PROCESS FOR THE PREPARATION OF N-PHOSPHONOMETHYLGLYCINE

METHODE DE PREPARATION DE DERIVES DE N-(PHOSPHONOMETHYL)GLYCINE

English Abstract

ABSTRACT
A process for the preparation of N-
phosphonomethylglycine isdisclosed which comprises:
preparing an N-alkyl-N-phosphonomethylglyaine or its
ester reprinted by the formula
<IMG>
wherein R is an alkyl group represented by the formula
<IMG>
and R1, R2 and R3 are independently selected from the
group consisting of hydrogen and alkyl having one to about
four carbon atoms, and R4, R5 and x6 are independently
selected from substituted and unsubstituted alkyl groups
having from one to about six carbon atoms wherein any
substitution on the alkyl group has electron withdrawing
properties, and hydrogen, provided that R4, R5 and R6 cannot
all be hydrogen; and thereafter
treating the N-alkyl-N-phosphonomethylglycine with an
acid, other than a hydrohalic aaid, having a pR? value below
about +3 in the presence of an organic acid to provide N-
phosphonomethylglycine.

Claims

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THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of N-
phosphonomethylglycine which comprises:
preparing an N-alkyl-N-phosphonomethylglycine or its
ester represented by the formula
<IMG>
wherein R is an alkyl group represented by tho formula
<IMG>
and R1, R2 and R3 are independently selected from the
group consisting of hydrogen and alkyl having one to about
four carbon atoms, and R4, R5 and R6 are independently
selected from substituted and unsubstituted alkyl groups
having from one to about six carbon atoms wherein any
substitution on the alkyl group has electron withdrawing
properties, and hydrogen, provided that R4, R5 and R6 cannot
all be hydrogen; and thereafter
treating ths N-alkyl-N-phosphonomethylglycino with an
acid, other than a hydrohalic acid, having a pK, value below
about +3 in the presence of an organic acid to provide N-
phosphonomethylglycine.
2. The process of claim 1 wherein R is isopropyl or
t-butyl.
3. The process of Claim 1 wherein R is t-butyl.
4. The process of Claim 1 wherein the acid having a pK,
value below about +3 is selected from the group consisting
of p-toluene sulfonic acid, methyl sulfonic acid, sulfuric
acid, trichloroacetic acid, phosphoric acid and phosphorous
acid.

- 8 -
5. The process of Claim 4 wherein the acid in sulfuric
acid.
6. The process of Claim 1 wherein the organic acid in
acetic acid.
7. The process of Claim 1 wherein in the N-alkyl-
phosphonomethylglycine is synthesized by reacting ethyl
chloroacetatic with an alkylamino, followed by ester
hydrolysis, followed by phosphonomethylation of the
resulting N-alkyl glycine.
8. The process of Claim 7 wherein the alkylamine in
t-butylamine.
9. N-Phosphonomethylglycine produced by any of the
processes in claims 1-8.

Description

2C)06270
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~ .
This in~ention relate~ to a p~oc-o~ for th~ prep~ration
of N-phosphonomethylglycine or it~ ~te~, and morQ
particularly to th~ pr-paration of N-phosphonomethylgly~ine
~r~m N-substituted glyc~ne derivatives
N-Phosphono~ethylglycine, known by it~ common name o~
glyphosate, i9 widely used around the world a~ a broa~-
spe¢trum herbicid~ to control th- gxowth o~ m~ny plant
specie8 Generally, it ~g u~ed in an aqueou~ solution ns
one of it~ salts for application to plant~ to control the
growth of woody plants, aquatic ~peci-~, qra~e~, ~nd the
like It i~ kno~n to be gen~rally non-toxio to ~umsn~ and
other mammals, and environment~lly ~- Millions of llter~ -
of the formulated product ar~ ~old each yea~ for such
purposes
It i~ kno~n that N-benzyl-N-phosphono~ethylglya$ne (or --
itR esters) unde~go~# hydrohal~c acid d-benzyl~tion to yield
benzyl halide and N-phosphono~ethylglyaine or it~ ester~
(see ~or example Briti~h Patent No 1 436 843) A large -
excess o~ very ~onc~ntrated (eg 48~) hydro~alic acid is
required, however, amounting to ~any mol-~ o~ ac~d ~or eacA ~-
mole o~ ~tarting co~pound Thls rendor~ ~h- proc-~ing ~nd
i~olation o~ the deslred glycin~ deriv~tive di~lcUlt,
mainly becau~e of th~ problem of r-moving thi~ large ~mount
o~ hydro~alia ac~d a~ter the reaction.
Attempts to lmprove the proce~- by the use o~ ~tarting
COmpOUnd# hav~ng other ~ubstitu~nts than b~n~yl on the
nitrogen atom, eg ts u~e N-alkyl-N-pho~phonomethylglya~ne~,
~0 have bccn ~tt~nded ~ith the sa~ proc~ing disAdvantag~
(se~ ~or exa~lQ US Patent ~o 3 g27 080) The lit~rature
contain~ no ~ugge~tiona as to the use o~ ~c~fl~ other than
th~ hydrohalla acldn to re~ove the ~lkyl group ~rom N-alkyl-

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N-phosphonomethylglyainn ~o produc~ tho d~irad nd ~roduct
Now, t~e~e is provided nn ~A~y procQdure to dealkylato a
wide variety o~ N-alkyl-N-pho~phono~ethylglycine~ to provid~
N-phosphonomethylglycine in hi~h yield~ at an ~¢onomical
~o~
The~e and other advantage~ aro achiev-d by ~ proaes~
for the pr~p~ration of N-phosphonomQthylgly~ine which
compr~ S-8:
prepa~ing An N-alkyl-N-pho~phonomethylglycln- or it~
ester represented by the ~ormul~
R ~ oR2
RlOOC - CHz -- I -- CH2 P\
oR3
:: 15
wh~rein R i~ an alkyl group repr~ented by th~ formula
R~
R~ - C -
R5
and Rl, RZ and R3 ar~ independently select0d from the
group consisting of hydrog~n and alkyl hav~ng on~ ~o about
four carbon ato~s, and R4, ks and R6 ~re independ~ntly
~elected from ~ubstit~ted and un~u~titut~a ~lk~l ~ruu~
having ~rom one to about ~ix c~bon atom~ wh~rein any
sub~ti~u~ion on th~ alkyl group ha~ atron wlthdrawing
prope~es, and hydrogen, provided that R~, R5 and R6 cannot
~11 be hydrogen; and therea~ter
treating the N-Alkyl-N-pho~phonom~thylglycine with an
acid, oth~r than a hydrohalic aoid, having a pR~ value ~-low
a~out ~3 in the ~re~enc- o~ an o~ganic acid to proviao N-
pho~phono~ thylgl~clne
- 35

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_ 3 _ 09~ 2945)A
.,' _ ~_
We have found that, apart from known proces~e~ u~ing
hydrohalic ac~ds, cort~in ~-~lkyl-N-phos~honom~hylglycine~,
: and t~eir ester~, in which the N-~lkyl aub-tituent ~
suitably chosen, can bo dealkylat-d by treatment not only
with a hydrohalic aoid ~ut with any ~aid whose ~K. value i6
below ~3. Pref~rably, the acid u~ed is solected ~rom th~
group that con~i~ts o~ sulfurio ~aid, ~-toluene ~ul~onic
acid, methylsul~onic acid (subgroup ~) and trichl~r~a~tic
acid, phosphori~ acid and phosphorou~ acid (subgroup B).
The acids of ~ubgroup A are p~eferred, and sulfuria acid i~
e~pecially pre~erred.
In the case of sulfuric Aaid, an adoquate molar
proportion is le~ than about 10%, ba~ed on the ~OlQ~ 0~ -
alkyl substituted glycine derivati~e used in the p~oC~
OE th~ other ~c~d~ n~ed, molar proportion~ o~ ~bout 5% t~ ~
about 50% can be used, the ~refexred range being 10% to 20~, -
based on the moles o~ alXyl ~ub~titut-d glycin~ ~erivativ~
used.
Any nu~ber of organic acids known to those ~illed in
- the ~rt c~n be used in the tr~atm~nt of the N-alkyl-N- ---
pho~phonomethylglycine with th~ ~c~d having a pK, value of
le~ than about ~3. It ~ 8 only nece~ary that the o~anlc
acid i~ water 301uble, and low~r molecular w~ight orqAnic
acids are pre~err~d. Suitablo organic ac~ds inolude formic
acid, acetic acid, propionic acid, butanol~ a~id, and th~
lik~, for u~e in the rea¢tion medium. Aa~tlc ~cid i~
pre~erred.
m Q temperatures to be u~ed in the pXe~ant proces~ aan
vary w~th~n wid~ rango~ Temperaturo~ be~ween a~out 20~C
an~ about 100C pro~ide nati~actory ~esult~. Lower
~QmpQrn~ur~s can be u#ed, but tho reactlon ~- ~omewhat ~low.
TQmp~aturQ~ above 100C can b~ u~ed, but a~ ~7ill ocour to
,

~~iZ7()
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~hose s~illed in the art, the reaat~on v~8~1 may h~v~ to ~e
pres~urized at such higher tem~erature~. Temp~ratur-~
between about 40C and 100C ar- pre~err~d. When sulfuria
a¢$d i~ used, d~alkylation bQgin~ at a temper~ture of about
50C, and become~ rapid ~t about 80C, with aopious
evolution o~ the relevant alkene.
In a preferred ombod~m-nt o~ the proan~ of the
invention the dealkylation i~ carried out in the pre-enc- of
acetic acid a~ a ~olvent. This h~ b~en ~hown to impart
economie~ to the proc-ss, ~nae the target aompound
crystallizes directly from the Acetic acid in th- cour~ of
the dealkylat~on reaction.
In another pre~erred e~bodi~ent, which can bo co~bined
with any of the ombodimentoe de~aribed above, the proce~ of
the invention compri~e~ pr~paring th- alkyl d~rivative in a
~anner Xnown E~E_~ and thereafter dealkylating it
according to the invention a~ ~ot out above, without
previous i~olation, in a one-pot procedure. More
~pecifically, in the preferred embodiment, the N-alkyl-N-
phosphonomethylglycine or e~t-r u~-d i~ synthe~izQd f~om
ethyl chloroa¢etate and an appropriat~ alkylamin~, ~ollowed
;- by Q~te~ hydroly3~s, ~ollow~d by pho~phonomethylation of the
re~ulting N-alkyl glycine or ester, and that ent~re proce~s
~ performed without i~olation or purifi~ation of any
intermediat-. ~n the pre~erred e~bodiment
N-t-butyl-N-phosphonomethylglyaine may be pr~par~d by
pho~phonomethyla~ion of N-~-butylglycin~ whiah in turn may
be th- produc~ o~ the coupling o~ ~-butylnmin~ ana ~thyl
chloroac~tat~, ~ollow~d by e~ter hydroly~
Wh~n thQ mo#t pr~erred glycin~ d~rivativ-, namQly N-~-
bUtyl-N-pho~phono~ethylgly~in~ dealkylated in accordance
with th~ invQntion~ eB~ccially wh~n ac~tic acid ~ used as a
~olven~ utylene iB e~olved. If, how~v~r, th~r- l- a

6270
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~igni~icant amount of water pre~ent ln the reac~ion ~ixturo,
then in addition t~ ~Q-butylon~, ~-butanol i~ obtained a~ a
by-product, As will occur to tho~- ~killed in the art,
corre~ponding produats are ob~a~ned when o~her glycine
derivat~ve are u~ed
As previou~ly ~tat-d, thQ dealkylation of N-~-butyl-N-
phosphonometh~lglyoine proceed~ moro rapidly in ~cetic ncid
than it does ~n water; however, it is the b¦5~L~ 1l of N-
phosphonomethyl~lya~ne from tho AC~tiC nc~d m-diu~, with
minimal processing, that provid-~ ~ m~or technical
advantage in the proc~ss of the invention
A final product of ~urity exceeding 90% by w-ight is
obtainablQ by the proces~ of th~ invention in a routinely
reproduaible ~anner Typical reaction times ar~ 2 to 4
hours With cooling and filtration over g0% yield~ ar-
obtainable
The following example~ s~rve ~urth~r to illu~trate tha
invention
Exa~pl~
N-t-Butyl-N-phosphonomethylglycino (100 g, 96~ ~ure,
0 426 mol) wa~ m~xed with ac~tic ~¢id (500 ml) and 97~
sul~uria acid (4 0 g, 0 04 mol) On h-ating the mixture to
50C in a round-bottomed fla~k fitted wi~h a Liebig
condense~ Q-butylen- was det~t~d down~tream o~ th~
conden~er At 80C large guant~ti~s o~ ~Q-butylene were
ev~lved and tho rate o~ evolution of this off-ga~ in~rea~ed
with te~perature. After 3 hour~ ~t 100C th~re w~ no N-~-
butyl-N-phosphonomethylglycine detectable by ~PLC in the
reac~ion v~sel, and l~rge quantitie~ of ary~talline N-
pho~phon~methylyglycine wer~ pre~nt. Cooling to ambi~nt,
f~ ring ~n~ drying g~e N-pho~phono~ethylglycine (6g 0 g,
g5~ pure, 91 2~ yield) Analy~i~ o~ th- mother l~quor

~00~i270
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showed a further 3.7 g of N-pho~phonomethylglycin-, giving a
total c~emical yield for this dQal~ylation of 96.3~.
E~amplç I~
~-t-Butyl-N-pho~phonom~thylylyc~no (100 ~, 96~ ~ur~,
0.42 mol) was ~ixed with acetic ac~d ~500 m~s) ~nd ~-toluen~
~ulfoni¢ acid (14.6 g, 0.085 mol). HQating at 100C for 4
hour.~ co~pleted the react~on and tha che~ical yield of the
dealkylation was 94~.
~e~
Ethyl chloroacetate ~1~2.5 g 1.0 mole) wa~ reAotQd with
exces~ t-butylamin~ in trichloromethane and the ethyl
gly~inate ~eparated ~rom the t-butyla~in~ hydrochlorid~.
The ethyl ~lycinate was hydrolyz~d with hyd~o~hloric acid
and the N-~-butyl-N-pho~phono~e~hylqlycine (167.6 g a~
deter~ined by HP~C) was reacted with suluric ac~d (3.8 mle,
0.07 mol) a~ ambient temperatur- and the ~ixture wa~ th~n
; heated at 100C for 4 hour~. Cooling to 20C, filto~ng and
drying gave N-pho~phonomethylyglycine (118.5 g, 95.8
purity, gO.3% y~eld). The overall yi~ld ~rom ~thyl
chloroacetate was ~7.2%.
The invention i~ not li~ited by or to tho de~ail~ ~f ~ -
the speci.~ic embadiments describ~d, ~any o which c~n
undergo wide variation without departing ~or fro~ the ~ope
of the invention.

Representative Drawing