160103718 total synthesis of ketamine

8/17/2019 160103718 Total Synthesis of Ketamine

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1111

Total Synthesis of

Ketamine[Type the document subtitle]

[Type the abstract of the document here. The abstract is typically a short summary of thecontents of the document. Type the abstract of the document here. The abstract is typically ashort summary of the contents of the document.]


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Total Synthesis of Ketamine

While there’s 11 steps in the synthesis, its longitude is explained by the fact that all the precursors and even some reagents are made from scratch, employing user-friendlytechniues and euipment !in fact, a need for vacuum is mentioned only once, and even that isfor the removal of solvent"# as $ell as only easy-to-get reactants.

%till the synth is obviously for the s&illed only# for one thing, it involves ma&ing a 'rignard.There is a potential possibility to use (inc organic compounds instead !discussed in detail

belo$" $hich is much cheaper and easier technically.

)lso there is added an alternate preparation of o-chloroben(onitrile

Experimental

sodium nitrite

Sodium nitrate is also synthesized industrially by neutralizing nitric acid with soda

ash

2 HNO3 + Na2CO3 2 NaNO3 + H2O + CO2

nitric acid HNO3 !olar mass "3#$% g mol&% ' (ensity %#)%2* g cm&3

soda ash !olar mass %$)#*,- g'mol .anhydrous/ %2-#$$ g'mol

.monohydrate/ 2,"#%- g'mol .decahydrate/

(ensity 2#)- g'cm3 .anhydrous/ 2#2) g'cm3 .monohydrate/ %#)% g'cm3

.he0tahydrate/

%#-" g'cm3 .decahydrate/

)" 1!S .-*, !45S/ N6T6C C6( HNO3

636 GRAMS (246 ML,S) SODIUM CARBONATE (SODA ASH)

…………………………………………………………………………………….

1. o-Chlorobenzoic acid

• )nthranilic acid 1*,+g

• l !conc., d1,1/"

• 0a02 3g ! sodium nitrite"

• ul 14g !opper hlorides"

1*,+ grams anthranilic acid is stirred in a glass bea&er in 54ml,s destiled $ater, 23ml,s

hydrochloric acid l and 24 grams ice. With constant stirring and cooling there6s added 3grams sodium nitrite 0a02 in 54ml,ss $ater. Thus obtained clear solution of dia(onium salt

http://www.answers.com/topic/nitric-acidhttp://www.answers.com/topic/sodium-carbonatehttp://www.answers.com/topic/sodium-carbonatehttp://en.wikipedia.org/wiki/Molar_masshttp://en.wikipedia.org/wiki/Molar_masshttp://en.wikipedia.org/wiki/Densityhttp://en.wikipedia.org/wiki/Molar_masshttp://en.wikipedia.org/wiki/Molar_masshttp://en.wikipedia.org/wiki/Densityhttp://www.answers.com/topic/sodium-carbonatehttp://www.answers.com/topic/sodium-carbonatehttp://en.wikipedia.org/wiki/Molar_masshttp://en.wikipedia.org/wiki/Densityhttp://en.wikipedia.org/wiki/Molar_masshttp://en.wikipedia.org/wiki/Densityhttp://www.answers.com/topic/nitric-acid


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is very slo$ly added $ith stirring into a soln. of 14 grams copper chloride ul in 27 gramshydrochloric acid l conc. ) vigorous evolution of nitrogen is observed.

When the rxn ends, the ppt is filtered, $ashed $ith cold $ater and reprecipitated from a.%odium carbonate 0a2*. The product represents fine crystals and melts at 154-1518.

o-9romoben(oic acid can be obtained in an analogous manner, substituting copper chlorideul for u9r.

u9r !ver"

Preparation of Copper Chlorides

I prepared cuprous chloride by mixing copper wire, CuCO3 and a excess of

commercial 20 % hydrochloric acid Cl and warming it near boiling point

until all copper was dissol!ed" It was the deposition of a white powder

#cuprous chloride$" his product can&t be dried because it oxydi'es

(uic)ly, it was washed with water"

*ormal reaction is with copper wire or powder, cupric chloride CuCl2 andhydrochloric acid Cl, but I had then CuCO3"

CuCO3 #!er$

+lso cupric chloride was prepared by reacting a solution of CuCO3 with an

slightly excess of hydrochloric acid Cl, then e!aporating water and

finally, when product starts to turn brown, air dried to gi!e a hydrate

form"

copper wire

CuCO3

20 % hydrochloric acid Cl solution

2. o-Chlorobenzonitrile

Preparation .

!:"2;n < =b!%0"2 2 :0 < ;n% < =b% < 2 2

The best results are obtained $hen a (inc salt is employed instead of free acid. This rxn isunsuitable for amino-, nitro- and oxy- acids, but can bee used for bromo- and chloroben(oicacids.

To a hot soln of 74 grams sodium hydroxide 0a in 544ml,s $ater there6s added 1/7 gramso-chloroben(oic acid. arefully neutrali(e $ith ammonium hydroxide 0* or sodium

bicarbonate 0a* and add $ith heating 147 grams !>7? excess" (inc sulphate ;n%5 in544 ml,s destiled $ater. The precipitated salt is dried for prolonged time at 2448 and mixedintimately $ith 247 grams !@ead!AA" thiocyanate" =b!%0"2. The mixture is coffee ground anddried at 124-1548 for a prolonged time, then heated on open flame - the mixture melts andgases are evolved.


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Bistilled nitrile is treated $ith hydroxide de ammonia 05, steam-distilled and salted out.Cield 1*+ grams !34?", mp 5*-5D8, bp 2*28. The rxn usually ta&es place $ithin *4-D4mins, but the duration of dryings ma&es the method uite time-consuming.

Preparation !.

This one doesn6t reuire a prolonged drying. %ulfaminic acid is dirt cheap and can be acuired$ithout causing any suspicion.

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Flectro$inning processing leaches (inc from the ore concentrate by sulfuric acidG[31]

;n < 2%5 H ;n%5 < 2

.............................................................................................................................................

o-!romobenzonitrile

74 grams o-9romoben(amide and *7 grams !27 grams theory" sulfaminic !sulfamic" acid isthoroughly mixed and heated in a Wurt( flas&. )t 274-2778 distillation begins, $hich is overat 237-2/78 !ta&es approx. 1.7-2 hrs". The collected product is redistilled, yield *D grams!34? of theory". mp 7*-7+8, bp 271-27*8

As I found recently, this can bee simplified yet more, by forming benzamides in situ from the

corresponding acid and urea..but since this is a very good route to subst’d benzaldehydes

from benzoic acids, I’ll post it later separately.

…………………………………………………………………………………………………………..

"#P#C C#"

Anto a *-litre three-nec&ed flas&, fitted $ith a dropping funnel, a mechanicalstirrer !1" and a long reflux condenser, place 1/44 ml. !2+44 g." of concentratednitric acid, sp. gr. 1-52. %ince oxides of nitrogen are evolved in the subseuentoxidation, the reaction should be carried out in a fume cupboard, or the oxides of

nitrogen are led by a tube from the top of the condenser to a $ater trap !Iig.JJ, 8,l,c". eat the nitric acid to boiling, set the stirrer in motion, add a fe$ drops ofciclohexanol and ma&e certain that these are acted upon by the acid beforeadding more # an explosion may result if cyclohexanol is allo$ed to accumulatein the acid. nce the reaction has started, add 744 g. of cyclohexanol throughthe dropping funnel at such a rate that all is introduced in 5-7 hours # if theaddition of the secondary alcohol is too slo$, the cor&s !2", $hich are attac&ed

by nitrous fumes, may have to be replaced before the operation is complete.Keep the reaction mixture at the boiling point during the addition of the

cyclohexanol and for a further period of about 17 minutes in order to complete

http://en.wikipedia.org/wiki/Sulfuric_acidhttp://en.wikipedia.org/wiki/Zinc#cite_note-82http://en.wikipedia.org/wiki/Sulfuric_acidhttp://en.wikipedia.org/wiki/Zinc#cite_note-82


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the oxidation. =our the $arm reaction mixture into a bea&er # upon cooling, theadipic acid crystallises.Iilter on a large sintered glass funnel, and $ash $ith 244 ml. of cold$ater. :ecrystallise the crude acid from +44 ml. of concentrated nitric

acid # filter and $ash as above. The yield of recrystallised adipic acid,m.p. 1728, is 544 g. !*".

2+44 grams concentrated nitric acid744 grams cyclohexanol244 ml,s destiled $ater.+44 ml,s concentrated nitric acid

………………………………………………………………………………………………………..

$. Cyclopentanone

144 grams adipic acid and 14 grams barium hydroxide 9a!"2 is intimately mixed and placed into a flas& $ith a thermometer. The rxn is heated to 234 8, the mixture initially meltsand then the distillation ta&es place, $hich lasts about 1-2 hrs. The hot distillate is saturated$ith sodium chloride 0al, the upper layer is decanted and distilled, collecting the fraction

boiling at 123-1*4 8. Bry $ith magnesium sulphate Lg%5.

CieldG 71 grams !3/? of theory".

Notes:

• a!"#$% may bee substituted for barium hydro&ide 'a!"#$% (ithout much loss in the

yield.

• if one is to use pre)made alcium oxide a or 'a adipinate, no temp control is

necessary.

a!"#$% !ver"

'a adipinate !ver$

.........................................................................................................................................

%. l&mini&m isopropoxide

)l!i-=r"* - 9p 1*4-1548 at +mmg# mp 1138.


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Anto a 274 ml,s :9I euipped $ith an efficient reflux condenser there6s added D grams )lfoil, +4 ml,s !71 ml,s in theory" abs. isopropanol A=) !commercial reagent grade isopropanolA=) $as used $ithout any drying" and 4,1 grams sulfuric acid g%5. The mixture is heated.

An the beginning of boiling 4,7 ml,s !Lacrophage inflammatory protein-1M !LA=-1M" is a

chemo&ine l5 'C(E)*+, Extremely toxic, and heating continued until hydrogen gas2 evolution starts, $hen it is stopped, sometimes even cooling6s needed. )fter the rxnsubsides, heating is continued until almost full dissolution of aluminium metal )l !7-+ hrs".The obtained solution is immediately used as is in the follo$ing preparation.

………………………………………………………………………………………………..

. Cyclopentanol

Anto a 274 ml,s :9I euipped $ith a 17 cm Nigreux column and distilling condenser there6sadded 7* ml,s !74 grams" cyclopentanone in 74ml,s isopropanol A=) and the solt from the

previous prep, $hich contains about 54 grams )l isopropoxide. The rxn is gently heated,$hich causes acetone $ith some $ater to distill off. The distillation is ended $hen the temp ofthe vapors rises to >378.

The ppt inside the flas& is carefully decomposed $ith 74? sulfuric acid 2%5 until acidicand saturated $ith sodium chloride 0al. The upper layer is decanted and distilled, collectingthe fraction boiling at 1*+-1548. Brying $ith magnesium sulphate Lg%5.

CieldG 5+grams !/5?"

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Sodi&m s&lfate synthesis

it can be made by the rxn of sulphuric acid 2%5 $ith sodium hydroxide 0a

acid


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""""""""""""""""""""""""""""""""""""""""""""""

/. Cyclopentylbromide

An a flas& there’s mixed 5+ml,s !57grams" cyclopentanol and D4ml,s !/4 grams" 53? a. 9r.14 grams sodium sulphate 0a2%5 is added. The rxn is left for 25hrs $ith vigorous stirring.)fter that it’s diluted $ith 244 ml,s $ater and the lo$er organic phase is separated and$ashed $ith $ater t$ice. Bistill, collecting the fraction bet$een 1*+-1*38. Bryed $ithmagnesium sulphate Lg%5.

Cield 73 grams !+5?"

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0ydrobromic acid

2%5 < K9r --O K%5 < 9r

224 grams of K9r !potassium bromide" or 1/4 gams of 0a9r !sodium bromide" is dissolvedin 244 ml,s of distilled $ater and chilled in an ice bath. /4 ml,s of concentrated sulphuric acid2%5 is chilled in the ice bath and then slo$ly added to the chilled bromide solution beingsure not to allo$ the temperature to rise above +78, in order not to form any free bromine.The solution is cooled to room temperature and the K2%5 ! by product" that $as formed isfiltered out. The solution is then placed in a 1444 ml,s boiling flas& in a simple distillationapparatus. )dd a fe$ boiling chips. %tart a flo$ of $ater through the condenser and heat $ith

flame through a $ire gau(e. Water $ill distill over first, but $hen the temperature reaches1278 replace the receiving flas& $ith a clean flas&. Lonitor the temperature as it $illcontinue to rise to 12D8 and remain there steadily until the constant boiling solution hasdistilled over. When the temperature begins to drop stop the distillation. [At is important to&no$ the correct temperature in order to collect the proper fraction. To calibrate thethermometer first boil $ater in the apparatus and note the temparature. Af it reads 144 8, thenthe thermometer reads correctly. Af it reads say 1418, you should substract one degree $henreading your thermometer. Af it reads say // 8, you should add one degree $hen readingyour thermometer.] Fven purer 9r can be obtained by redistilling and collecting the portion

boiling at 12D 8.The acid obtained is approximately 5+.7? 9r $ith a density of 1.5/gJml.

ydrobromic acid

224 grams of K9r !potassium bromide" or 1/4 grams of 0a9r !sodium bromide"

244 ml,s of distilled $ater

/4 ml,s of concentrated sulphuric acid 2%5

K2%5 by product

#odine Crystals


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Cou $ill needG9unsen burner and asbestos suare !or a hot plate"Tripod and tin lid9ea&er, 274 ml,s

%eparating funnel 144 ml,sFvaporating dish

ydrogen peroxide 24 volumeTetrachloromethane or dichloromethaneBistilled $ater 1L solution of %ulphuric acid%upply of ribbon sea$eed !@aminaria" - that you can obtain a a biological supply store orfrom the sea shore

=rocedure

!Cou must $or& at a fume cupboard"1-ollect and dry about a do(en 74 cm lenghts of the sea$eed and heat them strongly on a tinrecipient until they are reduced to ash# probably it $ill reduce a uite small uantity, about aspoonful.2- )dd to the ash 24 ml,s of distilled $ater in a bea&er, and heat the suspension until it boils.* - Iilter the suspension5 - )cidify the filtered $ith %ulphuric acid solution7 - )dd then the hydrogen peroxide solution Cou $ill observe the formation of a bro$n color due the iodine liberation from the iodineions presentD- Transfer the mixture to a separating funnel+ -Fxtract the Aodine $ith tetrachloro methane or other solvent. The result is an organicsolution of iodine.3 - An order to obtain crystals , the solvent may be allo$ed to evaporate at room temperature,

by placing it in an evaporating dish in a fume cupboard. At $ill result crystals of iodine or rather gray-blac& brilliant fla&es.

ope that satisfies you. Af you need a more sophisticated method, $ith a purifying step, Qustas& again.

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. Cyclopentyl manesi&m bromide

Anto a 274 ml,s three-nec&ed flas& euipped $ith a reflux condenser, addition funnel and inertgas inlet there’s placed 74 ml,s TI !&ept over potassium hydroxide K, prior to the rxn174 ml,s refluxed over *4 grams a for Dhrs and distilled". / grams of fine magnesium Lgturnings is added follo$ed by some iodine crystals. The apparatus is flushed $ith argon and agentle stream of gas is left flo$ing in. Lagnetic stirring is commenced. The mixture instantly

becomes cloudy from magnesium iodine LgA. Irom the addition funnel there’s dripped 77grams !54 ml,s" cyclopentyl bromide in 144 ml,s tetrahydrofuran TI so that the solt boilssmoothly. The rxn is usually over in an hour, it is accompanied by precipitation of a $hite

Qelly-li&e mass, and at the bottom there may bee left some unreacted magnesium Lg as adar&-grey po$der.


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a !ver"

Rsage of tetrahydrofuran TI instead of ether is preferred since the rxn in it proceeds betterand faster !tetrahydrofuran TI is a more specific solvent for 'rignards" , the yield is betteras $ell. 9esides, tetrahydrofuran TI can be dried $ith a, $hile for ether ,sodium metal is

usually employed.

Notes on the possible usage of *n)organics:

+.. Nitriles are not bad as electrophiles, so it is possible that despite smaller reactivity of *n %compounds, they (ould (or- eually (ell here ) esp. if the r&n conditions are made harsher

!gentle reflu& instead of /0$.

*n% !ver$

1hat one AN say for sure)is that the r&n (ith *n% (ill go 2ust fine if one is to use o)

chlorobenzoyl chloride instead of benzonitrile. #aloanhydrides generally are the best species for coupling (ith metalorganics.

'is)dicyclopentyl zinc is conveniently made from the corresponding bromide, no need to

ma-e iodide here. And o)chlorobenzoyl chloride can be easily prepared from o)chlorobenzoic

acid !obtained in Step 1 $ and 3l 4 or some such.+

……………………………………………………………………………………………………………

)mmonium chloride crystals

add dil. ydrochloric acid l acid to 0* amoniaco !a" or 05. don6t add 0*!a" to l because it can create a highly exothermic reaction $hich might damageyou.

05 < l --O 05l!a" < 2so according to this balanced euation do the amount calculations and add them in 1 G 1. thenheat the solution until you get the $hite crystals. $ater $ill be vapourised and you6ll be left$ith the crystals.

=):) SSSSSSSSSSSSSS BF )LL0ARL @:ABF :C%T)@%

1 @AT: )AB @:AB:A

1 @AT: BF )L0A)

3. o-Chlorophenyl cyclopentyl 4etone


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To the thus obtained 'rignard solt there’s added 53 grams o-chloroben(onitrile and themixture is stirred for * days at :T. At is then poured into a mixture of ice J ammoniumchloride 05l, $ith addition of some conc. a. )mmonia hydroxide 0 * and left at ambienttemp until all ice melts. The &etone partially floats, partially goes to the bottom. At’s extracted$ith ben(ene.

The yields fluctuate, but rarely drop belo$ 77?.

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5. alpha-!romo-'o-chlorophenyl-cyclopentyl 4etone

54 grams &etone is dissolved in +4 ml,s !Lacrophage inflammatory protein-1M !LA=-1M" is a chemo&ine l5 and $ith cooling in sno$ it is added into a solt of 53 grams dioxanedibromide in 74 ml,s dioxane, and stirred at :T for *4mins. Then *4ml,sdestiled $ater areadded and the solt is $ashed $ith sodium carbonate 0a2* a. until neutral. This may lead

to some preciptation of the bromo&etone, $hich stays in !Lacrophage inflammatory protein-1M !LA=-1M" is a chemo&ine l5. The solvent is removed, giving 5+ grams !37?" of the

bromo&etone.

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16. '1-hydroxy-cyclopentyl-'o-chlorophenyl-7-methyl4etimine

57 grams of the above bromo&etone is dissolved in 74 ml,s ben(ene, add there 74 ml,striethylamine !1+gJ2*m@ is reuired for neutrali(ation of potassium bromine 9r, but a 2xexcess is used". The solt is then saturated $ith 7 grams methylamine, obtained by dripping asaturated solt of 17 grams methanolic solution of methylamine hydrochloride Le0 2Plonto 14 grams sodium hydroxide 0a, dried thru sodium hydroxide 0a. The rxn is leftfor 1 day and the solvents are removed under aspirator vacuum, giving *4 grams !34?" ofmethyl&etimine.

777777777777777777777777777777777777777#

8an&fact&re 9f Ethyl #odide

This is usually prepared by the action of iodine on alcohol in the presence of red phosphorus,much as described under ethyl bromide. Narious proportions of ingredients have beenrecommended. Thus Wurt( indicates phosphorus + parts, alcohol *7, and iodine 2*# $hilstIran&land used these in the ratio of +G *7G 15. )ccording to 9eilstein,

1 part of red phosphorus is placed in a retort $ith 7 parts of /4 per cent. alcohol, and then 14 parts of iodine are added gradually, and the mixture allo$ed to stand for t$enty-four hours.)t the end of that period the retort is $armed, and the ethyl iodide distilled off. The crude

product is purified by $ashing first $ith dilute solution of sodium hydroxide, and then $ith$ater , after $hich treatment it is dried over fused calcium chloride, and redistilled ifnecessary.

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Wal&er1 recommends the use of both red and yello$ phosphorus, in eual uantities, andobtains about 7+4 grams of the iodide for 744 grains of iodine used, or /* per cent. of thetheoretical yield. )s the dissolving of the iodine in the alcohol is tedious, he has devised anarrangement to shorten the time and labour. This consists essentially in an adaptation of the

principle of the %oxhlet extractor to the purpose. ) $ide-mouthed, round-bottomed flas&, of

about 1 litre capacity, carries a t$o-holed cor& into $hich are fitted an adapter, serving asreceptacle for the iodine and a $ide side-tube, up $hich the alcohol vapour passes. These areconnected at the top $ith a tube $hich passes to a reflux condenser. The arrangement is suchthat $hen alcohol placed in the flas& is boiled, its vapour passes up the side tube, is condensedin the reflux condenser, falls bac& on the iodine contained in the adapter, dissolves more orless of this iodine, and carries it do$n into the flas&, $here the solution of iodine in alcoholreacts $ith the phosphorus present.

To obtain about 774 grams of ethyl iodide the ingredients used are 744 grams of iodine, 274of alcohol, *4 of yello$ phosphorus, and *4 of red phosphorus. The alcohol and the t$o &indsof phosphorus are placed in the flas&, $ith a fe$ fragments of porous tile to prevent bumping,

and 144 grams of the iodine are pac&ed tightly in the adapter. The flas& is then connected up,and heated on a $ater-bath to boil the alcohol. Bistillation should not be allo$ed to proceedtoo rapidly, as much heat is disengaged during the reaction. When all the iodine has beendissolved, the heating is continued until there is no longer any coloration in the liuid due toiodine. The flas& is then cooled, and a fresh charge of iodine placed in the adapter, after $hichthe heating is re-commenced, and the operations repeated until the $hole 744 grams of iodinehave been $or&ed up.

When the reaction is completed, a small uantity of $ater is poured do$n the condenser todestroy any phosphonium compounds $hich may have been formed. The flas& is thendetached, and the liuid distilled off by means of a $ater-bath. The distillate, after being$ashed $ith $ater, separated from the aueous layer, and dried, is practically pure ethyliodide.

The chief precaution to be ta&en is the proper regulation of the temperature $hen the finalcharge of iodine is being dealt $ith. Too much heat should be avoided, and the last stagesconducted slo$ly until experience has been gained.

Lethyl iodide can be prepared in a similar manner.

*4 'rams red phosphorus

*4 'rams yello$ phosphorus !optional"

274 'rams alcohol !synthesis"

iodine !super mercados"

744 grams iodine crystals !synthesis"

77777777777777777777777777777777777777##

Diethylamine and triethylamine

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The reaction which 0roduces diethylamine also yields as by0roductsethylamine and triethylamine The relati8e amounts of each com0ound0roduced de0ends u0on the molar ratio of the two starting materials#9se of only a little ethyl iodide fa8ors the formation of mostly ethylamine 9seof a lot of the ethyl iodide fa8ors the formation of triethylamine Somewhere in

the middle5 a roughly e8en s0lit occurs# This will be done here# section of clean steel 0i0e 2 or 3 inches in diameter is obtained5 and finethreads are cut into each end so that a ca0 may be screwed onto each end# really nice touch would be to ha8e all the 0ieces0lated with a half:thousandths:inch of electroless nic;el5 but the 0later maythin; you are constructing a 0i0e bomb when he sees the 0i0e and ca0s#

The bottom of the 0i0e is secured by screwing the ca0 on o8er threads coatedwith Teflon ta0e#


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The toluene e=tracts should then be transferred to a flas;5 and the mi=turefractionally distilled through an efficient column Ethylamine distills at16 °C, diethylamine distills at 55 °C, and triethlyamine distills at89 °C# The diethylamine fraction should be collected o8er a2$:degree range centered on )) >C5 and this fraction then redistilled to get

the 0ure 0roduct# The yield of diethylamine is about 40 ml,s#bsolute freedom from water in the 0roduct can be assured by letting thecrude distillate sit o8er a few chi0s of 0otassium hydro=ide KOH for a fewhours 0rior to the final distillation#

14744 ml,s ethyl iodide

*1744 ml,s liuid ammonia hydroxide

7544 grams sodium hydroxide

D444 ml,s destiled $ater

Toluene !for extraction"

2 &ilos potassium hydroxide K

9omb nic&el coted

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11. Ketamine

14 grams of methyl&etimine is dissolved in 144ml,s undecane and boiled at 1/78 for *-5hrs.Ketamine is extracted $ith 24? hydrochloric acid l. )cidic extract is basified andextracted $ith dichloromethane BL. %olvent is removed giving the product as an oil thatuic&ly crystalli(es. At can bee purified by recrystalli(ation from pentaneJether orhexaneJether.

The yields are close to uantitative.

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Preparation of Copper Chlorides

I prepared cuprous chloride by mixing copper wire, CuCO3 and a excess of

commercial 20 % hydrochloric acid Cl and warming it near boiling point

until all copper was

dissol!ed" It was the deposition of a white powder #cuprous chloride$" his

product can&t be dried because it oxydi'es (uic)ly, it was washed with

water"

*ormal reaction is with copper wire or powder, CuCl2 and hydrochloric acid

Cl, but I had then CuCO3"

+lso cupric chloride was prepared by reacting a solution of CuCO3 with an

slightly excess of hydrochloric acid Cl, then e!aporating water and

finally, when product starts to turn brown, air dried to gi!e a hydrateform"


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Total synthesis ' 166 rams

o-Chlorobenzoic acid

2+5 grams )nthranilic acid !synthesis"

244 ml,s 7? hypochlorite solution !anthranilic acid synthesis"!loQas de piscinas"

544 ml,s destiled $ater !anthranilic acid synthesis"

54 g phthalimide !anthranilic acid synthesis" !ebay ver"

ydrochloric acid l !conc., d1,1/" !chines"

1D4 grams 0a02 !sodium nitrite" !synthesis"

)" 1!S .-*, !45S/ N6T6C C6( HNO3

. 0a02 sodium nitrite"

636 GRAMS (246 ML,S) SODIUM CARBONATE (SODA ASH) . 0a02 sodium nitrite"

244 grams ul !opper hlorides" !synthesis"

300 grams copper wire .Co00er Chloridessynthesis/

CuCO3 !opper hlorides synthesis"

20 % hydrochloric acid Cl solution !opper hlorides synthesis"

o-Chlorobenzonitrile

1444 grams sodium hydroxide 0a !chines"

1D444 ml,s destiled $ater !synthesis"

*/44 grams o-chloroben(oic acid !synthesis"

0* or 0a* !sodium bicarbonate" !super mar&et"

2144 grams !>7? excess" ;n%5 !;A0 %R@I)TF" !ver synthesis"

5144 grams =b!%0"2 !@ead!AA" thiocyanate" !ver synthesis"

05 ! idrUxido de amVnio" !ver"

http://en.wikipedia.org/wiki/Leadhttp://en.wikipedia.org/wiki/Thiocyanatehttp://en.wikipedia.org/wiki/Leadhttp://en.wikipedia.org/wiki/Thiocyanate


15/36

%ulfaminic acid ! ver synthesis"

o-!romobenzonitrile

1444 grams o-9romoben(amide !synthesis"

+44 grams !744 grams sulfaminic !sulfamic" acid ! ver synthesis"

Cyclopentanone

2444 grams adipic acid ! synthesis"

2+44 grams concentrated nitric acid !adipic acid synthesis"744 grams cyclohexanol !adipic acid synthesis"244 ml,s destiled $ater !adipic acid synthesis"+44 ml,s concentrated nitric acid !adipic acid synthesis"

244 grams 9a!"2 !9arium hydroxide " ! ebay"

%odium chloride 0al !table salt" !super mar&et"

Lg%5 !magnesium sulphate" !farmacias"

l&mini&m isopropoxide

124 grams )l foil !super mar&et"

1544 ml,s isopropanol A=) !isopropanol" !conservar e restaurar , farmacias"

2 grams g%5 !sulfuric acid" !conservar e restaurar"

144 ml,s l5 !carbon tetrachloride" !ver"


16/36

Cyclopentanol

14D4 ml,s !1444 grams " cyclopentanone !synthesis"

1444 ml,s A=) !isopropanol" !famacias , conservar e restaurar"

344 grams )l isopropoxide !synthesis"

Cyclopentylbromide

/54 ml,s !/44 grams " cyclopentanol !synthesis"

1244 ml,s !1344 grams" 53? a. 9r !hydrobromic acid" !synthesis"

224g K9r !potassium bromide" or 1/4g 0a9r !sodium bromide"!!hydrobromic acid synthesis"

244 ml,s distilled $ater " !hydrobromic acid synthesis"

/4 ml,s concentrated 2%5 " !!hydrobromic acid synthesis"

K2%5 ! by product hydrobromic acid synthesis"

2444 grams 0a2%5 !sodium sulphate" !synthesis"

!060 ML,S SULfURIC ACID H2SO4 !sodium sulphate synthesis"

734 ML,S SODIUM HYDROXIDE !sodium sulphate synthesis"

5444 ml,s destiled $ater !synthesis"

Lg%5 !magnesium sulphate" !farmacias"

Cyclopentyl manesi&m bromide

1444 ml,s tetrahydrofuran Thf !ver $here to get"

K !=otassium hydroxide" !ebay"

D44 grams a !alcium oxide !ebay"


17/36

134 grams Lg turnings !ver $here to get"

iodine crystals !synthesis"

ydrogen peroxide 24 volume ! iodine crystals synthesis"

Tetrachloromethane !ver" or dichloromethane ! iodine crystals synthesis"

Bistilled $ater ! iodine crystals synthesis"

1L solution of %ulphuric acid ! iodine crystals synthesis"

%upply of ribbon sea$eed!@aminaria" - that you can obtain a a biological supply store or fromthe sea shore ! iodine crystals synthesis"

argon gas !cylinder or generator !ver"

1144 grams ! 344 ml,s " cyclopentyl bromide !synthesis"

2444 ml,s tetrahydrofuran TI !solvent" !ver $here to get"

o-Chlorophenyl cyclopentyl 4etone

/D4 grams o-chloroben(onitrile !synthesis"

05l !ammonium chloride" !synthesis"

1 @AT: )AB @:AB:A !)mmonium chloride synthesis"

1 @AT: BF )L0A) !)mmonium chloride synthesis"

0* !ammonia hydroxide" !chines farmacias"

alpha-!romo-'o-chlorophenyl-cyclopentyl 4etone

344 grams o-hlorophenyl cyclopentyl &etone !synthesis"

1544 ml,s l5 !carbon tetrachloride" !ver"

/D4 grams dioxane dibromide !ver"


18/36

1444 ml,s dioxane !solvent" !$here to buy"

D44 ml,s destiled $ater !synthesis"

0a2* !sodium carbonate" !super mar&et"

1-hydroxy-cyclopentyl-'o-chlorophenyl-7-methyl4etimine

/44 grams alpha-9romo-!o-chlorophenyl"-cyclopentyl &etone !synthesis"

1444 ml,s ben(ene !loQas de tintas"

1444 ml,s triethylamine !synthesis"

144 grams methylamine !synthesis"

14744 ml,s ethyl iodide !triethylamine and methylamine synthesis"

*1744 ml,s liuid ammonia !triethylamine and methylamine synthesis"

7544 grams sodium hydroxide !triethylamine and methylamine synthesis"

D444 ml,s destiled $ater !triethylamine and methylamine synthesis"

Toluene !for extraction" !triethylamine and methylamine synthesis"

2 &ilos potassium hydroxide K !triethylamine and methylamine synthesis"

9omb nic&el coted !triethylamine and methylamine synthesis"

D*4 'rams red phosphorus !synthesis" !ethyl iodide synthesis"

D*4 'rams yello$ phosphorus !optional" !ethyl iodide synthesis"

7274 'rams ethyl alcohol !synthesis" !ethyl iodide synthesis"

iodine !super mercados" !ethyl iodide synthesis"

14744 grams iodine crystals !synthesis" !ethyl iodide synthesis"

*44 grams methanolic solution methylamine hydrochloride Le02l !solution"

D44 grams sodium hydroxide 0a !chines"


19/36

Ketamine

244 grams methyl&etimine !synthesis"

2444 ml,s undecane !ver "

24? hydrochloric acid l !solution"

Bichloromethane BL !solvent" !loQas de tintas"

=entane J ether or hexane J ether !ver"

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Synthesis of Ketamine '2

Ketamine is more difficult to synthesi(e than the previously considered == derivatives.)lthough it is currently a popular and common drug on the illicit mar&et, it is obtainedexclusively by diversion of commercial sources rather than synthesis. This route has anoverall yield of >D4?, $ith a difficulty rating of 2-* out of 14 and a ha(ard rating of 1-2 outof 14 !ref. D5". The general necessity of producing anhydrous methylamine in a clandestinesetting, rather than purchasing it, increases the difficulty. Rse of propylamine rather thanmethylamine $ould simplify this reaction, as its boiling point is above room temperature vs.methylamine, $hich is a gas at room temperature.

The syntheis starts $ith the reaction of cyclopentyl 'rignard and o-chloroben(onitrile to giveo-chlorophenyl-cyclopentyl &etone, follo$ed by alpha bromination of the &etone, and thenreaction $ith methylamine to form an alpha-hydroxy imine !1-ydroxycyclopentyl-!o-chlorophenyl"-&etone-0-methylimine". eating this imine results in Ketamine via a novelalpha-hydroxyimine rearangement !refs. 24, 21, 22, 2*, 25 ". verall yields are >D4?.

Tiletamine is synthesi(ed by an analogous process in industry, substituting 2-thiophenylmagnesium bromide for the phenyl grignard and ethylamine for methylamine. T$o other&etamine analogs have been found on the blac& mar&etG the compound missing the 2-chlorogroup on the phenyl ring, and its 0-ethyl analog. 9oth of these compounds are most li&ely

more potent and longer lasting than &etamine.

http://www.erowid.org/archive/rhodium/chemistry/pcp/research_refs.html#Referenceshttp://www.erowid.org/archive/rhodium/chemistry/pcp/research_refs.html#Referenceshttp://www.erowid.org/archive/rhodium/chemistry/pcp/pcp_struc.html#Figure1http://www.erowid.org/archive/rhodium/chemistry/pcp/research_refs.html#Referenceshttp://www.erowid.org/archive/rhodium/chemistry/pcp/research_refs.html#Referenceshttp://www.erowid.org/archive/rhodium/chemistry/pcp/pcp_struc.html#Figure1


20/36

Synthetic proced&re for 4etamine synthesis: Step 1: 'o-chlorophenyl-cyclopentyl 4etone

Cyclopentanone

144 grams adipic acid and 14 grams 9a!"2 is intimately mixed and placed into a flas& $itha thermometer. The rxn is heated to 234 8, the mixture initially melts and then thedistillation ta&es place, $hich lasts about 1-2 hrs. The hot distillate is saturated $ith sodiumchloride 0al, the upper layer is decanted and distilled, collecting the fraction boiling at 123-1*48. Bry $ith magnesium sulphate Lg%5.

CieldG 71 grams !3/? of theory".



)l!i-=r"* - 9p 1*4-1548 at +mmg# mp 1138.

Anto a 274 ml,s :9I euipped $ith an efficient reflux condenser there6s added D gams )l foil,+4 ml,s !71ml,s in theory" abs. isopropanol A=) !commercial reagent grade A=) $as used$ithout any drying" and 4,1 grams sulfuric acid g%5. The mixture is heated.


21/36

An the beginning of boiling 4,7 ,ml,s Lacrophage inflammatory protein-1M !LA=-1M" is a chemo&ine l5 'C(E)*+, Extremely toxic, and heating continued until hydrogen gas2 evolution starts, $hen it is stopped, sometimes even cooling6s needed. )fter the rxnsubsides, heating is continued until almost full dissolution of aluminium metal )l !7-+ hrs".The obtained solution is immediately used as is in the follo$ing preparation

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Cyclopentanol

Anto a 274 ml,s :9I euipped $ith a 17 cm Nigreux column and distilling condenser there6sadded 7* ml,s !74 grams " cyclopentanone in 74 ml,s isopropanol A=) and the solT from the

previous prep6n, $hich contains about 54 grams )l isopropoxide. The rxn is gently heated,$hich causes acetone $ith some $ater to distill off. The distillation is ended $hen the temp ofthe vapors rises to >378.

The ppt inside the flas& is carefully decomposed $ith 74? sulfuric acid 2%5 until acidicand saturated $ith sodium chloride 0al. The upper layer is decanted and distilled, collectingthe fraction boiling at 1*+-1548. Brying $ith magnesium sulphate Lg%5.

CieldG 5+ grams !/5?"


Cyclopentyl bromide

An a flas& there’s mixed 5+ ml,s !57 grams" cyclopentanol and D4 ml,s !/4 grams" 53? a.9r. 14 grams sodium sulphate 0a2%5 is added. The rxn is left for 25hrs $ith vigorousstirring. )fter that it’s diluted $ith 244 ml,s $ater and the lo$er organic phase is separatedand $ashed $ith $ater t$ice. Bistill, collecting the fraction bet$een 1*+-1*38. Bryed $ithmangnesium sulphate Lg%5.

Cield 73 ramsg !+5?"

cyclopentyl ;rinard reaent

11/.4 grams of cyclopentyl bromide and 1/.5 grams of magnesium are reacted in ether or

tetrahydrofuran TI to give a cyclopentyl 'rignard reagent.

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Phthalimide to anthranilic acid

'o to the great big building supply house and pic& up a couple of gallons of s$imming poolchlorination liuid. This stuff is 7? sodium hypochlorite. Cep, the same stuff as lorox

bleach but t$ice as strong and several times less expensive. 0o$ go to the chemicalsupplyand get a pound or so of phthalimide. This stuff costs about R%X7.44 a pound and isun$atched and uncontrolled. Yuantities can be purchased also in 27 pound bags, but you have

to $ait for it to come in.

http://en.wikipedia.org/wiki/Macrophage_inflammatory_proteinhttp://en.wikipedia.org/wiki/Chemokine#CC_chemokineshttp://en.wikipedia.org/wiki/Chemokine#CC_chemokineshttp://en.wikipedia.org/wiki/Macrophage_inflammatory_proteinhttp://en.wikipedia.org/wiki/Chemokine#CC_chemokineshttp://en.wikipedia.org/wiki/Chemokine#CC_chemokines


22/36

An a 2 liter erlinmeyer flas& put 244 ml,s of the hypochlorite solution and 544 ml,s of destiled$ater. Lix $ell and cool to less than *4 8, 24 8 is a perfect temperature. 0o$ add 54grams of phthalimide all at once. This is about 5 rounded tablespoons for the scale imparedout there. %tir this mess rapidly. The phthalimide $ill not dissolve, it $ill get $et and mix inthe solution. At6ll also try to cra$l up the sides of the flas& a half inch or so. )fter a couple of

minutes of stirring !the $armer the solution, the less the time. :emember cooler is better" thereaction $ill happen. The solution6s temperature $ill rise and start to release gas. At $illappear to boil $ith the phthalimide changing into anthranilic acid and foaming on the top ofthe no$ yello$ colored liuid. %ha&e the flas& and try to &eep it all $et. @et the reaction

proceed for * minutes sha&ing often, add an eual volume of cold $ater, stir to cool do$n andvacuum filter to collect the solids. ne thing to note here is that you should use t$o coffeefilters to filter this. This is concentrated anthranilic acid and bleach, it $ill eat right throughthe filter if you ta&e too long filtering it. %o filter uic& and get the filter paper out and lay iton a couple of paper to$els to $ic& a$ay more of the solution. Biscard the filtered yello$solution, there isn6t enough product in there to bother $ith.

The anthranilic $ill try to cling to the sides of the flas& and you6ll have to rinse the flas& a fe$times to get it all into the filter paper, this is o& since it $ill also rinse a$ay the rest of the

bleach solution leaving slightly yello$ crystals.

Cou no$ have uite a pile of slightly impure anthranilic acid that needs to be recrystali(ed to purify. Bon6t you Qust love it $hen people say, recrystali(e from $ater.S Cou try this andeither nothing happens and you lose your product or it comes out dirtier than $hen youstarted. To clean this stuff dissolve it in boiling $ater, filter and let the $ater cool torecrystali(e the anthranilic. o$ever, it is not very soluble in boiling $ater and almost not atall in cold $ater, so it $ill ta&e a hec& of a lot of $ater to do the Qob.

Bo it li&e thisG put the anthranilic in a 1 liter flas&, add *44 ml,s of destiled $ater and boil. 9ecareful, $atching it for boil over. The anthranillic acid forms long thin needle crystal that Qustlove to attach to bubbles forming in the boiling $ater and foam up. This foam $ill easily boilout of the flac& if you don6t pay attention. =our the boiling solution through 2 coffee filterusing only gravity. When the boiling solution starts to cool, it $ill immediately crystali(e into

pretty $hite crystals. )s it cools off, more $ill form until at around 27 8 it6s all out ofsolution. The residual po$der in the filter and flas& needs another boiling $ater treatment toget some more anthranilic acid. Keep this put-po$der-in-flas&, boil, filter operation goinguntil you don6t get crystals in the filtered $ater. )fter all the solutions !you6ll have multiplecontainers" have cooled, vacuum filter and dry the po$der. This operation $ill ta&e as much

as 5 liters of $ater, so be patient and &eep $ith it.

=ossiblities of scre$ up. eat is your enemy in the first part of the reaction, start off cool, besure to add the $ater to cool it off and filter it uic&ly to ma&e sure the operation doesn6t

proceed to far. Af it gets too hot it6l turn dar& and clean up is horrible. When recrystali(ingdon6t boil the solution too long or it $ill turn dar&. Zust bring it to a boil and filter, then do thenext boiling operation. B 0T try to dissolve all of it in the $ater, you may be able to do it,

but it $ill certainly turn dar& and ruin the batch. %ome one may read ho$ the solubility of theanthranillic in $ater can be increased by adding sodium hydroxide 0a to the $ater. This istrue, but it $ill also result in the anthranilic decomposing. Keep the sodium hydroxide 0ain the cupboard on the other side of the room. At $ould be best if you ta&e it a half mile a$ay

Qust to be sure.


23/36

The crystals $hen dry are mostly small needles, that fluff up and ta&e a lot of space for the$eight. 0eedless to say there is substantial mechanical loss to this procedure, and it can be a

pain in the butt. The yield is only around 74?, but at R%X7.44 for the phthalimide and almostnothing for the sodium hypochlorite it is really cost effective and provides one $ith a goodsource of this controlled substance.

244 ml,s 7? hypochlorite solution

544 ml,s destiled $ater

54 grams phthalimide


)nthranilic acid 1*,+ grams !synthesis"


3 grams 0a02 !sodium nitrite" !synthesis"

14 grams ul !opper hlorides" !ver $here to get"

1*,+ grams anthranilic acid is stirred in a glass bea&er in 54 ml,s destiled $ater, 23 ml,shydrochloric acid l and 24 grams ice. With constant stirring and cooling there6s added 3grams sodium nitrite 0a02 in 54 ml,s $ater. Thus obtained clear solution of dia(onium salt

is very slo$ly added $ith stirring into a soln. of 14 grams copper chloride ul in 27 gramshydrochloric acid l conc. ) vigorous evolution of nitrogen is observed.

When the rxn ends, the ppt is filtered, $ashed $ith cold $ater and reprecipitated from a.%odium bicarbonate 0a2*. The product represents fine crystals and melts at 154-1518.

o-9romoben(oic acid can bee obtained in an analogous manner, substituting copper chlorideul for u9r

u9r

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o-chlorobenzonitrile

=reparation ).

!:"2;n < =b!%0"2 2 :0 < ;n% < =b% < 2 2

The best results are obtained $hen a (inc salt is employed instead of free acid. This rxn isunsuitable for amino-, nitro- and oxy- acids, but can bee used for bromo- and chloroben(oicacids.


24/36

To a hot soln of 74 grams sodium hydroxide 0a in 544 ml,s $ater there6s added 1/7 gramso-chloroben(oic acid. arefully neutrali(e $ith ammonia hydride 0* or sodium bicarbonate

0a* and add $ith heating 147 grams !>7? excess" (inc sulphate ;n%5 in 544 ml,sdestiled $ater. The precipitated salt is dried for prolonged time at 2448 and mixed intimately$ith 247 grams @ead!AA" thiocyanate =b!%0"2. The mixture is coffee ground and dried at

124-1548 for a prolonged time, then heated on open flame - the mixture melts and gases areevolved.

Bistilled nitrile is treated $ith hydroxide ammonia 05, steam-distilled and salted out.Cield 1*+ grams !34?", mp 5*-5D8, bp 2*28. The rxn usually ta&es place $ithin *4-D4mins, but the duration of dryings ma&es the method uite time-consuming.

=reparation 9.

This one doesn6t reuire a prolonged drying. %ulfaminic acid is dirt cheap and can be acuired$ithout causing any suspicion.

EEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEE..

The best yields are obtained if the ether solvent is distilled from the 'rignard under vacuumand replaced $ith hydrocarbon solvent, such as ben(ene.

77.2 grams of o-chloroben(onitrile is then added to the reaction mixture and stirred for threedays. The reaction is then hydroly(ed by pouring it onto a mixture of crushed ice andammonium chloride, containing some ammonium hydroxide. Fxtracion of the mixture $ithorganic solvent gives o-chlorophenylcyclopentyl&etone, bp /D-/+ !4.* mm g" !)%D+54-37-3".

Step 2: alpha-bromo 'o-chlorophenyl-cyclopentyl 4etone

To 21.4 grams of the above &etone is added 14.4 grams of bromine in 34 ml,s of carbon

tetrachloride drop$ise at 4 deg. . )fter all of the 9r2 has been added, an orange suspensionforms. This is $ashed $ith a dilute aueous solution of sodium bisulfite and evaporated togive 1-bromocyclopentyl-!o-chlorophenyl"-&etone, bp 111-115 !4.1 mm g". Cield is>DD?. This bromo&etone is unstable and must be used immediately. )lso attempts to distill itat 4.1 mm g lead to some decomposition, so it should be used $ithout further purification.

The bromination may also be carried out $ith 0-bromosuccinimide in some$hat higheryields !>++?".

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7-bromos&ccinimide '7!S


25/36

1.D2 mol !1D4 grams" succinimide is dissolved in a mixture of 1.D4mol !D5 grams" sodiumhydroxide 0a, *44 grams crushed ice and 544 ml,s destiled $ater. ool the mixture in anice bath, and add 37 ml,s !1.D7 mol, 2D5 grams" 9r2 at once $hile stirring violently. %tir fort$o more minutes, then filter the precipitated product and $ash $ith ice $ater. Bry in adesiccator. Cield +7-31?.

Bon6t clean up 09% too much, the stin&y yello$ stuff still containing a bit of 9r 2 $or&s best.

1.D2 mol !1D4 grams" succinimide

1.D4mol !D5 grams" sodium hydroxide 0a,

*44 grams crushed ice

544 ml,s destiled $ater

37 ml,s !1.D7 mol, 2D5 grams" 9r2

8ethylamine from mmoni&m Chloride and

)ormaldehydeLany bees are ma&ing methylamine out of hexamine and l acid. A thin& it6s very timeconsuming and l is pretty nasty. Thus A have found that one can easily ma&e lots of gooduality methylamine from ammonium chloride and formaldehyde !formalin". nly dra$bac&$ith this method is that one must have good uality formaldehyde. At may have

paraformaldehyde sediment in the bottom, it doesn6t hurt, not even a bit, but Iormaldehydehas to be strong and not some diluted shit, *7-54? is fine.

0o$ to the more-less foolproof method. Af you do li&e said belo$, you get around 544-574grams of pretty pure dimethylamine-free methylamine hydrochloride $hich is perfect for

)lJg reductive aminations.

Chemicals needed:

• 1144g of )mmonium hloride

• 2 liters of *7-54? Iormaldehyde

• about half a litre of chloroform

The process


26/36

=our your formaldehyde in a big round bottom flas& !use atleast one of 7 liter capacity" along $ith ammonium chlorideand stir a bit. A used a 12 @ :9 flas&. %tart heating slo$ly,and stir it every once in a $hile.

[ )t 548 ] - [)t 348]

)t about /48, an exothermic reaction &ic&s in !it needs to be cooled in a $ater bath once in a $hile at the beginningin order to &eep temperature belo$ 145-14D8".

http://www.erowid.org/archive/rhodium/clandestine/methylamine/methylamine-02.jpghttp://www.erowid.org/archive/rhodium/clandestine/methylamine/methylamine-03.jpghttp://www.erowid.org/archive/rhodium/clandestine/methylamine/methylamine-04.jpghttp://www.erowid.org/archive/rhodium/clandestine/methylamine/methylamine-04.jpghttp://www.erowid.org/archive/rhodium/clandestine/methylamine/methylamine-02.jpghttp://www.erowid.org/archive/rhodium/clandestine/methylamine/methylamine-03.jpghttp://www.erowid.org/archive/rhodium/clandestine/methylamine/methylamine-04.jpg


27/36

%oon reaction slo$s do$n and cooling isn6t needed anymore, reaction flas&must be heated carefully to &eep temperature at 145-14D8.

Keep that temperature *-5 hours or so, then turn heat up and boil $ater a$ay

until you see ammonium chloride coming out of solution. ool to 248 and


28/36

vacuum filter it off on large 9uchner funnel !A have one $ith \ 27 cm".Cou should get a clear yello$ish filtrate li&e in this picture.

Transfer it to a smaller flas& and boil $ater a$ay until you seethe internal temperature rise over 1D48, then turn on the vacuum and continue,

first temperature falls a fe$ tens of degrees and $hen it rises bac& to about1D48 the methylamine is almost free of $ater. Turn off the vacuum and the heat.


29/36

=our your crude methylamine hydrochloride in a bea&er. )t first it is still liuid!in this picture it has started to solidify, you can still see some orange liuidat the bottom of the bea&er".


30/36

When it has cooled do$n, you6ll have a big chun& of hard and dry methylamine.Wash it a fe$ times $ith chloroform and you6ll end up $ith a fully $hite mush.

Nacuum filter to get pure and dry Lethylamine.l $hich ree&s of chloroform.The smell can be removed by drying in a vacuum desiccator. "o not try to usethe oven to get rid of these traces of chloroform, the Lethylamine.l pic&s up$ater from air li&e nothing. Cou can only use vacuum for sucessful drying butthese l* traces don6t hurt the methylamine at all and may be left in, but youmight perhaps be a perfectionist...


31/36

Iinal yield of sno$ $hite non-stic&y po$der, !consisting of methylamine $ith afe$ percent ammonium chloride, but and almost no dimethylamine hydrochloride",easily exceeds 544g if everything done correctly, or even 744g if you used54? formaldehyde.

......................................................................................................................................................

Step $: 1-hydroxycyclopentyl-'o-chlorophenyl-4etone-7-methylimine

2/.4 grams of above bromo&etone is dissolved in 74 ml,s of liuid methylamine freebase.9en(ene may also be used as solvent. )fter one hour, the excess liuid methylamine isallo$ed to evaporate, although increasing the reaction time to 5-7 days may increase yield.The residue is then dissolved in pentane and filtered. The solvent is evaporated to yield 1-hydroxy-cyclopentyl-!o-chlorophenyl"-&etone 0-methylimine, mp D2 !yield >35?".

Step %: 2-8ethylamino-2-'o-chlorophenyl-cyclohexanone 'Ketamine

The final step is a thermal rearrangement, and gives almost uantitative yield after 134 for*4 min. )n alternative to the use of decalin as solvent in this step is to use a pressure bomb.

2.4 grams of the preceeding 0-methylimine is dissolved in 17 ml,s of decalin and refluxedfor 2.7 h. )fter evaporation of the solvent under reduced pressure, the residue is extracted$ith dilute hydrochloric acid, the solution treated $ith decolori(ing charcoal, and theresulting acidic solution is made basic. The liberated product, 2-methylamino-2-!o-chlorophenyl"-cyclohexanone !Ketamine", after recrystalli(ation from pentane-ether, has a mpof /2-/*. The hydrochloride has a mp of 2D2-2D* .


32/36

)s $ith =F, the freebase is too caustic to be smo&ed, and must be converted into thehydrochloric l salt in order to be consumed in this manner.


Total synthesis 166 rams

Step 1: 'o-chlorophenyl-cyclopentyl 4etone

Cyclopentanone

1+444 grams adipic acid ! ver"

1+44 grams 9a!"2 !9arium hydroxide " ! ebay"

%odium chloride 0al !table salt" !super mar&et"

Lg%5 ! magnesium sulphate" !farmacias"


+*55 grams )l foil !super mar&et"

37D34 ml,s isopropanol A=) !conservar e restaurar , farmacias"

12* grams g%5 !sulfuric acid" !conservar e restaurar"

D24 ml,s l5!Lacrophage inflammatory protein-1M !LA=-1M" is a chemo&ine " !ver"

Cyclopentanol

314/ ml,s !+D74g" cyclopentanone !synthesis"

+D74 m,ls A=) isopropanol ! conservar e restaurar , farmacias"

D124 grams )l isopropoxide !synthesis"

http://en.wikipedia.org/wiki/Macrophage_inflammatory_proteinhttp://en.wikipedia.org/wiki/Chemokine#CC_chemokineshttp://en.wikipedia.org/wiki/Macrophage_inflammatory_proteinhttp://en.wikipedia.org/wiki/Chemokine#CC_chemokines


33/36

cyclopentyl bromide

7*77 grams cyclopentanol !synthesis"

14+14 grams 53? a. 9r !hydrobromic acid" ! synthesis"

224g K9r !potassium bromide" or 1/4g 0a9r !sodium bromide"!!hydrobromic acid synthesis"

244 ml,s distilled $ater !hydrobromic acid synthesis"

/4 ml,s concentrated 2%5 !hydrobromic acid synthesis"

K2%5 ! by product hydrobromic acid synthesis"

11/4 grams 0a2%5 sodium sulphate !synthesis"

2*344 ml,s destiled $ater !synthesis"

%odium chloride 0al !table salt " !super mar&et"

74? sulfuric acid 2%5 !solution"

Lg%5 magnesium sulphate !farmacias"


17223 grams )nthranilic acid !synthesis"

172544 ml,s 7? hypochlorite solution !anthranilic acid synthesis"!loQas de piscinas"

*45344 ml,s destiled $ater !anthranilic acid synthesis"

*4534 grams phthalimide !anthranilic acid synthesis" !ebay ver"


3+*D grams 0a02 ! sodium nitrite" ! synthesis"

",$- 1!S N6T6C C6( HNO3

. 0a02 sodium nitrite"

6724 GRAMS SODIUM CARBONATE (SODA ASH) . 0a02 sodium nitrite"

14/24 grams ul !opper hlorides" !synthesis"

-2 )ilos copper wire ! opper hlorides synthesis"


34/36

#!er$ CuCO3 ! opper hlorides synthesis"

20 % hydrochloric acid Cl solution ! opper hlorides synthesis"

o-chlorobenzonitrile

1344 grams sodium hydroxide 0a !chines"

55344 ml,s destiled $ater !synthesis"

14/24 grams o-chloroben(oic acid !synthesis"

0* ammonia hydroxide or 0a* !sodium bicarbonate" !chines J super mar&et"

7334 grams !>7? excess" ;n%5 !(inc sulphate" !ver"

11534 grams =b!%0"2 !@ead!AA" thiocyanate" !ver synthesis"

05 !hydroxide de amonio"

cyclopentyl ;rinard reaent 'synthesis

11/44 grams cyclopentyl bromide !synthesis"

1/54 grams magnesium turnings !$here to get"

ether or thf !synthesis"

ben(ene !opitional" !loQas de tintas"

7724 grams o-chloroben(onitrile !synthesis"

ammonium chloride !synthesis"

1 @AT: )AB @:AB:A !)mmonium chloride synthesis"

1 @AT: BF )L0A) !)mmonium chloride synthesis"

ammonium hydroxide !chines e farmacias"

http://en.wikipedia.org/wiki/Leadhttp://en.wikipedia.org/wiki/Thiocyanatehttp://en.wikipedia.org/wiki/Leadhttp://en.wikipedia.org/wiki/Thiocyanate


35/36

Step 2: alpha-bromo 'o-chlorophenyl-cyclopentyl 4etone

2144 grams o-chlorophenyl"-cyclopentyl &etone !synthesis"

1444 grams bromine !loQas de piscinas e ebay"

3444 ml,s carbon tetrachloride !$here to buy"

sodium bisulfite !ebay"

0-bromosuccinimide !=ATA0)@" !synthesis"

1.D2 mol !1D4 grams" succinimide !0-bromosuccinimide synthesis"

1.D4mol !D5 grams" sodium hydroxide 0a !0-bromosuccinimide synthesis"

*44 grams crushed ice !0-bromosuccinimide synthesis"

544 ml,s destiled $ater !0-bromosuccinimide synthesis"

37 ml,s !1.D7 mol, 2D5 grams" 9r2 !0-bromosuccinimide synthesis"

Step $: 1-hydroxycyclopentyl-'o-chlorophenyl-4etone-7-methylimine

2/44 grams alpha-bromo !o-chlorophenyl"-cyclopentyl &etone !synthesis"

7444 ml,s methylamine !synthesis"

15*44 grams )mmonium hloride !methylamine synthesis"

2D liters *7-54? Iormaldehyde !methylamine synthesis"

D744 ml,s chloroform !methylamine synthesis"

15*44 @AT: )AB @:AB:A !)mmonium chloride synthesis"

15*44 @AT: BF )L0A) !)mmonium chloride synthesis"

9en(ene !opitional" !loQas de tintas"

pentane S !ver"


36/36

Step %: 2-8ethylamino-2-'o-chlorophenyl-cyclohexanone 'Ketamine

1744 ml,s decalin !solvent" !=ATA0)@" !ver"

244 grams 1-hydroxycyclopentyl-!o-chlorophenyl"-&etone-0-methylimine !synthesis"

hydrochloric acid !chines"

decolori(ing charcoal !ver"

pentane-ether !ver"

160103718 total synthesis of ketamine

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