JPS59148756A - Preparation of 3-benzyloxycarbonylamino-4- hydroxybutyric acid - Google Patents

Abstract

NEW MATERIAL:A 3-benzyloxycarbonylamino-4-hydroxybutyric acid shown by the formula I (Z is benzyloxycarbonyl). USE:A raw material for synthesizing 4-hydroxymehyl-2-azetidinone shown by the formula II (R<2> is H, lower alkyl, or hydroxy lower alkyl) useful as an intermediate for synthesizing beta-lactam antibiotics. PREPARATION:N-Benzyloxycarbonylaspartic acid anhydride is reduced with sodium boron hydride to give a compound shown by the formula I . The reaction is generally carried out in an inert organic solvent (e.g., THF) usually at 30- 80 deg.C preferably at 0 deg.C- room temperature. An amount of sodium boron hydride used is usually about 1mol based on 1mol anhydride of the raw material.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a process for producing 3-benzyloxycarbonylamino-hydroxybutyric acid by reducing N-benzyloxycarbonylamino-hydroxybutyric acid anhydride with sodium borohydride.

Conventionally, as a reduction method of aspartic acids.

Asparagine or aspartic acid is added to sodium bis-(
A method is known to obtain 3-amino-t-hydroxybutyric acid by reduction with aluminum hydride (Chemical Abstracts, Vol. I).
os, 2-t f m), this method is not particularly satisfactory in that it uses expensive and delicate reagents.

The present inventor has discovered that by using aspartic anhydride as a starting material and reducing it with sodium borohydride, an industrially available reagent, one carbonyl group is selectively reduced, 3-amino-≠- It has been found that hydroxybutyric acid derivatives can be obtained.

According to the present invention, there is thus provided a process for preparing 37-benzyloxycarbonylamino-4-hydroxybutyric acid by reducing N-penzyloxycarbonylaspartic anhydride with sodium borohydride.

The reduction reaction according to the invention is generally carried out in an inert organic solvent.
For example, the reaction can be carried out in tetrahydro7rane, dioxane, ethyl ether, dimethoxyethane, diethylene glycol dimethyl ether, and the like. Although the reaction temperature is not critical, a temperature of usually -30° to 10°C, preferably 0°C to room temperature is suitable.

The amount of sodium borohydride to be used with respect to the raw material N-penzyloxycarbonyl aspartic acid anhydride is 5. Usually, it is advantageous to use approximately 1 mole of sodium borohydride per 1 mole of the raw material anhydride. .

3-benzyloxycarbonylamino-gu-hydroxybutyric acid is thus formed in good yield, and this compound can be extracted from the reaction mixture by methods known per se, such as extraction, filtration, recrystallization, chromatography, photography, etc. The 3-benzyloxycarbonylamino-hiro-hydroxybutyric acid obtained by the method of the present invention is a novel compound and an advantageous intermediate in the synthesis of β-lactam antibiotics. An example of a route for synthesizing goo-hydroxymethyl-λ-azetidinones from 03-benzyloxycarbonylamino-hiro-hydroxybutyric acid, which is a useful raw material for synthesizing methyl-azetidinones, is shown in the form of a reaction formula. 0 HO20g In each of the above formulas, 2 represents a benzyloxycarbonyl group, R1 is an organic silyl group, and R8 represents a hydrogen atom, a lower alkyl group, a hydroxy lower alkyl group, or a lower alkanoyl group. In the reaction scheme, first, 3-benzyloxycarboylamino-gu-hydroxybutyric acid of formula (1) is silylated. The silylation is performed on organic silyl compounds such as t-butyldimethylsilyl chloride, t-butyldiphenylsilyl chloride, etc. in an inert organic solvent such as dimethylformamide, acetonitrile, tetrahydrofuran, etc. at a temperature ranging from about -20°C to room temperature. This can be carried out by applying a halide. Moreover, at that time, it is preferable to add a base such as triethylamine or imidazole to the reaction system. The resulting compound of formula (II) then has the formula ([
) can be converted into a compound of formula (N) by alkylating the compound of formula (■) when R2 represents a lower alkyl group in the compound of formula (I[), p, When R2 represents a hydroxy lower alkyl group, this can be accomplished by aldol condensation of an aldehyde or ketone, and when R2 represents a lower alkanoyl group, this can be accomplished by acylation. The alkylation can be carried out, for example, by first treating the compound of formula (II) with lithium diingrobilamide (hereinafter 1'
-LDA J) and then treated with an alkylating agent such as methyl iodide.

Similarly, aldol condensation can be carried out by allowing an aldehyde or ketone, such as acetone, to act on the LDA-treated compound.

Acylation can be carried out by reacting the LDA-treated compound with a reactive derivative of carboxylic acid, such as acetic anhydride. The resulting disilyl compound of formula (II) is then subjected to partial hydrolysis. Hydrolysis can be carried out by contacting with a dilute acid such as dilute hydrochloric acid for several minutes to several tens of minutes in a water-miscible organic solvent such as methanol or tetrahydrofuran at a temperature of water cooling or room temperature.

Deprotection of the resulting compound of formula (ff) (removal of the benzyloxycarboel group) can be carried out in a manner known per se, for example by treatment with hydrogen in the presence of 10% palladium on carbon in methanol. The resulting compound of formula (V) is then subjected to a ring-closing reaction. The ring-closing reaction is preferably carried out using triphenylphosphine and a heterocyclic disulfide, such as dipyridyl disulfide, as the condensing agent, by treating an alkylnitrile, such as acetonitrile, with a compound of formula ('V') at room temperature to the reflux temperature of the reaction mixture. This can be done by By removing the organosilyl group from the thus obtained λ-azetidinone derivative of formula (VI) by a method known per se, formula (■), which is an advantageous intermediate in the synthesis of β-lactam antibiotics, is obtained. A μm hydroxymethyl-coazetidinone derivative can be obtained in good yield.

The present invention will be further explained below with reference to Examples and Reference Examples.

Example/ Under water cooling, sodium borohydride 7j, 6~tetrahydrofuran 0. A solution of N-hensyloxycarbonyl-L-aspartic anhydride, r~ in tetrahydrofuran/, l=me is added dropwise to the '/'d suspension.

! The water bath was removed and the reaction was continued for an additional 7 hours. 2N hydrochloric acid was added to the reaction mixture to adjust the pH to /, then saturated brine was added, and the mixture was extracted three times with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off. Add methylene chloride to the resulting residue and crystallize it to give %(8)-
3-benzyloxycarbonylamino-≠-human xybutyrolytyl! , 27θ immediately obtained 0 melting point 10 ter/10°C. [α] Storage-io, t0 (0
=/, MθOH) The raw materials were synthesized by the following operations.

(a) Benzyloxycarbonyl chloride ti-o, ri-I was added to a 300-mL suspension of L-aspartic acid, 2t, ty, heavy magnesium oxide, and OI in water for about 30 minutes under cooling with water. After addition, vigorous stirring is continued overnight at room temperature. After the reaction, the insoluble matter is separated and washed with a small amount of water and ethyl ether, and the washing liquid is combined with the P solution. Extract the r solution twice with ethyl ether. Acidify the drained aqueous layer with concentrated hydrochloric acid. After extracting three times with ethyl acetate, add concentrated hydrochloric acid to the aqueous layer again and extract three times with ethyl acetate. Then, add the aqueous layer to the aqueous layer with salt. After saturation, the ethyl acetate extraction is repeated again. The extracts are combined, washed with saturated brine, dried over anhydrous sodium sulfate, and then the solvent is distilled off. The resulting residue was crystallized from ethyl ether-hexane to give Ii-oxycarbonyl-L-aspartic acid 4.9.

Furthermore, when the mother liquor is removed, the desired product of jg is obtained.

Melting point //j -120°C. [α] Learning + Ri, ♂30 (Q=
2. Ac0H) (b) N-benzyloxycarbonyl-
L-aspartic acid jt, I91 ethyl acetate 3! - Add thionyl chloride/lpme dropwise to the suspension and continue stirring for an additional 7 hours. After the reaction, the solvent and excess thionyl chloride are distilled off under reduced pressure, and the resulting residue is dissolved in dry ethyl ether,
- N-benzyloxycarbonyl-L-aspartic anhydride crystallized from petroleum ether! , 1017 were obtained.

Melting point 10♂−///”C0 [α catty eight (1(Q=/
, θf, Ac0H) Example In Example/, if the same reaction is carried out using racemic N-benzyloxycarbonylaspartic anhydride as the raw material, then racemic 3-benzyloxycarbonylamino- Gu-hydroxybutyric acid was obtained.

Melting point 101s -l01r ”C engineering R (liquid film) = 3 goo -, ztoθ, 3330
, /4zaj.

/26K, 102! (:rIL'-".

NMR (CD30D): 2. lit (/H,
(1(1, J=:/l, OHz.

7.4'H2), 2. AA (/H, da, J=
/1. OHz, A, 2H2), 3.・j3 (/
H, dd, J = / Hachiza I (z, Otsu 4Hz).

3.4J (/H, (1(1, J=//, IR7,
j, #H2), II-,07(/H, br quin
tet) , j, 10 (,2H, 8) , 7.
3 Otsu (' Ht day).

Reference Example / (a) To a solution of (S)-3-benzyloxycarbonylamino-μm hydroxybutyric acid jOt and 723m9 of t-butyldimethylsilyl chloride in dimethylformamide, add imidazole t♂/mg under water cooling,
The reaction mixture was stirred at room temperature overnight. After cooling with water, ethyl ether was added, and the mixture was washed with ice-cooled /N hydrochloric acid, ice water, and ice-cooled saturated saline in this order. After drying over anhydrous sodium sulfate, the solvent was distilled off. (S)'-J-benzyloxycarbonylamino-p-t-butyldimethylsilyloxybutyric acid t-butyldimethylsilyl ester is obtained.

(1)) Add 0.0% to a 1 ml tetrahydrofuran solution of the disilyl compound obtained above under ice cooling. Add 2me of N hydrochloric acid and stir for 25 minutes. Add cold water to the reaction mixture, extract with ethyl acetate,
The organic layer is washed with water and saturated brine, and then dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was subjected to silica gel column chromatography to obtain (S)-3-benzyloxycarbonylamino-4z-t-butyldimethylsilyloxybutyric acid.

(C) Add j to 10 ml of methanol solution of the silyl compound obtained above.
% palladium on carbon ROM9 was added, hydrogenation was carried out at normal pressure at 3-is"c for 7 hours, and then at room temperature for 7 hours (S)-J
-amino-t-7-butyldimethylsilyloxybutyric acid group 26 is obtained.

[α] Fu'/3. Otsu0 (C=7., Mθ0H) (d)
A suspension of 17 mg of β-amino acid obtained above, 2/2 mg of dipyridyl disulfide, and 31 parts of acetonitrile was heated to 10°C, and 2 parts of triphenylphosphine was added to it.
Slowly drop the acetonitrile 3πE solution of 2 to
Continue stirring for 2.5 hours. After the reaction, the solvent was distilled off and purified by silica gel column chromatography to obtain (S)
<' -t-butyldimethylsilyloxymethyl-λ-
Azetidinonta t, j immediately obtained 0 [α8 1382° (C near, rij, 0HC
I,) Reference Example 2 (a) (S)-1-Benzyloxycarbonylamino-4t-t-butyldimethylsilyloxybutyric acid t-butyldimethylsilyl ester i, srg was dissolved in 7 ml of tetrahydrofuran, and dissolved in advance under an argon atmosphere. Prepared lithium diisopropylamide (3 mmol)
, in tetrahydrone run/j-) at -70°C. 4tO of ridge acetonta stirred at -70℃ for 30 minutes
μ was added, and stirring was continued for another 10 minutes at the same temperature. Add a saturated aqueous ammonium chloride solution to the reaction mixture, pour it into saturated brine, and repeat the extraction with ethyl acetate. After drying the extract over anhydrous sodium sulfate, the solvent was distilled off, and the resulting residue/Tata 11 was subjected to column chromatography (Wakogel O-, 200° elution solvent; methylene chloride: ether-z).
% (3s)-2-
(l-Hydroxy-/-methylethyl)-3-benzyloxycarbonylamino-g-t-butyldimethylsilyloxybutyric acid/, 2AI was obtained as a pale yellow oil.

NMR (CDCl2.δ): θ, 02, 0.0Il (
A H,s).

Oo to j, 0.17 (9H, s), 822,
/, 3.2 (&H.

8) , -2, IO(/HT m) , 3.3
A ~3,7t (-2H, m).

3, lrl, ~p, -z4 (/H, m), 1
1.7A-3,31,(,2H.

m), j, 7 Otsu (2H9d, J-IR2), 7.33 (
jH2F3) IR (CHC!I3): 31r00~
2200, /720, /700儂-1Mass
(m/e): '12! r (M+)
, 31ta (M+ -c, a, ).

3g (b) Methanol the N-protected body Otsu 60.1ynp obtained above! , 10% palladium on carbon ga dissolved in O-,
IImy is added and hydrogenolysis is carried out under a hydrogen atmosphere. After stirring at room temperature for an hour and a minute, filter the liquid and concentrate under reduced pressure to give % (JS)-2-(/-hydroxy-
/-methylethyl)-3-amino-gut-butyldimethylsilyloxybutyric acid was obtained as a white powder. (C) 3.2.0 mg of the β-amino acid obtained above and rti-, smg of dipyridyl disulfide were mixed with 1 acetonitrile.
11.3 v of triphenylphosphine A dissolved in 10 mt of acetonitrile was added dropwise over 70 minutes at 0°C. Stirring was continued at 20° C. for 3 hours/j minutes after the dropwise addition. After the reaction, the solvent was distilled off, dimethylformamide/- was added to the residue, and 70 M of triethylamine and 73 cm of t-butyldimethylsilyl chloride were added under water cooling, followed by stirring at the same temperature for 7 hours. Ethyl ether was added to the reaction mixture, washed with water, and the organic layer was dried over anhydrous sodium sulfate. The residue /θ/, /η obtained after evaporating the solvent was subjected to column chromatography (Fuco-gel C-200, elution solvent: methylene chloride-?, l-methylene chloride: ethyl ether =
Purify using J-:/) to obtain (3B,≠E+)-/
(t-Butyldimethylsilyl)-3-(/-hydroxy-/-methylethyl)-4'-(t-butyldimethylsilyloxymethyl)-2-azetidinone≠6.6 sq. was obtained as a colorless oil.

NMR (CDO'l, , δ): 0. /j (&H,
e) , (7,/J' (t H, s ), 0-
I F (5' H2S) e O,9('' (PH
t').

8ri 0~2.10 (/H, broad s)
,,2.7j(/H,d.

J2, 2. jHz), 3,4tθ~3. ri0 (3
H, m) , /, 20 (3H, s) , /, 2g
(3H, θ)IR(C!H(!15): /7.
2jcrn-”Mass (m/e): 330
(Resistance -04H9) , , 27/ , 230 Patent applicant Teikoku Kinki Seiyaku Co., Ltd.

Claims (1)

[Claims] 3, characterized in that N-benzyloxycarbonyl aspartic anhydride is reduced with sodium borohydride.
-Method for producing benzyloxycarbonylamino-μm hydroxybutyric acid.