Replace Acetonitrile with DMSO

Dimethyl Sulfoxide (DMSO) can serve as a viable alternative to the use of acetonitrile in some applications. Most obviously, DMSO can perform most of the same chemical transformations that are used to manufacture pharmaceutical and agricultural active ingredients and intermediates.

Alkylation

Both DMSO and acetonitrile are excellent alkylation solvents, useful in the synthesis of various drug classes. A number of drug substances are manufactured using DMSO as a solvent in an alkylating step– including the interesting and selective MeI step to produce clarythromycin.5

Acetonitrile example (US 7501442, Theravance)6

DMSO example (US 4544657, Hoffmann-La Roche)7

There are many drug syntheses that incorporate alkylation steps. The table below provides some leading references.

Product Originator Drug Class
Brinzolamide8 Alcon Antiglaucoma Agent
Bimakalim9 Merck KGaA Antihypertensive
Indibulin10 Asta Medica Antimitotic
Etoperidone HCI11 ACRAF SpA Antidepressant

General procedure—piperizine alkylation. A mixture of alkyl halide (12.9 mmol), piperazine (13.4 mmol), and  triethylamine (26.4 mmol) in 50 ml of DMSO was heated at 80oC for one hour under argon. The mixture was cooled and diluted with water. The solids were recovered by filtration, dissolved in methylene chloride and washed with saturated sodium bicarbonate. After drying over sodium sulfate and charcoal treatment the solution was concentrated in vacuo. The residue was crystallized from an appropriate solvent.

SnAr Reactions

Both DMSO and acetonitrile are known as good solvents for nucleophilic aromatic substitution reactions. In some cases the higher boiling point of DMSO offers advantages– such as the ability to increase the reaction rate for KF-mediated exchange chemistry.12

Acetonitrile example (US 7501525, SCRAS13)

DMSO example: Flumezapine14 (US 6034078, Lilly Roche)

Azide Synthesis / Cyanation

Although cyanations and azidations are reported in acetonitrile, DMSO is perhaps the best solvent for these transformations. Following are two recent examples from the chemical literature; Table 2 provides more references.

DMSO example: NK1-antagonist intermediate15 (Eli Lilly, 2009)

The excellent paper by Kopach and coworkers15 describes the optimization of Alvarez conditions16 to minimize NaN3 and HN3 risk. They stated: “On the bases of environmental considerations, ease of workup, and cost, DMSO and DMF appeared to offer the best processing options.” Acetonitrile was among the other solvents tested but was deemed inferior.

     DMSO example: Atorvastatin precursor17  (US 7,414,141, Avecia)

Some syntheses which incorporate DMSO-based cyanations, azidations, and SnAr reactions are shown in the table below.

Product Originator Drug Class
 SnAr Examples Gatofloxacin18 Kyorin Antibiotic
Flumezapine14 Lily Antipsychotic
Enrofloxacin19 Bayer Antibiotic
Cyanation Examples Febuostat20 Teijun/Abbott Uricosurics
 Suprofen Alcon Ophthalmic Anti-Inflammatory
 Azidation Examples  Tamiflu® Gilead/Roche Antiviral

Comparative Properties

While there are similarities between DMSO and acetontrile which allow DMSO to serve as a substitute in many synthetic applications, there are some notable differences in the physical properties of these solvents.

Among these  differences are toxicity (DMSO is considerably less toxic than acetonitrile) and volatility (acetonitrile is more volatile, and can be easier to remove from product mixtures).  Table three provides some basic comparative properties for these solvents.

Some syntheses which incorporate DMSO-based cyanations, azidations, and SnAr reactions are shown in the table below.

Safety/Toxicological Indicators23
DMSO Acetonitrile
LD50 oral 14,500-28,600 mg/kg (rat) 2460 mg/kg (rat)
LD50 dermal 40,000 mg/kg (kat) 1250 uL/kg (rabbit)
PEL none established 40 ppm (TWA)
LC50 inhalation none established 7551 ppm/8H
flashpoint 95°C 5.6°C
Physical Properties
Density  1.1 (@ 20°C) 0.79 (@ 4°C)
Boiling Point 189°C 86.6°C
Freezing Point 18.6°C -45°C

References

  1. Hock, L. “The Hunt for Acetonitrile Alternatives”,  Drug Discovery and Development (18 March 2009)
  2. Tullo, A. “A Solvent Dries Up”,  Chemical and Engineering News  86, 47 (November 2008) p27  b) “Acetonitrile” Wikipedia entry accessed 4 April 2009
  3. “Acetonitrile” in The Kirk-Othmer Encyclopedia of Chemical Technology 17 (1995) p 232.
  4. Instrument and column manufacturers offer products which consume smaller volumes of acetonitrile. Examples include the Ascentis™ Express HPLC column (Sigma-Aldrich) and the Acuity™ UPLC HPLC system (Waters Corporation).
  5. EP 0147062, Taisho Pharmaceutical, assignee.
  6. Mammen, M.; Husfeld, C.; Ji, Y. US 7501442, Theravance assignee (2009).
  7. J. Michael Chong, Susanna Wong, Alkylation of stabilized acetylides in DMSO. Preparation of α,β-acetylenic alchohols and acetals, Tetrahedron Letters, Volume 27, Issue 45, 1986, Pages 5445-5448, ISSN 0040-4039, http://dx.doi.org/10.1016/S0040-4039(00)85233-8.
  8. Dean; T.; Chen, H.;, May, J., US 5240923, Alcon, Assignee (1991)
  9. EP 0273262, Assignee Merck.
  10. Lebaut; G.; Menciu;,C.; Kutscher, B.;), Emig, P.; Szelenyi, S.; Brune, K. US 6008231
  11. Palazzo; G. US 3857845, assignee A.C.R.A.F. S.p.A.
  12. Clark, J.; Wails, D.; Bastock, T. Aromatic Fluorination CRC Press, New York  (1996) p19-55.
  13. Isanbor, C.; Emokpae, T. A.; Crampton, M. R. “Steric and electronic effects on the mechanism of nucleophilic substitution (SnAr) reactions of some phenyl 2,4,6- trinitrophenyl ethers with aniline and N-methylanline in acetonitrile and in dimethyl sulfoxide”, Journal of the Chemical Society, Perkin Transactions 2 (2002) p 2019-2024.
  14. Fairhurst, J.;  Hotten, T.; Tupper, D.; Wong, D. US 6034078
  15. Kopach, M.; Murray, M. ;Braden, T.; Kobierski, M.; Williams, J. Org. Process Res. Dev. 2009 , 13 (2), 152-160
  16. Alvarez, S. G.; Alvarez, M. T. Synthesis 1997, 413.
  17. Moody, D.J.; Wiffen J.W US 7414141,assignee Avecia (2008)
  18. Matsumoto, T.; Hara, M.; Miyashita, K.; Kato, Y,  US 5880283, Assignee Kyorin (1999)
  19. Grohe, K; Klimetzek, V.; Metzger, K; Stunkel, K.;  Zeiler, H. US 4659603, Assignee Bayer AG (1985)
  20. Kondo, S.; Fukushima, H. ;Hasegawa, M. ;Tsuchimoto, M.; Nagata, I.; Osada, Y.; Komoriya, K.; Yamaguchi, H. US 5614520 Assignee Teijin (1995)
  21. Godtfredsen, W.; von Daehne, W.US 4840944, Assignee Leo Pharmaceutical Products Ltd (1980)
  22. Rohloff, J.; Kent, M.;  Postich, Mark W. Becker, Chapman, H., Kelly, D.;  Lew, W.  J. Org. Chem.; S. Louie, M; McGee, L.;  Prisbe, E.; Schultze, R.; Yu, H.; Lijun Z.  1998; 63(13) pp. 4545 – 4550

Related Resources