Author Topic: New high yield d-LSD synthesis  (Read 1829 times)

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AMARUK

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New high yield d-LSD synthesis
« on: July 16, 2004, 12:49:00 PM »
I have found new method of preparing lysergic acid amides with yield of 80%. In this method isomerisation  of d-lysergic acid amide to d-iso-lysergic acid amide never occurs. Czech Patent Aplication 287 047 describe this new superior  method of preparing only d-lysergic acid amides as end product  by treating d-lysergic acid in a solvent(i.e. DMF, ethyl acetate, toluene, acetone, THF, dioxan) with solution
(in one of above mentioned solvent) of propane phosphoric acid anhydride(coupling agent) of formula:
                        
                     I     O         I
                     I     II        I
                 ---I----P--O----I---
                     I     I         I
                     I     C3H7     I
                     I               I   m>3

with the aid of base(triethylamine, pirydine, N-ethylpiperidine, NaOH, KOH, anhydrous Na2CO3 or K2CO3) in temp. from -10 C deg to +130 C deg.

Example 1. d-lysergic acid S-(+)-1-buthanolamide (methylergometrine)
         
   To a  solution  of  1.3 g  of   d-lysergic    acid  in  50 ml of  dimethyl formamide (DMF) was added   0.8 ml    of    S-(+)-1-buthanolamine and mixture was cooled to +5 C deg and next 1,6 ml  of triethylamine was added and stirred  for 25 minutes in temp. of +5 C deg. The reaction was then treated with 5,3 ml of 50%propane phosphoric acid anhydride solution in DMF and stirred at room temperature for 1 hour. To the reaction mixture was then added 0,4 g of activated carbon an stired for 15 minutes and insoluble material was removed by filtration . To the reaction mixture was then added  50 ml of water and extracted with   50 ml of methylene chloride. The organic layer was separated and washed with two portion of 50 ml water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was chromatographed on 50 g of silica gel using 3% methanol in methylene chloride to yield 1.3 g (80%) of d-lysergic acid S-(+)-1-buthanolamide.

Example 6. N-[3-(dimethylamino)propyl]-6-methyl-ergolin-8b-carboxamid
         
   To a  solution  of  1.3 g  of   d-dihydrolysergic    acid  in  120 ml of ethyl acetate was added   2.0 ml    of  N,N-dimethyl-trimethylendiamine and mixture was cooled to +5 C deg and next 4,0 ml  of triethylamine was added and stirred  for 25 minutes in temp. of +5 C deg. The reaction was then treated with 8,0 ml of 50%propane phosphoric acid anhydride solution in DMF and stirred at room temperature for 1 hour. To the reaction mixture was then added 0,4 g of activated carbon an stired fo 15 minutes and insoluble material was removed by filtration . To the reaction mixture was then  extracted with   50 ml of saturated solution of NaHCO3. The organic layer was separated  and concentrated under reduced pressure. Yield 1.58 g (92,9%).

   This Patent(CZ287047) gives no information in which form lysergic acid was used(monohydrate or dry?). Could somebee find some articels described similar peptide condensation using propane phosphoric acid anhydride of above formula(reaction conditions, purity of reagents, water content in solvents, how dry must be carboxylic acid?).
   Where to buy propane phosphoric acid anhydride or how it prepare?
   What CAS Number have propane phosphoric acid anhydride?
  
Thanks for your HELP!!!   WILK    06:44 2004-04-05

Lilienthal

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CZ287047 (please use the patent markup!
« Reply #1 on: July 16, 2004, 02:05:00 PM »

Patent CZ287047

(please use the patent markup: ([patent]CZ287047[/patent]!)

hest

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Propylphosphonsaeureanhydrid made from the...
« Reply #2 on: July 16, 2004, 03:54:00 PM »
Propylphosphonsaeureanhydrid made from the acid chloride.
Newer heard about it before, Aldrich don't sell it.
Butt if siomeone would translate the interesting part's (p 6 and 7) of the patent ill look into it

longimanus

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Can someone, please, translate the ...
« Reply #3 on: July 16, 2004, 06:29:00 PM »
Can someone, please, translate the "PATENTOVÉ  NÁROKY" part, I`m not very good at Czech. It`s interesting that only the preparation of monosubstituted lysergamides was described. And the mentioned above part would tell us if the method is appropriate for LSD.
 
 UHH, and since 5gr propylphosphonic acid (not even the anhydride) cost ~$190 it won`t be the cheapest synthesis!

Nicodem

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We claim…
« Reply #4 on: July 16, 2004, 09:43:00 PM »
Here are the claims of the patent. I warn you that I don’t understand Czech good enough, so there might bee colossal mistakes in this translation. Italics are my comments.
 

1. Claims the preparation of substituted amides of the d-lysergic and d-dihydrolysergic acid and their derivates like shown on the structure I ( just a (dihydro)lysergic- amide-NR1R2 structure, see in the patent),

where

R1 - means a H atom, alkyl group with 1 to 4 carbon atoms or a 1-hydroxy-2-alkyl group with 2 to 4 carbons,

R2 - means a H atom, alkyl group with 1 to 2 carbon atoms, aryl group with 6 atoms in the ring or the group –(CH2)n-N(R5R6), where R5 and R6 is an alkyl with 1 to 3 carbon atoms, n is a full number from 1 to 5,

R3 - means a H atom, alkyl group with 1 to 4 carbon atoms or some alkenyl group with 2 to 4 carbon atoms (this is just the substituent on the basic N which is methyl in lysergic acid)

R4 - means a H atom, alkyl group with 1 to 4 carbon atoms (this is just the substituent on the indolic N which is hydrogen in lysergic acid)

x-y – means a single or double bond

and their pharmaceutically useful addition salts with organic or inorganic  acids, therefore claiming, that compounds of the structure II wherein
R3, R4 and x-y are like described in the above list
condense with the amino compounds of the structure III (R1R2NH)
wherein the R1 and R2 are already described in the above list,
in the presence of a base, organic solvent and the condensation reagent propylphosphate acid anhydride of the structure IV
where m>3.

2. …that the condensing reagent of the structure IV is used in the form of a solution in an organic solvent.

3. …that the solvent used is taken from the group composed of ethylacetate, toluene, DCM, DMF, acetone, CHCl3, THF, dioxane or a mixture of whichever of these.

4. …that the base used is taken from the group composed of pyridine, N-ethylpiperidine, triethylamine, hydroxide [draselnym?] (probably potassium?), NaOH, anhydrous potassium(?) carbonate or anhydrous sodium carbonate.

5. …that the reaction between compounds described with the structure II and the amine described by the structure III is performed at the temperature from -10°C up to 130°C or at the boiling temperature of the solvent.


longimanus

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just great
« Reply #5 on: July 16, 2004, 11:38:00 PM »
Don`t worry, Nicodem, that`s one of the best translations I`ve ever seen 8) . Couldn`t find any disparity between my translation and yours. Oh, yes, and draselným means potassium.

 So, the method is applicable for LSD-25, ETH-LAD, PRO-LAD, AL-LAD, DAM-57, maybe LSM-775 and LPD-824, but, I`m almost sure, not for N,N-dibutyllysergamides (not that someone is  interested in the synthesis of that compound).
The only problem would be the condensation reagent.