Metamifop on Kilogram Scale

Full text of DOI:10.1080/00304948.2020.1796157

Organic Preparations and Procedures International
The New Journal for Organic Synthesis
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Metamifop on Kilogram Scale
Wenxin Chen , Yongjun Mao , Xiaolei Zhu , Yurong Zhang & Lingzi Wan
To cite this article: Wenxin Chen , Yongjun Mao , Xiaolei Zhu , Yurong Zhang & Lingzi Wan
(2020): Metamifop on Kilogram Scale, Organic Preparations and Procedures International, DOI:
10.1080/00304948.2020.1796157
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Published online: 05 Sep 2020.
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ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL
https://doi.org/10.1080/00304948.2020.1796157
OPPI BRIEF
Metamifop on Kilogram Scale
Wenxin Chen , Yongjun Mao, Xiaolei Zhu , Yurong Zhang , and
Lingzi Wan
College of Chemistry and Chemical Engineering, Shanghai University of Engineering Science,
Shanghai, China
ARTICLE HISTORY Received 28 January 2020; Accepted 2 June 2020
Metamifop (1, Figure 1), developed by the Korea Research Institute of Chemical
Technology, is a post-emergent aryloxyphenoxypropionic herbicide, and only the R-iso-
mer has bioactivity. It is mainly used in the cultivation of rice and works against annual
perennial grass weeds.1 Metamifop is unusual among herbicides in being safe for rice. It
can effectively control major weeds in paddy fields, including valerian, ginseng, crab-
grass and goose grass.2 It had been introduced to China by FMC Corporation with great
success in 2010.3–5
The reported synthetic route of racemic metamifop ((þ/–)-1) was developed6 as
shown in Scheme 1. 2-Amino-5-chlorophenol (2) and potassium ethyl xanthogenate
were chosen as the starting materials, cyclized and chlorinated to give 2,6-dichlo-ben-
zo[d]oxazole (4) in 46% over-all yield. 2-Bromo-N-(2-fluorophenyl)-N-methylpropana-
mide (6) was prepared through the dehydrative coupling of 2-fluoro-N-methylaniline
(5) and 2-bromopropionic acid in 87% yield. Intermediate 7 was obtained by etherifica-
tion of 1,4-hydroquinone with 6 using K2CO3 and TBAB, in 79% yield. Compound
(þ/–)-1 was obtained in 78% yield by coupling compound 4 and 7 under similar etheri-
fication conditions. Notwithstanding the value of this preparation, the starting materials
are relatively expensive, and the over-all yield is not as high as desirable, making this
route less harmonious with industrial goals.
In order to develop a practical preparation of metamifop (1, R-isomer), we designed
a new convergent synthetic route, as shown in Scheme 2. The method is simple to com-
plete and has a high yield. It is suitable for large-scale industrial production. Two key
intermediates were prepared respectively, including compounds 4 and 14.
We prepared compound 4 on an 800 g scale in high purity, based on the reported
synthesis route after optimization.7,8 Commercially available materials 2-aminophenol
(8) and urea were heated in o-dichlorobenzene at 180 ꢀC for 2 h to give benzo[d]xazol-
2-(3H)-one (9) in 98% yield. Compound 9 was then treated with SO2Cl2 in chloroben-
zene at 45 ꢁ 50 ꢀC for 3 h to give 6-chlorobenzo[d]oxazol-2(3H)-one (10) in 86%
isolated yield. After chlorination of 10 by PCl5, 4 was obtained in 84% yield.
The (R)-propanoic acid compound 14 was prepared by a new method after optimiza-
tion.9 (S)-2-Chloropropanoic acid (11) and 1,4-hydroquinone (12) were used as the
starting materials through an SN2 type substitution reaction to give compound 13 in
CONTACT Yongjun Mao
yongjun.mao@hotmail.com
College of Chemistry and Chemical Engineering, Shanghai
University of Engineering Science, 333 Longteng Road, Shanghai 201620, China.
ß 2020 Taylor & Francis Group, LLC

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W. CHEN ET AL.
Figure 1. The chemical structure of metamifop.
Scheme 1. Reported synthetic route.
Scheme 2. New convergent route.
75% isolated yield.10 Compound 13 was reacted with 4 to give the intermediate 14 in
85% yield. At the last step, compound 14 was reacted with pivaloyl chloride to give the
propanoic pivalic anhydride intermediate 15, which was not isolated. Intermediate 15
reacted with 2-fluoro-N-methylaniline (5) directly to give the final product 1 in 85%
yield after purification, with 98% purity.
In summary, a new, practical, kilogram scale preparation of metamifop (1) has been
developed. Firstly, 2,6-dichlorobenzoxazole 4 was prepared on 800 g scale in 71% yield
over 3 steps, with 98.5% purity (HPLC). Secondly, (R)-2-(4-hydroxyphenoxy)-propanoic
acid 13 was prepared from 11 and 12 in 75% yield and 99% purity. Thirdly, compound
14 was obtained by reaction of compounds 4 and 13 in 85% yield and 99.2% purity.

ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL
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Finally, 1 was prepared from compound 14 under mild conditions in 85% yield over
two steps. The prepared compound 1, and compound (þ/-)-1 were compared with the
commercial metamifop through chiral HPLC and optical rotation tests (see
Experimental section and supplementary material).
Experimental section
All commercially available materials and solvents were used as received without any fur-
ther purification. 1H NMR and 13C NMR spectra were recorded on a Bruker
UltraShield 400 Plus spectrometer using TMS as an internal standard. Mass spectra
were obtained on a Finnigan MAT-95/711 spectrometer. Melting points were measured
on a Shenguang WRS-1B melting point apparatus and are uncorrected. The optical
rotation data were measured on a Jingruo SGWZZ-3 automatic polarimeter and are
uncorrected. The HPLC data were acquired using a Waters 2487 UV/Visible Detector
and Waters 515 Binary HPLC Pump. The purity of the compounds was based on the
areas of HPLC peaks (UV).
Benzo[d]oxazol-2(3H)-one (9)
A mixture of 2-aminophenol (8) (660 g, 6.04 mol), urea (400 g, 6.64 mol) in o-dichloro-
benzene (3 L) was heated and stirred at 180 ꢀC for 2 h to give a light-brown solution.
After cooling to room temperature, the resulting solid was collected by suction filtra-
tion, washed with o-dichlorobenzene (300 mL ꢂ 2), and dried at 80 ꢀC for 4 h to obtain
1
9 (799 g, 98%), as an off-white solid, mp 136.7 ꢁ 138.8 ꢀC (lit mp7 137 ꢁ 139 ꢀC). H
NMR (400 MHz, DMSO-d6) d 14.01 (brs, 1H), 7.72 (d, J ¼ 1.8 Hz, 1H), 7.33 (dd, J ¼ 8.4,
1.9 Hz, 1H), 7.31–7.19 (m, 2H). 13C NMR (100 MHz, DMSO-d6) d 154.85, 143.82,
130.82, 124.18, 122.25, 110.20, 109.91.
HPLC Conditions — Column: Acclaim C18 (150 mm ꢂ 2.1 mm ꢂ 5 mm); Detection:
254 nm; Flow rate: 0.8 mL/min; Temperature: 45 ꢀC; Injection load: 1 lL; Solvent:
methanol; Run time: 30 min; Mobile phase: methanol/water ¼ 80/20, tR: 4.33 min, pur-
ity: 99.55%.
Anal. Calcd for C7H5NO2: C, 66.22; H, 3.73; N, 10.37. Found: C, 66.03; H, 3.77;
N, 10.46.
6-Chlorobenzo[d]oxazol-2(3H)-one (10)
To a stirred suspension of 9 (740 g, 5.5 mol) in chlorobenzene (8 L) was slowly added
sulfonyl chloride (814 g, 6.03 mol) over 2 h at room temperature. The reaction solution
was stirred at 45–50 ꢀC for another 2 h. fSafety Notes: The reaction was accompanied
by gas generation (HCl), which should be safely vented and quenched by aqueous
NaOH solution. Workers must be thoroughly trained in the safe use of SO2Cl2 before
doing this operation.g Then the reaction solution was cooled to room temperature, the
solid was collected by suction filtration, washed with chlorobenzene (300 mL ꢂ 2), and
dried at 60 ꢀC for 5 h to obtain the product 10 (798.6 g, 86%), as a light yellow solid,
1
mp 194.2 ꢁ 196.0 ꢀC (lit mp11 196 ꢀC). H NMR (400 MHz, DMSO-d6) d 11.87 (s, 1H),

4
W. CHEN ET AL.
7.55 (d, J ¼ 1.8 Hz, 1H), 7.26 (dd, J ¼ 8.4, 1.8 Hz, 1H), 7.16 (d, J ¼ 8.4 Hz, 1H). 13C
NMR (100 MHz, DMSO-d6) d 154.61, 144.27, 129.94, 126.24, 124.11, 111.17, 110.67.
HPLC Conditions — Column: Acclaim C18 (150 mm ꢂ 2.1 mm ꢂ 5 mm); Detection:
254 nm; Flow rate: 0.8 mL/min; Temperature: 45 ꢀC; Injection load: 1 lL; Solvent:
methanol; Run time: 30 min; Mobile phase: methanol/water ¼ 70/30, tR: 5.03 min, pur-
ity: 97.46%.
Anal. Calcd for C7H4ClNO2: C, 49.58; H, 2.38; N, 8.26. Found: C, 49.70; H, 2.42;
N, 8.17.
2,6-Dichlorobenzo[d]oxazole (4)
Phosphorus pentachloride (Caution! Good ventilation and personal protective gear are
required.) (2.4 kg, 11.5 mol) and polyphosphoric acid (240 g, 0.71 mol) were added to
toluene (8 kg), the resulting solution was stirred and heated at 80 ꢀC. Then 10 (800 g,
4.72 mol) was added and the suspension was stirred at 80 ꢀC for 2.5 h to give a homoge-
neous reaction solution. The reaction mixture was cooled to 45–50 ꢀC and then added
to 10 kg warm water (30–40 ꢀC) over 1 h and stirred for another 1 h. Then the organic
layer was separated, washed by water (5 L ꢂ 1), and concentrated in vacuo to afford a
brown solid. The crude product was further purified through vacuum distillation
(120–130 ꢀC/18 mmHg), the fraction solidified at room temperature to give 4 (887 g,
84%) as a white solid, mp 55.8 ꢁ 57.0 ꢀC. 1H NMR (400 MHz, CDCl3) d 7.59 (d,
J ¼ 8.5 Hz, 1H), 7.53 (d, J ¼ 1.8 Hz, 1H), 7.35 (dd, J ¼ 8.5, 1.8 Hz, 1H). 13C NMR
(100 MHz, CDCl3) d 151.54, 151.41, 139.91, 131.36, 125.81, 120.23, 111.05.
HPLC Conditions — Column: Acclaim C18 (150 mm ꢂ 2.1 mm ꢂ 5 mm); Detection:
254 nm; Flow rate: 0.8 mL/min; Temperature: 45 ꢀC; Injection load: 1 lL; Solvent:
methanol; Run time: 30 min; Mobile phase: methanol/water ¼ 95/5, tR: 10.18 min, pur-
ity: 98.54%.
Anal. Calcd for C7H3Cl2NO: C, 44.72; H, 1.61; N, 7.45. Found: C, 44.89; H, 1.62;
N, 7.39.
(R)-2-(4-Hydroxyphenoxy)propanoic acid (13)
Flask A: 40% NaOH aqueous solution (840 g, 8.4 mol) was added over 2 h to the solu-
tion of (S)-2-chloropropanoic acid (11) (870 g, 8.0 mol) in 1 kg water at 5–20 ꢀC.
Flask B: 40% NaOH aqueous solution (2.1 kg, 21.0 mol) was added over 1 h to the
suspension of 1,4-hydroquinone (12) (1.0 kg, 10.0 mol) in 2 kg water at room tempera-
ture. Then the reaction solution was heated to 45–50 ꢀC.
The solution in Flask A was added to Flask B over 2 h at 45–50 ꢀC and stirred at
55–60 ꢀC for another 1 h. After cooling to 0–5 ꢀC, concentrated hydrochloric acid (ꢃ2 L,
24 mol) was added slowly to achieve pH 4 and the mixture was stirred at 0 ꢀC for 1 h.
The resulting solid was removed by filtration. Then concentrated hydrochloric acid
(200 mL, 2.4 mol) was added into the filtrate to achieve pH 1 and the mixture was
stirred at 0 ꢀC for 1 h, the resulting solid was collected by filtration, washed with water
(300 mL), and dried at 45 ꢀC for 6 h to give 13 (1.09 kg, 75%) as a white solid, mp
1
143.7 ꢁ 144.8 ꢀC (lit mp12 144 ꢀC). H NMR (400 MHz, DMSO-d6) d 12.88 (brs, 1H),

ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL
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8.97 (brs, 1H), 6.69 (q, J ¼ 9.2 Hz, 4H), 4.64 (q, J ¼ 6.7 Hz, 1H), 1.46 (d, J ¼ 6.8 Hz, 3H).
13C NMR (100 MHz, DMSO-d6) d 173.93, 152.07, 150.73, 116.56, 116.15, 72.86, 18.83.
Optical rotation [a]20 ¼ þ0.396 (c ¼ 0.1, MeOH).
D
HPLC Conditions — Column: Acclaim C18 (150 mm ꢂ 2.1 mm ꢂ 5 mm); Detection:
254 nm; Flow rate: 0.8 mL/min; Temperature: 45 ꢀC; Injection load: 2 lL; Solvent:
methanol; Run time: 30 min; Mobile phase: methanol/water ¼ 90/10, tR: 2.04 min, pur-
ity: 99.06%.
Anal. Calcd for C9H10O4: C, 59.34; H, 5.53. Found: C, 59.13; H, 5.55.
(R)-2-[4-((6-Chlorobenzo[d]oxazol-2-yl)oxy)phenoxy]propionic acid (14)
Flask A: Compound 4 (681 g, 3.62 mol), tetrabutylammonium bromide (TBAB) (35 g,
0.11 mol) and triethylamine (TEA) (11 g, 0.11 mol) were added to 1.8 L toluene respect-
ively, the resulting solution was stirred at 50 ꢀC.
Flask B: Compound 13 (550 g, 3.0 mol) was slowly added to a solution of NaOH
(435 g, 10.8 mol) in water (1.8 kg) at 5–20 ꢀC.
The solution in Flask B was added to Flask A over 1 h at 45–50 ꢀC and stirred at
55–60 ꢀC for 4 h to give a brown solution. The mixture was cooled to room temperature
and the toluene solution was separated. Then concentrated hydrochloric acid was added
to the aqueous solution to achieve pH 3 and stirred for 1 h until a voluminous solid
was formed. The brown solid was collected by suction filtration, washed with 95%
EtOH (100 mL ꢂ 2), dried at 45 ꢀC for 6 h to give 14 (851 g, 85%) as a light yellow
1
solid. H NMR (400 MHz, DMSO-d6) d 13.12 (brs, 1H), 7.86 (d, J ¼ 1.8 Hz, 1H), 7.52
(d, J ¼ 12.0 Hz, 1H), 7.43 (d, J ¼ 12.0 Hz, 2H), 7.35 (dd, J ¼ 8.4, 2.0 Hz, 1H), 6.99 (d,
J ¼ 12.0 Hz, 2H), 4.88 (q, J ¼ 6.8 Hz, 1H), 1.53 (d, J ¼ 6.8 Hz, 3H). 13C NMR (100 MHz,
DMSO-d6) d 173.42, 163.03, 156.16, 148.65, 146.62, 139.92, 127.94, 125.33, 121.95,
119.63, 116.23, 111.26, 72.51, 18.71.
HPLC Conditions — Column: Acclaim C18 (150 mm ꢂ 2.1 mm ꢂ 5 mm); Detection:
254 nm; Flow rate: 0.8 mL/min; Temperature: 45 ꢀC; Injection load: 1 lL; Solvent:
methanol; Run time: 30 min; Mobile phase: methanol/water ¼ 90/10, tR: 8.38 min, pur-
ity: 99.29%.
Anal. Calcd for C16H12ClNO5: C, 57.59; H, 3.62; N, 4.20. Found: C, 57.74; H, 3.60;
N, 4.22.
Metamifop (1)
TEA (327.5 g, 3.24 mol) was added into a mixture of compound 14 (900 g, 2.70 mol) in
toluene (3.0 L) at room temperature. The mixture was stirred for 1 h at 25 ꢀC, and then
cooled to 0–5 ꢀC. Pivaloyl chloride (341.4 g, 2.83 mol) was added dropwise to the reac-
tion solution over 1 h and stirred at 0–5 ꢀC for another 1 h to give a white suspension.
2-Fluoro-N-methylaniline (5) (354.4 g, 2.83 mol) was added slowly into the reaction
mixture over 1 h at 0–5 ꢀC, and the resulting suspension was stirred at room tempera-
ture 1 h until the solid was dissolved. Then it was stirred at 20–30 ꢀC for 12 h. The reac-
tion mixture was filtered to remove the salt (triethylamine hydrochloride), then washed
with toluene (200 mL ꢂ 2). The combined filtrate was washed with water (2 L ꢂ 1) and

6
W. CHEN ET AL.
saturated NaHCO3 aqueous solution (2 L ꢂ 1) respectively. The organic layer was con-
centrated in vacuo to obtain a yellow solid (1.2 kg). n-Heptane (5 L) was added into the
solid and the resulted mixture was stirred at room temperature for 5 h. The resulting
solid was collected by suction filtration, dried at 45 ꢀC for 6 h to give 1 (1010 g, 85%) as
1
a white solid. H NMR (400 MHz, CDCl3) d 7.46–7.38 (m, 3H), 7.28–7.19 (m, 5H),
6.84–6.79 (m, 2H), 4.70–4.65 (m, 1H), 3.30 (d, J ¼ 2.8 Hz, 3H, 3H), 1.48 (dd, J ¼ 18.4,
12.4 Hz, 3H). 13C NMR (400 MHz, DMSO-d6) d 170.20, 162.90, 155.52, 148.63, 146.69,
139.92, 130.60, 127.99, 125.32, 121.84 (d, J ¼ 19.5 Hz), 119.61, 117.39 (d, J ¼ 19.5 Hz),
116.65, 116.07, 111.21, 71.44, 37.20, 18.03, 17.73. MS (ESI): m/z ¼ 441.1 [M þ H]þ,
881.1 [2M þ H]þ. Optical rotation [a]20 ¼ –2.496 (c ¼ 0.1, MeOH). > 99% ee.
D
HPLC Conditions — Column: Acclaim C18 (150 mm ꢂ 2.1 mm ꢂ 5 mm); Detection:
254 nm; Flow rate: 0.8 mL/min; Temperature: 45 ꢀC; Injection load: 1 lL; Solvent:
methanol; Run time: 30 min; Mobile phase: methanol/water ¼ 80/20, tR: 14.95 min, pur-
ity: 99.95%.
Chiral HPLC Conditions — Column: (Daicel CHIRALPAK IC); Detection: 254 nm;
Flow rate: 1.0 mL/min; Temperature: 45 ꢀC; Injection load: 2 lL; Solvent: methanol; Run
time: 45 min; Mobile phase: n-hexane/i-PrOH ¼ 90/10, tR: 20.49 min (compound 1),
26.39 min (compound –1), purity: 95.42%, > 99% ee.
Anal. Calcd for C23H18ClFN2O4: C, 62.66; H, 4.12; N, 6.35. Found: C, 62.79; H, 4.10;
N, 6.38.
Acknowledgments
This work was supported by the Shenyang Photosensitive Chemical Research Institute and by
Zhejiang East Asia Pharmaceutical Co., Ltd.
ORCID
Wenxin Chen
Xiaolei Zhu
Yurong Zhang
Lingzi Wan
http://orcid.org/0000-0001-7319-7527
http://orcid.org/0000-0002-0121-5068
http://orcid.org/0000-0001-8972-7166
http://orcid.org/0000-0002-3752-5797
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