HA-DOB

4-bromo-2,5-dimethoxyhomoamphetamine hydrochloride
4-(4-bromo-2,5-dimethoxyphenyl)butan-2-amine hydrochloride
H3C

O

NH2 CH3

Br O CH3

SYNTHESIS: "4-[4-Bromo-2,5-dimethoxyphenyl]-butan-2-one". In a 250 mL flask on an oil bath and magnetic stirring was added 100 mL of 96% ethanol and 4 g of sodium hydroxide (94 mmol). Heating was applied to the oil bath and with stirring the sodium hydroxide soon dissolved. When the temperature of the solution reached 50 °C there was added 13 mL of ethyl acetoacetate (94 mmol). After 10 min there was slowly added also 20 g of “crude 4-bromo-2,5-dimethoxybenzyl chloride”1 (75 mmol) and the reflux condenser immediately set on the flask. The temperature of the oil bath was raised in order to maintain reflux for 1 h and 20 min. The suspension was vacuum filtered while still warm in order to remove the sodium chloride precipitate which was washed with 2×10 mL of ethanol. The filtrate was put back in the 250 mL flask, neutralized with 3 mL 30% hydrochloric acid and the solvent removed with the aid of vacuum until the volume of 50 mL was reached (marked on the flask earlier). Then 70 mL of 25% hydrochloric acid was added and the mixture heated at reflux on the oil bath with intensive magnetic stirring for 8 h when all CO2 evolution ceased. The evolution of CO2 gas was monitored with a bubbler or a balloon set on the condenser exit. The product was extracted with 40 mL toluene, washed with 40 mL 5% sodium bicarbonate and 2×30 mL brine. The toluene was stripped off and the resulting dark oil diluted with 50 mL ethanol. The resulting solution was added to the solution of 10 g sodium bisulphite in 20 mL water and 20 mL ethanol. The formed precipitate was vacuum filtered after 30 min of stirring and washed with 15 mL water and 2×15 mL ethanol but after air drying there was only 4.25 g of the bisulphite adduct left (14%).2 The filtrate was therefore diluted with an equal volume of water and the formed oil separated, the rest extracted with 2×7 mL methylenechloride, the combined organic fractions washed with 2×25 mL water and the solvent evaporated. There remained 14.1 g of a dark oil. This crude product was used without further purification or analysis.
Later, it was found by 1H NMR spectroscopy to consist of about 51% 4-bromo-2,5-dimethoxybenzyl chloride, 36% 6-bromo-2,5-dimethoxybenzyl chloride and about 13% diarylmethylenic side products. But since this was not known at the time of synthesis, the product was used without further purification. 2 The ketone made from the small amount of the bisulphite adduct was pure enough to crystallize. During the HA-DOC synthesis, it was found that the bisulphite method can efficiently be used, but 2 eq. of NaHSO3 must be used and the slow reaction left stirring for at least 24 h. The so purified ketone for HA-DOC crystallized in cold. The HA-DOC synthesis also highlighted that the yield of the benzylation/decarboxylation/bisulphite purification step is probably low. So the ketone used in the HA-DOB synthesis was seriously impure – thus the low yield after the reduction of the “oxime”.
1

H3C

O Cl

H3C

H3C O O OEt

O

O CH3

+ CH3COCH2COOEt, NaOH / EtOH - NaCl
Br O CH3 O

+ H2O / HCl, EtOH - CO2 , EtOH
Br O CH3

Br O CH3

CH3

"4-[4-Bromo-2,5-dimethoxyphenyl]-butan-2-one oxime". In a 250 mL flask there was added 3.20 g of hydroxylamine hydrochloride (45 mmol), 15 mL water and while stirring was slowly added also 2.40 g of anhydrous sodium carbonate (22.5 mmol). Then the solution of 10g “4-[4-bromo-2,5-dimethoxyphenyl]-butan-2-one” in 50 mL of methanol was added and the mixture stirred at reflux for 2 h. After the reaction mixture cooled, 50 mL of water was slowly added and a viscous oil precipitated. This refused to crystallize in the freezer thus the supernatant was decanted, the viscous oil washed with some water, dissolved in 15 mL methylenechloride washed with 2×25 mL water and the solvent stripped off. There remained 10.23g of the oily product.
H3C O O H3C O N OH

CH3

Br O CH3

+ H2NOH / MeOH , H2O

CH3

Br O CH3

4-(4-Bromo-2,5-dimethoxyphenyl)butan-2-amine hydrochloride. In a 1 L two neck flask was added 100 mL 96% ethanol, 10 mL water, 4 g aluminium foil in small pieces (cut in a mixer), 4 mL 2% aqueous HgCl2 and stirred intensively. To one neck a reflux condenser was set and to the other a dropping funnel with a solution of the above crude oxime in 20 mL ethanol and 20 mL 85% formic acid. After stirring for 15 min the aluminium apparently amalgamated and the solution of the oxime was slowly being added drop-wise at such a rate that the reaction mixture was mildly refluxing. After 15 min most of the aluminium got consumed and another portion of 4 g was added. The mixture was stirred for additional 2 h. The alumina slurry was vacuum filtered with some difficulty and washed with 2×20 mL ethanol. The clear filtrate was concentrated to about 45 mL volume, 20 mL 10M NaOH(aq) was added, extracted with 3×20 mL toluene. The joined extracts were washed with 3×40 mL water (an emulsion formed and was broken with adding some brine) and back extracted with 20 mL 2M and 2×10 mL 1M hydrochloric acid. The aqueous extract was evaporated using vacuum, adding 20 mL isopropanol and again evaporating under vacuum. There remained a slightly grey to pinkish paste which was triturated in acetone and filtered to give a grey powder. This was dissolved in dichloromethane and filtered to remove some insoluble material. After evaporating the filtrate there remained 2 g of an off-white powder, HA-DOB×HCl containing an NMR visible impurity that was assumed to be 4-(2-bromo2,5-dimethoxyphenyl)butan-2-amine hydrochloride (up to 10 mol%): mp 193-198°C; IR (KBr disc) 2940, 1603, 1499, 1387, 1211, 1057, 1029 cm-1. Free base 1H NMR (CDCl3) δ 1.10 (d, J = 6.3 Hz, 3H, CH3), 1.33 (broad, 2H, NH2), 1.48-1.67 (m, 2H, CH2), 2.62 (t, J = 7.9 Hz, 2H, CH2), 2.89 (m, 1H, CH), 3.78 (s, 3H, CH3O), 3.84 (s, 3H, CH3O), 6.74 (s, 1H, ArH), 7.01 (s, 1H, ArH).

H3C O N

OH

H3C O NH2

CH3

+ Al / EtOH , H2O, HCOOH
Br

CH3

Br O CH3

O CH3

DOSAGE: 60 – 120 mg DURATION: 8 - 12 h

(threshold 10 - 15 mg)

60 mg (male; 80 kg): I drank the solution of 60mg HA-DOB in water at 11AM. The taste is disgusting but not more than most other compounds. It slowly started after one hour and took further half hour to become intense. I have not eaten breakfast and expected I would not feel hungry during the experiment instead I got really hungry. I could not eat just anything. I wanted something good so I went cooking. This was quite an adventure in itself since I was quite tripping already. But it was worth it, the food tasted delicious. I was alone, but had a couple of phone calls during the experience and communication and “faking” was relatively easy even during the peak. This day I had to do some work, some translation of a certain text. I tried and the first paragraphs I did just fine, the second was a bit harder and when I came at the third I just closed the file. It was too annoying. I like this compound. I’m above everything, like a string in resonance with my own inner universe. Externalities don’t bother me much, or at least not as much as they should. At 2:30PM I went to rest a bit on the bed. Behind the closed eyes patterns soon emerged, but they are less marked than the influence on the mood and thoughts so that they don’t really entertain me. I could not rest for long and felt like the peak is about to end. I went on doing some lab work. I almost thought that it is quite similar to its regioisomer 4C-DOB, but now I see that there is a big difference in the length of action. At 4PM there was still activity, but now stabilized to a lower level. I haven’t even noticed the time passing. Two or three hours later it was nearly over, but it was not until midnight that I could say for sure that I’m at baseline. 90 mg (male; 80 kg): I drank the disgusting aqueous solution at about 1PM on an island together with Lucy who took 80mg. I had no watch, but it seamed to me that it passed way over an hour, or perhaps even two hours, before the effects became apparent. Perhaps it was because I eat dinner an hour earlier. The effects, though clearly psychedelic, were not dramatic at all, which I believe had to do with the strong sunlight and the absence of other humans. There were little visuals, but the stones, the sea and the whole natural ambient in itself had become so familiarly similar to what us two experienced a couple of years earlier while tripping on psilocybin containing mushrooms on this same spot. This time was however much less intense. I got a kind of a feeling that the psychedelic experience is nothing else but an enhanced state of the mind we already had while still children, a mind mode enabling us fast absorption and analysis of language, experiences and other data in order to learn fast for the life in adulthood. A couple of hours later we went walking trough a beautiful canyon of a dry stream into the interior of the island. I had a narcissistic urge to share my thoughts and chat about various things. We saw a snake and I wanted to observe it but Lucy got scared so rushed forward. We passed by several already decomposed carcasses of a dead sheep and one

ram. They probably fell into the canyon from the cliffs. So we talked about death and for fun I made up a linguistic theory on the origin of the word “died” in our language and why it is only used for humans and bees (while there are other, different words used for other animals). We then had to pass by a hive of wild bees, nesting in a fissure in a narrowing of the canyon. Luckily they were in a peaceful mood. There was little activity left from the drug and the peak experience was way behind. It was a beautiful excursion and it was already getting dark when we left the sheep herds behind. We had already changed the subject and talked about the cultural decadence the neoliberalism and consumerism brought us when we stumbled at the tourists in a nearby camp. The first sighting was truly a bizarre one, it was a women, all dressed in weird colorful clothes with a voluminous blond coiffure, standing immobile behind the sheep fence. Lucy first thought she was one of those shop-window dolls somebody left there as a joke, but when we came closer the doll moved and helped us opening the fence heading in the direction where we came from. Other tourists were similarly bizarre looking. We then went to the town where more weird people and some pathetic drunk tourists entertained us. We had a nice evening in a restaurant and went to sleep at about midnight. It took me some time and there were still some patterned closed eyes visuals interfering but I nevertheless efficiently felt asleep. Lucy was not equally satisfied with the experience. She reported nausea most of the time and felt the positive effects were not enough to compensate the negative ones. Instead I had experienced no nausea or other negatives whatsoever, but regretted a little that I haven’t took a higher dose. 120 mg (male; 80 kg): The transition was very fast. Half an hour after taking HA-DOB it took about 10 more minutes to rise from the zero level up to a full trip. At +1:20h I was already deeply involved into the trip and even typing on the keyboard was hard. Everything around me is covered in fractal patterns, some organic textures of rainbow colors. It is interesting that up to this moment I could retain the effects to some degree and was actually reading a mundane journal, but now it takes a lot of effort to get together from this very intense psychedelic trip almost comparable to 2 to 3 mg DOB by intensity, yet very different. It is very visual and deep yet… Then from +5h to +7h I got involved in a completely wild tripping by watching the movie The omega men, that looked so spacey and full of symbolisms of what I conceived as antagonisms between feelings of guilt and narcissism, and such similar concepts. I managed to feel asleep only in the middle of the night and the next day I was a very tired. COMMENTARY: To my knowledge this is the first phenylpropylamine tested in humans that showed undisputable psychedelic activity. The only other serotonergic 3phenylpropylamine I ever heard about being tested on humans is the MDPEA homologue called GAMMA and is described by Shulgin as having some central activity at 200mg. 3 The term 'homoamphetamine' was used by Brimlecombe and Pinder4 to reflect the homologation of the amphetamine structure at the root of the side chain with a methylene group. Adopting their nomenclature the code prefix 'HA-' was used to denote 1-arylbutan-3amines (as opposed to the prefix '4C-' used for the 1-arylbutan-2-amines). HA-DOB was to my knowledge newer tested, not even in animals. However, in one of the best sources of various side chain modifications, a paper by Pinder et al, 5 there are published tests done with HA-DOM, HA-TMA-2, HA-TMA-3, HA-TMA-6, HA-3,4-DMA and HAMDA. Of these only HA-DOM and HA-TMA-2 were active in animal models for detecting
3 4

A. & A. Shulgin, PiHKAL, #100 MDA (http://www.erowid.org/library/books_online/pihkal/pihkal100.shtml). R. W. Brimlecombe, R. M. Pinder, Hallucinogenic agents. Wright-Scientechnica, 1975, pp 74–79. 5 F. A. B. Aldous, B. C. Barrass, K. Brewster, D. A. Buxton, D. M. Green, R. M. Pinder, P. Rich, M. Skeels, K. J. Tutt; J. Med. Chem., 17 (1974) 1100-1111.

LSD-like activity at sublethal doses. However, they were both a hundred times weaker then their parent non-homologated compounds. If the same decrease would be valid for the activity of HA-DOB in humans then its dose should be from 100 to 300 mg. Instead 60 mg felt like comparable to 1 mg DOB by intensity. Nevertheless, from the limited bioassays from only three human subjects in the last four years since it has been synthesized, it is hard to say how general the described dosage is. The same dose was found intense one time and much less intense the next time in the same subject. It might also be that the sensitivity varies widely from subject to subject. The effects are also not to be confused with structurally related 4CDOB which is quite different in character. I think HA-DOB has some peculiarities, but it is also somewhat more related to the classical psychedelics than the 4C series is. It would be quite interesting to test 3-(4-bromo-2,5-dimethoxyphenyl)propylamine, that is HA-DOB lacking the alpha methyl group. I would suspect it might be similarly potent as I doubt the alpha methyl has any special function in HA-DOB. Though it might be essential for metabolic stability, in one or both enantiomers it might also cause some unwanted crowding in the receptor site. The reported activity of GAMMA at an unexpectedly low dose indicates the metabolism might not be a problem with arylpropylamines. DOB homologated with an oxy group to give 1-(4-bromo-2,5-dimethoxyphenoxy)propan-2-amine should in my opinion be more potent than HA-DOB since the oxygen at the side chain could potentially interact at the binding site of the 5-HT2A receptor with the same H-bond donor as the ortho-methoxy group does. This should give an affinity of somewhere in between DOB and HA-DOB. Indeed, one phenoxyethylamine was found to give physiological and behavioral responses characteristic of hallucinogenic drugs in animals. 6 Such a homologation should be open to all the potent 2,4,5-patterned amphetamine series which is about dozen new psychedelics. It is a small family of psychedelics, but at least a new one. The synthesis reported here is extremely clumsy in that it starts with a mixture of two regioisomeric benzyl chlorides and continues with mixtures of isomers at each step, with the side products cumulating till the last step. Since most of the intermediates were oils, no attempts was made to clean up the mess and at the stage of what should have been 4-(4bromo-2,5-dimethoxyphenyl)butan-2-one, this must have been already just a minor component of the mixture. Completely unprofessional, but it yielded the right compound at the end. It is thus a surprise to find out the resulting amine hydrochloride was obtained fairly pure and with the ortho-bromo isomer mostly removed, apparently due to their solubility differences in dichloromethane (HA-DOB hydrochloride is one of the few amine salts that are well soluble in this solvent). The synthesis was made without any lab equipment and no analytical method for following of the intermediates identity or purity was available. This should be repeated and done correctly one day. Another interesting property of HA-DOB hydrochloride is in that it is a surfactant and its aqueous solutions make foam when shaken. Soap psychedelics! Best regards, Demonic 7. June 2009
6

The compound is 2,4-dichloro-5-methoxyphenoxyethylamine (see reference 3 and references cited therein). To my knowledge it was tested only once in humans up to 150 mg with effects similar to psychedelics and intensity of 1 MU or slightly less (unpublished results) while animal tests predicted the potency of 2 MU. It is important to note that this compound only has the meta-methoxy group. Thus if the activity results from affinity to 5-HT2A receptors at all, the lack of the ortho-methoxy group is likely to be have been compensated by the H-bonding with the oxygen at the side chain.

7,264
0.91 0.96

3.17 3.00

1.05

2.16

2.24

2.72

3.32

7.0 ppm (t1) 7,011 6,742
HA-DOB, free base in CDCl3

6.0 5.0 4.0 3.0 2.0 1.0 0.0 0 500 1000 1500 2000

3,838 3,776 3,696 3,683 2,919 2,898 2,876 2,855 2,642 2,616 2,590 1,602 1,583 1,580 1,556 1,325 1,113 1,092 0,0000 2500 3000 3500

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