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Chimimanie

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J of Label Compounds and Radiopharmaceutical refs
« on: April 01, 2003, 04:10:00 PM »
These refs were requested by our Chief Bee, Rhodium.


Synthesis of bromine-77 labeled 2-(4-bromo-2,5-dimethoxyphenyl)isopropylamine with high specific activity.
Journal of Labelled Compounds and Radiopharmaceuticals  (1981),  18(5),  739-46.
abstract
2,5-(MeO)2C6H3CH2CHMeNH2 was protected as the trifluoroacetamide (CF3CO2H, 0°), brominated by carrier-free 77Br in the presence of N-chlorotetrafluorosuccinimide (CF3CO2H, dark, 20°, 0.5 h), and hydrolyzed (aq. NaOH, pH 10, 100°, 1 h) to give the title compd. I in 25% radiochem. yield and sp. activity 8 Ci/mmol.

http://members.lycos.co.uk/chimimanie/jlcarp1981-739.PDF






Synthesis of high specific activity 125I- and 123I-labeled enantiomers of [(2,5-dimethoxy-4-iodophenyl)isopropyl]amine (DOI)
Journal of Labelled Compounds and Radiopharmaceuticals  (1988),  25(11),  1255-65.
Abstract
The prepn. of high specific activity 125I- and 123I-labeled (R)- and (S)-DOI is described.  Three radiosynthetic routes, 2 of which involved use of amine protecting groups and 1 of which used the free base are compared.  The method giving the highest yields is to treat 2,5-(MeO)2C6H3CH2CHMeNH2 with Na125I (or Na123I) in aq. H3PO4 and then with chloramine-T. Final radiochem. yields are ca. 80%.  The sp. activities of the 125I-labeled products av. 1100 Ci/mmol; those of the 123I-labeled products, >20,000 Ci/mmol.

http://members.lycos.co.uk/chimimanie/jlcarp1988-1255.PDF






Synthesis of tritium-labeled trans-4-hydroxycrotonic acid (T-HCA), an endogenous substance interfering with 4-hydroxybutyrate (GHB).
Journal of Labelled Compounds and Radiopharmaceuticals  (1989),  27(1),  23-33.
Abstract
(E)-HOCH2CH:CHCO2H (I) has been identified in the central nervous system of mammalians as a naturally occurring substance, which may compete with HO(CH2)3CO2H for specific biol. targets.  I has been tritiated at the 2,3 positions, using a multi-step synthesis and a one-pot reaction for the three last crit. steps.  Thus, (E)-HOCH2C3H:C3HCO2H was obtained with a specific radioactivity of 45 Ci/mmole (1.66 TBq/mmole) and a radiochem. purity of 97%.

http://members.lycos.co.uk/chimimanie/jlcarp1989-23.PDF






Bonus:

C13-Labelling of N-Methyl-4-Phenyl-1;2;3;6-Tetrahydropyridine (MPTP)
Journal of Labelled Compounds and Radiopharmaceuticals  (1989),  27(1),  85-89.

http://members.lycos.co.uk/chimimanie/jlcarp1989-85.PDF


Chimimanie

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some dimethoxy-N,N-dimethyl amphetamines
« Reply #1 on: April 22, 2003, 02:08:00 PM »
Synthesis of 122I- and 125I-labelled meta-dimethoxy-N,N-dimethyliodophenylisopropylamines
Chester A. Mathis*, Alexander T. Shulgin, and Thornton Sargent III

J Lab Comp and Radiopharm 23 (2), 115

(http://members.lycos.co.uk/chimimanie/jlcarp-23-115.PDF)

Abstract

The syntheses of 122I- and 125I-labelled 2,4-dimethoxy-N,N-dimethyl-5-iodophenylisopropylamine, 3,5-dimethoxy-N,N-dimethyl-2-iodophenylisopropylamine and 2,6-dimethoxy-N,N-dimethyl-3-iodophenylisopropylamine are described. The speed (3 min, including purification) and yield (45=85%) obtained in direct iodination procedures utilizing chloramine-T have allowed the use of the short-lived positron emitter 122I (t1/2 = 3.6 min) in brain blood flow imaging studies. The three appropriate precursors (the meta-dimethoxy-N,N-dimethylphenylisopropylamines) were prepared from the corresponding phenylacetone analogues by reductive amination employing dimethylamine and NaCNBH3. The ketones were obtained from the appropriate nitrostyrenes through reduction with elemental Fe.

Key Words:   meta-dimethoxy-N,N-dimethyliodophenylisopropylamines, iodine-122, iodine-125, brain blood flow agents, iodinated amphetamines.

Introduction

Two classes of imaging agents for brain blood flow determination exist.

One has the properties of high extraction by brain tissue on the first pass and retention by brain for a time period sufficient for imaging; the other depends upon free diffusion in and out of brain tissue. The first example of a retained agent was 4-82Br-2,5-dimethoxyphenylisopropylamine (4-82Br-2,5-dimethoxyamphetamine) [1]. Two similar iodinated analogues have been described [2,3], and a chemically related diamine has also been utilized for brain imaging studies [4]. These compounds were prepared with gamma-emitting isotopes which were inappropriate for positron emission tomography (PET).

(...)

Previously, considerable synthetic time has been required for the incorporation of the radio-iodine into the iodinated amphetamine analogues, either because derivatization was needed to protect the amine from oxidation [2] or a slow halogen-halogen exchange process was used [3,4]. Syntheses utilizing 123I (t1/2 13 h) or 131I (t1/2 8 d) can be performed with little loss of the radionuclide in these relatively slow processes; iodinations involving 122I require fast synthetic routes. Iodination of the 2,5-dimethoxy-N,N-dimethylamphetamine with ICl required high temperature, an organic reaction medium and preformation of radio-labelled ICl [7]. The para-dimethoxy orientation of this 2,5-dimethoxy analogue did not activate the ring sufficiently for direct electrophilic iodination by methods such as chloramine-T [8]. The syntheses of the corresponding meta-dimethoxy-N,N-dimethylamphetamine counterparts are described here. These compounds have proven sufficiently activated to allow direct radio-iodination employing chloramine-T in an aqueous medium.

The synthetic procedures leading to the three meta-substituted compounds were the same, starting with appropriate precursors, and are outlined in Scheme 1. Dimethoxybenzaldehyde was reacted with nitroethane (as both reagent and solvent) with a catalytic amount of ammonium acetate via the Knoevenagel reaction [9]. The resulting nitrostyrene 1 was reduced to the phenylacetone 2 with elemental iron in acetic acid [10]. Reductive amination of the ketone with dimethylamine and sodium cyanoborohydride [11] yielded the tertiary amine 3 which was iodinated directly in an aqueous system containing either 122I-iodide or 125I-iodide and chloramine-T (CAT).
The resulting 122I-labelled meta-dimethoxy-N,N-dimethyliodoamphetamines 4 have been utilized in PET studies of cerebral perfusion in mongrel dogs. These agents demonstrate rapid brain uptake and long term retention in cerebral tissue and show promise as brain blood flow radiopharmaceuticals [12,13].

Experimental

(...)

2,6-Dimethoxybenzaldehyde was prepared by the procedure of Lambooy [14] except that butyllithium was used to form the lithiation product with meta-dimethoxybenzene (Aldrich Chemical Co.) followed by reaction with N-methylformanilide.

(...) Distillations were performed using a Kugelrohr apparatus at the temperatures and vacuum pressures indicated.

(...) (chromatography stuff)

2,6-Dimethoxy-beta-methyl-beta-nitrostyrene. 1a.

To a solution of 10.0 g of 2,6-dimethoxybenzaldehyde in 50 ml nitroethane there was added 0.5 g anhydrous ammonium acetate, and the mixture was held on the steam bath for 2 h. The solvent was removed in vacuo giving a heavy reddish oil which, upon dissolving in 25 ml hot methanol and cooling, yielded bright yellow crystals, 12.0 g (90% yield), m.p. 101.5-102.5°C.

In the same manner, 3,5-dimethoxy-beta-methyl-beta-nitrostyrene (1b) was prepared (94% yield), m.p. 87-88°C (lit. value m.p. 88°C [15]).

In the same manner, 2,4-dimethoxy-beta-methyl-beta-nitrostyrene (1c) was prepared (77% yield), m.p. 78-79°C (lit. value m.p. 76-78°C, [16]).


2,6-Dimethoxybenzylmethyl ketone. 2a.

A solution of 11.5 g of 1a in 80 ml warm acetic acid was added to a suspension of 35 g of electrolytic iron dust in 150 ml acetic acid. The mixture was heated on the steam bath until a vigorous reaction set in. The resulting paste was diluted with another 40 ml acetic acid and heated for an hour. The reaction was quenched in 1.5 L water with stirring, decanted from unreacted Fe and extracted with 3 x 100 ml methylene chloride. The pooled extracts were washed with 50 ml 5% NaOH and the solvent removed in vacuo to yield 10.5 g of a pale amber oil. This was distilled in vacuo giving 8.7 g (86% yield) of a colorless oil (95-105°C/0.4 mmHg).

In the same manner, the 3,5-dimethoxybenzylmethyl ketone (2b) colorless oil was prepared (83% yield; 110-130°C/0.3 mmHg).

In the same manner, 2,4-dimethoxybenzylmethyl ketone (2c) colorless oil was prepared (65% yield; 125-145°C/0.5 mmHg).


2,6-Dimethoxy-N,N-dimethylphenylisopropylamine. 3a.

A solution of 7.6 g of 2a in 100 ml methanol was added to a warm solution of 25 g dimethylamine hydrochloride in 60 ml methanol. With vigorous stirring there was added 3.3 g NaCNBH3, followed by conc. HCl dropwise as needed to maintain the reaction medium at a pH of about 6. When acid was no longer required (about 48 h) the methanol was removed in vacuo and the residue poured into 2 L of dilute sulfuric acid. The mixture was extracted with 2 x 100 ml methylene chloride (discarded), made basic with 25% NaOH and reextracted (3 x 100 ml methylene chloride). The pooled extracts were stripped of solvent, giving 2.38 g of a colorless oil which was distilled (110-120°C/0.4 mmHg), yielding 1.49 g (17% yield) of a white oil. The perchlorate salt was recrystallized from isopropanol and ether, m.p. 109-110°C.

In the same manner, 3,5-dimethoxy-N,N-dimethylphenylisopropylamine (3b) was prepared, 3.3 g, from 7.4 g of the ketone (39% yield), m.p. of the perchlorate salt 100-101°C.

In the same manner, 2,4-dimethoxy-N,N-dimethylphenylisopropylamine (3c) was prepared, 10.6 g from 12.4 g of the ketone (74% yield), m.p. of the perchlorate salt 98-98.5°C.


2,4-Dimethoxy-N,N-dimethyl-5-125I-phenylisopropylamine. 125I-4c.

(...) (ug synthesis, see the original text)

Employing the above optimum conditions, 2,6-dimethoxy-N,N-dimethyl-3-125I-phenylisopropylamine (125I-4a) was prepared (50% yield in 1 min).

In the same manner, 3,5-dimethoxy-N,N-dimethyl-2-125I-phenylisopropylamine (125I-4b) was prepared (83% yield in 1 min).


2,6-Dimethoxy-N,N-dimethyl-3-122I-phenylisopropylamine. 122I-4a.

(...) (ug synthesis, see the original text)

The assignment of the iodine substitution position and the chromatographic characteristics of nonradioactive 4a were established by a separate synthesis employing millimolar quantities of sodium iodide and 3a. To a solution
containing 150 mg (0.67 mmole) 3a and 120 mg (0.80 mmole) NaI in 30 ml 0.25 M H3P04 there was added 229 mg (1.0 mmole) CAT. The reaction was allowed to proceed at 60°C for 5 min and was quenched with 300 mg (1.6 mmole) Na2S205. The solution was made basic with NaOH and extracted with CH2Cl2 (3 x 30 ml). The iodinated product (46% yield) was separated from the starting material (3a) and side products by semi-preparative HPLC. The HPLC and TLC chromatographic   . characteristics of 4a were identical to 125I-4a and 122I-4a. The major side-product (20% yield) using a stoichiometric excess of CAT in these nonradioactive procedures proved to be the 3-chloro analog (3-chloro-2,6-dimethoxy-N,N-dimethylphenylisopropylamine) as established by NMR of a chromatographically separated sample. The positional assignment of both halides (as shown by NMR, q.v.) is the same as that reported for the bromination of 2,6-dimethoxyphenylisopropylamine [17].

In the same manner, 3,5-dimethoxy-N,N-dimethyl-2-122I-phenylisopropylamine (122I-4b) was prepared (68% incorporation of 122I removed from the loop). The synthesis of nonradioactive 4b (60% yield) was conducted as with 4a. The chromatographic characteristics of 4b were identical to 125I-4b and 122I-4b.

In the same manner, 2,4-dimethoxy-N,N-dimethyl-5-122I-phenylisopropylamine (122I-4c) was prepared (85% incorporation of 1221 removed from the loop). The synthesis of nonradioactive 4c (65% yield) was conducted as with 4a. The chromatographic characteristics of 4c were identical to 125I-4c and 122I-4c.

A summary of the yields of 125I- and 122I-labelled 4a, 4b and 4c and the chromatographic data is given in Table 3.

References

[1]. Sargent III, T., Kalbhen, D. A., Shulgin, A. T., Braun, G., Stauffer, H. and Kusubov, N. - Neuropharmacology 14:165 (1975).
[2]. Braun, U., Shulgin, A. T., Braun, G. and Sargent III, T. - J. Med. Chem. 20:1543 (1977).
[3]. Winchell, H. S., Baldwin, R. M. and Lin, T. H. - J. Nucl. Med. 21:940 (1980).
[4]. Tramposch, K. M., Kung, H. F. and Blau, M. - J. Med. Chem. 26:121 (1983).
[7]. Sargent III, T., Shulgin, A. T. and Mathis, C. A. - J. Med. Chem. 27:1071 (1984).
[8]. Seevers, R. H. and Counsell, R. E. - Chem. Rev. 82:575 (1982).
[9]. Jones, G. - Org. Reactions 15:204 (1967)
[10]. Heinzelman, R. V. - J. Amer. Chem Soc. 75:921 (1953).
[11]. Borch, R. F., Bernstein, M.D. and Durst,. H. D. - J. Amer. Chem Soc. 93:2897 (1971).
[12]. Mathis, C.A., Sargent III, T., Shulgin, A. T., Yano, Y., Budinger, T. F. and Lagunas-Solar, M. - J. Nucl. Med. 26:P69 (1985).
[13]. Mathis, C. A., Sargent III, T. and Shulgin, A. T. - "122I-Labeled Amphetamine Derivative with Potential for PET Brain Blood Flow Studies" -J. Nucl. Med., in press.
[14]. Lambooy, J. P. - J. Amer. Chem. Soc. 76:133 (1954).
[15]. Ahmad, S., Whalley, W. B. and Jones, D. F. - J. Chem. Soc. (C) 3590 (1971).
[16]. Glennon, R. A., Liebowitz, S.M. and Anderson III, G. M. - J. Med Chem. 23:294 (1980)
[17]. Bailey, K., Gagne, D. R. and Pike, R. K. - J. Assoc. Official Anal. Chemists 59:1162 (1976).

Chimimanie

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DOI
« Reply #2 on: May 13, 2003, 08:16:00 AM »
Synthesis of 123I-labelled 4-Iodo-2,5-Dimethoxyphenylisopropylamine
Gisela Braun, Alexander T. Shulgin, and Thornton Sargent III

Journal of labelled Compounds and Radiopharmaceuticals Vol XIV, No. 5, p 767-773

(http://members.lycos.co.uk/chimimanie/jlcarp-14-767.PDF)

Abstract

A rapid and convenient synthesis of the psychotomimetic agent 4-iodo-2,5-dimethoxyphenylisopropylamine is described, incorporating the radioisotope 123I (T1/2 13 hr). With the amine function of
2,5-dimethoxyphenylisopropylamine blocked as the phthalimide, it was found that the aromatic 4-position could be directly iodinated with iodine monochloride. The phthalic acid moiety was rapidly removed with hydrazine in butanol to provide the title compound, as the hydrochloride salt; in an overall yield of 10% and in a reaction time of less than one half-life.

Key words: 4-iodo-2,5-dimethoxyphenylisopropylamine, iodine-123, iodine monochloride, psychotomimetics.

Introduction

4-Bromo-2,5-dimethoxyphenylisopropylamine (DOB) is known to be a centrally active agent in man [1] and has been found, through labelling experiments em-ploying 77Br and 82Br, to be actively taken up in the brain and lung of human subjects [2]. The relatively high energies of the gamma radiation of these two isotopes limit their usefulness as visualization agents in scintigraphic studies. (...) These properties prompted the synthesis of the iodine analog of DOB, 4-iodo-2,5-dimethoxyphenylisopropylamine (DOI, 4) using 123I. However, its relatively short half-life (13 hr) requires an appropriately rapid synthetic method, the subject of this report.

The direct iodination of 2,5-dimethoxyphenylisopropylamine 1 was tried employing a variety of procedures. The attempted direct halogenation of the amine salt of 1 with I+ or ICl, a procedure which is successful with elemental bromine [1] and chlorine [3] leads to preferential oxidation of the amine function. Amine derivitization as the acetamide provided protection against oxidation, but deacetylation of the iodinated intermediate could not be achieved with an acceptable yield and speed [4]. Protection of the amine was also possible with the easily removable tertiary butyl carbamate, but this "t-BOC" derivative could not be successfully iodinated under neutral conditions, employing the usual forms of I+. More acidïc iodination conditions invariably hydrolysed the carbamate linkage of 5 preferentially, leading to decomposition.

The phthalide group was found to be sufficiently stable to allow iodination of the ring of 2 directly with iodine monochloride to provide the amide 3 which could be quickly hydrolized with hydrazine in butanol without isolation. The title compound 4 was then obtained by hydrolysis, as the hydrochloride salt with a radioisotopic incorporation efficiency of 10%. The identity of the incorporated halide (iodide rather than chloride) was established by chemical ionization mass spectroscopy. The in vivo distribution and brain uptake kinetics of 4 in experimental animals are reported elsewhere [5,6].

Experimental

2,5-Dimethoxyphenylisopropylamine. 1

A solution of 38 g of 1-(2,5-dimethoxyphenyl)-2-nitropropene in 200 ml THF was added to a well-stirred, refluxing suspension of 32 g LiAlH4 in 750 ml THF and 75 ml anh. ether, at a rate that maintained reflux temperature without external heat. The addition required about 3 hr. Following 20 hr of refluxing, the suspension was cooled externally in ice, and with strong stirring there was added in sequence (against a flow of nitrogen) 32 ml H20 diluted with 2x volumes of THF, 32 ml of 15 N NaOH, and finally 96 ml H2O. Stirring was continued until the resulting suspension was completely white. The salts were removed by filtration, and the filter cake was washed with additional THF. The mother liquor and washings were pooled, and the solvent removed in vacuo to provide a residual amber oil. This crude product (36.7 g) was dissolved in 200 ml CH2Cl2, extracted with 3x150 ml dilute HCl, the pooled extracts washed with CH2Cl2, made basic with 25% NaOH, and re-extracted with CH2Cl2. The pooled extracts were washed with saturated brine, and the solvent removed in vacuo to provide a colorless oil (28.5 g). This was dissolved in anh.  ether saturated with anh. HCl, filtered, washed with ether, and air-dried to provide the hydrochloride salt of 1 (27.4 g) with a yield of 70%. The m.p. was 115-118°; lit. 111.5-112.5° [7]; 105-106°, increasing with hydration [8].

Attempted iodination with hypoiodite ion

A solution of 1.15 g 1.HCl (5 mM) in 50 ml H20 was neutralized with NaOH and stabilized at pH 7.5 with 0.5 M phosphate buffer. With good stirring and at ambient temperature, a solution of 2.5 g KI in 50 ml pH 7.5 phosphate buffer (0.5 M) was added followed by a suspension of 4.2 g Chloramine T in 100 ml H20 containing 0.05 mol. NaH2P04 and adjusted to a pH of 7.5 with NaOH solution using an external pH meter. The mixture became immediately opaque, developed an orange-red coloration, and within a few seconds began to deposit a dark-colored insoluble oil on the walls of the flask. After one minute a solution of 3.0 g Na2S204 in 50 ml H20 was added. The entire reaction mixture was made basic (pH above 10) and extracted with 3x125 ml CH2Cl2. The pooled extracts were extracted with .5 N H2S04 (2x100 ml), these extracts were pooled, washed with CH2Cl2, made basic with 5% NaOH, and re-extracted with CH2Cl2. Removal of the solvent left an amber oil which was dissolved in 75 ml anh. ether. After standing for an hour, an insoluble gum was deposited. The solution was decanted and saturated with anh. HCl gas. The separated crystals proved to be unchanged 1.HCl (i.r., m.p. and m.m.p.). (0.65 g, 56% recovery).


N-[1-(2,5-Dimethoxyphenyl)-2-propyl]-tert-butylcarbamate. 5

A solution of 3.90 g 1 (20 mM, 3.4 ml N3C02C(CH3)3 (20% excess), and 4.1 ml triethylamine (100% excess) in 75 ml dry THF was held at reflux on the steambath for 1.5 hr. The volatiles were removed in vacuo, and the residual oil was flooded with water (600 ml) and extracted with CH2Cl2. The pooled extracts were evaporated to a residual oil which spontaneously set to a pale yellow solid. This was recrystallized from 20 ml of boiling methanol, washed sparingly with cold methanol, and air dried to yield the product as a white crystalline solid, m.p. 93-94°, 3.60 g (yield 61%).

Attempts to iodinate 5 in aqueous suspension under the hypoiodite conditions described above, or under homogenous conditions employing ICl (as described below for the phthalide derivative) resulted in no detectable nuclear iodination (as determined by the failure to incorporate 131I into the isolated organic base fraction).


N-[1-(2,5-dimethoxyphenyl)-2-propyl]-phthalimide. 2

A suspension of 14.8 g phthalic anhydride (0.1 mol.) in 19.5 g 1 as the free base (0.1 mol.) was heated gradually with a soft flame to 150°, and the temperature maintained until the evolution of water had ceased. The resulting clear amber solution was allowed to cool to about 50° and 100 ml of hot methanol was added. The solution was stirred until homogenous, seeded with product, and cooled in an ice bath to complete crystallization. The product was removed by filtration and washed with cold methanol. Weight 24.6 g, m.p. 105-106° (lit. 105.5-106°, ref. [9]).


4-123I-2,5-Dimethoxvphenylisopropylamine. 4

A fresh, cold solution of 0.12 ml ICl in 2.5 ml acetic acid was added directly to the aqueous 123ICl solution containing 62 mCi of 123I. The resulting pale-brown solution was added to a solution of 500 mg of 2 (1.54 mM) in 6 ml acetic acid which had been heated to 40° with an external water bath, and stirred with a magnetic stirrer. The stirring was continued for 45 min, and then the reaction solution was quenched by pouring into 200 ml of water containing a few hundred milligrams each of KI and Na2S204. The colorless aqueous suspension was extracted with CH2Cl2 (3x75 ml), the extracts pooled, washed with an aqueous solution of KI and Na2S204, and the organic phase evap-orated in vacuo. The residual colorless oil spontaneously crystallized, and was used directly in the following step without isolation or further purification. In non-radioactive runs, this product, N-[1-(4-iodo-2,5-dimethoxyphenyl)-2-propyl]-phthalimide 3 was isolated and characterized. Fine white crystals from methanol, m.p. 103-103.5°. Mixed melting point with 2, 85-98°. Anal: CHN.
 
The intermediate compound 3 was dissolved in 10 ml n-butanol containing 0.5 ml 95% NH2NH2. The clear solution was placed in a boiling water bath and swirled with occasional venting as needed. The solution became progressively cloudy and developed a yellow-brown color. After a few minutes, the cloudiness cleared, there was a deposition of a cottage cheese-like precipitate, and a concurrent fading of the color. An additional 2 ml of butanol was added, and the heating continued for a total of 15 min. The reaction mixture was cooled and the solids broken up under dilute HCl. The resulting suspension was filtered, and the solids washed with additional HCl. The combined mother liquor and washings were washed with methylene chloride (discarded), made basic with NaOH (pH above 9), and extracted with CH2Cl2 (3x50 ml). The combined extracts were washed with water, decanted to a fresh dry centrifuge tube to remove particulate water, and extracted with 3.5 ml 0.1 N HCl. The phases were separated by centrifugation, and the aqueous phase removed for sterilization (by millipore filtration) and radioactivity assay. The retained activity in the final product was 3.6 mCi representing a specific activity of 35.7 mCi/mM available at the time of animal administration. Non-radioactive preparations provided samples of 4 which were characterized physically and chromatographically.

The properties of these speciments were identical in all respects with those reported [9].

References

[1] Shulgin A.T., Sargent T. and Naranjo C. - Pharmacology 5: 103 (1971).
[2] Sargent T., Kalbhen D.A., Shulgin A.T., Braun G., Stauffer H. and Kusubov N. Neuropharmacology 14: 165 (1975).
[3] Shulgin A.T. - Unpublished data.
[4] Coutts R.T. and Malicky J.L. - Can. J. Chem. 51: 1402 (1973).
[5] Sargent III T., Budinger, T.F., Braun G., Shulgin A.T. and Braun U. - J. Nucl. Med., Submitted.
[6] Sargent III T., Braun G., Braun U., Budinger T.F. and Shulgin A.T. - J. Biol. Psychiat. Submitted.
[7] Ho B.T., McIsaac W.M., An R., Tansey L.W., Walker K.E., Englert L.F. and Noel M.B. - J. Med. Chem. 13: 26 (1970).
[8] Bailey K.. Legault D. and Verner D. - J.A.O.A.C. 57: 70 (1974).
[9] Braun U., Shulgin A.T., Braun G. and Sargent III T. - J. Med. Chem. In Press.

Chimimanie

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Deutero DMT
« Reply #3 on: May 13, 2003, 11:29:00 AM »
Indolealkylamine metabolism: synthesis of deuterated indolealkylamines as metabolic probes
Philip E. Morris, Jr. and Cheng Chiao

Journal of labelled Compounds and Radiopharmaceutical. Vol XXXIII, No. 6, p 455-465

(http://members.lycos.co.uk/chimimanie/jlcarp-33-455.PDF)

Abstract

The synthesis of the deuterium labeled, endogenously occurring, indolealkylamine hallucinogens N,N-dimethyltryptamine and 5-methoxy-N,N-dimethyltryptamine via reduction of amide intermediates with lithium aluminum deuteride is described. The compounds were characterized with 1H, 2H and 13C NMR. These compounds were synthesized for use as probes for investigating the metabolism of these compounds by MAO via the in vivo kinetic isotope effect.

Key words: Deuterium Label, Endogenous Hallucinogen, Indolealkylamine, Monoamine Oxidase, Metabolism, In Vivo Kinetic Isotope Effect.   '

Introduction

The indolealkylamine hallucinogens N,N-dimethyltryptamine (DMT, 4) and 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) have been identified as normal constituents of human blood, [1-6] urine, [7-10] cerebrospinal fluid [11,12] (CSF) as well as in a variety of plant species. DMT has also been identified as a putative neurotransmitter or neuromodulatory substance in rat brain.[13] The indole-N-methyltransferase enzymes capable of synthesizing DMT and 5-MeO-DMT from tryptamine derived from L-tryptophan and S-adenosyl-methionine have been described and characterized in human lung, brain, blood and CSF and in various mammalian species.[14]

Numerous groups have attempted to relate mental disorders such as schizophrenia to high brain concentrations of these compounds resulting from perhaps a metabolic error, but a clear relationship between the two has not yet been delineated. However, the in vivo production of these interesting compounds strongly suggests that they serve some physiological role which is not yet understood.

For a number of years our group has been interested in studying the pharmacological properties of DMT and related indolealkylamines, in particular the in vivo metabolism. Indole-3-acetic acid (IAA) has been identified as the major in vivo metabolite of DMT. IAA is formed presumably via rapid oxidative deamination by monoamine oxidase (MAO) and is then excreted in urine.[15] These studies are in good agreement with more recent studies which have shown that DMT is essentially cleared from whole rat brain in ca. 30 minutes and that DMT is undetectable in the liver and blood plasma after 30 minutes. [16]  The dominance of the deamination pathway makes it difficult to study the minor metabolites. Traditionally this difficulty has been surmounted by pre-treating animals with a MAO inhibitor such as pargyline. Inhibition of the major catabolic route leads to "shunting" to the minor metabolic routes, facilitating the study of the minor metabolites. Unfortunately pre-treatment of animals with pargyline can give experimental results which are difficult to interpret since pargyline also inhibits the N-oxidation and demethylation of DMT by 90%.[17] This observation suggests that the reported potentiation of the behavior-disrupting effects and the reported tissue levels of DMT measured in animals pre-treated with pargyline may not have been solely due to MAO inhibition.

Mechanistically, the deamination step presumably involves abstraction of an alpha-proton in the rate determining step of the reaction followed by deamination. This assumption led our group to speculate that substitution of the alpha and beta protons of the ethylamine side-chain with deuteriums would produce the same effect via an in vivo kinetic isotope effect as pre-treatment with an appropriate MAO inhibitor (3). Thus a 2H-labeled compound would be an attractive alternative to pre-treatment with a MAO inhibitor for metabolic studies.

The results of the metabolism study using alpha, alpha, beta, beta-tetradeutero-N,N-dimethyltryptamine ([2H]4DMT, 3) have been published.[18] The labeled compound was metabolized at a significantly slower rate than proteo-DMT (4) and has indeed proved useful as a metabolic probe for studying the minor metabolic products. Although we concluded that the alpha-deuteriums were responsible for the observed isotope effect it is impossible to measure the contribution of the  alpha-deuteriums alone, since the ethylamine side-chain was fully deuterated. Although the beta-deuteriums are not involved mechanistically, it has been demonstrated in a similar system that the beta-deuteriums of aromatic ethylamines change the rate of deamination and produce a small rate enhancement. We are now interested in demonstrating unambiguously that the alpha-position is responsible for the observed effect and is the only position involved in the deamination step. For this reason, our present study requires compounds labeled only in the alpha-position.

In this paper the synthesis and spectral properties of dimethyltryptamine (7) and alpha,alpha-[2H]2-5-methoxy-N,N-dimethyltryptamine (10) and a convenient synthesis of [2H]4DMT (3) is presented. Complete 1H, 2H and 13C NMR assignments for [2H]4-5-MeO-DMT (11, isotopic purity of 97.5%) are also described.[19]

Results and discussion

Benington and Morin previously synthesized 3 in four steps from indole for use as an internal standard, however, its synthesis was not reported [20] In their synthesis indole was acylated with oxalyl chloride to give the 3-substituted indole which was immediately reacted with etherial dimethylamine to give the keto-amide (2). Reduction of the keto-amide with lithium aluminum deuteride (LAD) gave (3). Our group now utilizes commercially available indole-3-glyoxylic acid which affords the compound of interest in three steps. In a one-pot reaction the acid is converted to the acid chloride 1 with thionyl chloride which is not isolated but is immediately converted to the same keto-amide 2 by saturating the solution with dimethyl amine gas. In our hands, the preparation of 1 from the acid required low temperature and low concentration in order to prevent highly colored by-products. Attempts to isolate the acid chloride for analysis failed. (...)

Reduction of the keto-amide 2 with LAD gave 3 which was readily purified by sublimation under diminished pressure. For spectral comparisons, we also reduced a small amount of 2 with LAH to give proteo-DMT (4). (...)

Reaction of indole-3-acetic acid with thionyl chloride gave the acid chloride 5 which was reacted with dimethylamine to give the amide 6. Reduction with LAD afforded 7 which was purified by sublimation. (...)

Using the same procedure, 5-methoxyindole-3-acetic acid was converted to the acid chloride 8 which was then converted to the amide 9. Usual reduction and purification afforded 10. (...)

Experimental

(...)

2-(3-Indolyl)-glyoxal Chloride (1).

A solution of indole-3-glyoxylic acid (1.0 g, 5.3 mmol) in ether (100 mL) was stirred and cooled in a dry-ice bath for 15 min. SOCI2 (2.0 mL, 17 mmol) was then gradually added to the solution. TLC analysis (10% MeOH-90% Tol) of the mixture showed complete disappearance of indole-3-glyoxylic acid after 1 h and formation of a higher running compound with Rf 0.39.  The product was diluted with a large amount of dry ether and used directly without purification.

2-(3-Indolyl)-N,N-dimethylglyoxalamide (2).

Dimethylamine gas was passed through the etherial solution of 1 for 3-5 min and the reaction mixture was stirred continuously for an additional 20-30 min. Excess solvent was removed to give 2 (0.89 g, 4.1 mmol) as a solid in 77% yield based on indole-3-glyoxylic acid. Mp = 184-185°C (lit. 184-185°C)[19]

alpha, alpha, beta, beta-[2H]4dimethyltryptamine (3).

 To a stirred suspension of LAD (0.1 g, 2.4 mmol, 98%) in dry ether (8 mL) was gradually added the amide 2 (0.1 g, 0.46 mmol) in CH2CI2 (5 mL). The mixture was refluxed for 3-4 h in an oil bath, cooled in an ice bath, and treated with several drops of water to decompose excess LAD reagent. The reaction was vacuum filtered to remove any remaining solids, dried (MgS04), and solvents removed. The yield was 67% ( 0.06 g, 0.31 mmol). Mp = 47-49°C; MS 192 [M+], 132, 60 (100%). Isotopic purity = 94%.

N,N-dimethyltryptamine (4).

LAH reduction of 2 gave 4 in 76% yield (0.066 g, 0.35 mmol). Mp = 44-46°C (lit. 45-46°C); MS 188 [M+], 130, 77, 58 (100%).

2-(3-Indolyl)-acetyl chloride (5).
 
Indole-3-acetic acid (2.0 g, 11.4 mmol) was converted to the acid chloride (ether, 200 mL; SOCl2, 2.0 mL, 17 mmol) using the procedure described for the synthesis of 1.

2-(3-Indolyl)-N,N-dimethylacetamide (6).

Acid chloride 5 was converted to the amide 6 using dimethylamine as described for the synthesis of 2. Sublimation under diminished pressure gave 1.6 g (7.9 mmol, 69%) based on indole-3-acetic acid. Mp = 117-119°C. MS 202 [M+], 130 (100%), 77, 72; IR 1634 cm' (CO).
Anal. Calcd for C1ZH,4N20: C, 71.26; H, 6.98; N, 13.85. Found C, 71.13; H, 6.96; N,13.75.

alpha, alpha-[2H]2-N,N-Dimethyltryptamine (7).
 
LAD (0.1 g, 2.4 mmol, 98%) was suspended in dry ether (8 mL). The mixture was stirred and the amide 6 (0.25 g, 1.24 mmol) in CH2Cl2 (100 mL) was added over 5 min. The reaction was refluxed for 2-3 h in an oil bath at which time TLC analysis (MeOH) indicated disappearance of 6 and formation of a new spot at the origin. Workup as described for the synthesis of 3 and sublimation gave 0.16 g (0.84 mmol) of 7 in 68% yield. Mp = 44-46°C (lit. Mp = 44-46°C).19 MS 190 [M+], 130, 60 (100%). Isotopic purity = 97%.
Anal. Calcd for C12Hl4D2N2: C, 75.76; H plus D as H, 9.52; N, 14.73. Found C, 75.09; H plus D as H, 8.56; N, 14.45.

2-(5-Methoxy-3-indolyl)-acetyl Chloride (8).

5-Methoxyindole-3-acetic acid (0.5 g, 2.44 mmol) was converted to the acid chloride (CH2Cl2, 100 mL; SOCI2, 1.0 ml, 8.5 mmol) using the procedure described for the synthesis of 1.

2-(5-Methoxy-3-indolyl)-N,N-dimethylacetamide (9).

The acid chloride 8 was diluted with CH2Cl2 and immediately treated with dimethylamine gas. The excess solvent was removed and the crude product sublimed under diminished pressure. The yield was 74% (0.42 g, 1.8 mmol) based on 5-methoxyindole-3-acetic acid. Mp = 78-80°C. MS 232 [M+], 160 (100%), 145, 117, 72; IR 1629 cm-' (CO).

alpha,alpha-[2H]2 5-methoxy-N,N-dimethyltryptamine (10).

A suspension of LAD (0.1 g, 2.4 mmol, 98%) in dry ether (8 mL) was stirred and the amide 9 (0.25 g, 1.08 mmol) in CH2Cl2 (10 mL) gradually added. The mixture was refluxed for 2-3 h in an oil bath and then cooled to room temperature. Usual workup and purification gave 10 in 68% yield (0.16 g, 0.73 mmol) based on the amide 9. Mp = 49-51°C. MS 220 [M+], 176, 160, 145, 132, 117, 60 (100%). Isotopic purity = 99.7%.

References

[1]   B. Angrist, S. Gershon, G. Sathananthan, R. W. Walker, B. Lopez-Ramos, L. R. Mandel and W. J. A. VandenHeuvel, Psychopharmology, 47, 29 (1976).
[2]   T. G. Bidder, L. R. Mandel, H.S. Ahn, W. J. A. VandenHeuvel, and R. W. Walker, Lancet, 1, 165 (1974).
[3]   B. Heller, J. Narasimhachari, J. Spaide, L. Hakovec and H. E. Himwich, Experientia, 26, 503 (1970).
[4]   J. F. Lipinski, L. R. Mandel, H. S. Ahn, W. J. A. VandenHeuvel, and R. W. Walker, Biol. Psychiatry, 9, 89 (1974).
[5]   N. Narasimhachari, B. Heller, J. Spaide, L. Haskovec, H. Meltzer, M. Strahilevitz and H. E. Himwich, Biol. Psychiatry, 3, 21 (1971).
[6]   R. J. Wyatt, L. R. Mandel, H. W. Ahn, W. R. Walker and W. J. A. VandenHeuvel, Psychopharmacology, 31, 265 (1973).
[7]   S. A Checkley, M. C. H. Oon, R. Rodnight, M. P. Murphy, R. S. Williams and J. L. T. Birley, Am. J. Psychiatry, 136, 439 (1979).
[8] M. C. H. Oon, and R. Rodnight, Biochem. Med., 18, 410 (1977).
[9]   M. Raisanen and J. Karkkainen, J. Chromatogr., 162, 579 (1979).
[10]   R. Rodnight; R. M. Murray, M. C. H. Oon, I. F. Brockington, P. Nicholls and J.   L. T. Birley, Psychol. Med., 6, 649 (1976).
[11]   S.T. Christian, F. Benington, R. D. Morin and L. Corbet, Biochem. Med., 14, 191 (1975).
[12]   L. Corbett, S. T. Christian, R. D. Morin, F. Benington and J. R. Smythies, Brit. J. Psychiatry, 132, 139 (1978).
[13] S. T. Christian, R. Harrison, E. Quayle, J. Pagel and J. Monti, Biochem. Med., 18, 164 (1977).
[14]   H. Rosengarten and A. J. Friedhoff, Schizophr. Bull., 2, 90 (1976).
[15]   S. A. Barker, J. A. Monti and S. T. Christian, Int. Rev. Neurobiol., 22, 83 (1981).
[16]   I. Cohen and W. H. Vogel, Biochem. Pharmacol., 21, 1214 (1972).
[17]   S. A. Barker, J. A. Monti and S. T. Christian, Biochem. Pharmacol., 29, 1049 (1980).
[18]   S. A. Barker, J. M. Beaton, S. T. Christian, J. A. Monti and P. E. Morris, Biochem. Pharmacol., 33, 1395 (1984).
[19]   We thank Professors Fred Benington and Richard Morin of the University of Alabama at Birmingham for an authentic sample of 11.
[20]   F. Benington and R. D. Morin, personal communication.
[21] M. S. Morales-Rios, J. Espineira and P. Joseph-Nathan, Magn. Reson. Chem., 25, 377 (1987).

Chimimanie

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Full text version
« Reply #4 on: May 13, 2003, 04:57:00 PM »
Those are the pdf of the three above posted articles.

They include the graphics, some tables, and the full text.


Synthesis of 122I- and 125I-labelled meta-dimethoxy-N,N-dimethyliodophenylisopropylamines
Journal of Labelled Compounds and Radiopharmaceuticals Vol XXIII, No.2, p 115-125

http://members.lycos.co.uk/chimimanie/jlcarp-23-115.PDF






Synthesis of 123I-labelled 4-Iodo-2,5-Dimethoxyphenylisopropylamine
Journal of Labelled Compounds and Radiopharmaceuticals Vol XIV, No.5, p 767-773

http://members.lycos.co.uk/chimimanie/jlcarp-14-767.PDF






Indolealkylamine metabolism: synthesis of deuterated indolealkylamines as metabolic probes
Journal of Labelled Compounds and Radiopharmaceuticals Vol XXXIII, No.6, p 455-465

http://members.lycos.co.uk/chimimanie/jlcarp-33-455.PDF







Enjoy :)

Chimimanie

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deutero pemoline
« Reply #5 on: May 14, 2003, 08:05:00 AM »
Synthesis of pemoline-d5: a metabolic probe for hyperactivity Brian D. Andresen and Dan E. Weitzenkorn Journal of labelled Compounds and Radiopharmaceuticals 1978(15) 469-476

Abstract

The drug, pemoline-d5, 2-imino-5-phenyl-d5-4-oxazolidinone, was prepared by a four step synthesis from benzene- d6. The synthetic sequence required the preparation of dichloroaceto-phenone- d5, mandelic acid-d5 and ethyl mandelate-d5. Mass spectral as well as infrared data of the labelled drug are also presented.

Key Words: Pemoline, Deuterium Labelling, Dichloroacetophenone-d5, Mandelic Acid- d5, Mass Spectral and Infrared Absorption Data.

Introduction

Hyperactivity is a condition manifested by many learning disabled children which results in an impairment to their academic performance. Common characteristics often exhibited by hyperactive children include poor attention span, motor difficulties, low frustration tolerance, low perseverance, and organizational problems. This condition is diagnosed predominantly more often for boys than for girls. One of the current treatment methods for hyperactivity is drug therapy. Stimulant drugs, such as caffeine [1], amphetamines [2], methylphenidate [3], and pemoline [4], have been prescribed for both school age and preschool age children. These drugs are prescribed on the premise that hyperactivity is a function of attention deficiencies, therefore the stimulant drugs elevate the hyperactive individual to a normal threshold of attention at which he or she can concentrate.

The newest member of the group of drugs used to treat this learning impairment is pemoline. This drug is chemically different from amphetamine, caffeine or methylphenidate, but does possess some structural similarities to this group of compounds.

Currently considerable controversy exists in the literature regarding the effectiveness of pemoline in hyperactive children [5]. Additionally, serious doubts and interest have developed concerning the claim that pemoline can reverse senility and enhance memory in adults [6]. Literature articles have stated that pemoline was superior [7] to other hyperactive psychotropic drugs, ineffective [8], nontoxic [9], toxic [10], a drug of abuse [11], and decreased [12] as well as increased [13], RNA-synthesis. In addition, pemoline has been proposed as a radioresistive compound during cancer chemotherapy [14].

With such a diversity of biological activity reported, concerning this compound, it would appear reasonable to first consider the metabolic pathways of this drug and confirm whether the metabolites of the parent drug are active, inactive, or toxic. However, little has been reported concerning the metabolism and identification of metabolites of this controversial drug. A comprehensive review of the literature concerning this compound reveals only two sources identifying metabolites of pemoline. The first source, a drug monograph [7], regarding Cylert, pemoline, revealed pemoline-dione, mandelic acid and other polar metabolites. A second report [11], revealed that 35% of the administered drug is unaccounted for after 48 hours.

Therefore, because such a scant amount of information was available pertaining to the metabolism of a compound used extensively in children and the intriguing reports [6] of memory enhancement in adults, a labelled pemoline-d5 probe, 2-imino-5-phenyl-d5-4-oxazolidione, was prepared to aid in metabolic studies of the parent drug.

The labelled pemoline-d5 (V) was prepared by condensation of ethyl mandelate-d5 (IV) with guanidine (free base) in ethanol [15]. The precursor ethyl mandelate-d5 (IV) was prepared from benzene-d6 by a three step sequence. This required a Friedel-Crafts alkylation of hexadeuterobenzene (I) with dichloroacetylchloride, treatment of the generated dichloroacetophenone-d5 (II) with KOH to form mandelic acid-d5, and finally esterification of the mandelic acid-d5 in ethanol with dry HCl. Crystals of pemoline-d5 (V) precipitated from solution and were easily isolated after condensation of ethyl mandelate-phenyl-d5 (IV) with guanidine in ethanol.

Experimental

Dichloroacetophenone-d5 (II)

Five grams (60 mmoles) of benzene-d6, I, (Stohler Isotope Chemicals, Inc.)were added slowly over 15 minutes to 8.77 g (59 mmoles) of dichloroacetylchloride and 7.94 g (60 mmoles) AlCl3 in 25 ml CS2. The reaction mixture was protected from atmospheric moisture using a rubber septum and a 15 gauge needle to exclude moisture and allow the release of DCl. The reaction mixture was stirred at 25°C for two hours and then poured into 400 ml ice and 20 ml concentrated HCl. The oil and CS2 which separated were washed with 1N NaOH, and then with water. Evaporation of the CS2 yielded 7.35 g (63% yield) of an oil.

Mandelic acid-d5 (III)

All 7.35 g (38 mmoles) of dichloroacetophenone-d5 were slowly added to 6.0 g (150 mmoles) of NaOH in 50 ml H2O maintained at 65°C for three hours. At the end of that time 6.2 ml of 12 M HCl was added to the reaction mixture. The acidic solution was placed in a liquid-liquid extractor and the mandelic acid-d5 extracted with ethyl ether for 24 hours. After evaporation of the ether and recrystallization from benzene and ethanol 5.9 g (>99%) of mandelic acid-d5 were obtained. M.p. 120-121°C

Ethyl mandelate-d5 (IV)

All 5.9 g (38 mmoles) of mandelic acid-d5 were dissolved in 75 ml absolute ethanol to which anhydrous HCl was bubbled (1 hr) into the solution until saturated with gas. After 60 minutes some ethanol and most HCl were rotary evaporated away. To the remaining ethanol, 20 ml of an aqueous saturated NaHC03 solution was added and the mixture extracted with excess ethyl ether. Evaporation of the ether yielded 5.0 g (71%) of an oil, ethyl mandelate-d5.

Pemoline-d5 (V)

All 5.0 g (26 mmoles) of ethyl mandelate-d5 were added to guanidine (free base) in ethanol. The guanidine was prepared from 2.58 g (27 mmoles) of guanidine hydrochloride in 22 ml absolute ethanol to which was added 1.10 g (27.5 mmoles) NaOH in 1.2 ml H2O and 12 ml ethanol. NaCl was filtered off and the ethanol evaporated to a clear 10 ml solution. Crystals, 0.9 g (18.4% yield) of pemoline-d5 were filtered after the guanidine and ethyl mandelate-d5 were allowed to react at 25°C overnight. M.p. 235-236°C

Discussion

The preparation of 2-imino-5-phenyl-4-oxazolidinone was first reported by Traube and Ascher in 1913 [15]. The synthesis required only the condensation of ethyl mandelate with guanidine. The reaction occurs spontaneously at room temperature. Therefore, to prepare the deuterium labelled drug it was necessary to syn-thesize ethyl mandelate-phenyl-d5. An initial attempt to utilize a Grignard condensation of phenyl-d5-magnesium bromide with ethyl glyoxalate proved unsuccessful. However, a very good yield of mandelic acid-phenyl-d5 and its ester was obtained following standard procedures [16,17] utilizing a base hydrolysis reaction with phenyl-d5-dichloroacetophenone. The precursor, phenyl-d5-dichloroacetophenone, was prepared conveniently by the Friedel-Crafts alkylation of benzene-d6 (Stohler Isotope Chemicals, Inc.) in carbon disulfide. In an additional study dichloroaceto-phenone-phenyl-d5 was also prepared by the Friedel-Crafts alkylation of benzene-d6 using acetyl chloride. Dichloroacetophenone-phenyl-d5 was generated by bubbling excess chlorine gas into glacial acetic acid containing acetophenone-d5, following standard procedures [16].

(...) (spectroscopy stuff)

Conclusion

A relatively inexpensive scheme has been developed for the preparation of pemoline-d5. This labelled probe appears well suited for metabolism studies in which new metabolites can be identified by mass spectrometry. In addition, this labelled drug would appear well suited for use as an internal standard while monitoring blood levels of the parent drug in body fluids by combined GC-MS-computer techniques. Currently, work is in progress using this labelled probe to identify new metabolites of the parent drug in rats.

References

[1] Schnackenberg   R.C. - Am. J. Psychiatry 130: 796 (7973).
[2] Groves P.M. and Rebec, G.V. - Annual Review of Psychology 27: 91 (1976).
[3] Sykes D.H. et al - Psychopharm. 25: 262 (1972).
[4] Page J.G. et al - J. Learn. Disabilities 7: 42 (1974).
[5] Aaron H. (ed.) - The Medical Letter, Medical Letter, Inc. 18: issue 444, p. 5 (1976).
[6] Gilbert J.G. et al - J. Aging and Human Develop. 4: 35 (1973).
[7] Drug Monograph, "Pemoline", Abbott Laboratories Pharmaceutical Product Division, pp. 1-59 (1975).
[8] Goldberg M.E. and Ciofalo V.S. - Life Science 6: 733 (1967).
[9] Raven H.M. et al - Arzneimittal-Forsch 22: 2069 (1972).
[10] Knights R.M. and Vïets C. - Pharm. Biochem. and Behavior 3: 1107 (1975).
[11] Johnston L. - The PharmChem Newsletter 4: 1 (1975).
[12] Stein H.H. and Yellin T.O. - Science 157: 96 (1967).
[13] Muset   P.et al - Science 215: 522 (1967).
[14] LeVan   H. and Hebron D.L. - J. Pharm. Sci. 57: 1033 (1968).
[15] Traube W. and Ascher R. - Ber. 46: 2077 (1913).
[16] Aston   J.G.   et al -

http://www.orgsyn.org/orgsyn/prep.asp?prep=cv3p0538


[17] Eliel E.L. et al -

http://www.orgsyn.org/orgsyn/prep.asp?prep=cv4p0169

.
[18] Conley R.T. - Infrared Spectroscopy, Allyn and Bacon, Inc., Boston, p. 279 (1966).

Rhodium

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Shulgin: Human Pharmacodynamics of DOB
« Reply #6 on: March 15, 2004, 09:41:00 AM »
In Vivo Human Pharmacodynamics of the Psychodysleptic 4-Br-2,5-Dimethoxyphenylisopropylamine Labelled With 82Br or 77Br
T. Sargent. D. A. Kalbhen, A. T. Shulgin, Gisela Braun, H. Stauffer And Natalia Kusubov

Neuropharmacology 14, 165-174 (1975)

(https://www.thevespiary.org/rhodium/Rhodium/pdf/shulgin/shulgin.dob-pharmacodynamics.pdf)

Summary
The psychodysleptic compound 4-Br-2,5-dimethoxyphenylisopropylamine (4-Br-DPIA) was synthesized with 82Br or 77Br and administered to live human subjects in three oral and three intravenous experiments. In vivo organ concentrations were measured by gamma ray scintigraphy with computerized area integration, and by whole-body counting. Urine was analyzed by solvent separation, and thin layer chromatography of dansylated metabolites. The urine contained less than 5% radiobromine precipitable by acidic AgNO3, demonstrating that the Br label remained organically bound. Upon intravenous administration. radioactivity appeared immediately in the lungs by first-pass extraction. was rapidly released and reached maximum concentrations in the liver at 0.5-1.5 hr, plasma at 2-3 hr and brain at 3-6 hr. Orally the pattern was the same except that the initial lung concentration did not occur. This sequence of maximum organ concentrations suggests that a metabolite of 4-Br-DPIA is the centrally active compound which concentrates in the brain. Solvent separation of urine showed 81.8% of metabolites to be aqueous soluble and 12.5% free base; slower whole-body excretion correlated with higher levels of free base in the urine. The methods used demonstrate a new approach to the study of in vivo distribution and kinetics of drugs which can be labelled with gamma-emitting radioisotopes.

This article has been referenced in the following posts:

Post 428748

(Chimimanie: "some dimethoxy-N,N-dimethyl amphetamines", Novel Discourse)

Post 432948

(Chimimanie: "DOI", Novel Discourse)




Rhodium

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Synthesis of Deuterio-l-Amphetamine
« Reply #7 on: September 30, 2004, 06:54:00 AM »
Synthesis of Deuterio-l-Amphetamine, d1 Sulfate
R.L. Foreman, F.P. Siegel, R.G. Mrtek

J. Pharm. Sci. 58(2), 189-192 (1969)

(https://www.thevespiary.org/rhodium/Rhodium/chemistry/alpha-deuterio.amphetamine.html)

Abstract
In order to investigate the isotope effect on the enzymatic deamination of amphetamine, deuterio-l-amphetamine, d1 sulfate was synthesized by the selective reduction of phenyl-2-propanone oxime with lithium aluminum deuteride, followed by resolution of the racemic product. The yield of racemic amphetamine was 46% when approximately equimolar quantities of the oxime and LiAlD4 were employed. The identity of the deuterated amphetamine base was confirmed by determination of the physical properties of the racemic mixture. From NMR data, deuterium was found exclusively in the methine hydrogen position at a purity of greater than 99 atom%. The optical isomers of deuterioamphetamine were resolved through repeated fractional crystallization of the d-amphetamine-d-bitartrate and l-amphetamine-l-bitartrate diastereomers. The isomers were found to possess 97-99% optical purity, based on values for pure isomers of protioamphetamine. In vitro metabolism studies indicate that a significant deuterium isotope effect operates in the oxidative deamination of deuterio-l-amphetamine. Under specified conditions, the ratios of apparent rate constants (kH/kD) based on initial velocities, yield a value of 2.0±0.3.


Rhodium

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Synthesis of Deuterium-Labelled Drugs of Abuse
« Reply #8 on: October 01, 2004, 03:46:00 AM »
Synthesis of Deuterium-Labelled Drugs of Abuse. 1.
2,5-Dimethoxy-4-methylamphetamine (DOM) - Methamphetamine - Phencyclidine (PCP) - Methaqualone

Allison F. Fentiman, Jr. and Rodger L. Foltz

J. Label. Comp. Radiopharm. 12(1), 69-77 (1976)

(https://www.thevespiary.org/rhodium/Rhodium/chemistry/deuterated.psychoactives.html)

Summary
Four deuterium-labelled compounds were prepared for use as internal standards in the quantification of methamphetamine, DOM, PCP, and methaqualone at low levels in body fluids by selected ion monitoring. The need for standards containing more than three deuterium atoms per molecule and having high isotopic purity is discussed.