The short answer is: It is highly unlikely that acetoacetanilide can be used to produce BMK (phenylacetone) via any intermediate or a known route, particularly not on a commercial scale. However, some synthetically non-obvious, poorly-known transformations could exist, in principle.
Analysis:
1. The scientific paper in question[1] does claim that acetoacetanilide (CAS No: 102-01-2, IUPAC name
3-oxo-N-phenylbutanamide) is a precursor to APAAN (structure
5, Fig. 1, in this document), and consequently precursor to BMK, i.e. phenylacetone.
The analysis of the integral text of the paper (as an accepted manuscript), revealed some significant facts. Thus, on p. 4 ,
Figure 1 in the manuscript, a total of nine precursors of BMK are listed, one of them being
acetoacetanilide, structure 9
, Fig. 1 below. The remaining eight compounds are known BMK precursors, although some are more significant than the others. The syntheses of eight of those compounds (
1-
8),
Fig. 1, as well as their transformations to BMK, are not discussed herein since they are simple, well-known and straightforward. (These reactions can be explained in detail, if requested).
Fig. 1 Structures of eight known BMK precursors, and acetoacetanilide
9.
2. Concerning the use of acetoacetanilide as BMK pre-precursor, the cited paper quotes EMCDDA publication, which is freely accessible.2 However, the document ("EU Drug Markets Report 2016, In-depth Analysis") apparently does not mention acetoacetanilide at all, according to a visual search and using find command (various keywords). The document does mention APAAN 5 and APAA 6, pp. 127-129, and some other precursors, shown in Fig. 1, above. (It should be noted that the Report is rather chemically incompetent).
3. The original publication (Ref. 1), primarily analyzes the trace compounds in waste-waters as an indicator of illegal drug manufacturing. Given the fact that the acetoacetanilide is an industrial chemical, it is not surprising that it is detected in wastewater, even thought it is unlikely to be involved, in any way, in BMK production.
4. Searches of other sources, including but not limited to, Pub Chem,[3] GSRS,[4] Insight Drugs,[5] Organic Syntheses,[6] Wikipedia[7] and others, revealed a wealth of information on acetoacetanilide. In general, the compound is an industrial chemical and the precursor to several final products. However, none of the sources mention that acetoacetanilide could be a BMK precursor.
5. Brief description of acetoacetanilide
Solid white crystalline compound, of moderate human toxicity
5a. Synthesis
Only two synthetic methods were identified, also known from the general organic synthesis, Scheme 1A and 1B bellow.
The first method involves the aminolysis of ethylacetacetate using aniline at elevated temperatures,[8] while the second one consists of acylation of aniline using diketene.[6] (Diketene reacts as an anhydride of acetoacetic acid, it is commercially available and a relatively stable compound).
Scheme 1. Methods for the preparation of acetoacetanilide
9
5b. Use of acetoacetanilide
It is an industrial chemical, produced in multi-ton quantities annually (e.g. >500 t, USA, 2019).
Significant applications: as a chemical precursor only.
Specifically:
a) in rubber compounding
b) manufacturing hansa yellow dyes, benzidine yellow pigments,
c) fungicides: carboxin and methfuroxam,
d) heterocyclic compounds: pyrazolones and pyrimidines
6. Apart from the above discussion, it should be noted that BMK (phenylacetone) as well as many other aryl-subsituded derivatives thereof, can be efficiently and inexpensively produced by the modified Meerwein reaction, according to the Scheme 2.[9] (Commercial viability of the procedure has not been assessed). A similar reaction (in aqueous medium, without Cu2O catalyst) has also been published.[10]
Scheme 2. Synthesis of phenylacetone (BMK), via modified Meerwein reaction
7. Based upon the reaction in Scheme 2, a prophetic reaction sequence, shown in Scheme 3, can be envisaged, although it is unlikely that the transformation would be successful, much less profitable.
Scheme 3. A prophetic synthesis of phenylacetone (BMK) from acetoacetanilide
8. Possible reasons that the acetoacetanilide was found and seized in a clandestine laboratory
a) Misidentification of the compound structure by forensic chemists (unlikely)
b) The compound was obtained as a BMK precursor by some trivial error ( acetoacetanilide is readily available)
c) Ignorance: someone believed that acetoacetanilide could be converted into BMK
Conclusion: Almost certainly, acetoacetanilide cannot be converted into BMK
REFERENCES
Note: Refs 1, 8, 9 and 10 can be obtained from the site
https://sci-hub.se/ (and other domains, if available), using DOI number to search database. In some countries, the
site is blocked, but should be accessible via Tor browser or VPN (set to the countries where it is not blocked, by trial and error). Other references are free to access and download, with no limitation.
1. Emke E, Vughs D, Kolkman A, de Voogt P. Wastewater-based epidemiology generated forensic information: Amphetamine synthesis waste and its impact on a small sewage treatment plant. Forensic Sci Int. 2018 May; 286:e1-e7. doi:
10.1016/j.forsciint.2018.03.019. Epub 2018 Mar 19. PMID: 29602535.
2. European Monitoring Centre for Drugs and Drug Addiction and Europol,
2016 EU drug markets report – In-depth analysis, Publications Office, 2016,
https://data.europa.eu/doi/10.2810/219411
3.
https://pubchem.ncbi.nlm.nih.gov/compound/7592
4.
https://gsrs.ncats.nih.gov/ginas/app/ui/substances/ed4048d5-e24c-4509-92d1-fb7682465b57
5.
https://drugs.ncats.io/drug/W35JB9PY3X
6.
https://www.orgsyn.org/Content/pdfs/procedures/CV3P0010.pdf
DOI:
10.15227/orgsyn.021.0004 Organic Syntheses, Coll. Vol. 3, p.10 (1955); Vol. 21, p.4 (1941).
ACETOACETANIL. Jonathan W. Williams and John A. Krynitsky
7.
https://en.wikipedia.org/wiki/Acetoacetanilide
8. Reactions of β-Keto Esters with Aromatic Amines. Syntheses of 2- and 4-Hydroxyquinoline Derivatives1 Charles R. Hauser and George A. Reynolds Journal of the American Chemical Society 1948 70 (7), 2402-2404 DOI:
10.1021/ja01187a025
9. Li, L., Chen, H., & Lin, Y. (2007). Facile Synthesis of 1‐Aryl‐2‐propanones from Aromatic Amine. Synthetic Communications, 37(6), 985–991.
https://doi.org/10.1080/00397910601163950
10. Molinaro C, Mowat J, Gosselin F, O'Shea PD, Marcoux JF, Angelaud R, Davies IW. A practical synthesis of alpha-aryl methyl ketones via a transition-metal-free Meerwein arylation. J Org Chem. 2007 Mar 2;72(5):1856-8. doi:
10.1021/jo062483g. Epub 2007 Jan 31. PMID: 17263583.
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