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All 17 posts Subject: Nichols: First synthesis of DOB (1971) Please login to post Down

Rhodium
(Chief Bee)
08-15-03 16:56
No 453757
User Picture       Nichols: First synthesis of DOB (1971)
(Rated as: good read)

Potential psychotomimetics. Bromomethoxyamphetamines
Charles F. Barfknecht, David E. Nichols
J. Med. Chem. 14(4), 370-372 (1971) (https://www.rhodium.ws/pdf/nichols/nichols-bromomethoxyamphetamines.pdf)

The article describes the synthesis, as well as the first animal trials ever, of the following compounds:

Compound (Pihkal Name) Active Rat Dose Effect

1) 2-Bromo-5-Methoxyamphetamine >25 mg/kg Inactive

2) 3-Bromo-4-Methoxyamphetamine 9 mg/kg CNS Stimulation (onset of amphetamine-type toxicity at 18 mg/kg)

3) 4-Bromo-3-Methoxyamphetamine 7.5 mg/kg Mescaline-like

4) 2-Bromo-4,5-Dimethoxyamphetamine (ORTHO-DOB) >25 mg/kg Inactive

5) 4-Bromo-3,5-Dimethoxyamphetamine (4-Br-3,5-DMA) <10 mg/kg Mescaline-like (Some deaths at 10 mg/kg, inactive at 5 mg/kg)

6) 4-Bromo-2,5-Dimethoxyamphetamine (DOB) <2.5 mg/kg Mescaline-like, effect much more profound than 2.5 mg/kg of DOM

^{Note: Compounds were considered inactive if they did not give any effect at 25 mg/kg, the rat activity level of mescaline.}

Could someone please type this article (with formatted tables) and post it below?

weedar
(martha stewart's little bitch)
08-16-03 10:02
No 453897
User Picture       J. Med. Chem. 14(4), 370-372 (1971)
(Rated as: excellent)

Will this do? smile

J. Med. Chem. 14(4), 370-372 (1971)

Potential Psychotomimetics.
Bromomethoxyamphetamines

Charles F. Barfknecht AND David E. Nichols

In the study of psychotomimetic amphetamines, 2,5-dimethoxy-4-methylamphetamine (DOM) is the
most potent compound yet discovered (50-150 times mecaline).² At least part of its
potency is related to the nature of the para substituent. In the light of Knoll's³
studies on the psychotomimetic effects of p-bromo-methampethamine and its
cross-tolerance to LSD, the synthesis and evaluation of bromomethoxyamphetamines appeared to
be a logical extension. Br has a comparable size, but different electronic character than
Me. Kand and Green⁴ have recently demonstrated a correlation between the electronic
character of the ring and the hallucinogenic potency of the methoxylated amphetamines. The
substitution of Br into various ring positions of methoxylated amphetamines allows for several
electronic arrangements.

Chemistry.-- The general synthetic route involved preparation of the appropriately
substituted benzaldehydes, condensation with EtNO₂ and reduction to the
bromomethoxymethamphetamines. Tables I and II summarize the compounds which have been prepared.
Attention is called to the report by Pandya and co-workers⁵ concerning the bromination
of m-hydroxybenzaldehyde. The product of this reaction is claimed to be
3-hydroxy-4-bromobenzaldehyde; however the product which we isolated proved to be
2-bromo-5-hydroxybenzaldehyde. This assignment was verified by nmr spectroscopy and chemical
conversion by O-methylation and permanganate oxidation to 2-bromo-5-methoxybenzoic acid. The
physical properties of this material agree with the literature values.⁶
The LAH reduction of 1-(bromomethoxyphenyl)-2-nitropropenes was complicated by the extreme ease
of debromination. Low temperatures and equimolar amounts of reagents prevented the debromination,
but resulted in poor yields of the bromomethoxyamphetamines.
Biological Results.-- The compounds were tested for an effect on a conditioned avoidance
response in male rats. The detailed procedure has been reported previously.⁷ The effects
were compared with those produced by mescaline, 3,4-dimethoxymethamphetamine, DOM, and the
CNS-stimulant dextroamphetamine. This assay gives an indication wether the compound possesses
stimulant action or one more like that of mescaline, 3,4-DMA, and DOM. Table III summarizes
the biological data. All the compounds which exhibited an effect similar to mescaline-type
compounds have the p-Br substituent.⁸ The data on the 2-bromo-5-methoxy
analog(3) must be considered tentative, since 2,5-dimethoxyamphetamine which does not
have a para substituent is active in humans but inactive in rats.⁹ A correlation
has been demonstrated between the degree of fluorescence and the psychotomimetic potency for
methoxylated amphetamines; no such relationship seems to exist for this series.¹⁰
For example, 2 and 6 have nearly the same degree of fluorescence, but differ
widely in their biological effects. A detailed study of the pharmacology is in progress.

Experimental Section¹¹

Bromomethoxybenzaldehydes.--All substituted benzaldehydes have been reported previously
with the exception of 2,5-dimethoxy-4-bromobenzaldehyde and 3,5-dimethoxy-4-bromobenzaldehyde,
whose syntheses are described below.

3,5-Dimethoxy-4-bromobenzaldehyde.--3,5-Dihydroxy-4-bromobenzoic acid (K & K Laboratories,
Inc.) was di-O-methylated with Me₂SO₄ in the usual manner: yield 78%
(EtOH-H₂O); mp 249-250° (lit.¹² 249-50°). The acid chloride was obtained
by reaction with SOCl₂. The crude product (mp 124-128°) was used in the next step
without further purification. The aldehyde was obtained by reduction of the acid chloride by
LiAlH(O-tert-Bu)₃ as described by Ho, et al.¹³ The crude
aldehyde was recrystd from MeOH-H₂O; yield 52%; mp 112-114°.

2,5-Dimethoxy-4-bromobenzaldehyde.--2,5-Dimethoxybenzaldehyde (66.5 g, 0.4 mole) was
dissolved in 300 ml of CH₂Cl₂. Anhyd SnCl₄ (115 g, 0.44 mole)
was added, followed by 64 g of Br₂ over a 1-hr period. The resulting soln was
refluxed for 2 hr and stirred overnight at room temp. The orange suspension was poured over
500 g of ice, and the layers were sepd. The CH₂Cl₂ layer was washed with
10% NaHCO₃ and H₂O and dried (Na₂SO₄). After
filtration the solvent was removed in vacuo, and the solid residue recrystd from
MeOH-H₂O to yield 64 g (66%) of the aldehyde, mp 132-3°. The structure was
confirmed by the oxidation with MnO₄- to 2,5-dimethoxy-4-brombenzoic acid, mp 170°
(lit.¹⁴ mp 170°).

Substitued-1-phenyl-2-nitropropenes.-- The substitued benzaldehydes were refluxed with
EtNO₂ and NH₄OAc in AcOH as described by Gairaud and Lappin.¹⁵

Bromomethoxyamphetamine Hydrochlorides.-- All amphetamines were prepared from the
corresponding 1-phenyl-2-nitropropenes by LAH reduction.¹⁶

Table I
Substitued 1-Phenyl-2-nitropropenes

R₂ R₃ R₄ R₅ R₆ Mp, °C Yield, %

Br H H OCH₃ H 73-74.5 61.8

H Br OCH₃ H H 73-74 45

H OCH₃ Br H H 73-74.5 36.8

Br H OCH₃ OCH₃ H 105-106 59.4

H OCH₃ Br OCH₃ H 121-121.5 46.8

OCH₃ H Br OCH₃ H 113.5-115 57

Table II
Bromomethoxyamphetamine hydrochlorides

Compd R₂ R₂ R₂ R₂ R₂ Mp, °C Yield, %

1 Br H H OCH₃ H 151.5-153 20

2 H Br OCH₃ H H 210-213 28.8

3 H OCH₃ Br H H 161.5-163 32

4 Br H OCH₃ OCH₃ H 214-215.5 42

5 H OCH₃ Br OCH₃ H 221-222 36.8

6 OCH₃ H Br OCH₃ H 198-199 29.5

Table III
Biological Results

Compd Treshold_alpha dose, mg/kg Action

1 25 Inactive

2 9 CNS stimulation;onset of amphetamine-type toxicity at 18 mg/kg

3 7.5 Mescaline-like

4 25 Inactive

5 <10 Mescaline-like with some deaths at 10; inactive at 5 mg/kg

6 <2.5 Mescaline-like; effect much more profound than that caused by 2.5 mg/kg of DOM

alpha Dose at which action was observed; any compd which does not show mescaline-like
effect at 25 mg/kg (the "effective" dose of mescaline) is considered inactive. The treshold dose
of 3,4-dimethoxyamphetamine.Hcl and DOM.Hcl are 12.5 and 2.5, resp.

References:
(1)
(2) A.T. Shulgin, T. Sargent, and C. Naranjo, Nature(London), 221, 537 (1969).
(3) J. Knoll in "amphetamiens and Related Compounds," E. Costa and S. Garttini, Ed., Raven Press,
New York, N. Y., 1970, p 761.
(4) S. Kang and J.P. Green, Nature(London), 226, 645 (1970).
(5) K. C. Pandya, R. B. K. Pandya, and R. N. Singh. J. Indian Chem. Soc., 29, 363 (1952).
(6) P. H. Beyer, Red. Trav. Chim. Pays-Bas, 40, 621 (1921).
(7) C. F. Barfknecht, J. M. Miles, and J. L. Leseney, J. Pharm. Sci., 59, 1842(1970).
(8) During the revision of this manuscript, Dr. A. T. Shulgin informes us that
4-bromo-2,5-dimethoxyamphetamine has a potency in humans greater than DOM and an effect similar to
3,4-methylenedioxyamphetamine; Pharmacology, in press.
(9) J. R. Smythies, Neurosci. Res. Program Bull., S, 79(1970).
(10) F. Antun, J. R. Smythies, F. Benington, R. D. Morin, C. F. Barfknecht, and D. E. Nichols,
Experentia, in press.
(11) Melting points were taken on a Hoover Uni-Melt apparatus and are corrected. Where analyses are
indicated only by symbols of the elements, anal. results obtained for those elements were within +/- 0.4%
of the theoretical values. Nmr spectra for all compounds were obtained on a Varian Associates T-60 and
are consistent with the assigned structures.
(12) H. Erdtman and B. Leopold, Acta Chem. Scand., 2, 34(1948).
(13) B. T. Ho, W. M. McIssac, R. An, L. W. Tansey, K. E. Walker, L. F. Englert, Jr., and M. B. Noel,
J. Med. Chem., 13, 26(1970).
(14) A. Luttringhaus and H. Gralheer, Justus Liebigs Ann. Chem., 550, 67(1941).
(15) C. B. Gairaud and G. R. Lappin, J. Org. Chem., 18, 1(1953).
(16) L. F. Fieser and M. Fieser, "Reagents for Organic Synthesis," Wiley, New York, N. Y., 1967, p 581.

Edit: Some "minor" typos corrected, thanks Chimimanie! smile

Tant pis!

Aurelius
(Active Asperger Archivist)
08-16-03 17:51
No 453936
      Changes

In the table? is this Lilienthal's work, or did you write the table differently yourself?

Act quickly or not at all.

weedar
(martha stewart's little bitch)
08-17-03 01:46
No 453997
User Picture       I can't take credit

seems like Lili is playing with the style-sheet configuration,
so if the tables change (in appearance), it is Lili's work,
not mine.
(although I'd love to hear of ways to make tables look more
"readable" using this board-software)

Tant pis!

Aurelius
(Active Asperger Archivist)
08-17-03 06:50
No 454059
      Lilienthal

BTW, yes, some of us do notice the subtle differences made.

Act quickly or not at all.

Rhodium
(Chief Bee)
08-17-03 12:22
No 454098
User Picture       Hive layout changed to HTML4/CSS2

It is not as subtle as you think, Lili has changed the whole Hive layout to HTML4/CSS2 (check the source). Don't you all notice that the pages are loading a lot faster, due to far shorter code needed to display the same page?

Nicodem
(Hive Bee)
03-12-04 08:56
No 494577
      The ref. 13 of the above post
(Rated as: excellent)

Analogs of alpha-Methylphenethylamine (Amphetamine). I. Synthesis and Pharmacological Activity of Some Methoxy and/or Methyl Analogs.
Ho, McIsaac, An, Tansey, Walker, Englert, Noel
Journal of Medicinal Chemistry 13, 1970, 26-30.

Abstract: A series of amphetamine derivatives substituted on the benzene ring with MeO and/or Me groups was synthesized. The pharmacological activity of these compounds was evaluated for toxicity, effects on barbiturate sleeping time, and ability to disrupt mouse behavior. Those which were active in behavioral disruption included 1-(2,5-dimethoxy-4-methylphenyl)-, 1-(2,4,5-trimethoxyphenyl)-, 1-(2,4-dimethoxy-3-methylphenyl)-, and 1-(3,4-methylenedioxyphenyl)-2-aminopropanes. In addition, 1-(3-methoxy-4-methylphenyl)-2-amino-propane, structurally resembling 1-(2,5)-dimethoxy-4-methylphenyl)-2-aminopropane (DOM), was found to be just as active and long lasting as DOM. The amphetamine derivatives either diminished or prolonged the barbiturate sleeping time. 1-(3,4-Methylenedioxyphenyl)-2-aminopropane and DOM were equally effective in decreasing the sleeping time, while 1-(2,4,6-trimethylphenyl)- and 1-(3,5-dimethyl-4-hydroxyphenyl)-2-amino-propanes were the most active in the potentiation of the sleeping time.

Besides the well known ones featuring also:
2-MeO-4-Me-amphetamine
3-MeO-4-Me-amphetamine (MMA)
3,5-diMeO-amphetamine
2,3-diMeO-amphetamine
2,4-diMeO-3-Me-amphetamine
3,5-diMe-4-MeO-amphetamine
3,5-Me-4-OH-amphetamine
2,4,6-triMe-amphetamine

“The real drug-problem is that we need more and better drugs.” – J. Ott

_mu_
(Newbee)
03-13-04 15:32
No 494849
      Does this mean that DOB was first synthesized...

Does this mean that DOB was first synthesized by Nichols, and not by Shulgin?

Rhodium
(Chief Bee)
03-13-04 18:35
No 494862
User Picture       Nichols made it, Shulgin tasted it

Yes, but the first article about its human psychopharmacology was published by Shulgin, see Ref #8 from Nichols' article above, which corresponds to this one: Post 495305 (Rhodium: "Shulgin: First Human Evaluation of DOB", Methods Discourse) Also see Post 495313 (Rhodium: "Shulgin: Human Pharmacodynamics of DOB", Novel Discourse)

^{The Hive - Clandestine Chemists Without Borders}

cattleprodder
(Hive Bee)
03-13-04 19:58
No 494873
      3-methoxy-4-methylamphetamine

I find it very interesting indeed that 3-methoxy-4-methylamphetamine was found to be "just as active and long-lasting as DOM."

Does anyone else agree?

azole
(A Truly Remarkable HyperLab Bee)
03-14-04 12:27
No 495020
      No, MMA is less potent than DOM

MMA is definitely less potent than DOM. SWIM found that MMA hydrochloride (orally) at 4 mg level produces only threshold effects, mostly physical (tension of facial muscles). Higher dosages are still untested.

Rhodium
(Chief Bee)
03-15-04 16:52
No 495305
User Picture       Shulgin: First Human Evaluation of DOB
(Rated as: excellent)

4-Bromo-2,5-Dimethoxyphenylisopropylamine, a New Centrally Active Amphetamine Analog
A. T. Shulgin, T. Sargent and C. Naranjo
Pharmacology 5, 103–107 (1971) (https://www.rhodium.ws/pdf/shulgin/shulgin.dob.pdf)

Abstract
A new centrally active halo-amine, 4-bromo-2,5-dimethoxyphenylisopropylamine, is described. In clinical evaluation it proved to enhance effectively both emotional and intellectual perception, without the imagery and perceptual distortions commonly encountered with many of the chemically related psychotomimetics. These properties suggest a potential valuable role in conjunction with psychotherapy.

_{This article has been referenced in the following post: Post 432948 (Chimimanie: "DOI", Novel Discourse)}

^{The Hive - Clandestine Chemists Without Borders}

Tricky
(Stunning)
03-15-04 19:52
No 495333
      MMA...

Azole, you've trien' to tell, MMA is an PSY- ... for your SWYL opinion and testin' it's not empathohene???

If you've an time for such lesses, pliz write PM to me (in russian pliz :) - cause this theme is my huge paine in da butt :))...

PS for (everybee else around - sorry for my terrible english)...

-who dares, wins-

_mu_
(Hive Bee)
03-16-04 17:44
No 495516
      In clinical evaluation it proved to enhance...

In clinical evaluation it proved to enhance effectively both emotional and intellectual perception, without the imagery and perceptual distortions commonly encountered with many of the chemically related psychotomimetics.

Errr? DOB not being visually active? Is that correct, or is there some wierd dosage-response curve?

Rhodium
(Chief Bee)
03-16-04 21:18
No 495555
User Picture       DOB is not that heavy on the visuals

You need to up the dosage of DOB to 2-3 times the minimum psychoactive dosage for any significant visuals to occur... And you can take over 10 times the minimum psychoactive dosage and the visual field is still not as clogged as it becomes on ~30mg 2C-B.

^{The Hive - Clandestine Chemists Without Borders}

_mu_
(Hive Bee)
03-16-04 21:50
No 495566
      Is that a typical for DOB, or do the other...

Is that a typical for DOB, or do the other 4-substituted dimethoxyphetamines (DOC/DOI/DOM/..) also have that particular characteristic?

Rhodium
(Chief Bee)
05-06-04 23:06
No 505421
User Picture       Psychoactivity, Toxicity & Analysis of DOB
(Rated as: excellent)

4-Bromo-2,5-Dimethoxyamphetamine: Psychoactivity, Toxic Effects and Analytical Methods
D. Delliou
Forensic Science International 21, 299-267 (1983) (https://www.rhodium.ws/pdf/forensic/dob.forensic.review.pdf)

Summary
4-bromo-2,5-dimethoxyamphetamine (bromo-DMA) is a drug of special interest as it is available in forms which are seldom seen elsewhere in the world. Data of interest to the Forensic Chemist is summarized. The psychoactivity of bromo-DMA is discussed and a number of case histories involving higher doses are related. A description of dosage forms has been included and variations in drug concentration is discussed. Chemical properties and various methods of quantitative and qualitative analysis, eluding the use of high performance liquid chromatography, mass spectrometry and infrared spectroscopy are listed.

^{The Hive - Clandestine Chemists Without Borders}

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