posted 12-04-1999 05:31 PM         

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I read this in the Merck recently, it said you could produce d-amphetamine from plain
raciemic or l-amphetamine to the dextro-rotary isomer. This is all it said,
rather simple as it is though. And I believe
that the addition of H2SO4 was to make the
at room temprature solid salt. HCl salt must stay as a liquid of this d-amphetamine. I never see it mentioned in the merck. They always make the Phosphate, Oxalate or Sulphate. But any way here is what it said.

"Preperation of d-amphetamine is by the
resolution of amphetamine with d-tartaric
acid followed by treatment with 10% H2SO4."

Merck index pg. 500

Couldn't this H2SO4 salt be basified and
methylated to D-methamphetamine then. Or maybe even raciemic or even 80% d and 20%
isomers of meth also converted to the d-isomer by the above process.

note; they might be leaving alot out, I don't know it might be easier to just start from
d-pfed but then I read you always end up
witha little to alot of the l-isomer.

posted 12-04-1999 05:51 PM         

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In what edition of the Merck is this on page 500, please?

Stonium

posted 12-04-1999 09:38 PM         

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the tartaric might be drived from fermentation your information seems inacurate. Ya dont use the but ya might use it, as well as any other I suppose I just aint gona spell it out humm?

Maybe dont use the search engine on this one humm

posted 12-05-1999 12:12 AM         

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D-tartaric acid can also be used to isolate d-methamphetamine from l-methamphetamine.
The freebase is formed then the tartaric salt of meth is created.
The D and L meth have differing solubilities, and are separated by filtration.

To make Tartarate
-------------------
Old method for making the acid in solution was to add
a concentrated solution of potassium iodide in water to a concentrated
solution of tartaric acid in water. Potassium-acid tartrate precipitated
quickly, to leave 10% HI acid. They decanted the liquid and added a little
alcohol to the solution to force more of the tartrate out of solution, and
decanted again. The product still contains a little bit of tartaric acid
and both salts of course; but it's pure enough for pharmaceutical uses.
Chilling everything before adding the small amt. of alcohol would probably
improve the product.

A second method
---------------
PREPARATION OF ROCHELLE SALT
Here you will learn how to prepare Rochelle salt from baking soda and cream of tartar, which are available from a grocery store.
It will involve two chemical steps (reactions) prior to the actual growing of the crystal. The procedures are safe and can be conducted in your kitchen, with appropriate adult supervision.

The only restriction for the purposes of the Crystal Growing contest is that 200 g of cream of tartar is the MAXIMUM starting amount of that reagent that may be used to prepare a given crystal.

HERE's WHAT YOU NEED
500 g (1 lb) of baking soda (sodium bicarbonate)[NaHCO3]
200 g (7 oz) of cream of tartar (potassium bitartrate)[KHC4H4O6] [see note below]
Oven
Pyrex container
Jar with lid
500 mL (2 cup) glass beaker or Pyrex measuring cup
Sauce pan with water
2 mL (1/2 tsp) measuring spoon
Spoon for stirring
Coffee Filter
Filter paper or paper towelling
NOTE: Some people have gone to bulk food or health food stores where they found a less expensive cream of tartar. Unfortunately, what is sold there as "cream of tartar" frequently has been NOT potassium bitartrate, but rather a mixture of calcium sulfate (Plaster of Paris), monocalcium phosphate, fumaric acid, and corn starch. This mixture definitely WILL NOT WORK. If the sales person cannot guarantee that what they offer is potassium bitartrate, don't buy it, at least for this purpose.

HERE's WHAT YOU DO FOR THE FIRST REACTION
This involves the conversion of baking soda (sodium bicarbonate)[NaHCO3] to sodium carbonate(washing soda)[Na2CO3]
Place the contents of a 500 g box of baking soda into a suitable Pyrex container.
Heat in an oven at about 150 deg F (65 deg C) for one hour.
Increase the temperature to 250 deg F (120 deg C) and hold there for about an hour.
Repeat this increase for 350 and 450 deg F (175 and 230 deg C), for an hour each.
Remove the container and allow to cool to room temperature.
Place the sodium carbonate into a sealed container until used further.

HERE's WHAT YOU DO FOR THE SECOND REACTION
This involves the reaction of cream of tartar (potassium bitartrate formulation only)[KHC4H4O6] with sodium carbonate [Na2CO3] to produce Rochelle salt (potassium sodium tartrate)[NaKC4H4O6].
Place a suspension of 200 g (7 oz) (maximum) of cream of tartar in 250 mL (one cup) of water into a beaker of at least 500 mL (2 cups) capacity.
Heat the beaker by placing it into a saucepan containing water.
Heat the saucepan (e.g. on a stove or laboratory hot plate) until the outer water is just simmering.
Add about half a teaspoon (2.5 mL) of sodium carbonate to the beaker and stir the contents. The solution will bubble.
Add more sodium carbonate stepwise until no more bubbles form.
Filter the hot solution by using filter paper of a coffee filter.
Concentrate the solution (by evaporation) to about 400 mL or a little less by heating.
Allow the filtrate to cool and then store in a cool place for several days.
Collect the resulting crystals by decantation (pouring the excess liquid into another container) or by filtration.
Dry the crystals by blotting with clean filter paper or paper towelling.
For a better yield, concentrate again this solution left over after step 9 by heating and repeat steps 7 to10 above.
This should yield about 210 g of Rochelle salt.

WHAT's NEXT?
You can now recrystallize your Rochelle Salt, by using a single good crystal obtained above or by making a seed crystal.
Now go to procedures for growing single crystals.
It will be helpful to know that about 60 g of Rochelle salt will dissolve in about 100 g of water at room temperature. As you warm the water, you can dissolve more Rochelle salt.

This procedure is adapted from that used by Malgorzata Kaminska, an Ottawa high school student, in her Science Fair project.

************************************
A taste of the genius of FMAN
************************************
The separation of the six natural ephedra bases.
l-Ephedrine was first separated as hydrochloride, then
pseudoephedrine as the free base,
l-methylephedrine as the oxalate,
d-methyl-pseudoephedrine as the d-bitartrate and
finally nor-d-pseudo-ephedrine, from alcohol, asthe sulfate. Norephedrine, which crystallizes together with nor-d-pseudo-
ephedrine was separated in the form of its l-bitartrate.
References:150 " Ber 63, 95 (1930)
--------------------Amethystium--------------

posted 12-05-1999 02:06 AM         

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Details, details, details

Two patents for optically active amphetamine resolution.
British Patent no: 508,757

It has been unexpectedly ascertained that , optically active amines of higher efficacy can be obtained from amphetamine and its N homologous derivatives by splitting racemate into its active components by means of optically active acids.
Example:
85 parts of racemic methamphetamine are introduced into a solution of 100 parts of d-tartaric acid in 1000 parts of methyl alcohol. After protracted standing about 100 parts of the precipitated salt are aspirated off and extracted with hot ethyl alcohol. Since the d-tartrate of dextrorotary methamphetamine is readily soluble in both methyl and ethyl alcohol whereas the d-tartrate of levorotary methamphetamine is sparingly soluble both in methyl alcohol and hot ethyl alcohol an extremely simple separation of the d-tartrates of the optical antipodes of the base is effected.
===========================================================================

US patent : 2,276,508

my invention relates to a novel method for the separation of the optically active isomers of amphetamine and it compromises methods wherein the laevo and dextro isomers, in the form of their neutral salts with d-tartaric acid, are separated by the fractional crystallisation from an alcohol solution of such salts, the neutral d-tartrate of the laevo amine being obtained as a crystalline material, and it more particularly relates to the separation of the laevo-isomer, in the form of its neutral salt with d-tartaric acid, and the recovery of the laevo amine, as free base, from such neutral salt; all as more fully hereinafter set forth and as claimed.
It is known in the art (leithe,- "Ber. D. Chem. Gesell." (1932) p664) that d-amphetamine d-bitartrate may be obtained as a crystalline acid tartrate, from the racemic (- methylphenethylamine, by reacting the racemic amine with sufficient d-tartaric acid to form a mixture of the tartrates of the d- and l- amine and then fractionally crystallising the bitartrate of the d-amine from an alcohol solution of the mixture of acid tartrates so obtained. To obtain the d-amine as the free base, the acid tartrate may be decomposed with caustic alkali and the free base recovered by distillation in vacuo. By using l-tartaric acid in such method, the l-amphetamine l-bitartrate is obtained as a crystalline material by fractional crystallisation. This acid tartrate may likewise be decomposed with alkali to obtain the l-amine as a free base.

That is, either dextro or laevo -amphetamine have been previously obtained from the racemic form by certain known prior methods. But in such prior methods, the separation of the desired isomer is effected by the fractional crystallisation of acid tartrates. And in those methods, d-tartaric acid is used to obtain the dextro amine and l-tartaric acid to prepare the laevo amine. However while those processes are operable chemically, they have serious disadvantages, particularly with regard to the separation of l-amphetamine by means of d-tartaric acid, in that while d-tartaric acid is readily available and comparatively cheap, l-tartaric acid at the present time is both difficult to obtain and expensive in pure form (d tartaric acid comes from fruit, l-tartaric acid is 'unnatural'). Thus by the method outlined above d-amphetamine may be readily and cheaply prepared while the laevo form can only be obtained at great expense.

I have discovered a method whereby both optically active forms of amphetamine, and especially the laevo form may be prepared by the use of d-tartaric acid alone. This novel method greatly simplifies the process and makes the therapeutically useful isomers readily available.
Broadly, the method according to this invention comprises the separation of l-amphetamine from dl-amphetamine by treatment with d-tartaric acid for the production of a mixture of neutral d-tartrates and crystallisation from a solution, it having been found that l-amphetamine may be readily separated by crystallisation from a solution of the neutral d-tartrates.

The method according to this invention may be applied to , for example, racemic amphetamine, or to any mixture of the optically active isomers thereof in which the laevo form is present in amount not substantially less than the dextro form.

Again, the method according to this invention is applicable to mixtures rich in the laevo form, such as result from initial separation of the dextro form by methods heretofore known, as, for example, by crystallisation from a solution of a mixture of acid d-tartrates.

Where it is desired to effect separation of the laevo form from a mixture a mixture rich in the dextro form, it will usually be necessary to first effect separation of a part of the dextro form by methods heretofore known and then to apply the method in accordance with this invention to the remaining mixture.

As will be appreciated, the method in accordance with this invention, while primarily of the greatest advantage for effecting separation of l-(- methylphenethylamine, provides also procedure for the separation of d-amphetamine.

As more specifically illustrative of the method in accordance with this invention for the separation of the l-enantiomorph form, for example, racemic amphetamine, by the use of d-tartaric acid alone and with separation also of d-amphetamine, the following procedure may be employed and will be found to be efficient. Two mols, for example, 270 grams, of racemic amphetamine base are reacted with one mol (150 grams) of d-tartaric acid, thereby forming a dl-amphetamine d-tartrate, a neutral salt. The neutral salt thus obtained is fully dissolved by the addition of sufficient, say about 1 litre, of absolute ethanol, and heating to about boiling point. The solution is then allowed to cool to room temperature with occasional stirring to effect crystallisation. The crystals are filtered off and will be found to contain a preponderance of the laevo enantiomorph. On recrystallisation the preponderance of the l-enantiomorph is increased and the process is repeated until no further change in optical rotation is effected and a reading of [(]20(D = -6.5 is obtained in a concentration of 8 grams per 100 cc of aqueous solution. The product thus obtained is l-amphetamine d-tartrate. The residual solid in the mother liquors is repeatedly and systematically crystallised, yielding a further fraction of l-amphetamine d-tartrate which may be purified by recrystallization. d-amphetamine may be readily recovered from the mother liquors by the addition of tartaric acid thereto for the formation of acid tartrates and separation of d-amphetamine d-bitartrate by crystallisation.
The free base of either optically active isomer may be obtained by addition to the d-tartrate in the case of the laevo isomer and the d-bitartrate in the case of the dextro isomer of alkali in excess, as for example, by the addition of an aqueous solution of caustic soda, which will cause the base to separate as an oil which may be recovered and purified by any well known procedure.

As a further example, one mol of racemic -amphetamine base is reacted with 1.2 mols of tartaric acid and the resulting bitartrate is dissolved in, for example, 80% ethanol, with heating almost to the boiling point. The solution is then allowed to cool to about 60(C and filtered hot. Repeated crystallisation is then carried out until crystals having an optical rotation [(]20(D = +30.8 are obtained in a concentration of 8 grams per 100cc of aqueous solution. The product thus obtained is pure d-amphetamine d-bitartrate. The residual solid in the mother liquors is repeatedly and systematically crystallised, yielding a further fraction of d-amphetamine d-bitartrate which may be purified by recrystallisation.

The residual solid in the mother liquors now remaining comprises a preponderance of l-amphetamine d-bitartrate, which may now be separated by effecting neutralisation of the excess of d-tartaric acid present with production of neutral tartrates and effecting separation of the l-amphetamine d-tartrate by crystallisation. Neutralisation of the excess tartaric acid may be effected where, as in the case of the example above, the mother liquors comprise alcoholic solutions by dividing the total volume of the mother liquors into equal parts, removing, for example, by evaporation, the alcohol from one part, adding excess alkali, liberating the free base, which, as has been indicated, separates as an oil, separating and drying the free base with for example, caustic potash and then adding the free base to the other portion of the mother liquors with heating to forma solution. Such procedure will result in the formation of a neutral d-tartrate solution. From the solution so formed l-amphetamine d-tartrate may be separated by repeated crystallisation and the free base may be recovered as described above.

Following the procedure in accordance with this invention, other salts of the optically active isomers may be obtained from the free bases of the isomers by exact neutralisation of either base, with an organic or inorganic acid corresponding to the salt desired. Thus, by way of example, any desired organic or inorganic salt of the optically active isomers, in addition to the tartrates initially obtained, as for example, sulphates, hydrochlorides, oleates, etc., may be obtained by exact neutralisation of either optically active base with the acid corresponding to the desired salt. Following the procedure according to this invention it will be apparent that the l-enantiomorph may be initially separated from the racemic amphetamine, or from any mixture of the optically active isomers in which the dextro form is not in substantial excess; and that following the separation of the laevo form the dextro form may be recovered from the mother liquors by the addition thereto of d-tartaric acid for the formation of acid d-tartrates and crystallisation.

Again, as will now be evident, where the l-amphetamine is to be separated from a mixture of the optically active isomers in which the dextro form is in substantial excess, or in preponderance, the dextro form will first be separated by crystallisation following treatment with d-tartaric acid to form d-bitartrates and the laevo form will then be recovered by crystallisation following neutralisation with the formation of neutral d-tartrates.

Thus, it will now be understood that the method in accordance with this invention comprises essentially the separation of l-amphetamine from a racemic amphetamine and from the various mixtures of d- and l-amphetamine in which the laevo form is present in amount not substantially less than the dextro form with the use of d-tartaric acid for the formation of neutral d-tartrates and separation of l-amphetamine d-tartrate by crystallisation , whether the procedure be for the initial separation of the l-amphetamine d-tartrate, as from racemic amphetamine, or a mixture in which the dextro form is not in substantial excess, or is preceded by preliminary separation of the dextro form by known methods, as in the case of mixtures in which the dextro form predominates.

It will be understood that proceeding in accordance with this invention the free base, l-amphetamine may be readily obtained from the l-amphetamine d-tartrate by treatment of the d-tartrate with alkali in excess, resulting in separation of the free base as an oil which may be recovered and purified by any well known method.

posted 12-05-1999 05:43 AM         

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RESOLUTION OF AMPHETAMINE AND METHAMPHETAMINE

The dextro isomer of amphetamine and methamphetamine is the d, (+),
D or S isomer; the levo isomer is the l, (-), L or R isomer. The racemic
mixtures may be referred to as d,l or (+,-) or DL or (R)(S).
Classical resolution techniques are often tedious and usually
afford poor yields. The best published procedure seems to be that of
Rusznak et al. below which utilizes a selective extraction rather than the
usual crystallization.

Selective Extraction of d-Methamphetamine with d-Tartaric Acid:

Rusznak et al., Resolution of Phenylisopropylamines, Hung. Teljes, 12,208
(Cl. C07B), 28 Sep. 1976, Appl. 1,516, 08 Nov. 1974; CA 85, 192337q (1976).

Phenylisopropylamines and phenylisopropylmethylamines and various
substituted amines were resolved with 0.5 mole tartaric acid in benzene-water
containing 0.5 mole sodium hydroxide or potassium hydroxide by selective
extraction of either enantiomer.
A mixture of 0.1 mole (13.52 g.) phenylisopropylamine (or 14.92 g.
methamphetamine base) in 60 ml benzene, 0.05 mole d-tartaric acid (7.50 g.)
in 30 ml water, and 2 g sodium hydroxide (reagent grade or titrated equiv.)
in 3 ml water was kept 4 hours with intermittent shaking, and the organic
phase evaporated to give 98% L-phenylisopropylamine. The aqueous phase was
extracted with benzene at pH 13 and evaporated to give 96% D-enantiomer.

Other solvents such as toluene or xylene are likely to give similar results.

yup

.

All times are CT (US)