Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
;~3~3
~3221-4115
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The invention relates to a novel process for the
preparation of 4-(hydroxymethylphosphinyl)~2~aminobutYric
acid t- phosphinothri~;n) of the formula I
o NH2
3 P C~l2-cH2-cH-cooH (I)
OH
and its salts in particular the ammon;um salts.
The compound I us known end is described as 3
bactericide or herbicide in, for example, Help. Chum.
Act 55~ 224 ~1972~ and Herman Offenlegungsschrift
2,717~440~ Numerous methods for the preparation of I
have already been described in the literature Shelve. Chimp
Act 55f 229 (1972); Japan. Cook Shea (27.11.
1973); Rock. Chum. 49~ 2 127 ~1975); J. Pratt. Chemise 318,
157 (1976); ETA 9~022 (12.07.1979); Pot. J. Chew. 53,
~37, (1979); ETA 18 145 (13.12.1979~; AYE Shea 595;
KIWI. 94, 84 295 b (15.05.1980) and ETA 11 245], but, with
few exceptions, these do not give satisfactory yields.
According to the process described in ETA 11,245,
I is formed by the following reaction
I.) NH3
OH --P-CH OH --CHICANO
3 2 2 2 . ) OH
Oboe OAT 3. ) H2SO4
in a yield of about 85%.
The disadvantage of thus process is the quite sub
staunchly amount of salt obtained and the expensive swooper-
lion of I from the reaction mixture, since the Amman
'
23221-4115
acid formed has volubility properties like those of inorganic
salts. Impurities which are formed in the preparation of the
starting compound by addition of the methanephosphonous acid ester
onto acrolein-cyanohydrin acetate likewise have an adverse effect
on the course of the last stage and significantly reduce the
yield. An additional disadvantage is that it is not possible to
synthesize optically active I by this process.
It has now been found that the disadvantages described
are avoided, without the yield being reduced, by treating 4-
(hydroxymethylphosphinyl)-2-oxobutyric acid of the formula II
O O
If 11
H3C-P-CH -OH -C-COOH (II)
1 2 2
OH
or its salts, with ammonia or a primary amine in which the C-N
bond is split hydrogenolytically by means of hydrogenation
catalysts, in the presence of a hydrogenation catalyst at
temperatures of -10 to +150C in a hydrogen atmosphere.
The reductive lamination of ~-oxycarboxylic acids to the
corresponding ~-aminocarboxylic acids is known per so. Never the-
less, the result of the process according to the invention is in
many respects to be regarded as surprising.
On the one hand, it had to be assumed that the
phosphinic acid part of the ~-oxobutyric acid II would also be
reduced under the hydrogenation conditions [Help. Chimp Act 49,
842 (1966); J. Am. Chum. Sock 90, 3 4~9 (1968); J. Organometallic
Chum. 97, C 31 (1975); and Chum. Ben. 113, 1 356 (1980)}. On
the other hand, it was
- 3 -
- 4 - 2322l-4ll5
to be expected that the undesired 4 thydroxymethylphosph;-
Noel hydroxybutyric acid of the formula III
I
H3c-p-cH2-cH2 - Schick ( I I I )
0~1
or its salts, would be formed Doreen the reaction. For
example, it is known from pull. Chum. Sock Japan 36, 763
(1~63) that, besides the desired aminoglutaric acid a
substantial amount of cC-hYdroxYglutaric acid is formed
on reductive am;nat;on of ~-ketoglutaric acid (the car-
boxy analog of II).
In view of these facts, the high chemical yield
and the purity of the process product on application of
the process according to the invention were not to be ox-
pealed.
The extent to which such a process was unexpected
us made particularly clear by the fact that, although many
professes for the preparation of I have been described,
not a single one has considered thus possibility, even
though a large number of Amman acid syntheses are based
on reductive lamination of ~-oxocarboxylic acids.
The compound II required as the starting compound
for the process according to the invention and its salts
can be prepared from commercially available 3-(alkoxyme-
thylphosphinyl)-propion;c acid esters of the general for-
mule IV O
if
H C-PCCH -OH -COO (IV)
OR
I I
in itch R and R1 can be identical or different and each
denote a (c1-c4)-alkyl radical accordir10 to ETA 30"424~
Possible salts are the Mooney and bis-sal-ts of II, on par-
titular the sodium, potassium and ammonium salts.
Solvents or delineates which are preferably suitable
for the process according Jo the invention are lower Alcoa
hots, such as methanol, ethanol and isopropanol, and
water, and also mixtures of these solvents and d;luents.
The WriteNow temperatures are in general ~10 to
150C, preferably 20-100C.
Hydrogenation catalysts which can preferably be
used are heterogeneous catalysts, such as for example,
platinum, palladium, nickel, cobalt and rhodium catalysts
in their most diverse use forms. It is also possible lo
use homogeneous catalysts, such as, or example, potassium
pentacyano-cobaltate or metal hydrides (for example
Lyle or Nub).
Possible amine for the process according to the
invention are, besides ammonia, also those primary amine
in which the C N bond us split hydrogenolytically by the
hydrogenation catalysts mentioned. These amine aver in
particular, benzylamine, benzhydrylamine, tr;~ylaMine,D~L-
1-phenyle~hylarnine, (I phenylethylamine and (I
phenylethylamine.
An equilnolar amount or up to a 10-fold excess of
the ammonia or primary amine is employed
The process according to the inventiol1 is carried
out in a hydrogeli atmosphere, in general under pressures
of between 1 and 20n bar, preferably between 1 and 50 barn
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.
depending on the nature of the catalyst used
The reaction can be regarded as having ended when
no further hydrogen us consumed under the given reaction
conditions constant pressure).
In the process according to the invention the
apparatus for isolation of the process product is very
simple especially when heterogeneous catalysts which
can easily be separated off by filtration and/or centric
fugat;on are used since the process product us already
it obtained on a sufficient chemical purity after evapora
tying off the solvent or delineate under reduced pressure
The yields are about 85-95%.
The crude process product can additionally be
subsequently luncher purified either by recrystallization
or by chromatography.
The process according to the invention is thus-
treated on more detail with the aid of the following prop
ration examples
to 1
Ammonium salt of 4-(hydroxyme hylphosph-iry l? -2-
aminobutyric acid
9~0 9 (0.05 mole of 4-(hydroxymethylphosphinyl~
2-oxobutyric acid were dissolved in 50 ml of methanol
Shea had been saturated with ammonia at 10C. After
addition of 1 g of Haney nucleoli hydrogenation was car
fled out under 100 bar and at 50C on a shaken autoclave
join the uptake of hydrogen held ended the autoclave was
let down the catalyst was f;lteled of-F and the excess
amlnonia and the solvent were distilled off under reduced
pressure. 9.8 g of colorless product which hack solidified
to a glass-like solid and could be powdered in a mortar
were obta1rled as the distillation residue. Melting range:
205-215C (decompos;t;on). The product consisted o-f
the desired ammonium salt of phosph;nothricin to the en
tent of 90% (HPLC analysis).
Example 2
9.0 9 (O.G5 mole of 4--(hydroxymethylphc)sph;nyl)-
2-oxobutyric acid were hydrogenated in the presence of
1 g of s% strength palladium-on-active charcoal under 5
bar and at 5nc analogously to Example 1.
After drying in vacua, 9.8 9 of powdered, color-
less product which melted at 208-215C,. with decolnpos;-
lion, and consisted of the ammon;um salt of , to the ox-
tent of 93% tHPLC analysis), Syria obtained.
En e 3
Roy g (0~1 mole) of hydroxymethylphosph;nyl)-
Z-oxobutyr;c acid Lowry hydrogenated, after addition of
1 9 of 10% strel1gth of platinum-on-act;ve charcoal, under
5 bar and at 50C analogously to Example 1.
After dry;nt~ on vacua, 19.5 9 of a colorless pow-
don weaken had a melting range of 205-210C (decornposit;on)
and consisted of the ammon;um salt of I to the extent of
87% (HPLC analysis, were obtained.
9~0 9 (0.05 mole) of 4 thydroxymethylphosphinyl)~
2-oxobutyr;c acid were dissolved on 50 ml of methanol and
the saltier juicy added drops at 20 25C under a ho
drocJen pressure of about 1~0 to 1.2 bar Al the course of
1 hour, to a vigorously stirred suspension of 1 9 of 5%
strength palladiurn-on-active charcoal in 50 ml of Matthew
not saturated with ammonia. An apparatus built in-house
and correspontling to Hillel Lyle, Volume IV/1c, page 34
et seq. was used When the uptake of hydrogen had ended,
the mixture was worked up analogously to Example 1.
9.8 9 of a colorless powder which melted between
208 and 213C, with decomposition and consisted of the
ammonium salt of phosphinothricin to the extent of 95%
10 (HPLC analysis), were obtained. It was possible to oboe
lain 8 of pure I (ammonium salt) of melting point 210C
(decomposition) from the crude product by crystallization
from methanol water
Exampif~ 5
2. 0 g (OWE mole) of 4-(hydroxymethylphc)s~
ph;nyl)-2-oxobutyr;c acid were dissolved in 50 ml of
water, into which about 0.5~0~6 (mole) of ammonia had
been passed at 1ûC, and, after addition of Do g of 5%
strength pi l ladium-on-active charcoal, hydrogenation was
carried out under 2 bar and at 25C in a shaken auto-
slave. When the uptake of hydrogen had ended, the mix-
lure was worked up as in Example I After drying in
vacua, 2.1 g of a colorless powder which consisted of the
ammonium salt of I to the extent of 89% (HPLC analysis)
were obtained.
example 6
11.Z (aye mole) o-f the bus sodium salt of 4-
~hydroxylnethylphosphinyl)~2 oxobutyr;c acid anal 5~4 to
(OOZE m()lej of ben~ylarnir~e were dissolved on 50 fill of
;.L~3~3
_ 9 _
r,lethanol and after addition of 2 g of 5% strength pall-
d;um-on-act;ve charcoal, hydrogenation was carried out
under 5 bar and a'; 50C in a shaken autoclave I~Jhen the
uptake of hydrogen had ended, the catalyst was filtered
off and the filtrate was distilled under reduced pros-
sure During this procedure, most of the methanol passed
over together with Tulane and traces of unrequited Ben
~ylamine. After drying the oily roused on vacua, 11 g
of a colorless powder which consisted of the bus sodium
salt of 4-(hydroxymethylphosphinyl)-2-aminobutyric acid
to the extent of 90% (HPLC analysis) were obtained.
