Rare Methamphetamine Synthesis

RARE CLANDESTINE SYNTHESIS ROUTE FOR METHYLAMPHETAMINE AND ITS PRECURSOR IN NSW Todd McBriar and Una Culllinan Division of Analytical Laboratories (DAL), Sydney, NSW, Australia BACKGROUND In December 2009, the NSW police drug squad submitted to the NSW illicit drug laboratory a number of items that were related to the clandestine manufacture of methylamphetamine (MA) and its controlled precursor-phenyl-2-propanone (P2P). Several factors made these submissions worthy of note (Table 1): • The submission consisted of a commercial quantity of high purity methylamphetamine •5.6 kgs of an unusual precursor- -acetylphenylacetonitrilewhich indicated a rare synthesis procedure was being utilised. Presumably to avoid detection from the relevant authorities

DISCUSSION-SYNTHESIS

FIG 4a

FIG 4C

PIC 1

[X]

[X]

PIC 2

•To outline and discuss the Schiff base and Leuckart pathways for the synthesis of methylamphetamine •To present the analytical data (GCMS, UPLC & FTIR) from the examination of the submitted items •To undertake preliminary qualitative GC-MS profiling based on previous work by the UNDCP (1999) [1], Zhang et al [2] and Sasaki et al [3] . This was attempted to ascertain the probable route used by the illicit chemist •NOTE: The profiling was attempted utilising the current inhouse columns available (30m D-17 & 15 m HP-1)

6f

6g

-keto ester

MA

MA

PROFILING ANALYSIS: Preliminary profiling analysis was based on previous work [1]-[3]. Due to availability, analysis was attempted on DB-17 & HP-1 columns (vs DB-5 & Ultra 2).The HP-1 proved to be more selective in resolving impurities vs the DB-17. Samples were dissolved in 4:1 buffer:10% Na2CO3 and extracted in 0.5mL solvent. GCMS parameters were: 1.0µL pulsed splitless injection, Oven 50oC (1min), then 10oC/min to 300oC (10min). He carrier gas at 1.0mL/min, inj/transfer line 230oC/300oC. Fig 7a outlines the “fingerprint” overlay profile of the MA samples. Refer to Table 1 [1] -[5]. Fig 7b-7d tentatively indicates the impurities/route markers of the MA synthesis. 7a

-acetyl-phenylacetonitrile: Reflux 2 moles of benzyl cyanide and 3 moles of ethyl acetate in a hot solution of sodium ethoxide for 2 hours, stand overnight (fig 1). The sodium salt product (69-76% yield) is dissolved in water, cooled and acidified. Producing the dry base product (5964% yield) [6] & [7] . Refer to pic 3 and pic 3 zoom for submitted case items.

7b

TIC PROFILES OF MA SAMPLES [5]

7c

7d

N,Ndimethylamphetamine

[4] [2]

PIC 3

PIC 3 zoom

[1] [3]

P2P: The dry -keto ester product is distilled with conc H2SO4 and water for several hours. The ketone layer is separated, washed and filtered (77-86% yield) [7] & [4]. Based on 200g lots of the -keto ester starting material the submitted quantity of 5.6kgs could yield up to 4.2kgs of P2P. MA synthesis: The Schiff base pathway involves the condensation of P2P with methylamine, which is reduced via an imine intermediate to MA (fig 2). The methylamine can be present in solution (40%) or as a salt. (Typical yield = 70%) [8].

FIGURE 1

6c

6e

Benzyl cyanide

Based on 586.1 g of ammonium chloride submitted. The total amount of methylamine HCL produced = 370g (assume 50% yield). Refer to pic 2 for submitted case item.

6b

6d

FIG 4b

•To outline the reaction pathway to synthesise starting materials like methylamine HCL and dimethylamine HCL •To outline the stepwise reaction pathway to synthesise firstly, -acetylphenylacetonitrile, then P-2-P

6a

METHYLAMINE SYNTHESIS: The acidic condensation of ammonium chloride (refer to pic 1) with formaldehyde (fig 4a) in a 1:2 molar ratio produces the imine intermediate [X]. The imine is reduced to methylamine (fig 4b). Obtain 50-95% yield. The excess formaldehyde condenses the methylamine to dimethylamine (fig 4c). The dimethylamine impurity in the starting material produces the side-product N,N-dimethylamphetamine in the finished product. The lower the reflux temperature the better the yield [4] & [5].

•The identification of two materials that indicated a series of clandestine procedures to synthesise not only finished product, but starting reagents and precursors such as P2P

AIMS/OBJECTIVES

DISCUSSION-ANALYSIS-CONT

MA synthesis: The Leuckart pathway (fig 3) involves the substitution of a formamide with a ketone. Based on 4.0g lots of methylamine HCL starting material the submitted quantity of 2.63kg could yield up to 2.28kg of the formamide (99% yield). Refluxing the formamide with P2P (170-1900C) produces the N-formyl intermediate which via acid hydrolysis produces MA (Typical yield=43%) [4], [8]-[9] . MA yield-Schiff base: Based on 4.2kgs of P2P with Al metal would yield 4.07kgs MA HCL (requires 11.76kgs of 40% methylamine). Based on 3.0kgs of methylamine HCL, with NaBH4 would yield 3.0kgs of MA HCL (requires 2.97kg P2P) . Based on 3.0kgs of methylamine HCL would produce 5.0kgs of 40% solution (assume 0.7 density), yielding 1.7kgs MA HCL (requires 1.8kgs of P2P with Al metal) [10].

RESULTS Synthesis: The use of -acetylphenylacetonitrile to produce P2P is a dated method that is rarely seen in Australian clandestine operations, and the first to be seen in NSW. It appears illicit chemists are attempting to avoid detection by producing starting material “in-house’ rather than importing or diverting it from other means. Depending on the synthetic route use, Schiff vs Leuckart, the MA HCL produced varies (4.07kgs vs 2.52kgs). Profiling: The preliminary findings indicate the MA submitted could possibly originate from the same batch (7a). Based on the impurities found (7b & 7d) and the route specific marker/intermediate (7c), the likely synthesis method was tentatively identified as the Leuckart method (refer to figure 3). REFERENCES [1] B.Remberg, A.H. Stead, Drug characterization/impurity profiling, with special focus on methamphetamine: recent work of the United Nations Drug Control Programme, Bull. Narcotics LI (1999) 97-117. [2] J.X. Zhang, D. M Zhang, X.G. Han, Identification of impurities and statistical classification of methamphetamine hydrochloride drugs seized in China, Forensic Sci. Int, 182 (2008) 13-19. [3] T. Sasaki, Y.Makino, Effective injection in pulsed splitless mode for impurity profiling of methamphetamine crystal by GC or GC/MS, Forensic Sci,. Int 160 (2006) 1-10. [4] U.Fester, Secrets of methamphetamine manufacture, 7th ed Loompanics Unlimited, Washington, Chapter 13 pgs 109-111. [5] H.I, Jones, The Preparation of Methylamine, J.Am.Chem. Soc, (1918) pgs 411-1515 [6] Organic Syntheses, Coll. Vol. 2, p.487 (1943); Vol. 18, pgs.487-489 (1938). [7] Organic Syntheses, Coll. Vol. 2, p.487 (1943); Vol. 18, pgs 391-392 (1938). [8] M.White, FSS report on methylamphetamine, The ACMD working group on methylamphetamine, Oct 2004. [9] J.Cappon, Preparation of N-Methylformamide, Rec.Trav.Chim.Pays-Bas (1994) 113,318. [10] M.Pearson, J.Hugel, T.Evoy, Drug Yield Calculator, Software Application, Ver 7.0.

TABLE 1: INVENTORY OF SUBMITTED ITEMS

FIGURE 2

MA yield-Leuckart: Based on 4.2kgs of P2P would yield 2.52kgs of MA HCL (requires 10.92kgs of 40% methylamine). Based on 3.0kgs of methylamine HCL would produce 5.0kgs of 40% solution, yielding 1.15kgs MA HCL (requires 1.9kgs of P2P) [10].

DISCUSSION-ANALYSIS

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FIGURE 3

CASE WORK ANALYSIS: The items in Table 1 were examined using a combination of GCMS, FTIR & UPLC. Fig’s 6a-6g outline the typical results obtained for ammonium chloride (FTIR-6a), -keto ester (FTIR & GCMS-6b, 6e), methylamine HCL (FTIR- 6c) benzyl cyanide (GCMS6d), MA (GCMS & UPLC-6f, 6g).

PACKAGING

FORM

COMPOUND

USE/ROLE

MASS (GRAMS)

%PURITY

plastic bag

compressed substance

methylamphetamine [1]

illicit drug

229.0

77.5

3 plastic bags

compressed substance

methylamphetamine [2]

illicit drug

286.2

77.0

2 plastic bags

compressed substance

methylamphetamine [3]

illicit drug

57.1

73.5

plastic bag

compressed substance

methylamphetamine [4]

illicit drug

28.4

74.5

plastic bag

pasty substance

methylamphetamine [5]

illicit drug

5.7

61.5

2 plastic bags

lumpy substance

methylamphetamine

illicit drug

231.5

8.5

7 plastic bags

green powder

-acetylphenylacetonitrile (REFER PIC 3)

precursor to P2P

5600

not determined

4 plastic bags

compressed or wet crystalline substance

methylamine HCL (REFER PIC 2)

starting material for MA synthesis

2627.9

not determined

3 plastic bags & plastic container

powder

ammonium chloride (REFER PIC 1)

starting material for methylamine synthesis

586.1

not determined