New Manufacturing Route to Picoxystrobin

Article abstract of DOI:10.1021/acs.oprd.5b00371

A new and efficient manufacturing technology is disclosed in the present work for the preparation of picoxystrobin in which all of the intermediates can be used directly in the next step of the process without purification.

Full text of DOI:10.1021/acs.oprd.5b00371

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Full Paper
A New Manufacturing Route to Picoxystrobin
Yu Chen, Huan Lu, Hui Dai, Wansheng Yu, and Xianhua Pan
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.5b00371 • Publication Date (Web): 26 Jan 2016
Downloaded from http://pubs.acs.org on January 27, 2016
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A New Manufacturing Route to Picoxystrobin
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Yu Chen,1),2) Huan Lu,2 )Hui Dai,2) Wansheng Yu,2) Xianhua Pan1),2)
*
1) School of Perfume and Aroma Technology, Shanghai Institute of
Technology, 100 Haiquan Rd., Shanghai, 201418, P.R. China.
2) Shanghai Research Institute of Fragrance and Flavor Industry, 480
Nanning Rd., Shanghai, 200232, P.R. China.
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ABSTRACT: A new and efficient manufacturing technology is disclosed in present work for the
preparation of picoxystrobin, in which all the intermediates can be used directly for the next step
without purification.
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Key Words: picoxystrobin, strobilurin fungicides, new route, synthesis.
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INTRODUCTION
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Picoxystrobin (1, Figure 1) belongs to the group of strobilurin compounds, which delivers a
breadth of spectrum and level of activity on cereals that is superior to other current commercial
strobilurin fungicides.1 It has moderate uptake into host leaves through the xylem and exhibits
translaminar movement. Picoxystrobin (1) was first developed by Syngenta but is now
commercialized by Dupont with the trade name Aproach.2 Several synthetic methods of
picoxystrobin (1) have been disclosed by Zeneca (the predecessor of Syngenta).3–6 However,
these methods suffer from several drawbacks such as use of toxic or highly volatile reagent:
Me2SO4, CCl4 and HCO2Me (Bp: 32 oC), separation by chromatography for several steps as well
as low total yield., Herein we describe a new manufacturing route to picoxystrobin (1) to expand
its application.
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Figure 1. Picoxystrobin (1).
RESULTS AND DISCUSSION
A novel process is shown in Scheme 1, making it possible to avoid drawbacks of the previous
methods. This process started from 2, and none of the intermediates were needed for separation.
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Scheme 1. The whole process to the synthesis of 1
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The original plan was to transform compound 2 to compound 16 directly. In order to shorten the
reaction steps and avoid the highly volatile or toxic reagent (HCO2Me, Me2SO4), we firstly chose
widely used CH(OMe)3 as the reagent. However, to our surprising, CH(OMe)3/Ac2O, which were
efficient reagents for 2(3H)-benzofuranone (Figure 2) in the synthesis of azoxystrobin,7 proved
very poor for 2. As can be seen from Table 1 and Scheme 2, 16 was hardly produced in the
presence of anhydrides such as acetic anhydride or isobutyric anhydride, two effective anhydrides
for azoxystrobin7 (Table 1, entries 1–5).
Figure 2. 2(3H)-benzofuranone.
Scheme 2. The reaction of 2 with CH(OMe)3 in the presence of anhydrides
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Table 1. The reaction of 2 with CH(OMe)3 in the presence of anhydridesa
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Entry
CH(OMe)3
2.0 equiv
8.0 equiv
15.0 equiv
Anhydrides
Yieldb
<5%c
<5%c
<5%c
1
2
3
acetic anhydride (8.0 equiv)
acetic anhydride (2.0 equiv)
acetic anhydride (5.0 equiv)
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isobutyric anhydride (5.0
equiv)
4
15.0 equiv
<5%c
c, d
5
5.0 equiv
acetic anhydride (5.0 equiv)
-
aAll reactions were carried out both at room temperature and at refluxed temperature equipped
with Dean-Stark apparatus for 48 h. Isolated yield. c2 was recovered in more than 95% yield.
b
dThe reaction was carried out in various solvent such as toluene, DCM, CH3CN, THF.
This great difference between 2 and 2(3H)-benzofuranone, which has one less carbon than 2,
attracted our attention and compelled us to explore it. At the beginning, the reaction, which was
catalyzed by Lewis acid, was evaluated, and good results were expected. BF3OEt2 was first
chosen to test the reaction in various solvents. From Table 2, we can see that toluene, THF and
DMF were unable to facilitate the reaction, and compound 2 was recovered largely (Table 2,
entries 1–3). Compound 168 was the main product when DCM was used as the solvent in spite of
the lower yield (Table 2, entry 4). CH3CN seemed to be useful for the formation of compound
159 (Table 2, entry 5). No good results were obtained with these solvents, so the next reaction
was conducted in CH(OMe)3 alone, which acted as both reagent and solvent. The yield of 16 was
found similar to that in DCM (Table 2, entry 6). After simple screening for the amount, 10 equiv
of CH(OMe)3 proved to be the best for compound 16, and more compound 15 was formed in the
presence of more CH(OMe)3 (Table 2, entries 7–8). The yield was not improved even though the
reaction time was prolonged to 48 h at room temperature (Table 2, entry 9). Surprisingly,
orthoformate 3 was produced largely when the reaction was heated (Table 2, entries 10–11).
Nevertheless, the yield dropped at much higher temperature, such as 80oC, probably due to the
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instability of CH(OMe)3 in the presence of Lewis acid catalysts at that temperature (Table 2,
entry 12). Luckily, we found that the reaction proceeded quite well when MeOH was used as the
solvent. The maximum of 90% yield was reached even at lower temperature (40 oC) without any
starting material 2 (Table 2, entries 13–14).
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Scheme 3. The reaction of 2 with CH(OMe)3 catalyzed by BF3OEt2
a
Table 2. The reaction of 2 with CH(OMe)3 catalyzed by BF3OEt2
CH(OMe)3
(equiv)
Entry
Solvent
Temp (°C)
Yield (%)b, c
1
2
5.0
Toluene
25
25
25
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25
25
25
25
25d
40
60
80
40
15: 0%, 16: <5%, 3: 0%
15: 0%, 16: <5%, 3: 0%
NR
5.0
5.0
THF
3
DMF
4
5.0
DCM
15: trace, 16: 18%, 3: 0%
15: 13%, 16: 8%, 3: 0%
15: trace, 16: 19%, 3: 0%
15: 4%, 16: 32%, 3: 0%
15: 8%, 16: 30%, 3: 0%
15: 6%, 16: 33%, 3: 0%
15: trace, 16: 23%, 3: 41%
15: 0%, 16: 24%, 3: 58%
15: 0%, 16: 8%, 3: 44%
15: 0%, 16: 0%, 3: 90%
5
5.0
CH3CN
6
5.0
-
7
10.0
15.0
10.0
10.0
10.0
10.0
10.0
-
8
-
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-
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-
-
-
MeOH
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10.0
MeOH
30
15: 0%, 16: 10%, 3: 75%
aAll reactions were carried out with 2 (0.01 mol) catalyzed by 0.5 eq BF3OEt2 for 24 h. 10 mL
solvent was used if necessary. bIsolated yield. cNo other evident compounds except for the listed
were found. dThe reaction time was 48 h.
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Next, the amount of BF3OEt2 was screened, and the results are listed in Scheme 4 and Table 3.
Decreasing the amount of BF3OEt2 resulted in a lower yield of 3, for example only 48% of 3 was
obtained when there was only 0.1 equiv of BF3OEt2 (Table 3, entry 1). The main reason for this
low yield was the low transformation of 2 (20–40% was recovered) catalyzed by a small amount
of BF3OEt2. It is unnecessary to use more BF3OEt2, such as 1.0 equiv, which gave similar result
to 0.5 equiv (Table 3, entry 3). As expected, nothing happened when no catalyst was added
(Table 3, entry 4). Other common Lewis acids, such as TiCl4 and AlCl3, produced only 16 in less
than 20% yield without 3.
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Scheme 4. Comparison of the amount of BF3OEt2 for the formation of 3
Table 3. Comparison of the amount of BF3OEt2 for the formation of 3a
Entry
Lewis acid
BF3OEt2
BF3OEt2
BF3OEt2
-
Equiv
0.1
0.2
1.0
-
Yield of 3b
48%c
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4
71%c
90%
d
-
o
aAll reactions were carried out with 10 equiv of CH(OMe)3 in MeOH at 40 C for 24 h.
c
d
bIsolated yield. 2 was recovered in 20–40 yields. No reaction happened and 2 was recovered
completely.
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The intermediate was considered likely to be compound 16 or 15. It was heated with CH(OMe)3
and BF3OEt2 independently. It was clear that 16 or 15 was easy to be transformed to 3, with
CH(OMe)3 even when 0.1 equiv of BF3OEt2 was used (Scheme 5).
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Scheme 5. The formation of 3 through 16 or 15
Several proton acids were also examined (Table 4). TsOH exhibited the best activity among these
proton acids. For others such as TFA and HOAc, 16 was obtained only in less than 25% without
3 even when the reaction was allowed to run for 72 h at reflux. For this reason, after the
screening, BF3OEt2 was concluded to be the best catalyst for this reaction.
Table 4. The reaction of 2 with CH(OMe)3 catalyzed by proton acida
Entry
1
Proton acid
Temp (°C)
Time (h)
24
Yieldb
40c or
refluxedd
40c or
TFA(0.5 to 3.0 equiv)
3: 0%, 16<10%e
2
3
HOAc(0.5 to 3.0 equiv)
TsOH (0.5 equiv)
36–72
3: 0%, 16: 5–25%e
3: 65%, 16: 0%e
refluxedd
40c
24
aAll reactions were carried out in 10 equiv of CH(OMe)3.bIsolated yield. cMeOH was added
dMeOH was not added. e2 was mainly recovered.
With 3 in hand, we then tried to synthesize 4 through ring-opening reaction. It was found that 3
could be easily converted back to 16 in the presence of excessive BF3OEt2 (3.0 equiv) after
distillation of CH(OMe)3 and MeOH. Compound 4 was then formed smoothly when the reaction
was carried out step-wisely. MeOH was mixed after the reaction of 16 with SOCl2 was finished
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to produce 4 in 88% from 3. This compound was used for the next step without purification. It is
very interesting that Z-form of compound 16 was formed along with 4 when SOCl2 was added to
16 in MeOH. Unlike 16, (Z)-16 remained unchanged, once it was formed (Scheme 6). The
structure of (Z)-16 was identified by NMR and MS(EI), and compared to that of 16.8, 10 The
possible course for the formation of (Z)-16 was postulated as described in Scheme 7.
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Scheme 6. Synthesis of 4
Scheme 7. Postulated course for the formation of (Z)-16
The final step was the coupling reaction of 4 with 5 to construct the ether bond. The base was
found to be the key factor. Different bases were screened for this reaction, and the results are
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listed in Table 5. As shown, no product was observed by organic base such as Et3N, DIPEA or
pyridine in different solvents (Table 5, entries 1–3). On the contrary, inorganic base showed good
activity, either Na2CO3, K2CO3 or NaOH, KOH gave desired product 1 in different yields at
elevated temperature (Table 5, entries 4–7). Finally, the reaction temperature and the solvent
were evaluated after K2CO3 was selected as the base. It could be seen that the yield was
negatively influenced by both higher and lower temperature (Table 5, entries 8–9). Besides, other
solvents, such as THF and toluene, were proved to be inferior to DMF (Table 5, entries 10–11).
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Scheme 8. Synthesis of 1
Table 5. Condition screening for synthesis of 1a
Entry
Base
Et3N
Solvent
DMF or THF or tol
DMF
Yieldb
NR
1
2
3
4
5
6
7
8
9
DIPEA
Pyridine
Na2CO3
K2CO3
NaOH
KOH
NR
DMF
NR
DMF
80%
DMF
95%
DMF
79%
DMF
80%
K2CO3
K2CO3
DMF
15–86%c
88%d
DMF
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K2CO3
K2CO3
Tol
NR
THF
54%
aAll reactions were carried out with 4 (0.05 mol), 5 (1.3 equiv) and base (2.0 equiv) in solvent
o
b
c
o
d
at 70 C for 24 h. Isolated yield. The reaction was carried out at 30–60 C. The reaction was
carried out at 80 oC.
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CONCLUSION
A new and efficient manufacturing technology was developed for the preparation of
picoxystrobin (1). Isochromanone (2) was used as the stating material which was transformed to
3 catalyzed by acid catalyst such as BF3OEt2. 1 was finally obtained after ring-opening and
coupling reaction. In this process, routinely used reagents were employed and all the
intermediates could be used directly for the next step without purification.
EXPERIMENTAL SECTION
General. Melting points were recorded on an RY-1 melting point apparatus and were
uncorrected. 1H (400 MHz) and 13C (100 MHz) NMR spectra were recorded on a Bruker Avance
400 spectrometer in CDCl3 using tetramethylsilane (TMS) as internal standards. J values were
given in hertz. Mass spectra were recorded on a Finnigan MAT-95/711 spectrometer. HPLC
analysis was performed by a standard method on a Diamonsil C18 column, 250 mm × 4.6 mm (5
m);  = 210 nm; mobile phase: A (CH3CN) and B (H2O), 70:30 v/v. The HPLC analysis data is
reported in area % and is not adjusted to weight %.
(E)-3, 3-dimethoxy-4-(methoxymethylene)isochroman (3). To a stirred solution of 2 (592.5 g,
4.0 mol) and CH(OMe)3 (4.24 kg, 40.0 mol) in MeOH (4 L) was added BF3OEt2 (284.0 g, 2.0
mol) at 25 oC. Then the mixture was stirred for 24 h at 40 oC. After concentration of CH(OMe)3
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and MeOH, crude 3 (P: 90%) was used directly for next step. A sample of purified 3 as pale-
yellow oil was analyzed as follows: 1H NMR(CDCl3, 400 MHz):  = 3.30 (s, 3H), 3.68 (s, 3H),
3.79 (s, 3H), 4.34 (s, 2H), 7.12 (dd, J = 0.8, 7.2 Hz, 1H), 7.25−7.32 (m, 2H), 7.46 (t, J = 7.2 Hz,
1H), 7.55 (s, 1H); 13C NMR(CDCl3, 100 MHz):  = 51.4, 58.0, 61.7, 72.2, 110.3, 127.1, 127.5,
127.8, 130.8, 131.5, 137.4, 159.8, 167.9; ESI-MS (m/z) 259 [M + Na]+.
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(E)-methyl 2-(2-(chloromethyl)phenyl)-3-methoxyacrylate (4). The mixture of crude 3 from
last step in BF3OEt2 (1.53 kg, 10.8 mol) was heated for 2 h at 50 oC. After distillation of BF3OEt2,
the residue was refluxed in SOCl2 (2.14 kg, 18.0 mol) for 24 h. After SOCl2 was eliminated, the
liquid mixture was added dropwise to MeOH (5.76 kg, 180.0 mol) at 25 oC and stirred for 2 h at
that temperature. After MeOH was evaporated, sat NaHCO3 aq (5 L) and DCM (2 L) was added.
The separated water layer was extracted with DCM (2 L). The combined organic layer was
washed with water (2 L), dried with anhydrous Na2SO4, filtered and concentrated to afford 4
(812.0 g) as yellow oil. Crude 4 was used directly for next step. A sample of purified 4 as off-
white solid was analyzed as follows: Mp: 94~95 oC. 1H NMR(CDCl3, 400 MHz):  = 3.70 (s,
3H), 3.79 (s, 3H), 4.50 (s, 2H), 7.14−7.17 (m, 1H), 7.32−7.34 (m, 2H), 7.49−7.51 (m, 1H), 7.62
(s, 1H); 13C NMR(CDCl3, 100 MHz):  = 44.5, 51.7, 62.0, 109.7, 128.32, 128.34, 129.6, 131.3,
132.4, 136.4, 160.5, 167.8; ESI-MS (m/z) 263, 265 [M + Na]+.
Picoxystrobin (1). The mixture of crude 4 from last step, 5 (672.0 g, 4.12 mol) and K2CO3
(875.0 g, 6.34 mol) in DMF (5 L) was stirred at 70 oC for 24 h. EtOAc (10 L), water (6 L) and
brine (6 L) was subsequently added to the mixture. The aqueous layer was extracted with EtOAc
(3 × 3 L) after separation. The combined organic layer was concentrated after washed with brine
(10 L) and dried with anhydrous Na2SO4 to give an oil, which was dissolved in MeOH (600 mL)
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at 60 oC. An off- white solid precipitated when the mixture was cooled to 5 oC, then standing at -
15 oC. This solid was filtered, washed with hexane (800 mL), and dried at 40 oC under vacuum to
afford 1 (1 kg, 68% from 2) as a white solid with 99% purity by HPLC (retention time: 9.1 min).
Mp: 74–75 oC (lit. mp 73–74).3a 1H NMR(CDCl3, 400 MHz):  = 3.57 (s, 3H), 3.68 (s, 3H), 5.25
(s, 2H), 6.78 (d, J = 8.4 Hz, 1H), 7.08−7.14 (m, 2H), 7.23−7.25 (m, 2H), 7.45−7.48 (m, 2H), 7.56
(t, J = 8.0 Hz, 1H); 13C NMR(CDCl3, 100 MHz):  = 51.5, 61.8, 66.3, 110.2, 113.3 (d, J = 2.8
Hz), 114.7, 121.4 (d, J = 272.7 Hz), 127.8, 127.9, 128.8, 131.1, 132.3, 135.7, 139.4, 145.3 (q, J =
35.3 Hz), 159.9, 163.6, 168.0; ESI-MS (m/z) 390 [M + Na]+. The data conforms to that described
in known publication.3a
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(Z)-4-(methoxymethylene)isochroman-3-one Z-(16). To a stirred solution of 3 (5.0 g, 21.2
mmol) in MeOH (6.8 g, 212.0 mmol) was added SOCl2 (10.1 g, 84.8 mmol) at 25 oC. Then the
mixture was stirred for 24 h at 40 oC. After concentration, water (50 mL) was added and
extracted with DCM (2×50 mL). The combined organic layer was washed with brine (100 mL),
dried with anhydrous Na2SO4, filtered and concentrated to afford yellow oil. Z-(16) was purified
via silica gel column chromatography using EtOAc/hexane (1:10) as eluent to yield 0.99 g (25%)
as light-yellow oil. 1H NMR (CDCl3, 400 MHz):  = 3.81 (s, 3H), 5.12 (s, 2H), 7.01 (d, J = 7.2
Hz, 1H), 7.21 (dt, J = 1.2, 7.2 Hz, 1H), 7.31 (dt, J = 1.2, 7.6 Hz, 1H), 7.71 (s, 1H), 8.10 (d, J =
7.6 Hz, 1H); 13C NMR (CDCl3, 100 MHz):  = 51.2, 69.3, 109.2, 123.6, 123.9, 126.6, 127.2,
127.5, 128.6, 157.5, 166.0; EI-MS m/z: 190 (M+, 85.21), 135 (100), 118 (44.69), 90 (35.15), 77
(50.65).
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ASSOCIATED CONTENT
Supporting Information.
1H and 13C NMR spectra.
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AUTHOR INFORMATION
Corresponding Author
*E-mail: panxh@sit.edu.cn. Tel: +86(21)54961786. Fax: +86(21) 54961786.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We thank for the cooperation from the colleagues of analytic department.
REFERENCES
1. Understanding the Strobilurin Fungicides. Bartett, D. W.; Clough, J. M.; Godfrey, C. R. A.;
Godwin, J. R.; Hall, A. A.; Heaney, S. P.; Maund, S. J. Pestic. Outlook. 2001, 12, 143.
2.
http://www.dupont.com/content/dam/assets/industries/agriculture/assets/cp_PSD-95_K-
27702-1.pdf
3. (a) Process for the Preparation of 2-(6-Substituted pyrid-2-yloxymethyl)phenylacetate.
Worthington, P. A.; Munns, G. R.; Jones, R. V. H.; Standen, M. C. H.; Ritchie, D. J.; Forrester,
J. W. O. patent 9701538, 1997; CAN 126:171489. (b) One-step Process for Preparing Methyl 2-
(halomethyl)phenylacetate from 3-Isochromanone. Ritchie, D. J.; McCann, H. S. R.; Standen, M.
C. H.; Jones, R. V. H. U. S. patent 6048998, 1998; CAN 128:75194.
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4. Process for the Preparation of 2-(Pyrid-2-yloxymethyl)phenylacetates as Pesticide
Intermediates. Williams, A. G.; Munns, G. R.; Worthington, P. A. W. O. patent 9712864, 1997;
CAN 126:317320.
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5. (a) Stilbene Derivatives, and Fungicides which Contain These Compounds. Schirmer, U.;
Karbach, S.; Pommer, E. H.; Ammermann, E.; Steglich, W.; Schwalge, B. A. M.; Anke, T. U. S.
patent 4723034, 1987; CAN 106:101890. (b) Fungicides. Clough, J. M.; Godfrey, C. R. A.; De
Fraine, P. J.; Hutchings, M. G.; Anthony, V. M. E. P. patent 278595, 1988; CAN 109:210725.
6. Chemical Intermediates Useful in Agriculture. Brown, S. M.; Bowden, M. C. W. O. patent
9525729, 1995; CAN 124:86816.
7. Process for the Preparation of Pyrimidine Compounds. Jones, J. D.; Deboos, G. A.; Wilkinson,
P.; Cox, B. G.; Fielden, J. M. W. O. patent 9208703, 1992; CAN 117:131219.
8. A sample of 16 as an off-white solid purified by column chromatography was analyzed as
follows: Mp: 89.5–90.5 oC. 1H NMR(CDCl3, 400 MHz):  = 4.03 (s, 3H), 5.24 (s, 2H), 7.11 (d, J
= 7.2 Hz, 1H), 7.20 (t, J = 7.2 Hz, 1H), 7.31 (t, J =7.2 Hz, 1H), 7.73 (s, 1H), 7.89 (d, J = 8.0 Hz,
1H); 13C NMR(CDCl3, 100 MHz):  = 63.1, 69.1, 103.3, 123.9, 126.2, 126.6, 127.9, 128.90,
128.93, 160.8, 168.4; EI-MS m/z: 190 (M+, 100), 135 (34.18), 118 (70.83), 90 (46.04), 77
(31.15).
9. A sample of 15 as a yellow solid purified by column chromatography was analyzed as follows:
o
1
Mp: 105–106 C. H NMR(CDCl3, 400 MHz):  = 5.30 (s, 2H), 7.04 (d, J = 7.6 Hz, 1H), 7.15
(dt, J = 1.6, 7.6 Hz, 1H), 7.22-7.25 (m, 1H), 7.25-7.29 (m, 1H), 7.86 (d, J = 7.6 Hz, 1H); 12.38
(d, J = 12.8 Hz, 1H). The data conforms to that described in known publication.6
10. EI-MS was specially run to obverse the fragment peaks for the comparison of (Z)-16 with 16.
For details, please see experimental section.
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