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There is a NEW version of the GHB Synthesis FAQ available at :
rhodium/chemistry/ghb.html

GHB Synthesis FAQ
version 1.5 - HTML version
last update 8/05/99

By Rhodium [rhodium@hushmail.com]
HTML by Erowid


Erowid continues to revisit the question of whether it's a good idea to provide access to synthesis information. Because of the fairly large number of people who are producing their own GHB for personal use...with or without the use of premade kits...it seems best to help provide access to accurate and safe information on the topic.




Table of Contents

  1. Introduction
  2. Chemistry and Synthesis
  3. Analogues
  4. Precursors
  5. Physical/Chemical Properties
  6. References
  7. Sources


Introduction:

This file deals with the synthesis of GHB and related compounds. It is assumed that the reader already know about the pharmacological aspects of GHB (or else shuld consult the "General Info" references below). It is highly dangerous to attempt a synthesis of GHB without the proper knowledge in chemistry, and illegal and immoral to even try to sell such a product. This text does not in any way encourage anyone to break the law. Where this is written, GHB is completely legal to manufacture and consume, but the laws in your country may say otherwise [GHB is illegal to possess or sell in the United States as of March 2000]. I suggest you check out your local laws before doing anything stupid. And - please don't mix GHB with alcohol.

Chemistry and Synthesis:

The far most simple way to produce GHB is by the hydrolysis of the corresponding lactone (a cyclic intramolecular ester) to the desired hydroxy acid. Ester hydrolysis can be done in two ways: An acid catalyzed reaction or a base catalyzed reaction. The base catalyzed reaction is our choice here, because the reaction is not reversible like the acid catalyzed one and therefore we will get higher yields, and we will get the sodium salt of GHB, which is more rapidly absorbed by the body, and also more stable.

                       O
                      / \                               O
                   H2C   C=O                           //
                     |   |   + NaOH => HO-CH2-CH2-CH2-C
                   H2C---CH2                           \
                                                        O-Na


Gamma-Butyrolactone + NaOH => Sodium Gamma-Hydroxy Butyrate (Na-GHB)

The reaction is equimolar, and the reaction is driven to the right more readily in a dilute ethanol solution than in a plain aqueous soln. There are *no* byproducts produced in this reaction, such as hydrogen gas, water, or anything as proposed in several other texts.

All published preparations of GHB, or more correctly Na-GHB, refluxes butyrolactone with sodium hydroxide in various solvents, usually alcohol in combination with water.



In JACS 51, 260 (1929) we find the following, just using water:
16.3g butyrolactone and 7.4g NaOH were dissolved in 30cc. of water and boiled under reflux for three hours. At the end of this time more water was added to dissolve the salt and the solution was filtered and evaporated to dryness under reduced pressure. Yield was 11.5g.



This method works OK, but the yield is poor and the product does certainly contain a lot of lactone, as it still is very basic before neutralizing. It is not neccessary to add more water after the reaction has subsided, I really do not understand why their product precipitates at all. It may be necessary to filter the solution though as it is commonly hazy. The reaction flask may be covered with a grey-white solid on the inside, which is easily removed by swirling it with a little concentrated NaOH solution.



CA 59:11234e; Using dilute ethanol.
To a hot solution of 225ml rectified EtOH, 45ml H2O and 220g NaOH, 489g gamma-butyrolactone was slowly added and the mixture kept boiling for 30 min. The ppt. crystallized from EtOH yielded 560g Na-gamma-hydroxybutyrate.



225ml EtOH and 45ml H2O gives around 80 percent ethanol, and the method works for ethanol solutions as dilute as 40%, which makes plain vodka usable as solvent. Personally, I prefer other base/lactone proportions.




Lab procedure for the synthesis of GHB:

Please follow common Lab Safety procedures. Wear a lab coat and protective glasses. You will work with hot caustic solutions and solvents! Be aware of the risks associated with the manufacture of GHB! Never work alone!

Place 30 grams of pure NaOH (do not use lye!) and 100 ml of 40% ethanol in a 250 ml two-necked round-bottomed flask and swirl it and dissolve as much of the NaOH as will be dissolved in the ethanol (Caution! The dissolution of NaOH is very exothermic!). All of the NaOH won't dissolve. Add some boiling stones. Place the flask in a heating mantle (do not turn it on yet!) and fit a condenser at the top neck of the flask, I use a 20 cm Graham condenser, but any water-cooled condenser will probably suffice. Connect the cooling water supply to the condenser and start the water flow. Fit a 100 ml addition funnel in the other neck of the RB flask and pour 65 ml of gamma-butyrolactone into it. Turn on the heating mantle, and bring the NaOH/EtOH mixture to a gentle boil. When all NaOH has dissolved, begin adding the gamma-butyrolactone from the addition funnel, a little at the time, if you add too much at once, the solution will start to boil heavily and choke in the condenser.

Ideally, you should monitor the reaction with TLC, but a simple pH check with universal pH paper will suffice. When the pH comes down to 7, stop the heating. This normally occurs within an hour, probably after just half an hour. If the pH isn't down to 7 after an hour of refluxing, adjust the pH to neutral with dilute HCl or conc. citric acid. Watch out, as the addition of acid is exothermic and makes the solution boil again. You can also add some more of the lactone, and let the solution boil for another minute.

Now reduce the volume of the solution through boiling it in the flask without the condenser attached to approx. 75-100 ml. You can recover the solvent with a distillation setup here, and recondense the ethanol, water and excess butyrolactone if you wish. When the solution is down to 75 ml, the temperature of the solution is usually around 135øC. Dilute the stirred solution while still hot to 150 ml with distilled water to prevent it to solidify when it returns to room temperature again. With this dilution, the dosage is around 5 ml, as it is approx. a 50% GHB solution.

The solution is perfectly clear and tastes slightly salty. It may be very slightly yellow colored, but not much if pure enough butyrolactone was used. If any neutralizing acid was used in the process, crystals of Na-citrate or NaCl may deposit in the solution, as well as the taste is severly impaired. Better dissolve some in a glass of OJ before experiencing.

An HPLC analysis on a batch made as above gave the following result:

Weight %
Na-GHB54.4
Water39.5
Ethanol5.6
Lactone0.3
Other0.2


Reagents used was Aldrich 99%+ Butyrolactone, Eka Nobel Pro Analysi NaOH, and Absolut Vodka as the 40% Ethanol. The "other" 0.2% is probably higher alcohols found in the Vodka. You will probably get a purer product using lab grade ethanol.

I was surprised to find that, with enough pure reagents, recrystallization of the GHB is not necessary to achieve an acceptable purity. If you are using butyrolactone of a grade lower than around 97%, I reccommend that you recrystallize the crude GHB, though. This can be done from boiling ethanol.

Different salts:

Substituting NaOH for KOH (molarly, that is, use 42 grams of KOH in the above synth instead of NaOH) gives a similar product, and also gives users of this chemical that Potassium supplement that is by some said to be needed in connection with administration of GHB. It is not clear (for me at least) if it is the sodium intake or the GHB intake that gives the drop in plasma potassium levels. Better use a mixture of the two. Bear in mind that K-GHB is slightly less active (by weight) than Na-GHB as the K ion is heavier than the Na counterpart. Differences between K-GHB and Na-GHB is that the K salt is more soluble in water than the Na salt, and the taste is more like salt/licorice instead of the salt/soap taste of Na-GHB. In the book "Better Sex Through Chemistry" by John Morgenthaler it is pointed out that "[GHB] has a salty/licorice flavor" and it is obvious that the author tried the K salt. The purer the lactone used in the synthesis, the better the taste of the final product. LiOH or Mg(OH)2 could be dangerous to use, as would NH3 (formation of pyrrolidon). Ca(OH)2 *could* work, but I cannot find any point in using it.

Q&A's:

Q: Can I use Red Devil Lye instead of pure sodium hydroxide?
A: No, that could have unpredictable results on your health.

Q: I do not have the glassware you say are needed, can I boil the solution in a pot on the stove instead?
A: No, you can not. The sodium hydroxide will corrode the metal pot, and assorted metal ions will get into your product. You can of course use simpler glassware than my suggestions, and make the neccessary adjustments of the procedure.

Q: I cannot recrystallize the GHB from ethanol. It forms a sticky mess.
A: Your GHB is not dry, or your ethanol is not anhydrous. Water makes the recrystallation almost impossible. The fact that the sodium GHB is deliquescent does not make this better. You must dry the GHB thoroughly preferably in a vacuum desiccator before attempting recrystallization, or any other improvised alternative. The 95% ethanol you are planning to use must be dried with calcium oxide or calcium sulfate and redistilled with adequate measures taken to exclude moisture from the reaction.

Analogues:

Attempts have been made to prolong and/or slightly modify the effects of GHB, with small alterations of the GHB molecule. Check out the following patents for details:
US Pat. 4,738,985 (Esterification at both ends of the GHB molecule)
US Pat. 5,380,937 (New salts and amides of GHB)
Here is an excerpt from US Pat No 4,738,985.

EXAMPLE 1
Preparation of Ethyl 4-acetoxybutanoate This is a modification of the methods of Spencer and Wright (J.Am. Chem. Soc., 63, 128 (1941) and Meerwein, Borner, Fuchs, Sasse, Schrodt and Spille (Berichte, 89, 2060 (1956).

Eighty grams of butyrolactone was dissolved in 500 ml absolute ethanol containing 8 gms 99% sulfuric acid in a one litre erlenmeyer flask. After 5 days, with powdered sodium carbonate (added carefully until further additions did not produce foaming). Then 20 g anhydrous sodium sulfate was added to dry the solution. The solution was filtered and the filtrate was concentrated on a rotary evaporator in a two litre round bottom flask. The concentrated residue was taken up in 300 ml water and was extracted with three 200 ml portions of chloroform. The chloroform extracts were combined and dried over magnesium sulfate, the solution decanted then concentrated by rotary evaporation. The concentrate was placed in a 1 litre flask clamped in an ice bath, and 80 g acetic anhydride and 100 ml pyridine were added . After addition was complete, the stoppered flask was left overnight with the ice allowed to melt. A solution of 100 ml concentrated hydrochloric acid (12M), 100 ml water and 200 g of ice was prepared and carefully added. Two layers formed, and 100 ml chloroform was added. The aqueous layer was extracted with three 100 ml portions of chloroform. The nonaqueous layer was taken up in chloroform and combined with the extracts. The extract was treated carefully with saturated aqueous sodium bicarbonate in a separatory funnel, followed by shaking, and the aqueous layer was removed. The chloroform layer was then extracted with saturated sodium chloride solution then dried over anhydrous magnesium sulfate, and filtered. The dried solution was concentrated on a rotary evaporator, then distilled at 0.1 torr on a 1 cm by 10 cm vacuum jacketed column. The product is collected at 56 deg. C, and shown by nmr spectroscopy to be pure ethyl 4-acetoxybutanoate Yield: 35 g.

By repeating the above procedure, but substituting methanol for ethanol, methyl 4-acetoxybutanoate was similarly prepared.


Their tests of this compunds reveals a longer duration of effects
"A large dose can have an extremely long duration of action (up to 12 hours) without toxic consequences. The duration of action can be controlled by the size of the dosage."
at the same dosage levels as GHB
"A single dosage unit for once-nightly administration is suitably in the range 0.1-10 g in adult humans, preferably 0.25-5 g, and most preferably 250-1000 mg."
as well as a low toxicity just like GHB
"In tests conducted with laboratory rats as reported below, doses as high as 3000 mg per kilogram body weight are required, before a toxic level is reached."
This patent is well worth looking up.

Precursors:

The obvious precursor for the synthesis of GHB is gamma-Butyrolactone. It can be made from pre-precursors such as Tetrahydrofuran (THF) and also gamma-halogen derivatives of butyric acid, for example 4-bromobutyric acid. The following abstracts deals with the conversion of 4-Br-butyric acid to gamma-Butyrolactone, but one can also imagine a synthesis of GHB by direct hydrolysis of the bromo acid to Na-GHB.


JACS 51:260(1929)
To a solution of 7.8 g of sodium in 500 cc of absolute alcohol was added 60.5 g of 4-bromobutyric acid. The reaction mixture was boiled under a reflux condenser for about five hours. During this time sodium bromide separated. The alcohol was distilled from a steam bath, and the lactone was separated from the sodium bromide by extraction with ether. The ether was evaporated and the lactone distilled under ordinary pressure. The yield was 21.2 gram (67%) of product boiling at 202-206øC.


In this abstract the 4-bromobutyric acid is made from 3-phenoxypropyl- cyanide. I have just one question. Why? :-)

An alternative may be to chlorinate butyric acid with sulfuryl chloride, as in JACS 62, 925-929 (1940) and separate the isomers through distillation, make the sodium salt of 4-chlorobutyric acid, and cyclize to the lactone as with the 4-bromo derivative above.

Other more or less interesting approaches to gamma-butyrolactone manufacture can be found in the following publications:

  • JACS 51; 260 (1929) Silly synthesis, silly precursors. Easy.
  • JACS 52; 3702-4 (1930) High yield, but a remarkable complicated synthesis.
  • JACS 63; 2488 (1941) Ok yield, but a rare precursor, 4-MeO-(CH2)3COOH.
  • JACS 71; 2825-26 (1949) Ok yield, but the purification may be complicated.
  • JACS 80; 6682-84 Quantitative yield, but expensive. Requires RhO4.
  • CA 53; 15050 Low yield, but easy. HNO3 oxidation of THF.
  • CA 54; 4393i Outlines of a purification of gamma-butyrolactone.
  • CA 59; 11234e Synthesis of GHB and GABA


Physical/Chemical Properties:

gamma-Butyrolactone:
mol wt: 86.09
mp: -43.53øC bp: 204øC
CAS No: 96-48-0
Flash point: 98øC
Soly: miscible with water, soluble in methanol, ethanol, acetone, ether, benzene
LD50: 1720 mg/kg (orally, mouse) 1540 mg/kg (orally, rat)
Uses: Solvent, paint remover, capacitor electrolyte, intermediate
Synonyms: GBL, BLO, butyrolactone, gamma-hydroxy butyric acid lactone, 1,2-butanolide, 1,4-butanolide, 4-butanolide, 2-oxanolone, tetrahydro-2-furanone, dihydro-2(3H)-furanone.

Na-GHB:
mol wt: 126.09
mp: 142øC
Synomyms: Gamma-OH, sodium oxybate, sodium gamma-oxybutyrate, Somatomax PM, Wy-3478, NSC-84223, Somsanit, Anetamine.

Info Resources:

General info:
Cognitive Nutrition Update: GHB, J. Morgenthaler, Smart Drug News, Vol 3, No 6 1994
Better Sex Through Chemistry, J. Morgenthaler, Smart Publications 1994 ISBN: 0-9627418-2-5
(US Pat No 4,983,632 with the title "Use of gamma-hydroxybutyric acid salts for preparing pharmaceutical compositions for use in the treatment of alcoholism, and the compositions obtained" is interesting both from the aspect of alcoholism treatment, and the aspect of hiding the taste of GHB.)

Internet Resources: