DE1044087B - Process for the preparation of 4-amino-isoxyzolidone (3) compounds - Google Patents

Description

GERMAN

The present invention relates to a process for the preparation of 4-amino-isoxazolidon- (3) -verbin fertilize, which consists in mixing a mixture of hydroxylamine with an ester of the general formula

R ₁ -CH-CH-COOR ₂

X NH ₂ I.

in which R ₁ denotes hydrogen, an alkyl, aryl or aralkyl group, R ₂ denotes an alkyl group and X denotes a halogen atom, treated with a strong base in the presence of water and the 4-amino-isoxazolidone- (3) obtained is optionally known per se Way into the optical antipodes.

In formula I above, R _{1 can} e.g. B. hydrogen, an alkyl group, especially a lower alkyl group such as methyl, ethyl, propyl, isopropyl, or an aryl group such as phenyl, p-tolyl, o-tolyl, xylyl, or an aralkyl group such as benzyl, phenethyl. X denotes a halogen atom, e.g. B. chlorine, bromine or iodine. Examples of starting compounds of the above general formula I are: a-amino- ^ chloropropionic acid methyl ester, a-amino- /? - chlorobutyrate methyl ester, a-amino-ß-chloro-ß-phenylpropionic acid ethyl ester, a-amino-zS-bromo-y-phenylbutyric acid methyl ester, Propyl α-amino - /? -] odpropionate. Instead of the free starting compounds, their salts, e.g. B. hydrochlorides, hydrobromides or sulfates, which allow easier and more convenient handling, use; In the treatment according to the invention with strong bases, the free hydroxylamine and the free α-amino / 3-halocarboxylic acid esters are first formed from these salts.

From Karrer, Textbook of Organic Chemistry, 11th Edition (1950), p. 255, and Houben-Weyl, Methods derorganic chemistry, 3rd edition, vol. 3 (1930), p. 947, the general principle is known, hydroxamic acids by reacting acid esters with hydroxylamine. The ones used according to the invention However, acid esters contain a reactive halogen atom, so that different reactions must be expected. For example, when implementing Hydroxylamine with an ester of the general formula I can be expected to result in the formation of the following substances:

Process for the production of
4-amino-isoxyzolidone (3) compounds

Applicant:

F. Hoffmann-La Roche & Co.
Aktiengesellschaft, Basel (Switzerland)

Representative: Dr. G. Schmitt, lawyer,
Loerrach (Bad.), Friedrichstr. 3

Claimed priority:

Switzerland from December 2 to December 19, 1955
and July 17, 1956

Dr. Hans Kirchensteiner, Dr. Reinhard Schläpfer

and Dr. Hans Spiegelberg, Basel (Switzerland),

have been named as inventors

R ₁ NH ₂

! I.

3. X -CH-CH-CONHOH
R ₁ NH ₂

4. HONH-CH-CH-CONHOH

R ₁ NH ₂

[I.

5. HnN-0-CH-CH-CONHOH

R ₁ NH ₂

i 1

L HONH-CH-Ch-COOR ₂
R ₁ NH ₃

2. H ₂ NO-CH-CH-COOR ₂

Despite the large number of possible reactions, the process according to the invention leads directly and in surprisingly good yield to 4-amino-isoxazolidone- (3) compounds and thus allows these compounds to be prepared in a manner compared to that described in J. Am. Chem. Soc., 77 (1955), p. 2346, known method significantly shortened way.

The starting compounds can, for. By the action of phosphorus pentachloride on the corresponding a-amino) S-hydroxy acid ester according to E. Fischer, reports of the German Chemical Society, 40 (1907), p. 3719.

An advantageous embodiment of the reaction according to the invention is that one as strong

«09 679/365

3 4

Base an inorganic base, ζ. B. an alkali hydroxide, the process products have the following general

such as sodium, potassium or lithium hydroxide, e.g. B. in. My formula
In the form of an aqueous solution. To the educated

deten 4-amino-isoxazolidone (3) compounds of the ι r "j ²

5 resulting from this procedure during the reaction. . I I

To separate alkali salts, one can after a pre- O- _: "C = G" II

preferred embodiment of the invention proceed in such a way that ^ NH '
that the alkaline reaction solution

first with a mineral acid, e.g. B. by means of hydrochloric acid, in which R _{1 has} the same meaning as above. It is acidified to a p _H of about 6, then characterized by antibiotic and sedative own organic amine, for by means of an i °. B. methyl, diethyl or trihydrates and represent colorless, crystallized Verbinäthylamin, fertilize on phenolphthalein-alkaline reaction, which is easy and practical in water and poured into alcohol or acetone, so that they do not dissolve in organic solvents ,
Halogen salts, which are sparingly soluble in alcohol or acetone, can be precipitated and separated off, while the example 1
alcohol-soluble amine salts of 4-amino-isoxazolidone- (3) -

connections remain in solution. This solution can be converted into 13.2 g of sodium hydroxide in 60 cm ^{3 of} water

the 4-amino-isoxazolidone (3) compound is dissolved by adding and gradually increasing with ^{stirring below 0 ° C.}

would release of acid and added by cooling to crystallize 7.1 g of hydroxylamine hydrochloride. To be clear

bring sation. 20 solution is added 17.4 g of DL-a-Ammo-ß-chloropropionic acid

Another advantageous embodiment for isomethyl ester hydrochloride such that the temperature

lation and separation of the 4-amino-isoxazolidone- (3) - O ⁰ C does not exceed. The mixture is stirred for 15 minutes at 0 ^° C.

compounds of the halogen salt is that by represents the p _H of the solution with alcoholic hydrochloric acid to 6

Addition of acid to the alkaline reaction, adds up to the phenolphthalein alkaline reaction

solution of the 4-amino-isoxazolidone (3) compounds from 11 to 13 g of triethylamine and mixed with 800 cm ³

their alkali salts are set free and the ethanol. After standing in the cold for a short time, the

Solution is poured into alcohol or acetone, where the precipitated salt is separated off. The alcohol

through the 4-Amino-isoxazolidon- (3) compounds and the holic filtrate is made up with alcoholic hydrochloric acid

Halogen salts are deposited. Adjusted for separation of p _H 6.2 and then in a refrigerator overnight

Brought 4-amino-isoxazolidone (3) compounds from the halogen salt 30 to crystallize. After removal and

the precipitate obtained is suspended in alcohol. Washing of the crystals with absolute alcohol is obtained

or acetone, treated with an organic base, e.g. B. one 3.2 to 3.5 g of DL-4-amino-isoxazolidone- (3). To the

Diethylamine separated, the other in the organic solvent cleaning is dissolved in 2 _^1/2 times the volume

poorly soluble halogen salts and brings the dissolved water and falls with 15 to 20 times the volume

4-Amino-isoxazolidone (3) compounds by adding 35 ethanol. The well-formed crystals melt

an acid, preferably glacial acetic acid, for separation. at 142 ⁰ C (decomposition).

An advantageous embodiment of the reaction according to the invention is that in aqueous Beismel 2
Methanol is used as a solvent. The iso- "

lation and separation of the 4r-amino-isoxazolidone- (3) -ver- 4 ° 70.4 g of sodium hydroxide are dissolved in 400 cm ^{3 of} water

Bonds of the inorganic salts can be in and cools to about 5 ⁰ C. Then one carries in small

in this case, simply by precipitating these inorganic portions 39.2 g of hydroxylamine hydrochloride, so that

Perform salts. According to two particularly expedient the temperature ^{does not exceed 10 0} C, then in

Embodiments for isolation and separation, the small portions 69.6 g DL-a-amino - ^ - chloropropionic acid-

4-Amino-isoxazolidone- (3) -compounds of the halogenated 45 methyl ester hydrochloride are added and the mixture

these salts are salted by adding alcohols, with stirring for 3 ^x / ₂ hours while cooling with ice

especially ethanol, or left to stand by adding a water. Now it is heated for 12 minutes

withdrawing agent, e.g. B. from anhydrous sodium to 6O ⁰ C, immediately cools with ice and the solution is concentrated

sulfate, precipitated and separated by filtration. Circulation evaporator to about 275 cm ³ . By adding

Finally, which is in the alkaline filtrate 50 from alcoholic hydrochloric acid ance with the p _H to 6.2

dissolved 4-amino ~ isoxazolidone (3) compound from their represents. After adding 4000 cm ^{3 of} alcohol with stirring

Alkali salt with an organic acid, preferably a mixture of halogen salt and DL-4-amino

Acetic acid, released and precipitated by cooling to crystallize isoxazolidone- (3). After the reaction solution

sation brought. Has stood in the refrigerator for 20 hours, you vacuum

According to a further preferred embodiment 55 and after drying 123 g of a salt

According to the invention, an aliphatic mixture containing 29 g of DL-4-amino-isoxazolidone- (3) can be used as a strong base.

Use base. As such, z. B. lower To separate the DL-4-amino-isoxazolidons- (3) is

Trialkylamines, especially triethylamine or trimethyl- the salt mixture finely powdered and in a mixture

amine. For this embodiment of the invention, 4100 cm ^{3 of} absolute alcohol, 41 cm ^{3 of} water and

best aqueous reaction medium as alcohol, for example heated 60 68 g of diethylamine for 15 minutes at 6O ⁰ C,

aqueous ethanol or methanol is used. Since the hydro- it is filtered from the halogen salts, it cools down

Halide salts of the strong organic bases used Filtrate to about 5 ° C, mixed with 40 g of animal charcoal, nitrated

are alcohol-soluble, there is no need to separate them and give as much glacial acetic acid while stirring and cooling with ice

the reaction solution before the crystallization of the overall factor is that a dilute with water sample, a p _H of

formed 4-amino-isoxazolidone- (3) compounds 65 shows 4.8 to 5.0, whereupon the DL-4-amino-isoxazolidone- (3)

can be directed. The 4-amino-isoxazolidone- (3) can be deposited in pure form. After standing,

can also be isolated with the help of an ion exchanger. rend 20 hours in the refrigerator is vacuumed and the

The sequence of reactions described can be dried with the filter residue. 20 g of pure are obtained

racemic a-amino-zS-chloropropionic acid esters as well as DL-4-amino-isoxazolidone- (3) from melting point 140 to

with their optical antipodes. 70 142 ° C.

5 6

Example 3 win phosphorus pentachloride). One stirs during one

In a mixture of 49 cm ^{3 of} 30% sodium hydroxide solution, at ⁰ ° C. for one hour and heated for a further 80 cm ^{3 of} water and 40 cm ^{3 of} ice, 10 g hourly at 25 to 28 ^° C. After cooling to -10 ⁰ C hydroxylamine hydrochloride and subsequently acidified with alcoholic hydrochloric acid to p _H 5.6 cooling 17.4 g of DL-a-amino-z S-5 and then chlorpropionsäuremethyl- hydrochloride ester in an ice-cooled solution of 40 g so entered, that the temperature ^{0 0} C diethylamine poured into 100 cm ^{3 of} ethanol. The diet does not exceed. After completion of the addition aminalkalische solution stirred allowed in 1100 cm ³ of ethanol is during l ^x / ₂ hours under ice cooling, heated from 60 ° C flow, holding for 10 to 15 minutes at finally for 15 minutes at 45 ⁰ C and cools down. this temperature, cools down to -5 to -10 ° C and the alkaline reaction solution contains 8 g io separates from the common salt. The clear filtrate becomes DL-4-amino-isoxazolidone- (3) at -12 ° C. 6 set for the isolation of DL-4-amino having about 23 g glacial acetic acid to p _H and no-isoxazolidons- (3) The procedure of Example 2. D-4-amino-isoxazolidon- seeded (3). You let yourself go

- 18 ° C crystallize with occasional stirring and

BeisDiel 4 sucks off the crystals. 8.2 g of crude D-4-amino

15 soxazolidone- (3). D-4-amino-isoxazolidone- (3) can be about

Obtainable according to Example 3, 8 g of DL-4-amino-isoxazo- the Diäthanolaminsalz or gelidon- through the acidic tartrate (3) containing solution is to be purified, with cooling, and then displays the following characteristics: acetic acid to p _H 7 buffered, and on a polyvinyl \ _a] f - + 114.5 to 115 ° (c = 1 in water); Melting point benzylammonium resin adsorbed. The resin is washed at 140 ^° C.

acid-free with water and the DL-4-amino-isoxazoli- 20 example 7 elutes

don- (3) with 0.5 η-ammonia. If necessary after development

coloring of the ammoniacal solution with charcoal is 87.5 g of sodium hydroxide and 0.5 g of sodium sulfide

in a high-speed vacuum evaporator at 35 ° C. to 60 cm ³ are stirred with 35 cm ^{3 of} water. After the largest narrowed. It is with 15% hydrochloric acid to p _H 6.2, a part of the Natriumhydroxyds has gone into solution, added added 300 cm ³ of absolute ethanol and allowed to at - 10 ⁰ C 25 to 350 cm ³ of methanol to and holds at about 5O ⁰ C until crystallize. The crystals are ten times the entry of the clear solution. Thereupon one cools to - 9 amount of methanol triturated, the crystal ^{powder in the down to - 10 0} C and leaves at this temperature under 2 ¹ ZaUaChCn amount of water and by careful intensive stirring a 3O ⁰ C warm solution of 50 g addition of ethanol the Crystallization of the DL-4-amino hydroxylamine hydrochloride, 15 cm ^{3 of} water and 150 cm ^{3 of} isoxazolidone- (3) initiated in the cold. 30 methanol run in. Subsequently, under steady

Stir a solution of 87 g of DL-a-amino-jff-chlorpro-

Example of methyl pionate hydrochloride in 125 cm ^{3 of} methanol

at - 10 ° C is added dropwise and for a further 17.6 g of sodium hydroxide are ^{stirred in 70 cm 3 of} water for an hour.

dissolved and cooled to 5 ° C. To separate off the inorganic salts, 9.8 g of hydroxylamine hydrochloride are stirred and then for 3 hours with 60 g of sodium sulfate at -15 ° C., then 17.4 g of methyl La-amino-β-chloropropionic acid are separated from the inorganic salts and washes the ester hydrochloride in such a way that the temperature 10 ⁰ C does not salt with methanol. The combined filtrates are exceeded. Then the mixture is stirred for 3 hours in the cold with glacial acetic acid to p _H 6 introduced under ice-cooling, then warmed for 12 minutes at 40 provides. After risk of seeding with DL-4-amino-60 ° C, cooled to about 5 ⁰ C and, with alcoholic isoxazolidon- (3) is the crystallization at -10 to hydrochloric acid to a p _H of 6.2, a. This mixture is added - 15 ° C ended after 3 to 4 hours. 30.6 g of crude DL-4-amino-isoxazolidone- (3) are obtained with stirring and ice-cooling with 200O cm ^{3 of alcohol.} DL-4-amino-isoxazo- and after 6 hours sucks the amount of 25.5 g, of lidon- (3) can possibly also consist of beige sodium chloride and L-4-amino-isoxazolidone- (3) for removal Sodium acetate via the diethanolamine salt de salt mixture. This residue is finely pulverized to be cleaned and then shows a melting point and in a mixture of 400 cm ³ alcohol, 2 cm ³ water from 140 to 141 ° C.
and 6.7 g of diethylamine for 15 minutes at 6O ⁰ C Example 8

heated with stirring. The precipitated is filtered off

Sodium chloride, the clear solution cools to about 5 ° C. to a diluted water sample with a p _H of to 45 minutes with 700 cm ³ of ethanol at - 10 to - 15 ° C 4,8bis5,0zeigt, woraufsichdasL-4-amino-isoxazolidon- (3) is stirred, the separated sodium chloride with little Separates methanol in crystallized form. It is suctioned after washed out and then the combined Fütrate 4 hours, then 4.5 g of pure L-4-amino-isoxazo- 55 in the cold with acetic acid to p _H 6.0 abgelidon- to 6.05 (3) of melting point 156 ° C, [a] | ² - 115 ° (c = 1.0 buffers. Isolation of the crystalline DL-4-aminoin water). isoxazolidons- (3) is according to the instructions in Example 7

". . ,. carried out. 30.6 to 33.2 g of HL-4-amino

Example isoxazolidone).

35 g of sodium hydroxide are dissolved in 75 cm ^{3 of} water 60 Example 9

and - cooled 5 ⁰ C. Then one carries below

- 3 ° C in portions, first 20 g of hydroxylamine hydro- 35 g of sodium hydroxide are in 75 cm ^{3 of} water

chloride and then 34.8 g of D-a-amino - ^ - chloropro- dissolved and cooled to -5 ° C. One wears on this pionic acid methyl ester hydrochloride. (D-α-amino- / 3- below - 3 ° C in portions, initially 20 g of methyl hydroxylchloropropionate hydrochloride from the melting amine hydrochloride and then 37.6 g DL threopoint 156 ° C can be added according to that of E. Fischer, Be a-Amino-zS-chlorobutyric acid methyl ester hydrochloride richte der Deutschen Chemischen Gesellschaft, 40 [1907], (DL-threo-a-Amino - ^ - methyl chlorobutyrate-hydro-S. 3719, for the representation of L-a-amino-zS-chloroprochloride with a melting point of 159 to 161 ° C [decomposition] Pionic acid methyl ester described by can be chlorinated by chlorinating DL-erythro-threonine of D-serine methyl ester hydrochloride with phosphorus methyl ester hydrochloride from melting point 144 to

145 ° C. [decomposition] with phosphorus pentachloride according to M. Kinoshita and S. Umezawa, Chemical Abstracts, 46 [1952], p. 3005). The mixture is stirred for 3 hours at 0 ⁰ C and heated for a further hour at 25 to 28 ^P C. After cooling to - 10 ⁰ C was acidified with alcoholic hydrochloric acid to p _H 5.6 and 40.2 g 0 ⁰ C chilled diethylamine added. The solution is allowed diäthylaminalkalische in 800 cm ³ of ethanol at 60 ⁰ C flow, holding for 10 to 15 minutes at this temperature, cooled to + 2 0 of about ⁰ C and separates off from the precipitated sodium chloride. The clear filtrate -is at ⁰ ° C with glacial acetic acid to p _H 6.0 adjusted; overnight is allowed in - crystallize 10 ⁰ C and filtered off the crystals. 16 g of raw material are obtained. DL-erythro-5-methyl-4-amino-isoxazolidone- (3). The compound can be recrystallized from water-alcohol or reprecipitated in aqueous alcohol with the aid of diethylamine and glacial acetic acid. It then shows the following chaiacteristics; No specific melting point, but decomposition between 160 and 170 ^° C. (depending on the conditions). Paper chromatography (paper Schleicher-Schüll No. 2043 b, descending): Solvent: i-propanol conc. NH ₁ OH - H ₂ O, 80: 2: 18, ^R _F = 0.27, detection with ninhydrin. UV absorption: X _max - 224 ταμ, ε = 4200, in water.

25th

Example 10

35 g of sodium hydroxide dissolved in 75 cm ³ of water and to - S cooled ^0C. Then, at below -3 ° C., 20 g of hydroxylamine hydrochloride and then 37.6 g of DL-erythroa-amino-1S-methyl chlorobutyrate hydrochloride are introduced in portjonen. (DL-erythro-a-ATnino-jff-chlorobutyric acid methyl ester hydrochloride from melting point 167 to 169 ° C [decomposition] can be obtained by chlorinating DL-threo-threonine methyl ester hydrochloride from melting point 122 to 124 ° C [decomposition] with phosphorus pentachloride according to M Kinoshita and S. Umezawa, Chemical Abstracts, 46 [1952], p. 3005). The mixture is stirred for one hour at 0 ⁰ C and heated for a further hour at 25 to 28 C. After cooling to ⁵ - 10 ⁰ C was acidified with alcoholic hydrochloric acid to p _H 5.6 and 40.2 g O ⁹ C chilled diethylamine added. The solution is allowed diäthylaminalkalische in 800 cm ³ of ethanol of 60 ° C flow, holding for 10 to 15 minutes at this temperature, cooled to ⁰ -f 2 through 0 C and separates off from the precipitated sodium chloride. The clear filtrate is adjusted ⁰ C with glacial acetic acid to p _H 6.0 at O; overnight is allowed in - crystallize 10 ⁰ C and filtered off the crystals. 16 g of crude EL-threo-5-methyl-4-amino-isoxazolidone- (3) are obtained. The compound can be recrystallized from water-alcohol or reprecipitated in aqueous alcohol with the aid of diethylamine and glacial acetic acid. It then shows the following characteristics: Cores have a certain melting point, but decomposition between 280 and 300 ^° C. (depending on the conditions). Paper chromatography: the same conditions as in Example 9, ^r f = 0.22. UV absorption: l _max = 226 ταμ, ε = 3820, in water.

Claims (7)

Patent claims: 1. A process for the preparation of 4-amino-isoxazolidone (3) compounds _J, characterized in that a mixture of hydroxylamine with an ester of the general formula R ₁ -CH-CH-COOR ₂ NH, in which R _{1 is} hydrogen, an alkyl, aryl or aralkyl group, R _{2 is} an alkyl group, and X is a halogen atom, treated with a strong base in the presence of water and the 4-amino-isoxazolidone- (3) obtained optionally in an is known to split into the optical antipodes. 2. The method according to claim 1, characterized in that the strong base is an alkali metal hydroxide used. 3. Process according to claims 1 and 2, characterized in that acidifying the alkaline reaction solution, first with a mineral acid to a p _H of about 6, then adjust to phenolphthaleinalkalische reaction by means of an organic amine, pouring in alcohol, poorly soluble, deposited The halogen salt is separated off, and finally the 4-aminoisoxazolidone (3) compound dissolved in the filtrate is liberated from its amine salt with acid and crystallized by cooling. 4. Process according to claims 1 and 2, characterized in that the 4-amino-isoxazolidone (3) compound is released from its alkali salt by adding acid to the alkaline reaction solution, then the solution is poured into a lower alcohol, the separated crystal pulp of the halogen salt and the 4-amino-isoxazolidone- {3) -compound, then suspended in alcohol, the 4-amino-isoxazolidone- (3) -compound in solution by adding an organic amine and finally after separating the undissolved Halogen salt sets the 4-amino-isoxazolidone (3) compound with acid in freedom and brings it to crystallization by cooling. 5. Process according to Claims 1 and 2, characterized in that the reaction is carried out in aqueous methanol can go ahead. 6. Process according to claims 1, 2 and 5, characterized in that a dehydrating agent is added to the reaction solution, the excreted The inorganic salt is separated off and the 4-amino-isoxazolidone- (3) -compound remaining in solution is released from its alkali salt with an organic acid and crystallizes by cooling. 7. The method according to claims I ₁ 2 and 5, characterized in that the sparingly soluble inorganic salt is precipitated by adding ethanol, separated off and finally the 4-amino-isoxazolidone (3) compound remaining in solution from its alkali salt with a releases organic acid and crystallizes by cooling. © »679ß65 11.58