Note: Descriptions are shown in the official language in which they were submitted.
~L22~S2~
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METHOD FOR PREPAR~TION OF N-PHOSPHOWOMETHYLGLYCINE
Field of the Inverlt'i'on
This invention i5 a new process for
preparing N-phosphonomethylglycine.
Background of the Invention
N-Phosphonomethylglycine and certain salts are
particularly effective as post-emergence herbicides. The
commercial herbicide is sold as a formulation containing
the isopropylamine salt of N-phosphonomethylglycine.
N-Phosphonomethylglycine can be made by a
number of methods. One such method, as described in
U.S. Patent 3,160,632 is to react N-phosphonomethylglycine
(glycinemethylenephosphonic acid~ with mercuric chloride
in water at reflux temperature, and subsequently separating
the reaction products. Other methods are phosphonomethylation
of glycine and the reaction of ethyl glycinate with
formaldehyde and diethylphosphite. The latter method is
described in U.S. Patent No. 3,799,758~ In addition,
there is a series of patents relating to the preparation
of N-phosphonomethylglycine, including U.S. Patent Nos.
3,868,407, 4,197,254 and 4,199,354.
Close prior art is U.S. Patent 3,923,877, which
teaches the reaction of 1,3,5-tricyanomethylhexahydro-
1,3,5-triazine with excess disubstituted phosphite to form
(RO)2P(O~CH2NHCH2CN (R is hydrocarbyl or substituted
hydrocarbyl) which is hydrolyzed to yield N-phosphonomethyl-
glycine.
Because of the commercial importance of N-
phosphonomethylglycine and certain salts as herbicides,
improved methods of preparing these compounds are
valuable.
; ' ~
~ . .
.
5;~4
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~rief Descriptio'n of the `I'n~enti'on
This invention relates to a process for
preparing N-phosphonomethylglycine which comprises:
(l) reacting 1,3,5-tricyanomethylhexahydro-
1,3,5-triazine with an acyl halide, preferably acyl
chloride to form the N-cyanomethy:L-N-halomethyl amide of
the acyl halide;
(2) reacting the amide with a phosphite to
form N-acylaminomethyl-N-cyanomethyl phosphonate; and
(3) hydrolyzing this phosphonate to yield
N-(phosphonomethyl)-glycine.
More specifically in accordance with the
invention there is provided a compound of the formula
~0~ ~ CH2CN
R-C-N
\ CH2X
wherein R is Cl -C4 alkyl or ethoxy and X is chlorine,
bromine or iodine.
Detailed Desc'r'iption o~ the Invention
The process of ~his invention may be
illustrated by the following reaction scheme:
O O CH CN
~ ll ~I / 2
a~ 2N-CH2CN + R-C-X -~ R-C-N
~N CH2X
CH2CN
wherein R is an aliphatic or aromatic group as defined
hereinafter, preferably Cl-C4 alkyl, most preferably
methyl or ethyl and X is chlorine, bromine, or iodine,
preferably chlorine
O CH2CN OR O /CH2CN
b) R-C-N + Rlo-p-oR3 ~ R-C-N Rl + R3X
CH2X CH2P
o\OR2
wherein R and X are defined as above and Rl and R2 are both
aromatic groups or both aliphatic group, preferably Rl
~7~
_ 3 _ ~2~%52~
and R2 are Cl-C6 alkyl, more preferably Cl-C4 alkyl, and
R3 is an aliphatic group, preferably R is Cl-C6 alkyl,
more preferably Cl-C4 alkyl or R is an alkali metal (m),
preferably sodium or potassium.
O
O /CH2CN H or OH / 2
c) R-C-N OR ~ H2O~ -~ HN / OH
O \ OR CH2P\
wherein R, Rl and R2 are as defined ahove and H+ is a
strong acid such as hydrochloric, hydrobromic, hydriodic,
nitric, sulfuric, phosphonic or chloroacetic acid.
Preferably H is hydrochloric or hydrobromic acid and OH
is a strong base such as sodium hydroxide or potassium
hydroxide, pre~erably in an aqueous, aqueous-alcoholic or
alcoholic solùtion. Preferably, the hydroylsis is run in
the presence of a strong acid.
In the above reaction scheme the group R is not
directly involved in reaction step (a~ between 1,3,5-
tricyanomethylhexahydro-1,3,5-triazine and the acyl
chloride. Groups R, Rl or R2 are not directly involved
in reaction step (b) between the N-cyanomethyl-N-chloromethyl
amide reaction product of step (a) and the phosphite.
Groups R, Rl and R are removed in reaction step (c) when
the phosphonate reaction product of reaction step ~b) is
subjected to hydrolysis. Therefore, the nature of groups
R, Rl and R2 is not critical, although groups which would
interfere with reaction steps (a) and (b) are to be
avoided.
The group "Cl-C4 alkyl" encompasses methyl,
ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,
and tert-butyl. The group "C1-C6 alkyl'l encompasses the
same radicals as Cl-C4 alkyl plus the 6 pentyls and the
16 hexyls.
The term "aliphatic group'l is used in a broad
~2~S2~
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sense to cover a large class of organic groups
characterized by bein~ derived from (1) an acylic (open-
chain structurel of the paraffin, olefin and acetylene
hydrocarbon series and their derivatives or (2) alicyclic
compounds. The aliphatic group can have from 1 to 10
carbon atoms.
The term "aromatic group" is used in a broad
sense to distinguish from the aliphatic ~roup and includes
a group derived from (l~ compounds having ~ to ~0 carbon
atoms and characterized by the presence of at least one
benzene ring, includin~ monocyclic, bicyclic and polycyclic
hydrocarbons and their derivatives and (2) heterocyclic
compounds having 5 to 19 carbon atoms which are similar in
structure and are characterized by having an unsaturated
ring structure containing at least one atom other than
carbon such as nitrogen, sulfur and oxygen and derivatives
of these heterocyclic compounds.
Reaction step (a~ preferably is run at a
temperature between about 0 to about 150C, more preferably
between about 40 to about 110C and most preferably
between about 75 to abcut 85C. This reaction step can
be run at atmospheric, sub-atmospheric or super-atmospheric
pressure, preferably at atmospheric pressure. Preferably
the reaction is run in a solvent for the acyl halide, such
as ethylene dichloxide, methylene chloride, tetrahydrofuran
or toluene.
Three moles of the acyl halide are needed to
react with one mole o the 1,3,5-tricyanomethylhexahydro-
1,3,5-triazine. An excess of acyl halide can be used to
insure complete reaction with the triazine. A lar~e excess
of the acyl halide can serve as a solvent in this reaction
step. The solvent or any excess acyl halide can be removed
to isolate the N-cyanomethyl-N-chloromethyl amide of the
acyl halide in high yields~ However, this amide quickly
degrades ther~ally and by hydrolysis and should be kept
~L2~
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in an iner-t atmosphere if isolatecl.
Most preferably no excess acyl halide is used
and the solvent used in reaction step ~a) is also used as
the solvent in reaction step (bl. Thus~ no solvent need
be removed after completion of step (a) and it is used in
reaction step (b~.
In reaction step (b~, most preferably about
equal mole amounts of N-cyanomethyl-N-halomethyl amide of
the acyl halide and the phosphite are reac-ted. Less
preferably, up to 2 mole excess can be used and least
preferably up to a 10 mole excess can be used.
The reaction is exothermic and can be run at
a temperature between about 0 to about 150C, more
preferably between about 40 to about 100C; most
preferably between 75 to about 85C.
No solvent is needed for the reaction, however,
any inert solvent can be used, preferably the solvent
having a boiling point between about 40 to about 100C.
Examples of such solvents are ethylene chloride, methylene
chloride, tetrahydrofuran and toluene. The use of an
inert solvent helps dissipate the heat of reaction. Most
preferably the solvent is the one used in reaction step
~a~. Any solvent used in this reaction step will be removed
after completion of reaction step (c), so preferably it is
one that can be removed by evaporation.
Alkali metal phosphites having the formula
oR2
R10--1--oR3
wherein Rl and R are as defined and R3 is an alkali metal
are reacted with N-cyanomethyl-N-halomethyl amide under
an inert atmosphere such as nitrogen. The alkali metal
phosphite can be prepared by reacting an alkali metal
alkoxide, alkali metal hydride or alkali metal with an
equal mole amount of a disubstituted phosphite of the
~ormula
- 6 - ~2~2~
oR2
RlO-I_H
o
wherein Rl and R2 are as de~ined. This reaction is run
in an inert atmosphere such as nitrogen.
Alkali metal phosphites of the formula
oR2
R10--P--OM
where Rl, R2 and M are as defined can, because of
tautomerism, have the following additional structural
formula
O O
~ ~'P/
\ oR2
wherein Rl and R2 are as defined and M is an alkali
metal.
In reaction step (c~, a mole of the phosphonate
reaction product from reaction step (b) is hydroly~ed
With 5 moles of water. The hydrolysis is run in the
presence of a strong acid or base as defined above.
Preferably the hydrolysis is acid-catalyzed, preferably
with an inorganic acid, and most preferably with
hydrochloric or hydrobromic acid. The hydrolysis yieIds
the desired N-phosphonome-thylqlycine. Preferably at
least 2 moles of the acid are used. More preferably, a
; lar~e excess over the 2 mole amount is used. The preferred
hydrochloric or hydrobromic acid can be used in concentrated
or aqueous form.
This last reaction step is run at a temperature
between about 0 to about 200C, preferably between about
50 to about 125C and most preferably between about 100
to about 125C.
Atmospheric, sub-atmospheric or super
~ atmospheric pressure can be used. Preferably atmospheric
; 35 pressure is used during the hydrolysis.
,,
~22ZS2~
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The solid N-phosphonomethylglycine can be
recovered by conventional techniques ln reaction step
(c). ~olatile liquid products such as alcohols (methanol)
chlorides ~methyl chlorideJ, acids ~acetic acid), water,
and excess acid can ~e removed by standard stripping
techniques. The desired N-phosphonomethylglycine is
recovered in high purity by disso:Lving it in water,
adjusting the pH of the solution to between l and 2,
allowing it to crystallize from solution and removing it
by filtration.
The process of this invention can be better
understood ~y reference to the following specific
examples.
''EX'~MPLE 1
Preparati-on -o~ N-cya'n'om'ethyl--N-ch-loromethylac-etamide
O CH2CN
CH -C-N
CH2Cl
Seventeen grams (gJ (0.0835 mole) of 1,3,5-
tricyanomethylhexahydro-1,3,5-triazine were slurried in a
round-bottom flask with 150 milliliters (ml) of 1,2-
dichloroethane. Forty ml C0.563 mole) acetyl chloride
were added all at once and the reaction mixture was
refluxed 3 hours, then stripped under reduced pressure to
yield 26.9 g (79.85%J N-cyanomethyl-N-chloromethylacetamide.
Structure was confirmed by usual analytical methods
Cinfrared, proton nuclear magnetic resonance, and mass
spectroscopy).
'EX'AMPLE 2
Preparati~on'o~' O,O-dimethyl-N-cyanomethyl-N-acetylaminomethyl
-ph~sphonate
O ~CH2CN
CH2P-~OCH3)2
O
:
~L2;2Z~i2~
The amide compound prepared in Example 1
(26.9 g, 0.2 mole~ was diluted with 75ml o~
dichloromethane. Trimethyl phosphite (25,5 g, 0.206
molel was added and the mixture was stirred at room
temperature overnight, refluxed 0.5 hour and stripped
under reduced pressure to yield 34.9 g (79.32%) of the
desired product. The structure was confirmed by infrared
~irl, proton nuclear magnetic resonance (nmr~ and mass
spectroscopy (msl.
'EX'AMPLE 3
Preparati'on of N-phosphonomethylglycine
o
/CH2-C-OEI
H-N
1 5
The phosphonate reaction product of Example 2
~12.5 g, 0.09 molel was combined with 100 ml (1.21 mole)
of concentrated hydrochloric acid, refluxed 3 hours, and
stripped under reduced pressure. After dissolving the
residue in 30 ml water, the pH was adjusted to 10 with 50%
sodium hydroxide, the mixture was stripped under reduced
pressure. The product was again dissolved in 30 ml water
and the pH was adjusted to 1 with concentrated hydrochloric
acid. The mixture was refrigerated overnight and the next
morning 5.4 g ~98~3% purity by weight) of the desired
product were isolated by filtration (35.49% yield).
Structure was confirmed by ir, nmr, and liquid chromatograph
(lc~ .
EXA~PLE 4
-Preparat'ion of N-phosphonomethylglycine
Fifty milliliters of 1,2-dichlorethane were
heated to reflux in~a 50 ml round-bottom flask. Acetyl
chloride (505ml, 0.077 mole~ and 3~4 g (0.0167 mole) o~
1,3,5-tricyanomethylhexahydro-1,3,5-triazine were added
.
~22'~2~
simultaneously over 10 minutes while maintaining an excess
of the acetyl halide in the reaction vessel. The mixture
was refluxed for 0.5 hours after addition was complete
then stripped under reduced pressure.
Five milliliters of to:Luene and ~.6 ml (0.05
mole~ of trimethyl phosphite were added ko the residue
and this mixture was refluxed 15 minutes, stirred at room
temperature for 2 hours and stripped under reduced pressure.
Thirty milliliters l0 n 36 mole) of concentrated
hydrochloric acid were added to the residue and the mixture
refluxed for 3 hours and stripped under reduced pressure
to yield 11.3 ~ solids containing 47.9% by weight of the
desired N-phosphonomethylglycine as determined by lc.
Structure was confirmed by C13 and proton nmr. Overall
yield of ~-phosphonomethylglycine was 64%.
EXAMPLE 5
Preparation of o~o-dimethyl-N-cyanoethyl-N-carboethoxyaminometh
-phosphonate
` O ~CH2CN
C H50-C-N
CH2~-(OCH3)2
Ethylchloroformate (8 ml. 0.083 mole) dissolved
in 8 ml methylene chloride and 3.4 g 1,3,5-tricyanomethylhexahydro-
1,3,5-triazine (0.0167 mole~ were combined in a 50 ml round-
bottom flask equipped with a stirrer and reflux condenser.
The mixture was refluxed for 1 hour and stripped under
reduced pressure. The residue was dissolved in 5 ml
methylene chloride. Trimethylphosphite (5 ml, 0.042 mole)
dissolved in 15 ml methylene chloride was added. This
reaction mixture was refluxed for 1 hour. To the cooled
; mixture 50 ml of water was added. The mixture was
extracted three tim~es with 50 ml of methylene chloride.
The organic portions were combined and dried with magnesium
sulfate and stripped under vacuum to yield 6.9 g of the
: ,r
: ` ,', .
. ~
2~ii2~L
~ 10 --
desired product which is a 50 percent yield. The
structure was confirmed by ir, nmr and ms.
'EXAMPLE 6
Prepar'ation of N-phosph'onom-e'thylgly'c'ine
The phosphonate reaction product of Example 5
~4.9 g, 0.02 mole) was combined with 20 ml (0.24 mole) of
concentrated hydrochloric acid, re:Eluxed 3 hours, and
stripped under reduced pressure. After dissolving the
residue in 30 ml water, the pH was adjusted to 10 with
lQ 50% sodium hydroxide, and the mixture was stripped under
reduced pressure. The product was again dissolved in
a~out 5 ml water. Structure was confirmed ~y nmr, and
liquid chromatograph (lc).
'EXAMPLE 7
Preparation of'O,O-di'e't-hy'l-N-'cyanome'thyl-N-acetylaminomethyl
phosph-onate
R /CH2CN
C 3
CH2ll_(OC2H5)2
O
Five and six-tenths grams (5.6 g, 0.05 m) of
potassium-t-butoxi'de were slurried in a round bottom flask
with 25 ml of tetrahydrofuran (dried over molecular
sieves~ and the slurry was cooled in a water bath. Next
6.44 ml (0.05 m) of diethyl phosphite were added dropwise
to the slurry over 5 minutes, under nitrogen. This mixture
was cooled in an ice bath and 7.33 g (0.05 m) of N-cyanomethyl-
N-chloromethylacetamide diluted with 50 ml of tetrahydrofuran
were added dropwise over 15 minutes. The mixture was allowed
to warm to room temperature and stirred ~or 3 hours. The
mixture was filtered through dicalite and the tetrahydrofuran
stripped under reduced pressure to yield 9.0 g of the desired
product. Structure was confirmed by ir, nmr, ms, C-13 nmr~
~22Z~;2~
- EXAMPLE 8
-
Preparation of Phosphon-omethyLglycine
101
CH -C-OH
H-N \
CH2~-(OH12
Five and four-tenths grams ~5.4 g, 0.022 m) of
the compound prepared in Example 7 were combined with
30 ml (0.363 m~ of concentrated HCl, refluxed 3 hours and
then stripped under reduced pressure to yield 10.8 g of
the desired product, a brown semi-solid. Structure was
confirmed by ir, nmr, C-13 nmr, and lc techniques.
EXAMPLF 9
Preparation of O,O-dimethyl--~-cyanome*hyl-N-acetylaminomethy
pho-sp onate
1l /CH2CN
CH3C N \
CH211 (OCH3~2
One and forty-four-one hundredths grams
(1.44 g, 0.06 m~ of sodium hydride were slurried with 25 ml
of tetrahydxofuran Cdried over molecular sieves) under dry
nitrogen. Six and four-tenths ml (0.05 m) of
dimethylphosphite were added dropwise over 15 minutes. When
all hydrogen gas had evolved the mixture was cooled in an
ice bath and 7.33 g (0.05 m) of N-cyanomethyl-N-
chloromethylacetamide, diluted with 50 ml dry tetrahydrofuran,
~ were added dropwise over 15 minutes. The mixture was
; 30 stirred overni~ht, filtered and stripped at reduced pressure
to yield 11.5 g of the desired product, a yellow oil.
Structure was confirmed by ir, nmr, ms, C-13 nmr
and ~lpc techniques~
The compound of Example 9 can be hydrolyzed to
phosphonomethylglycine accordin~ to the teaching of Example
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