A practical preparation of ethyl N -acyl-2-(dimethoxyphosphoryl)glycinate

Article abstract of DOI:10.1021/op1000594

A practical, cost-effective preparation of ethyl N-acyl-2- (dimethoxyphosphoryl)glycinate has been developed. The two-step process achieved an 80% overall isolated yield.

Full text of DOI:10.1021/op1000594

Organic Process Research & Development 2010, 14, 666–667
A Practical Preparation of Ethyl N-Acyl-2-(dimethoxyphosphoryl)glycinate
Feng Xu* and Paul Devine
Department of Process Research, Merck Research Laboratories, Rahway, New Jersey 07065, U.S.A.
Scheme 1. Two-step preparation of 1
Abstract:
A practical, cost-effective preparation of ethyl N-acyl-2-(dimethox-
yphosphoryl)glycinate has been developed. The two-step process
achieved an 80% overall isolated yield.
Introduced by Ratcliffe and Christensen in 1973,1 ethyl
N-acyl-2-(dimethoxyphosphoryl)glycinate (1) as well as its
derivatives are useful synthetic building blocks with wide
applications in organic synthesis. For example, R,ꢀ-unsaturated
R-amino acid derivatives, which are also common moieties of
natural dehydropeptides, can be prepared easily via a Horner-
Wadsworth-Emmons reaction by coupling 1 with an aldehyde
or ketone.2 Furthermore, subsequent asymmetric hydrogenation
of R,ꢀ-unsaturated R-amine acid derivatives provides one of
the most desirable ways to access natural and unnatural amino
acids.2,3 In addition, 1 and its derivatives have also been applied
to prepare various important ꢀ-lactam antibiotics.1,4
prepare 1 as well as its derivatives in the past decades.1,6
Most of the reported methods either offered poor to
moderate yield or were not atom-economically efficient.
However, the approach7 to install a phosphoryl group by
applying a Michaelis-Arbuzov reaction on R-halo glycine
esters is scientifically sound and attractive. After further
study/modification of this strategy, we herein report a
practical two-step process, which is suitable for large-
scale preparation, to afford 1 in 80% overall isolated yield
(Scheme 1).
Readily available ethyl glyoxalate (2) became our inexpen-
sive starting material of choice.8 Efficient condensation of the
derivative of 2, hemiacetal MeOCH(OH)CO2Me, with aceta-
mide has been reported.9 However, attempts to follow the
similar procedure to condense 2 with acetamide in refluxing
toluene did not give satisfactory conversion and yield.10 After
several experiments, we found that introducing HOAc to the
reaction solution improved the reaction rate as well as the
conversion significantly. The HOAc charge could be varied
from 0.05 to 2 equiv with 0.4-0.6 equiv being optimal (Table
1). In order to directly isolate the product 3 from the reaction
mixture, a combination of i-PrOAc and heptane became solvents
of choice. In practice, after aging the mixture of 2 (1.05 equiv,
50 wt % solution in toluene) and acetamide in the presence of
40 mol % of HOAc at 55-60 °C for about 1 h (∼30%
conversion), the reaction solution was then seeded to relieve
Although analogues of 1 are commercially available,
the use of these reagents in large-scale synthesis is limited
due to cost.5 Various methods have been developed to
* Author to whom correspondence may be sent. E-mail: feng_xu@merck.com.
(1) (a) Ratcliffe, R. W.; Christensen, B. G. Tetrahedron Lett. 1973, 4645.
(b) Ratcliffe, R. W.; Christensen, B. G. Tetrahedron Lett. 1973, 4649.
(2) For recent examples, see: (a) Okuma, K.; Ono, A. M.; Tsuchiya, S.;
Oba, M.; Nishiyama, K.; Kainosho, M.; Terauchi, T. Tetrahedron Lett.
2009, 50, 1482. (b) Elaridi, J.; Patel, J.; Jackson, W. R.; Robinson,
A. J. J. Org. Chem. 2006, 71, 7538. (c) Liu, Y.; Ding, K. J. Am. Chem.
Soc. 2005, 127, 10488. (d) Aguado, G. P.; Moglioni, A. G.; Garcia-
Exposito, E.; Branchadell, V.; Ortuno, R. M. J. Org. Chem. 2004, 69,
7971. (e) Aguado, G. P.; Moglioni, A. G.; Ortun˜o, R. M. Tetrahedron:
Asymmetry 2003, 14, 217. (f) van den Berg, M.; Minnaard, A. J.;
Schudde, E. P.; van Esch, J.; de Vries, A. H. M.; de Vries, J. G.;
Feringa, B. L. J. Am. Chem. Soc. 2000, 122, 11539. (g) Burk, M. J.;
Gross, M. F.; Martinez, J. P. J. Am. Chem. Soc. 1995, 117, 9375. (h)
Lorenz, J. C.; Busacca, C. A.; Feng, X.; Ginberg, N.; Haddad, N.;
Johnson, J.; Kapadia, S.; Lee, H.; Saha, A.; Sarvestani, M.; Spinelli,
E. M.; Varsolona, R.; Wei, X.; Zeng, X.; Senanayake, C. H. J. Org.
Chem. 2010, 75, 1155.
(3) For recent reviews, see: (a) Minnaard, A. J.; Feringa, B. L.; Lefort,
L.; de Vries, J. G. Acc. Chem. Res. 2007, 40, 1267. (b) Ma, J.-A.
Angew. Chem., Int. Ed. 2003, 42, 4290. (c) Cativiela, C.; D´ıaz-de-
Villegas, M. D. Tetrahedron: Asymmetry 2000, 11, 645. (d) Brown,
J. M. ComprehensiVe Asymmetric Catalysis; Springer: Berlin, 1999;
Vol I, p 121.
(6) For lead references, see: (a) Mazurkiewicz, R.; Kuznik, A. Tetrahedron
Lett. 2006, 47, 3439. (b) Mauldin, S. C.; Hornback, W. J.; Munroe,
J. E. J. Chem. Soc., Perkin Trans. I 2001, 1554. (c) Ferries, L.; Haigh,
D.; Moody, C. J. J. Chem. Soc., Perkin Trans. I 1996, 2885. (d)
Shankar, R.; Scott, A. I. Tetrahedron Lett. 1993, 34, 231. (e)
Narukawa, Y.; Juneau, K. N.; Snustad, D.; Miller, D. B.; Hegedus,
L. S. J. Org. Chem. 1992, 57, 5453. (f) Daumas, M.; Vo-Quang, L.;
Goffic, F. L. Synth. Commun. 1990, 22, 3395. (g) Shiraki, C.; Saito,
H.; Takahashi, K.; Urakawa, C.; Hirata, T. Synthesis 1988, 399. (h)
Schmidt, U.; Lieberknecht, A.; Wild, J. Synthesis 1984, 53, and
references cited therein.
(4) For recent examples, see: (a) Norris, T.; Nagakura, I.; Morita, H.;
McLachlan, G.; Desneves, J. Org. Process Res. DeV. 2007, 11, 742.
(b) Hakimelahi, G. H.; Moosavi-Movahedi, A. A.; Saboury, A. A.;
Osetrov, V.; Khodarahmi, G. A.; Shia, K.-S. Int. J. Sci. Res. 2005,
14, 59. (c) Seki, M.; Kondo, K.; Iwasaki, T. J. Chem. Soc., Perkin
Trans. I 1996, 1, 3. (d) Narukawa, Y.; Juneau, K. N.; Snustad, D.;
Miller, D. B.; Hegedus, L. S. J. Org. Chem. 1992, 57, 5453, and
references cited therein.
(7) For lead references and examples, see: refs 6d,e,g,h.
(8) Ethyl glyoxalate (∼50% in toluene): ∼$34/kg at 1000 kg scale from
Clariant (France).
(9) Alks, V.; Sufrin, J. R. Synth. Commun. 1989, 19, 1479.
(10) Condensation of 2 with acetamide in acetone gave moderate
yield. Schmitt, M.; Bourguignon, J.-J.; Barlin, G. B.; Davies, L. P.
Aust. J. Chem. 1997, 50, 719.
(5) For example, methyl 2-acetamido-2-(dimethoxyphosphoryl)acetate:
∼$3780/kg at 100 kg scale Digital Specialty Chemicals Ltd. (Canada);
methyl tert-butoxycarbonylamino(dimethoxyphosphoryl)acetate: ∼$2370/
kg at 500 kg scale from Sigma-Aldrich (USA).
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Vol. 14, No. 3, 2010 / Organic Process Research & Development
10.1021/op1000594  2010 American Chemical Society
Published on Web 04/29/2010

Table 1. Preparation of 3: HOAc effect on conversion in
i-PrOAc at 55 °C
in i-PrOAc (770 mL) and heptane (440 mL) was heated to
55-60 °C for 1 h. The resulting homogeneous solution was
seeded with <500 mg of the seeds and aged for additional 3 h
at 55-60 °C to form a thick slurry. The slurry was cooled to
ambient temperature and aged for 2 h before filtration. The white
solid was filtered, and the wet cake was washed with 50%
i-PrOAc in heptane (200 mL × 2). Drying by suction gave
127 g of the desired product as white solid; 85% yield.15 1H
NMR (400 MHz, CDCl3): δ 7.08 (d, J ) 7.8 Hz, 1 H), 5.60
(d, J ) 7.8 Hz, 1 H), 4.81 (s, br, 1 H), 4.28 (q, J ) 7.2 Hz, 2
H), 2.05 (s, 3 H), 1.32 (t, J ) 7.2 Hz, 3 H). 13C NMR (100
MHz, CDCl3): δ 171.4, 169.8, 72.2, 62.7, 23.3, 14.2.
entry
HOAc (equiv)
ratio12 of 3 vs 2
1
2
3
4
5
6
7
0.0
0.05
0.25
0.4
4.5:1
24:1
23:1
40:1
71:1
39:1
23:1
0.5
0.6
1.0
supersaturation.11 Once >95% conversion was achieved, the
batch was then cooled to ambient temperature. Thus, without
any aqueous workup, the desired product was isolated in 85%
yield and >99% purity through simple filtration.
Ethyl N-Acyl-2-(dimethoxyphosphoryl)glycinate (1). To
a slurry of 3 (100 g, 0.680 mol) in i-PrOAc (1.0 L) at ambient
temperature was added SOCl2 (54.4 mL, 0.748 mol) dropwise
over 30 min. The reaction mixture was aged at 30-35 °C for
1 h, and the solution was concentrated in Vacuo to about 500
mL. The solution was further distilled at constant volume (∼500
mL) by feeding i-PrOAc (∼600 mL). Then, the solution was
diluted to ∼1 L with i-PrOAc and warmed to 55 °C. P(OMe)3
(84 mL, 0.714 mol) was added dropwise over 1 h. The resulting
solution was aged at 55 °C for 3-4 h. The batch was then
concentrated in Vacuo to a volume of 450 mL while the internal
temperature was kept between 30-40 °C to maintain a
homogeneous solution. The solution was seeded with <500 mg
of the seeds at 30 °C, and heptane (700 mL) was added
dropwise at 25-30 °C over 2 h. Then, the slurry was aged at
0-5 °C for 2 h before filtration. The wet cake was washed
with 20% i-PrOAc in heptane (250 mL × 2). Drying by suction
To convert 3 to its corresponding chloride 4, the use of a
combination of SOCl2 and i-PrOAc13 made the process practical
and effective. Within 1 h at 30-35 °C, the chlorination was
complete12 (>99% conversion) in the presence of 1.1 equiv of
SOCl2. Without isolation of the intermediate 4, most of the HCl
formed during the reaction, as well as unreacted SOCl2, was
removed via distillation with i-PrOAc in Vacuo before 1.05
equiv of P(OMe)3 was added. The desired product 1 was
obtained effectively via a Michaelis-Arbuzov reaction at 55 °C.
Again, the use of a combination of i-PrOAc and heptane was
chosen for direct isolation/crystallization of 1 from the crude
reaction mixture without any aqueous workup. Through simple
filtration, 1 was obtained in 94% isolated yield.
This two-step process could also be carried out in one-pot
without isolating the aminal 3.14 However, the overall isolated
yield was decreased by approximately 15%.
In summary, a practical preparation of ethyl N-acyl-2-
(dimethoxyphosphoryl)glycinate (1) has been developed. The
easily operated, two-step process afforded 1 in 80% overall
isolated yield. Suitable for large-scale preparation, this process
does not generate any aqueous waste.
1
gave 153 g of 1 as white solid; 94% yield, >99% purity. H
NMR (400 MHz, CDCl3): δ 6.88 (d, J ) 9.0 Hz, 1 H), 5.20
(dd, J ) 9.0, 22.3 Hz, 1 H), 4.24 (q, J ) 7.1 Hz, 2 H), 3.80 (d,
J ) 10.6 Hz, 3 H), 3.78 (d, J ) 10.6 Hz, 3 H), 2.04 (s, 3 H),
1.27 (t, J ) 7.1 Hz, 3 H). 13C NMR (100 MHz, CDCl3): δ
169.9 (d, J ) 6.0 Hz), 166.8 (d, J ) 2.4 Hz), 62.6, 54.2 (d, J
) 6.8 Hz), 54.1 (d, J ) 6.8 Hz), 50.3 (d, J ) 147.6 Hz), 22.8,
14.1.
Experimental Section
Acetylamino Hydroxy Acetic Acid Ethyl Ester (3). A
slurry of AcNH2 (55 g, 0.931 mol), ethyl glyoxalate (50 wt %
in toluene, 200 g, 0.978 mol), and AcOH (21.3 mL, 0.372 mol)
Supporting Information Available
1H and 13C NMR spectra of 1 and 3. This material is
available free of charge via the Internet at http://pubs.acs.org.
(11) It is recommended to seed the batch at 55-60 °C to relieve
supersaturation and obtain a stirrable slurry during the reaction.
(12) Unless otherwise mentioned, the ratio and conversion were determined
by high performance liquid chromatography (HPLC) analysis: Zorbax
RX-C8 column, 4.6 mm × 250 mm, 5 µm particle size, 45 °C, mobile
phase: aq H3PO4/MeCN; flow rate: 0.5 mL/min; detection: UV
absorbance at 205 nm.
Received for review February 26, 2010.
OP1000594
(13) Xu, F.; Simmons, B.; Reamer, R. A.; Corley, E.; Murry, J.; Tschaen,
D. J. Org. Chem. 2008, 73, 312.
(15) The spectroscopic data (1H and 13C NMR) are identical with those
reported.4c,9
(14) A quantity of 0.1 equiv of HOAc was used.
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