DD215554A5 - PROCESS FOR THE PREPARATION OF PHOSPHINOTHRICINE - Google Patents

Abstract

1. A process for the preparation of 4-(hydroxyme-thylphosphinyl)-2-aminobutyric acid of the formula see diagramm : EP0121226,P5,F1 and its salts, which comprises reacting 4-(hydroxynethyl-phosphinyl)-2-oxobutyric acid of the formula see diagramm : EP0121226,P6,F2 or its salts, in the presence of a hydrogenation catalyst at -10 to +150 degrees C in a hydrogen atmosphere, with ammonia or with a primary amine the C-N bond of which being capable of hydrogenolytic cleavage by means of said hydrogenation catalyst.

Description

Berlin, June 20, 1984 63 642 11

Process for the preparation of 4- (hydroxymethyl-1-phosphinyl) -2-aminobutyric acid

Field of application of the invention

The invention relates to a novel process for the preparation of ^ - (hydroxymethylphosphoryl) -2-arabinobutyric acid ^! (sPhosphinothricin) of the formula I.

   .1I .- ·

 H-.O-P-CHp-GBL-CH-POOH (I)

° I:, .- ν, · -.

and their salts ι in particular of the ammonium salt » Characteristic of the known technical solutions

The compound I is known and is z. In HeIv. Chim. Acta 2%, 224 (1 ^ 2) and DE-OS 27 17 440 described as a bactericide or herbicide. For the preparation of I, numerous methods have already been described in the literature ^! Elv. Chiin. Acta, 229 (1972); Japan. Kokai Sho ~ 48-091019 (27.11.1973); Rocz. Chem. ΆΘ, 2,127 (1975); J. expresses. Chemistry 218, 157 (1976); EP-A 9 022 (12.07.1979); Pole. J. Chem. , 937 (1979); Ef-A 18,145 (13,12.197V); JA-A Sho-55-064 595; OA 94, 84 295 b (May 15, 1980); EP-A 11 24 ^ 7, which, however, with few exceptions, do not give satisfactory yields. i ^: '··'. ''';':'.'.'' - '' '. ·''' · According to the procedure described in EP-A 11 245 I is produced according to the following reaction

ii. ; .: ^;:. - "^'-. - ^{3 v}

o ₀

j "; .... · j 2.) KOH

Oibii OAC 3.) H ₂ S

in a yield of approx. 85 % ·

A disadvantage of this process is the considerable amount of salt attack and the complicated removal of I from the reaction mixture, since the ^ -amino acid formed has solubilities such as those of inorganic salts. Likewise, impurities which are present in the preparation of the starting compound are added by addition of the lethane-phosphorous acid ester Acichelcyanohydrin · *, acetate are negative for the course of the last step and significantly reduce the yield. Sin ^additives: Licher disadvantage is the fact that the synthesis -. of optically active I is not possible by this method. "- ·. · ^{.; ;;} '... ^; ·"'/;'::;'.

Aim of the invention . "'. :: ... ^; .'. ' - '.''·^Ν;'

2iel the invention is the provision of an improved, simple and economical process for the preparation of 4-hydroxymethyl-phosphinyl) -2-aminobutter ^! acid, with which the desired product can be obtained in good yield and higher purity. _;

Explanation of the essence of the invention

The invention is based on the object ,, 4-hydroxymethyl-phospM.nyl) -2-aminobutyric from suitable Aus ^! - To produce transition under appropriate reaction conditions.

It has now been found that avoids the disadvantages described without reducing the yield, uieun one 4-CHydroxymethylphosphinyl) -2'-oxobutyric acid of the formula XI ^: '".- ^.: ''Οο". , '

H ₂ -GH ₂ -C-COOH ^Γ

or its salts in the presence of a hydrogenation catalyst at temperatures from -10 to + 150 ⁰ C in a hydrogen atmosphere with ammonia or primary amines treated ·

The reductive amination of OC-oxocarboxylic acids to the corresponding ^ o -Iminocarbonsäuren is known per se. Nevertheless, the result of the process according to the invention can be described as surprising in many respects.

On the one hand, it had to be expected that under the hydrogenation conditions, the phosphinic acid portion of the .gamma.-oxbutyric acid II would also be reduced. ^ SeIv. Chim. Acta 49, 842 (1966); J. Am. Chem. Soc. 90, 3, 459 (1968); J, Organometallic Chem. 9, C 31 (1975); Chem. Ber. 113 , 1 356 (1980) 7. On the other hand, it was to be expected that in the reaction, the unwanted 4- (hydroxymethylphosphinyl) -2-hydroxybutyric acid of formula III

0 OH

: .. I

  H-O-P-CHx-OHp-CH-COOH (III)

, · ·. ^y \ ·. -V ::. .- ..,

'ν. OH ·. -. , ·. , '

or "her oalze would arise. For example, it is off

i. 4 ~

Bull; Ghein. Soc. Japan; ^ 6, 763 (1963) discloses that in the reductive amination of cC-ketoglutaric acid (the carboxyl, analog of II), uc-1-hydroxyglutaric acid is formed to a considerable extent in addition to the desired OC-aminoglutaric acid.

In view of these facts, the high level of chemical

·. , . '· ··' ''. '· ·' ':. ·. Λ

booty and the purity of the process product when using the method according to the invention is not expected.

However unexpected such a process has been, it is particularly clear that, although many methods have been described for the preparation of I, not a single one has considered this possibility, although a whole series of efc-amino acid syntheses on the reductive amination of £ * ^^ - Oxpcarbonsäuren build on.

The II or its salts required as starting compound for the process according to the invention are commercially available 3- (alkoxymethylphosphinyl) propionic acid esters

of general formula IV,:.

P-GH ₂ -CH ₂ -COOH ¹ (IV)

in which R and R may be identical or different and each represent a (C 1 -C 4) -alkyl radical, preparable according to EP-A 30424. The salts used are the mono- and bis-salts of II, in particular the sodium, potassium 'and ammonium salts in embossing.

Suitable solvents or diluents for the process according to the invention are preferably lower alcohols, such as methanol, ethanol and isopropanol or water, or mixtures of these solvents or diluents.

The reaction temperatures are generally from -10 ⁰ C to 150 ⁰ C, preferably 20 to 100 ⁰ C.

As hydrogenation catalysts are preferably heterogeneous catalysts, such as ζ.B. Platinum, palladium, nickel, cobalt and rhodium catalysts in their various applications in question. The use of homogeneous catalysts such. B. potassium pentacyano-cobaltate or ¹ metal hydrides (eg LiAlH ₄ , NaBH ₄ ) is possible.

Suitable amines for the process according to the invention in addition to ammonia and those primary amines whose C-N bond is hydrogenolytically cleaved by said .Hydrierungskatalysatoren in question. These are in particular benzylarain, BenzhydrylaininvTritylaminjDiL-i-phenylethylamine, C +) - 1-phenylethylamine, (-) - i-phenylethylamine.

Ammonia or the primary amine are used in equimolar amounts or in an excess of up to 10 times. , The erfindüngsgemäße process is carried out, depending on the nature of the catalyst used in a hydrogen atmosphere generally at pressures between 1 and 200 bar, preferably between 1 and 50 bar.

The reaction can be considered completed when under the given reaction conditions no more hydrogen is consumed (constant pressure).

In the method according to the invention, the isolation of the process product, in particular when working with heterogeneous catalysts, the designed. can easily be separated off by filtration and / or centrifuging, "in terms of apparatus, it is very simple, since the decomposition product, after evaporation of the solvent or diluent, already gives rise to sufficient chemical resistance under reduced pressure." The yields are about 85 to 93 %. *

Bas crude; product of the process may additionally followed by either chromatography or by ümkristallisation be .gereinigt ^*:. - .. ".."' : ..'. ' ,

Embodiment - '- ''' \. ''

Bas inventive method is based on the following. Series examples are explained in more detail ».

Example 1 · ^: ( . ·. · ''. ..,. ^: '"

Ammonium salt of ^ - (hydroxyniethylphosphinyl) -2-aminobutter acid ".. / ':. ·.', ''. ·::;; '. _; , , ,

     "· - ·. ';' Ο -:". ", '" "'

9.0 g (0.05 mol) ^ -CHydroxymethylphosphinyl ^^ - oxo-butyric acid were dissolved in methanol 50 ml, daa had been saturated at 10 ⁰ C with Immoniafc ·. After addition of 1 g of Raney nickel was hydrogenated at 100 bar and 50 ⁰ G in a Schuttelautoklaven »still completion of the hydrogen uptake was ent spanns, filtered from the catalyst and

distilled off the excess ammonia and the solvent under reduced pressure. Ala distillation residue were obtained 9.8 g of colorless, glass-like solidified product which could be pulverized in a mortar, "melting range 205-215 ⁰ Q (dec.). The product consisted of 90 % (HPLC analysis) of the desired ammonium salt of phosphinothricin.

Example 2

9.0 g (0.05 mol) of 4- (hydroxymethylphosphinyl) -2-oxobutyric acid were hydrogenated in the presence of 1% palladium on Α-carbon at 5 bar and 50 ° C., analogously to Example 1. · ',' \. · "· ·." .. .. "" - .. ... \ ·. · ''. ',,.;

After drying in vacuo 9 * 8 g of powdered, colorless product were obtained, which melted at 208 to 215 ⁰ C with decomposition and to 93 % (HPLO analysis) consisted of the ammonium salt of I.

Example 3 ; ^; '''....':'.'''.'-.

Analogously to Example 1, 18.0 g (0.1 mol) of 4-hydroxymethylphosphinyl) -2-oxobutyric acid were hydrogenated after addition of 1 g of 10% platinum on Α-carbon at 5 bar and 50 ⁰ O »

After drying in vacuo, 19.5 g of colorless powder of the melting range 205 to 210 ⁰ C were obtained (Zers.) That to 8? % (HPI ^ C · ^ · analysis) - consisted of the ammonium salt of I.

Example 4 ; .. '' :: '.''''....' - v -. '' V /.,

9.0 g (0.05 mol) of 4- (hydroxymethylphosphinyl) -2-oxobutyric acid were dissolved in 50 ml of methanol and within,

1. Juice at 20 to 25 ⁰ G to an intensive fermented suspension of 1 g $%. Palladium on A-Colile in 50 ml 'with ammonia' saturated ¹ methanol at one. Hydrogen pressure of about 1.0 to 1.2 bar added dropwise. In this case, a Sigenbauapparatur according to Houben-Weyl, BeU, I7 / 1c, 3. 34 ff. Was used. After completion of hydrogen absorption, the procedure was as in Example 1. . '..''

9-8 g of colorless powder were obtained, melting between 208 and 213 ⁰ G with decomposition and 95% (HPLC analysis) of the immmop.iumsalz of phosphinothricin. From the crude product, by crystallization from methanol / water 8 g of pure I (ammonium salt) of melting point 210 ⁰ G (Sers.) Are obtained. ''>'

2i9 g (0.011 mol) ^ - (hydroxymethylphosphinyl) -2-oxobutyric acid were in 50 ml of water, in the. At 10 ⁰ C about 0.5 to O ₄ ^ (mol) of ammonia had been initiated-dissolved, and after addition of 0.5 g of 5% palladium on activated carbon. 2 bar and 25 ⁰ G in a rubble el. , . ·. autoclaved hydrogenated. After completion of the hydrogen absorption 'was' worked up as in Example 1. After drying in vacuo, 2.1 g of colorless powder were obtained which consisted of 89 % (HPLC analysis) of the ammonium salt of I.

Bejgg'iel 6 . . ''' .. ·

11.2 g (0.05 mol) of bis-Netriumsalz of M- (hydroxymethylphosphinyl) -2> -oxobutyric acid and 5. ^ S (0.05 mol) ßenzy ^. Amine were dissolved in 50 ml of methanol and after addition of ? .. g 5A> palladium on charcoal at -5 bar and

50 ' ⁰ G hydrogenated in a ochüttelautoklaven. After completion of the hydrogen uptake, the catalyst was filtered off, and the filtrate distilled under reduced pressure. Here, the bulk of the methanol went over along with toluene and traces of unreacted benzylamine. After drying the oily residue in vacuo, 11 g of colorless powder were obtained which consisted to 90% (HPLO-Analyae) of the bis-sodium salt of 4 ~ (hydroxymethylphosphinyl) -2-aminobutyric acid.

Claims (1)

63 642 11 Invention; sanspr och Process for the preparation of ^ - (hydroxymethyl-phoaphinyl) -2-aminobutyric acid of the formula Λ 0 NH _(J ; ι ν ₃ ^ ₂ and their salts, characterized in that ^ - (hydroxyethyl-phosphonyl ) -S-oxobutyric acid of the formula :.): ':': '. '. <:. ^: ... ' ^: , - "'."'; -O .''.- v · O-: '-' ^: I! ii Ho G ^ P-GHp-GH ..-0-GOOH (II)     ','. : ι:. .. ·. , /   "OH - ..":. or their salts in the presence of a Hydrogenationakatalysa "tors''-1Ö to + 'ifjO ⁰ G in a hydrogen atmosphere with .. ^ arapniak or primary amines treated.