yl-acetic acid is obtained. Melting point: 13
5℃ IR (KBr): 3500-2400, 1730
(sh), 1710.

1600 units.

'H-NMR (CDCj, ): δ2.63 g (3
H) ; 3.76 s (3H) : 3.88 s (2
H): 10.10s (IH).

A2) 5-methyl-4 obtained according to step A1)
-Methoxycarbonylisoxazol-3-yl-acetic acid 1.99 g (10 mmol), 10 g water and 1 g
0 g of concentrated hydrochloric acid is added and the resulting emulsion is then refluxed for 2 hours. The resulting solution is clarified in the hot state, filtered and concentrated to half its volume. The residue crystallizes on cooling. The crystalline product was filtered and dried to a 4-force Nyl? x-5-methylisoxazol-3-yl-acetic acid is obtained. Melting point 2
30℃ (water).

IR (KBr): 3600-2400, 1720
, 1690, 1610, -1°'H-NMR (D20): 62.55g (3H); 3
．． 85s (2H).

1H-NMR (DMSO-d6): δ2.4s (3H
): 3.55 (2H).

A3) 13.9 (70
, 2 mmol) of 4-carboxy-5-methyl-inoxazol-3-yl-acetic acid in a mixture of 60 M n-butanol, 15 Qm benzene and 15 Qm concentrated sulfuric acid in a reflux condenser equipped with a water separator. Reflux for 16 hours. The reaction mixture is then poured onto ice. The phases separate. The aqueous phase is extracted twice with 75M benzene. The organic phases were combined and washed twice with 100 ml of water, then twice with 75 ml of a 5% sodium bicarbonate bath and again with 75 ml of water.
Wash twice with nl. The organic phase is dried over calcium chloride and the solvent is then distilled off under vacuum to give 23 g of product as an oil. This oil can be applied directly without further purification. If desired, distillation under vacuum (Bp, :
130~b, pure n-butyl-5-methy/l/-4-n-
Butoxycarzenyl isoxazol-3-yl-acetate is obtained.

Method B B1) 350.9 (1.88 mol) of α-ethoxymethylene acetoacetate are dissolved in 400111 of ethanol. To the resulting solution are added xs412.2 mol) of hydroxylamine hydrochloride dissolved in 500 mJ of water and 180 g (2.2 mol) of sodium acetate, and the resulting solution is then refluxed for 30 minutes. 2 of the reaction mixture! When poured into water, the phases separate. 250d of water phase
of dichloromethane, the extracts are combined with the organic phase and washed twice with 300 d of water. The phases separate,
Dichloromethane was distilled off from the organic phase under vacuum to obtain 2811 (
96%) of ethyl 5-methyl-4-isoxazole carboxylate) t-boiling point 58-60°C (0,3 Hgw
). This can be further used in the next reaction step without purification.

'H-NMR (CDC2,): δ1.4t (3H)
:2.7s(3H) :4.25q(2H), 8.5s
(IH).

B2) Product obtained in step B1 281.9 (1,
81 mol) are refluxed for 8 hours in a mixture of 200 ml of glacial acetic acid, 200+y/ml of water and 200 ml of concentrated hydrochloric acid. The reaction mixture is then evaporated to dryness.

Residue K, 400r! Add tl of acetone and then
Make it disappear. Dry the residue, 201g (87q6)
5-methyl-4-ynoxazolecarboxylic acid with a melting point of 146 DEG -147 DEG C. (toluene) is obtained.

B3) 201 g of the product obtained in step B2 (1,5
8 mol), 350 d of thionyl chloride was added with stirring to 1
It is added within 0 minutes and the reaction mixture is then refluxed on a 120° C. oil bath for more than 1 hour. Excess thionyl chloride was distilled off and the residue was purified by distillation under vacuum to obtain 1911 (
83 H) 5-methyl-4-isoxazolecarboxylic acid chloride is obtained. Boiling point = 100-102℃ 718H,
Dew.

Theoretical elemental analysis value for C3H4CtNO2 (145,55): C41,25; B2.77: N9.
68: CA24.36; Experimental value: C41,19: B2.92: N9.
57: C124, 22chi.

B4) Fine magnesium powder 66.5F! (2,3 gram atoms) is refluxed in a mixture of 201d ethanol and 1d carbon tetrachloride. To this boiling mixture add 43
6rnlC2,73 mol) of malonic acid diZ f ,11
/ is added within 1 hour in a mixture of 6001111 benzene and 140d ethanol, after which the reaction mixture is refluxed for a further 3 hours. Approximately 50011 of the solvent was distilled off from the reaction mixture and then to the residue was added first 400 g of dioxane and then 200+1 Ej of benzene.
The product 1911 obtained in step B3) is added at 35-40° C. with vigorous stirring. The reaction mixture was further diluted with 10
Stir for 1 minute, then cool, and add 400 ml of concentrated hydrochloric acid.
Pour into 600 g ice and 11 water mixture. The phases are separated and the aqueous phase is extracted twice with 300 d of benzene. The organic phases are combined and washed first with a mixture of 89 ml of concentrated hydrochloric acid and 400 ml of water and then twice with 4001 d of water.

The organic phase is filtered and then its benzene content is distilled off. To the residue, 1 part of dichloromethane was first added and then distilled off, and then the excess diethyl malonate was removed by 1 part of dichloromethane.
Remove on an oil bath at 0.4 °C (boiling point near 0-80 °C/0.4
Hg; about 23 Q+aj). After cooling, crystalline ethyl 1-ethoxycarbonyl-2-hydroxy-
- Obtain 2-(5-methyl-4-ynoxazole)acrylate in a yield of 330 g (94 units). Boiling point: 140
~bQ, 4) (gm'', melting point: 56°C (1:1 ether-hexane).

'H-NMR (CDCl2): δ1.3t (3H)
:2.7g(3H) :4.25q(2H);4.9s
(IH): 8.5s (IH).

B5) Product 292I (1,
08 moles) are refluxed with 10011.45 moles of hydroxylamine hydrochloride in 11 moles of ethanol. The reaction mixture is then concentrated and the hot residue is dissolved in 1.21 g of dichloromethane and then filtered. 200d of sediment
Wash twice with dichloromethane. Combine the washing liquid with the change and wash twice with 300ml of water. Concentrate the organic phase in vacuo. 750 R1 of dichloromethane are added to the residue and evaporated, the residue is triturated with 1201 nl of ethyl acetate and left at 0°C. The crystals were filtered, washed twice with 251/2 cold ethyl acetate and twice with 2001d n-hexane, and dried to give ethyl 3-(5-methyl-4-isoxazole)-5-hydroxy-4-. 154 g (62%) of isoxazolka/l/goxire, melting point 15
Obtained at 3-154°C (ethyl acetate).

'H-NMR (DMSO-δ6): δ1.1t (3a
): 2.4m (3H): 4.0q (2H); 8.6
s(IH): 11.0s(IH).

B6) 154 g of the product obtained in step B5) (0,
646 mol) in the presence of 141/650 ml of concentrated sulfuric acid
of acetic acid for 15 minutes. After the release of carbon dioxide is completed, 40. Sodium acetate 40I of F! is added to the solution and then concentrated in vacuo.

To the residue, 3001114 of water was added and then 500 m
Extract twice with 1 dichloromethane. The organic phases are combined, washed twice with 250M water and the organic phase is concentrated. First 500 d of dichloromethane and then 300 d of n-hebutane were distilled off from the residue, and this residue was finally converted to 13
04 2-f lobanol recrystallized and water-cooled 2-
Washed twice with 15 ml of grononol, then 7 ml with n-hexane.
93.411 (
87%) of 3-(5-methyl-4-isoxacylyl)
-4,5-dihydro-5-ynoxacilone with melting point of 94
~95%.

1H-NMR (CDCA 3) 2 62.7m (3
H): 3.8m (2H): 8.4s (IH).

B,) 57.9 (1,4
93.410.563 mol) of the compound obtained in step B6) are added in one portion to the 2 mol) sodium hydroxide solution at 25° C. with stirring. Continue stirring for about 2 minutes,
During this time the temperature rises to about 70°C.

The reaction mixture is cooled in an ice-water bath, then 150 rIll of concentrated hydrochloric acid is added to the reaction mixture, which is then cooled repeatedly. The reaction mixture was first heated to 300 tA! of dichloromethane and then twice with 150 g of dichloromethane.

Separate the phases and add the organic phase to 80r! Wash twice with saturated aqueous sodium chloride solution and concentrate under vacuum. First, 250-dichloromethane was distilled off from the residue, and then 15-dichloromethane was distilled off.
0d n-hexane is distilled off. After standing, crystalline 4-cyano-5-methyl-3-isoxazole acetic acid is obtained from the residue in a yield of 91.5.9 (98%). Melting point: 90~
91°C (benzene).

'H-NMR (CDC43): δ2.6 g (3H
): 4. Os (2H).

B8) 100 d of water and 100 ml of concentrated hydrochloric acid 91
．． Reflux the compound obtained in step B,) in the mixture of 5.9 for 3 hours. The reaction mixture was cooled and the precipitated product was washed twice with ice-cold running water and dried in air to give 95.719
2%) of 4-carboxy-5-methyl-3-isoxazole acetic acid. This product has the same properties as the compound obtained in step A2).

Example 2 (2R8,3R8,4SR)-4-Amino-2-methyl-6-oxtatetrihydrobilane-3-cargonic acid chloride Diptyl 1)-2-acetyl-3 obtained according to Example 1
-amino-2-pentensooate 10g (0,033
4 mol) is dissolved in 60d of glacial acetic acid. In this solution,
3.8. ! i+ (100 mmol) of sodium borohydride are added over about 2 hours with stirring and external cooling. The reaction mixture is allowed to stand at room temperature and then concentrated in vacuo.

The residue was mixed with 100 d of 10% aqueous sodium carbonate solution and 100 d of ethyl acetate! 1 and then solid sodium carbonate is added until bubbling stops. Separate the phases and add the aqueous phase to 201! Back-extract twice with Ll of ethyl acetate. The organic phases are combined, dried over magnesium sulfate, strained, and concentrated. 40 d of 20% hydrochloric acid are added to the residue, the mixture is refluxed for 5 hours and then concentrated. 40 to 5 residue
Dissolving in IQ ml of concentrated hydrochloric acid at 0°C and then cooling to -10°C gives 3 g (43%) of the title compound as a crystalline solid.

Melting point: 150-155°C (decomposition).

1H-NMR (CD300): δ1.36 d (3
Ht J=6.5 Hz);2.82t(IH,J
=3.5Hz):2.85d(2H, J=6.5Hz)
;3.98dt (IH, J=6.5 and 3.5Hz
) :4.30 dq (J=6.5 #FG3.5H
z).

Example 3 (2R8,3R8,4SR)-4-Amino-2-methyl-6-oxtutetrahydropyran-3-caldenate hydrochloride 7 (1 (0,235 mol)) of n-butyl (5-methyl-
4-n-Butoxycarbonylisoxazol-3-yl)-acetate is dissolved in 350 ml of glacial acetic acid and then hydrogenated at atmospheric pressure in the presence of parasium catalyst 14.9 on charcoal.

The temperature of the reaction mixture rises to about 40°C. After the reaction is complete,
Cut out the catalyst, then add 26 ounces of sodium borohydride to the tip.
．． 8 g (0,705 mol) with external water cooling for approx.
Add within hours. The reaction mixture is stirred at room temperature for 3 hours, heated overnight and concentrated in vacuo. Reduce the residue to 30 (
Partition is made between 1/1 part of ethyl acetate and 300 rnl of saturated sodium hydrogen carbonate solution, then the sodium hydrogen carbonate solution is added with vigorous stirring until bubbling stops. The phases are separated and the aqueous phase is extracted twice with 50 rnl of ethyl acetate.

The organic phases are combined, dried over magnesium sulfate, filtered and concentrated.

The residue is taken up in 200 ml of 20% strength hydrochloric acid, refluxed for 5 hours and concentrated. The residue is dissolved in 70 rnl of concentrated hydrochloric acid under suitable heating and then crystallized in a deep freezer to give 19.8 g of the title compound (40 rnl). The physical constants match those obtained in the previous example.

Below margin

Claims (1)

[Claims] 1. Formula I: ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) A method for preparing an aminolactone represented by a_
1) Formula III: ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (III) (In the formula, R represents a C_1_-_6 alkyl group) The compound represented by is reduced, Formula II: ▲ Numerical formulas, chemical formulas, tables, etc. ▼(II) Obtain a compound represented by (in the formula, R represents a C_1_ to_6 alkyl group) and treat this compound with a complex hydride in the presence of an alkane carboxylic acid having a lower alkyl chain in the alkane moiety. and then treated with concentrated hydrochloric acid to further recover the aminolactone, or a_2) the compound of formula II (wherein R has the same meaning as defined above) is treated with an alkane having a lower alkyl chain in the alkane moiety. The above-described method comprises treating with a complex hydride in the presence of a carboxylic acid, followed by treatment with concentrated hydrochloric acid, and further recovering aminolactone. 2. The method according to claim 1, wherein the reduction in the method a_1) is carried out by catalytic hydrogenation. 3. The method according to claim 1, wherein the complex hydride in the method a_1) or a_2) is sodium borohydride or sodium cyanoborohydride.