An improved process for the synthesis of DMTMM-based coupling reagents

Article abstract of DOI:10.1016/j.tetlet.2008.12.047

A simple, robust and high-yielding process for the preparation of 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium tetrafluoroborate (DMTMM BF₄) and hexafluorophosphate (DMTMM PF₆) has been developed, which avoids the use of expensive or unusual reagents.

Full text of DOI:10.1016/j.tetlet.2008.12.047

Tetrahedron Letters 50 (2009) 946–948
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Tetrahedron Letters
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An improved process for the synthesis of DMTMM-based coupling reagents
Steven A. Raw *
AstraZeneca, Process Research and Development, Silk Court Business Park, Charter Way, Macclesfield, Cheshire, SK11 8AA, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple, robust and high-yielding process for the preparation of 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-
Received 10 November 2008
Revised 1 December 2008
Accepted 9 December 2008
Available online 16 December 2008
methylmorpholinium tetrafluoroborate (DMTMM BF
developed, which avoids the use of expensive or unusual reagents.
4 6
) and hexafluorophosphate (DMTMM PF ) has been
Ó 2008 Elsevier Ltd. All rights reserved.
In recent years, 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-meth-
ylmorpholinium chloride 1a (DMTMM Cl)1 has come to promi-
nence as an effective coupling agent, finding applications in
To avoid this degradation, Kami n´ ski et al. have developed
7
DMTMM BF
4
1b as an alternative to 1a. The non-nucleophilic
À
BF4 counterion does not take part in the degradation process
2
2b,3
4
5
and organic solutions of 1b are stable for several days at least.6
amidation, esterification,
glycosidation and phosphonylation
methodology. However, the utility of DMTMM Cl 1a as a coupling
agent is compromised, especially at large scale, by its instability in
organic solution as it undergoes self-immolative degradation,
yielding 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-morpholine 2 and
chloromethane (Scheme 1). In chloroform at ambient temperature,
4
DMTMM BF 1b has been shown to be equally effective in peptide
7
a
couplings as 1a and can be considered as a direct replacement.
As part of a recent multi-kilogram scale development pro-
gramme, the use of a DMTMM-based amidation was investigated.
In early development, some of the main issues encountered when
using DMTMM Cl 1a were, as mentioned above, the distortion of
stoichiometry and esterification of our carboxylate coupling part-
1a
this results in complete degradation in just 3 h (97% degradation
6
is observed in 2 h ).
4
ner by methyl transfer. Consequently, the use of DMTMM BF 1b
was considered. In order to complete the development studies, a
O
N
O
N
practical, robust, high-yielding process for the generation of 1b
Cl
was required.
N
N
N
N
The two published methods7 for the preparation of DMTMM
+
MeCl
O
N
O
O
N
BF
4
1b have significant drawbacks, especially if one intends to
e.g. CHCl3
operate on large scale, and these impact upon its utility in pro-
O
1
a
2
7
a
cess research and development. One method employs initial
formation of DMTMM Cl 1a in dichloromethane followed by pre-
cipitation of DMTMM BF 1b by addition of silver tetrafluorobo-
4
Scheme 1. Self-immolative degradation of DMTMM Cl.
rate suspended in acetonitrile. This is followed by isolation by
filtration and a subsequent recrystallisation. The yield reported
is 73%. The issues here are: (1) Given its sensitivity in chloro-
form, one may expect significant degradation of the DMTMM
Cl 1a to occur in dichloromethane, even at the suggested tem-
perature of 5 °C, distorting stoichiometry and eroding yield. (2)
Slurry transfers can be problematic in a pilot plant, and any dis-
ruptions in transfer will have significant impact on such a sensi-
The second order rate constants for this degradation in DMF and
DMSO at ambient temperature have been determined as 1.06 ±
À2
À3
3
À1 À1
6
0
.48 Â 10
and 1.42 ± 0.12 Â 10 dm mol
s , respectively.
So, for example, at a typical process concentration of 0.1 M,
DMTMM Cl 1a would degrade by 50% in approximately 15 min in
DMF and approximately 120 min in DMSO (assuming 1a is com-
pletely dissolved). For further qualitative stability studies on
DMTMM, see Kunishima et al.2b This degradation will of course
have an impact on the stoichiometry of the reaction. The produc-
tion of chloromethane will also have ramifications for the yield
and purity of the final products as it could methylate carboxylate
substrates (giving the corresponding esters) or alkylate elsewhere
in the substrate or product.2
4
tive first stage. (3) Use of AgBF may be prohibitively expensive
7b
on multi-kilo scale. The second method involves long reaction
times (normally 20 h) and requires N-methylmorpholinium tet-
rafluoroborate, which is not commercially available (presumably
this is synthesised from N-methylmorpholine and tetrafluorob-
oric acid). The yield reported is 75%.
d
Unlike in most organic solvents, DMTMM Cl 1a is stable as an
aqueous solution for significant time periods, i.e., over 24 h at
*
Corresponding author. Tel.: +44 (0)1625 232848.
E-mail address: Steven.Raw@astrazeneca.com.
2
b,6
ambient temperature.
4
It was postulated that DMTMM BF 1b
0
040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.12.047

S. A. Raw / Tetrahedron Letters 50 (2009) 946–948
947
could be precipitated from an aqueous solution of 1a by addition of
sodium tetrafluoroborate. Initial small-scale trials (approximately
triazin-2-yl)-4-methylpiperidinium tetrafluoroborate (DMTMP
8
13
4
BF ) 1d has been developed, which provides material of high
2
50 mg) showed immediate success: when aqueous NaBF
added dropwise to an aqueous solution of 1a at ambient tempera-
ture, DMTMM BF 1b precipitated immediately, and was easily
4
was
quality. The process avoids all the drawbacks associated with pre-
vious syntheses, as it does not involve the use of expensive AgBF ,
4
7
4
unstable solutions of DMTMM Cl 1a and non-commercially avail-
able reagents. It also delivers the products 1b and 1d in higher
recovered in a good yield (approximately 75%).
7
Though DMTMM Cl 1a is commercially available, even in the so-
yields than previously reported syntheses. An added benefit from
7
a
lid state it can degrade via the mechanism discussed above, and
so we were keen to develop a synthesis of 1b from the cheaper and
more stable precursor, 2-chloro-4,6-dimethoxy-1,3,5-triazine
a process perspective is that the only effluent stream is aqueous,
and the main by-product of the process is NaCl (alongside small
excesses of N-methylmorpholine and NaBF or NaPF ).
4 6
(
CDMT) 3. Furthermore, the ideal was a one-stage, two-step pro-
cess, avoiding any isolation of 1a. Given the initial success of the
precipitation of DMTMM BF 1b from aqueous solution and the
Acknowledgements
4
proven stability of aqueous solutions of 1a to degradation, the for-
mation of 1a from 3 in aqueous media was investigated. To this
end, CDMT 3 was suspended in water and N-methylmorpholine
The author would like to thank Ian W. Ashworth and Brian R.
Meyrick for their contributions to the investigations concerning
the degradation of DMTMM salts in various solvents6 and for the
useful discussions with respect to the work reported herein. The
author also thanks Anthony W.T. Bristow for HRMS analysis.
(
NMM) added. Analysis by HPLC showed complete consumption
of the CDMT 3 in just 20 min. Dropwise addition of an aqueous
solution of NaBF to this mixture over 5 min caused precipitation
of DMTMM BF 1b. The product was isolated by filtration in an
4
4
References and notes
overall yield of 80% from CDMT 3 (Scheme 2).
1.
(a) Kunishima, M.; Kawachi, C.; Iwasaki, F.; Terao, K.; Tani, S. Tetrahedron Lett.
1
1
999, 40, 5327–5330; (b) Kami n´ ski, Z. J.; Paneth, P.; Rudzi n´ ski, J. J. Org. Chem.
998, 63, 4248–4255.
O
2.
(a) For recent examples see: Štimac, A.; Mohar, B.; Stephan, M.; Bevc, M.; Zupet,
R.; Gartner, A.; Krošelj, V.; Smrkolj, M.; Kidemet, D.; Sedmak, G.; Benki cˇ , P.;
Kljaji cˇ , A.; Plevnik, M. Int. Pat. Appl., 2008, WO2008/089984; Chem. Abstr. 2008,
N
Y
N
N
DMTM(M/P) Cl
1
49, 224074.; (b) Kunishima, M.; Kawachi, C.; Morita, J.; Terao, K.; Iwasaki, F.;
O
N
Cl
o
1a/b
Water, 20 C,
Tani, S. Tetrahedron 1999, 55, 13159–13170; (c) Kunishima, M.; Kawachi, C.;
Hioki, K.; Terao, K.; Tani, S. Tetrahedron 2001, 57, 1551–1558; (d) Kjell, D. P.;
Hallberg, D. W.; Kalbfleisch, J. M.; McCurry, C. K.; Semo, M. J.; Sheldo, E. M.;
Spitler, J. T.; Wang, M. Org. Proc. Res. Dev. 2005, 9, 738–742.
20 min
CDMT 3
O
3. (a) For recent examples see: Yasude, Y. Int. Pat. Appl., 2007, WO2007/126154;
Chem. Abstr. 2007, 147, 522516.; (b) Kolesinska, B.; Kaminski, Z. J.; Kaminska, J.
E. Int. Pat. Appl., 2004, WO2004/056790; Chem. Abstr. 2004, 141, 106635.
1b, X=BF -
, Y=O, 80%
, Y=O, 89%
6
X
4
NaX(aq)
N
N
0 oC, 5 min
1c, X=PF -
4.
For recent examples see: (a) Tanaka, T.; Noguchi, M.; Kobayashi, A.; Shoda, S.-I.
Chem. Commun. 2008, 2016–2018; (b) Paoline, I.; Nuti, F.; de la Cruz Pozo-
Carrero, M.; Barbetti, F.; Kolesi n´ ska, B.; Kami n´ ski, Z. J.; Chelli, M.; Papini, A. M.
Tetrahedron Lett. 2007, 48, 2901–2904.
2
O
N
N
-
1
d, X=BF , Y=CH , 68%
4 2
1
Y
5.
For a recent example see: Wozniak, L. A.; Góra, M.; Stec, W. J. J. Org. Chem. 2007,
7
2, 8584–8587.
Scheme 2. Synthesis of DMTMM BF
4
, DMTMM PF
6
and DMTMP BF
4
.
6. Ashworth, I. W.; Meyrick, B.; Raw, S. A., Unpublished results. Our investigations
into the degradation kinetics of DMTMM Cl 1a and related salts in a variety of
solvents will be fully disclosed in due course.
With a viable process for the synthesis of DMTMM BF
hand, we were keen to investigate its application to other related
salts. Accordingly, synthesis of DMTMM PF 1c was attempted by
4
1b in
7. (a) Kami n´ ski, Z. J.; Kolesi n´ ska, B.; Kolesi n´ ska, J.; Sabatino, G.; Chelli, M.; Rovero,
P.; Błaszczyk, M.; Głowka, M. L.; Papini, A. M. J. Am. Chem. Soc. 2005, 127,
1
6912–16920; (b) Kami n´ ski, Z. J.; Papini, A. M.; Jastrabek, K.; Kolesi n´ ska, B.;
6
Kolesi n´ ska, J.; Sabatino, G.; Bianchini, R. Int. Pat. Appl., 2007, WO2007/051496;
an analogous procedure (Scheme 2). Gratifyingly, the desired prod-
uct 1c was isolated in 89% yield. Furthermore, the protocol is appli-
cable to other amines, such as N-methylpiperidine, delivering
Chem. Abstr. 2007, 146, 482097.
À
8
.
NaBF
than HBF
handle than HBF
9. Preliminary small-scale studies indicate that DMTMP BF
4
is a very economic commercial source of BF4 (being marginally cheaper
4
4
and less than 1% of the cost of AgBF ). Furthermore, it is far easier to
4
.
7
a
DMTMP BF
modified procedure.
4
1d in an unoptimised yield of 68%, using a slightly
4
1d is more soluble
9
than the analogous DMTMM BF4 1b in both acetonitrile and water. When the
unmodified process is used, the isolated yield of 1d is 47%, product loss to the
mother liquors accounting for this significantly lower yield. Conducting the
reaction at higher concentration significantly improves recovery.
6
To prove that the novel DMTMM PF 1c is as active as DMTMM
BF 1b in coupling reactions, both salts were employed in the ami-
4
1
0. 4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium
tetrafluoroborate
dation of benzoic acid with pyrrolidine (Scheme 3), following a
protocol developed by Kami n´ ski et al.7a In directly comparable
(1b): 2-Chloro-4,6-dimethoxy-1,3,5-triazine (7.39 g, 41.4 mmol) was
3
suspended in water (110 mL). To this was added N-methylmorpholine
(5.0 mL, 45.6 mmol) in one portion. After 20 min, the solid had dissolved to
give a colourless solution (analysis by HPLC showed complete consumption of
reactions, the yields obtained were essentially identical, being
7
8% with 1b and 79% with 1c.
3
). Sodium tetrafluoroborate (5.57 g, 49.7 mmol) was dissolved in water
(
37 mL), and the resulting solution charged to the reactor dropwise over 5 min.
Crystallisation began immediately and continued throughout the addition. The
mixture was stirred for a further 45 min before the solid was collected by
vacuum filtration. The cake was washed sequentially with water (2 Â 22 mL)
and methanol (37 mL). The material was dried to a constant weight in vacuo to
O
O
i) 1b/1c, NMM,
MeCN, RT, 2 h
OH
N
11
ii) Pyrrolidine,
RT, 2 h
give the title compound 1b (11.12 g, 97.4% (w/w) strength, 33.0 mmol, 80%
yield) as a colourless crystalline solid: 1H NMR (400 MHz, MeCN-d
.39 (3H, s), 3.68–3.79 (4H, m), 3.95–4.04 (2H, m), 4.12 (6H, s), 4.40–4.49 (2H,
3
): d(ppm)
3
13
m); C NMR (100 MHz, MeCN-d ): d(ppm) 56.9, 57.8, 61.1, 62.8, 171.2, 175.0.
3
Scheme 3. Amidations with DMTMM BF
4
6
and PF .
7a
The data are in good agreement with those published in the literature.
1
1. Material strength was determined by 1H NMR spectroscopic assay in DMSO-d
6
,
using 1,2,4,5-tetrachloro-3-nitrobenzene as an internal standard.
In conclusion, a new practical, robust and high-yielding process
12. 4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium
hexafluorophosphate (1c): This was synthesised in a manner analogous to that
described above for 1b, using 2-chloro-4,6-dimethoxy-1,3,5-triazine 3 (7.50 g,
for the production of 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-meth-
) 1b,10 its hexa-
ylmorpholinium tetrafluoroborate (DMTMM BF
fluorophosphate (DMTMM PF
) 1c12 and 4-(4,6-dimethoxy-1,3,5-
4
42.0 mmol) and sodium hexafluorophosphate (8.56 g, 50.4 mmol) with the
6
other reagents scaled accordingly. This gave the title compound 1c (14.85 g,

9
48
S. A. Raw / Tetrahedron Letters 50 (2009) 946–948
6.9% (w/w) strength,11 37.3 mmol, 89% yield) as a colourless crystalline solid:
colourless solution (analysis by HPLC showed complete consumption of 3).
9
1
H NMR (400 MHz, DMSO-d
6
): d(ppm) 3.47 (3H, s), 3.78 (2H, ddd, J 13.3 Hz, J
Sodium tetrafluoroborate (5.69 g, 50.8 mmol) was dissolved in water (15 mL),
and the resulting solution charged to the reactor dropwise over 5 min.
Crystallisation began after approximately 40% of the solution had been
charged and continued throughout the remainder of the addition. The
mixture was stirred for a further 75 min at ambient temperature. It was then
cooled to 0 °C (ice/acetone bath) and stirred for a further 30 min before the
solid was collected by vacuum filtration. The cake was washed twice with
chilled water (15 mL and 8 mL). The material was dried to a constant weight in
1
1
0.2 Hz, J 1.6 Hz), 3.88 (2H, ddd, J 12.7 Hz, J 10.2 Hz, J 2.8 Hz), 4.01 (2H, ddd, J
3.3 Hz, J 2.8 Hz, J 2.8 Hz), 4.10 (6H, s), 4.36 (2H, br d, J 12.7 Hz); C NMR
13
19
(
(
100 MHz, DMSO-d
6
): d(ppm) 55.2, 56.6, 59.5, 61.3, 170.2, 173.4; F NMR
31
470 MHz, DMSO-d
6
): d(ppm) À70.6 (6F, d, J 710 Hz); P NMR (200 MHz, DMSO-
1
d
3
1
1
C
6
): d(ppm) À143.0 (1P, septet, J 710 Hz); H NMR (400 MHz, MeCN-d
.38 (3H, s), 3.66–3.79 (4H, m), 3.93–4.05 (2H, m), 4.11 (6H, s), 4.44 (2H, br d, J
0.6 Hz); 13C NMR (100 MHz, MeCN-d
): d(ppm) 56.9, 57.8, 61.1, 62.8, 171.2,
75.0; m/z (Positive ion ESI) 241 (DMTMM ) [HRMS (Positive ion ESI) calcd for
241.1295. Found 241.1297 (0.6 ppm error)].
3
): d(ppm)
3
+
11
vacuo at 40 °C to give the title compound 1d (9.75 g, 99.2% (w/w) strength,
28.6 mmol, 68% yield) as a colourless crystalline solid: 1H NMR (500 MHz,
10
17 4 3
H N O
1
3. 4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylpiperidinium
1d): 2-Chloro-4,6-dimethoxy-1,3,5-triazine (7.55 g, 42.3 mmol) was
suspended in water (60 mL). To this was added N-methylpiperidine (5.7 mL,
6.6 mmol) in one portion. After 20 min, the solid had dissolved to give a
tetrafluoroborate
MeCN-d
ddd, J 12.5 Hz, J 12.5 Hz, J 2.7 Hz), 4.11 (6H, s), 4.41 (2H, br d, J 12.5 Hz);
NMR (125 MHz, MeCN-d ): d(ppm) 21.3, 21.9, 55.5, 57.7, 62.6, 171.8, 175.0. The
data are in good agreement with those published in the literature.
3
): d(ppm) 1.50–1.81 (4H, m), 1.85–1.96 (2H, m), 3.29 (3H, s), 3.52 (2H,
13
(
3
C
3
7a
4