A novel procedure for the synthesis of ammonium glufosinate

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Organic Preparations and Procedures
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Organic Synthesis
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A Novel Procedure for the Synthesis of
Ammonium Glufosinate
Yi-Ming Lia, Xiao-Hua Dub, Qin-hua Zhoua & Shu-Da Chena
a College of Biological, Chemical Sciences, and Engineering, Jiaxing
University, No. 118, Jiahang Road, Jiaxing City, Zhejiang, 314001, P.
R. China
b Zhejiang University of Technology, Hangzhou, Zhejiang, 310014, P.
R. China
Published online: 19 Nov 2014.
To cite this article: Yi-Ming Li, Xiao-Hua Du, Qin-hua Zhou & Shu-Da Chen (2014) A Novel Procedure
for the Synthesis of Ammonium Glufosinate, Organic Preparations and Procedures International: The
New Journal for Organic Synthesis, 46:6, 565-568, DOI: 10.1080/00304948.2014.963461
To link to this article: http://dx.doi.org/10.1080/00304948.2014.963461
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Organic Preparations and Procedures International, 46:565–568, 2014
Copyright © Taylor & Francis Group, LLC
ISSN: 0030-4948 print / 1945-5453 online
DOI: 10.1080/00304948.2014.963461
OPPI BRIEF
A Novel Procedure for the Synthesis of Ammonium
Glufosinate
Yi-Ming Li,1 Xiao-Hua Du,2 Qin-hua Zhou,1
and Shu-Da Chen1
1College of Biological, Chemical Sciences, and Engineering, Jiaxing University,
No. 118, Jiahang Road, Jiaxing City, Zhejiang, 314001, P. R. China
2Zhejiang University of Technology, Hangzhou, Zhejiang, 310014, P. R. China
Ammonium glufosinate [5, ammonium 2-amino-4-(hydroxymethylphosphinyl)butanoate]
is a highly effective and non-selective herbicide widely used in genetically modified
and glufosinate-tolerant crops.1 Various processes for preparation of ammonium glufos-
inate have disadvantages, such as the use of high pressure2 and expensive and unstable
materials,3–5 lengthy operational steps and low yields.6–8 Ammonium glufosinate is gener-
ally obtained (Scheme 1)9 from the addition of diethyl methylphosphonite (1) with acrolein,
followed by a Strecker synthesis and subsequent hydrolysis of the aminonitrile, and ad-
dition of aqueous ammonia. However, this method requires the use of and also generates
large excess amounts of ammonium chloride (about 4–5 equivalents to 5), which cannot be
easily separated from the product and may cause environmental pollution.
O
NH4Cl, NaCN
25%NH3 H2O
Adduct
CH3P CH2CH2CHCN
OH NH2
+
CH3P(OC2H5)2
CH2=CHCHO
O
.
1
6
O
NH3 H2O
HCl aq
CH3P CH2CH2CHCOOH
ONH4 NH2
CH3P CH2CH2CHCOOH
OH NH2
5
4
Scheme 1
Received July 3, 2014.
Address correspondence to Yi-Ming Li, College of Biological, Chemical Sciences, and Engi-
neering, Jiaxing University, No. 118, Jiahang Road, Jiaxing City, Zhejiang, 314001, P. R. China.
E-mail: lym4241986@163.com
565

566
Li et al.
O
OC2H5
CH3P CH2CH2CH
OC2H5 OCOCH3
C2H5OH, 25-3
(CH3CO)2O
CH3P(OC2H5)2
CH2=CHCHO
O
+
1
2
O
O
NaCN, 60
(NH4)2CO3
Ba(OH)2
H2SO4
NH
CH3P CH2CH2CHCOOH
OH NH2
CH3P CH2CH2
HN
OC2H5
O
3
4
O
ꢀ
NH3 H2O
CH3P CH2CH2CHCOOH
ONH4
NH2
5
Scheme 2
The present report describes a novel procedure for the preparation of 5. 1-Acetoxy-
1-ethoxy -3-(ethoxymethylphosphinyl)propane (2) was obtained in 95% yield from
the reaction of 1 with acrolein in the presence of ethanol and acetic anhydride at
25◦C to 30◦C (Scheme 2). The treatment of 2 with sodium cyanide and ammonium
carbonate yielded 5-[2-(ethoxymethylphosphinyl)ethyl]hydantoin (3) in 78% yield. Fi-
nally, 3 was hydrolyzed with aqueous barium hydroxide for 30 h to afford 2-amino-4-
(hydroxymethylphosphinyl)butanoic acid (4) which was converted to 5 in 96% yield by
addition of aqueous ammonia. The fact that the mp. of 5 is above 200◦ (and thus not a
reliable criterion) and close to that reported for the acid 4,10 prompted us to isolate and
characterize phosphinothricin (4). It was then converted to 5 to confirm its identity as
ammonium glufosinate (5) (see Exterimental Section].
The proposed synthesis of 5 via a hydantoin intermediate (3) avoids the use and
generation of ammonium chloride in contrast with the previous method (Scheme 1), reduces
waste generation and simplifies the purification of the product.
Experimental Section
1H Nuclear magnetic resonance (NMR) spectra were obtained using a Bruker AC-500
instrument. Spectra from gas chromatography–mass spectrometry (GC–MS) were ac-
quired using Agilent 6890 N GC system equipped with a 5973 N mass-selective detector.
Atmospheric-pressure chemical ionization–mass spectrometry (ACPI–MS) spectra were
determined using a LCQ Deca XP Plus ion-trap mass spectrometer equipped with an ACPI
source and controlled by Xcalibur software. The purity of the products was determined us-
ing a Hitachi L-7000 high-performance liquid chromatograph (HPLC) with SAX Nucleosil
100-5 SB column (250 mm × 4.6 mm) and Thermo Scientific gas chromatograph with TR
SMS SQC column (15 m × 0.25 mm). The melting points were obtained on a Buchi Melting
Point B-545 and are uncorrected. Spectra from high-resolution mass spectrometry (HRMS)

Novel Procedure for the Synthesis of Ammonium Glufosinate
567
were obtained using Agilent 6210 TOF LC–MS. Elemental analyses were performed using
an EA-1110 instrument.
Preparation of 1-Acetoxy-1-ethoxy-3-(ethoxymethylphosphinyl)propane (2). A
solution of freshly distilled acrolein (5.60 g, 0.10 mol) and acetic anhydride (10.20 g,
0.10 mol) at room temperature was added dropwise to a solution of 1 (13.60 g, 0.10 mol) in
ethanol (4.60 g, 0.10 mol) under N2 atmosphere at 25◦C to 30◦C for 20 min. The mixture
was then stirred for 2 h at 30◦C and evaporated under vacuum to remove volatiles to leave
2 (25.50 g, 95% yield, 94.1% purity) as a colorless liquid that was further purified by
high-vacuum distillation (boiling point, 93–95◦C/23 Pa).
1H NMR (500 MHz, DMSO-d6): δ1.12 (3H, t, J = 7.0 Hz), 1.22 (3H, t, J = 7.0 Hz),
1.40 (3H, d, J = 13.8 Hz), 1.71–1.79 (4H, m), 2.05 (3H, s), 3.47–3.53 (1H, m), 3.61–3.67
(1H, m), 3.90–3.95 (2H, m), and 5.78–5.80 (1H, m). 31P NMR (500 MHz, DMSO-d6):
δ 53.39; MS (m/e): 209, 193, 165, 136, 119, 79, 57, and 43. HRMS (ESI): Calcd for
C10H21NaO5P: 275.1024, Found: 275.1029.
Anal. Calcd for C10H21O5P: C, 47.62; H, 8.39. Found: C, 47.56; H, 8.43.
Preparation of 5-[2-(Ethoxymethylphosphinyl)ethyl]hydantoin (3). A mixture of 2
(26.80 g, 0.10 mol, 94.1% purity), ethanol (80 ml), and sodium cyanide (4.90 g, 0.10 mol)
into a 250 ml four-necked flask was stirred at room temperature for 20 min. Then an
aqueous solution of ammonium carbonate (19.20 g, 0.20 mol) in water (80 ml) was added
and the reaction mixture was heated at 60◦C for 4 h and then at 75◦C for 0.5 h. Ethanol and
water were removed under reduced pressure. The residue was dissolved in ethyl acetate
(150 ml), and insoluble materials were removed by filtration. The filtrate was evaporated
under vacuum to afford 3 (20.50 g, 78% yield, 89.2% purity) as a yellow oil. It was purified
by chromatography on a silica column (ethyl acetate:ethanol 4/1) to yield a colorless oil.
1H NMR (500 MHz, DMSO-d6): δ 1.20–1.23 (3H, m), 1.41 (3H, d, J = 13.8 Hz),
1.65–1.90 (4H, m), 3.90–3.96 (2H, m), 4.08 (1H, t, J = 5.6 Hz), 7.99 (1H, s), 10.68 (1H,
s). 31P NMR (500 MHz, DMSO-d6): δ 53.73. MS (m/e): 235, 218, 207, 190, 164, 136,
127, 119, and 99. HRMS (ACPI) Calcd for C8H15N2O4P [M + H]+: 235.0842, Found:
235.0839.
Anal. Calcd for C8H15N2O4P: C, 41.03; H, 6.46. Found: C, 41.09; H, 6.41.
Preparation of Ammonium Glufosinate (5) and Isolation of Phosphinothricine (4).
A mixture of 3 (26.20 g, 0.10 mol, 89.2% purity), barium hydroxide octahydrate (31.60 g,
0.10 mol), and water (200 ml) into a 500 ml three-necked flask was heated to reflux for 30 h
with stirring. After cooling to 60◦C, the mixture was neutralized to 30% H2SO4 (32.7 g,
0.10 mol) and the precipitate was filtered and washed with water (50 ml × 2). The pH of the
combined filtrate and washes was adjusted to ∼9 by addition of 25% aqueous ammonia. The
solution was then evaporated to dryness under vacuum and the residue was recrystallized
from methanol to give 5 as a white solid [19.30 g, 96% yield, 98.5% purity (HPLC)], mp.
214–215◦C, lit.11 215◦C. 1H NMR (500 MHz, D2O): δ 1.26 (3H, d, J = 13.5 Hz), 1.54–1.70
(2H, m), 2.00–2.14 (2H, m), 3.79 (1H, t, J = 6.0 Hz). 31P NMR (500 MHz, D2O): δ 41.99.
Anal. Calcd for C5H15N2O4P: C, 30.31; H, 7.63; N, 14.14. Found: C, 30.24; H, 7.66;
N, 14.21.
For the isolation and identification of phosphinothicine (4), a small portion of the
filtrate and washes obtained after the addition of 30% sulfuric acid as described above,
was evaporated to dryness under vacuum and the solid residue was recrystallized from

568
Li et al.
1:1 EtOAc-ethanol to give 4 as a white solid, mp. 209–212◦C, lit.10 211–213◦C, 1H NMR
(500 MHz, D2O): δ 1.55 (3H, J = 14 Hz, 1.89–2.04 (2H, m, 2.19–2.28 (2H, m), 4.18 (1H,
t, J = 6.0 Hz). It was dissolved in methanol and 25% aqueous ammonia was added to
adjust the pH to 9. The resulting solution was evaporated to dryness under vacuum to afford
ammonium glufosinate (5), identical with the sample prepared directly above.
Acknowledgment
This work was supported by Zhejiang Key Course of Chemical Engineering and Technology
of Zhejiang University of Technology.
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