I am not sure if this is right or not. I will not be trying it out but thought it had potential. It is a proposed route for a synephrine based carfentanil analog that would not require any difficult to obtain reagents. It would be 4,beta-dihydroxy, 2,3 seco acetyl carfentanil.
The procedure and details were lifted from US patents 4,179,569 and 5,106,983 which can be found by searching for 'carfentanil synthesis'. Where it mentions colors and things like that, it is likely wrong, but could be used as a guide. I tried to put everything in grams instead of parts by weight and to correct the molar mass differences. I think the correct name would be something like: 4-((1-oxoacetyl)-phenylamino)- 1-(2-(4,b-dihydroxyphenylethyl))- 4-(2,3 secopiperidine)carboxylic acid methyl ester.
I have no idea what the potency would be if it is active. The seco change reduces potency 30x and the acetyl instead of propionyl reduces it 10x but the carboxylic acid methylester increases it 100x. thene there are the hydroxyl groups.
The shopping list:
167g synephrine (search for buy synephrine bulk, its a supplement)
58g acetone (the paint store)
50g paraformaldehyde (OTC as mildewcide or from chem supply store)
47g aniline (most easily bought as HCl salt from chem supply store or could be synthesized by reduction of nitro benzene or possibly replaced with 70g of p-aminobenzoic acid from health store(thanks to poster who mentioned this))
Glacial Acetic Acid (photo or chem supply store)
36g Potassium Cyanide (difficult to obtain but can be made, albeit with extreme caution, from potassium ferrocyanide, sulfuric acid, and potassium hydroxide (recipe is in rhodium archive)
Potassium Hydroxide (soapmaking supply)
Concentrated Sulfuric Acid (online, chem supply or by boiling battery electrolyte)
Hydrochloric Acid (online or pool supply)
Ammonium Hydroxide or other suitable base
Methanol (heet in auto aisle)
Cloroform (easily made or online)
diethyl ether (starting fluid or online)
acetic anhydride (online auction site or chem supply store)
a few other solvents
1. Mannich rxn with Synephrine HCl+Acetone+Paraformaldehyde
In a 1ml. round-bottomed flask attached to a reflux condenser are placed 190 g. (1 mole) of Synephrine HCl, 60 g. Acetone, and 50 g.paraformaldehyde. After the addition of 2 ml. of concentrated hydrochloric acid (sp. gr. 1.19) in 150 ml. of 95% ethanol (perhaps a different solvent might be better), the mixture is refluxed on a steam bath for 2 hours. The solution is filtered, and is transferred to a 2-l. wide-mouthed Erlenmeyer flask. While still warm, it is diluted by the addition of 400 ml. of acetone (Note 5), allowed to cool slowly to room temperature, and then chilled overnight in the refrigerator. The large crystals are filtered and washed with 25 ml. of acetone. Which should yield N-((4,b-dihydroxy)-2-methylaminophenethyl)-2,3 seco-piperidine. (1)
2. strecker type synthesis with aniline and KCN to yield 4-anilino, 4-cyano derivative
To a mixture of 119g (1), 47g aniline and 370g of acetic acid is added dropwise a soln of 36 g of KCN in 100mL of water, at a temperature between 35-45°C (exotermic reaction). After the addition complete, the cooling-bath is removed and the whole is stirred for 20 hrs at room temperature. The reaction mixture is poured into 650 parts of ammonium hydroxide and 500 parts of crushed ice are added. The mixture is extracted with chloroform. The organic extract was dried over potassium carbonate, filtered and evaporated. to yield (II)
3. Sulfuric acid to yield carboxamide
To 900g of conc. H2SO4 are added portionwise 157g of (II), while keeping the T below 25 C. Upon completion, stirring is continued overnight at RT. The reaction mixture is poured onto a mixture of 2.000 parts of crushed ice and 800 parts of ammonium hydroxide. The product was extracted with chloroform, extract dried, filtered and evaporated. The residue is stirred in 140 parts of Ether, cooled, the product filtered off and dried to yeild (III) (carboxamide)
4. KOH in ethylene glycol to yield piperidinecarboxylic acid
A mixture of 116g of (III), 53.7 parts of KOH and 275g of ethylene glycol is stirred and refluxed for 20 hrs. After cooling the RM is poured onto 1L of water and the whole is filtered. The filtrate is strongly acidified with HCl soln till the formed precipitate enters solution. Then the soln is strongly alkalized with a conc NaOH soln (exotermic rxn) and filtered hot.The sodium salt is allowed to crystallize from the filtrate. It is filtered off and recryst from water, yielding the corresponding 4-piperidinecarboxylic acid, sodium salt
here the other patent adds HCL to above to yield free acid (im switching to the other patent here)
The reaction mixture was poured into 1L of ice-water and made acidic to pH 6-6.5 with concentrated hydrochloric acid during which a tan solid precipitated out. The solid was filtered and washed with cold water. The solid was suspended in benzene and water was removed by azeotropic distillation. The mixture was cooled and filtered to yield (IV) (piperidinecarboxylic acid)
5. Methylation (i would add some oleum to this step if I tried it)
Concentrated sulfuric acid (60 mL) was added slowly to a stirred suspension of 132g of (IV) in 570 mL of anhydrous methanol. The resulting solution was refluxed for a total of 73 hours. The reaction mixture was cooled and poured into 2 L of icewater, upon which a gummy brown solid precipitated out. The mixture was made basic to pH 7.4 with dilute sodium hydroxide solution and extracted with methylene chloride. The extracts were dried over magnesium sulfate and evaporated to givecrude product which was recrystallized from N-hexane to give (V) (methyl ester)
6. A mixture of 11g (V) and 80 g Acetic anhydride was heated to reflux for 6 hours. Most of the propionic anhydride was then removed by distillation under reduced pressure. The residue was slurried in about 100 mL of ice-water and made alkaline to pH 8 with ammonium hydroxide. The mixture was extracted with chloroform and the extracts dried over magnesium sulfate and evaporated under reduced pressure. The residue, was dissolved in 50 mL of isopropanol and treated with a solution of 3.8 g (0.03 mole) of oxalic acid dissolved in 50 mL of isopropanol. The product was allowed to crystallize out overnight at room temperature. When filtered and dried, there was obtained dihydroxy acetyl seco carfentanil oxalate.
The procedure and details were lifted from US patents 4,179,569 and 5,106,983 which can be found by searching for 'carfentanil synthesis'. Where it mentions colors and things like that, it is likely wrong, but could be used as a guide. I tried to put everything in grams instead of parts by weight and to correct the molar mass differences. I think the correct name would be something like: 4-((1-oxoacetyl)-phenylamino)- 1-(2-(4,b-dihydroxyphenylethyl))- 4-(2,3 secopiperidine)carboxylic acid methyl ester.
I have no idea what the potency would be if it is active. The seco change reduces potency 30x and the acetyl instead of propionyl reduces it 10x but the carboxylic acid methylester increases it 100x. thene there are the hydroxyl groups.
The shopping list:
167g synephrine (search for buy synephrine bulk, its a supplement)
58g acetone (the paint store)
50g paraformaldehyde (OTC as mildewcide or from chem supply store)
47g aniline (most easily bought as HCl salt from chem supply store or could be synthesized by reduction of nitro benzene or possibly replaced with 70g of p-aminobenzoic acid from health store(thanks to poster who mentioned this))
Glacial Acetic Acid (photo or chem supply store)
36g Potassium Cyanide (difficult to obtain but can be made, albeit with extreme caution, from potassium ferrocyanide, sulfuric acid, and potassium hydroxide (recipe is in rhodium archive)
Potassium Hydroxide (soapmaking supply)
Concentrated Sulfuric Acid (online, chem supply or by boiling battery electrolyte)
Hydrochloric Acid (online or pool supply)
Ammonium Hydroxide or other suitable base
Methanol (heet in auto aisle)
Cloroform (easily made or online)
diethyl ether (starting fluid or online)
acetic anhydride (online auction site or chem supply store)
a few other solvents
1. Mannich rxn with Synephrine HCl+Acetone+Paraformaldehyde
In a 1ml. round-bottomed flask attached to a reflux condenser are placed 190 g. (1 mole) of Synephrine HCl, 60 g. Acetone, and 50 g.paraformaldehyde. After the addition of 2 ml. of concentrated hydrochloric acid (sp. gr. 1.19) in 150 ml. of 95% ethanol (perhaps a different solvent might be better), the mixture is refluxed on a steam bath for 2 hours. The solution is filtered, and is transferred to a 2-l. wide-mouthed Erlenmeyer flask. While still warm, it is diluted by the addition of 400 ml. of acetone (Note 5), allowed to cool slowly to room temperature, and then chilled overnight in the refrigerator. The large crystals are filtered and washed with 25 ml. of acetone. Which should yield N-((4,b-dihydroxy)-2-methylaminophenethyl)-2,3 seco-piperidine. (1)
2. strecker type synthesis with aniline and KCN to yield 4-anilino, 4-cyano derivative
To a mixture of 119g (1), 47g aniline and 370g of acetic acid is added dropwise a soln of 36 g of KCN in 100mL of water, at a temperature between 35-45°C (exotermic reaction). After the addition complete, the cooling-bath is removed and the whole is stirred for 20 hrs at room temperature. The reaction mixture is poured into 650 parts of ammonium hydroxide and 500 parts of crushed ice are added. The mixture is extracted with chloroform. The organic extract was dried over potassium carbonate, filtered and evaporated. to yield (II)
3. Sulfuric acid to yield carboxamide
To 900g of conc. H2SO4 are added portionwise 157g of (II), while keeping the T below 25 C. Upon completion, stirring is continued overnight at RT. The reaction mixture is poured onto a mixture of 2.000 parts of crushed ice and 800 parts of ammonium hydroxide. The product was extracted with chloroform, extract dried, filtered and evaporated. The residue is stirred in 140 parts of Ether, cooled, the product filtered off and dried to yeild (III) (carboxamide)
4. KOH in ethylene glycol to yield piperidinecarboxylic acid
A mixture of 116g of (III), 53.7 parts of KOH and 275g of ethylene glycol is stirred and refluxed for 20 hrs. After cooling the RM is poured onto 1L of water and the whole is filtered. The filtrate is strongly acidified with HCl soln till the formed precipitate enters solution. Then the soln is strongly alkalized with a conc NaOH soln (exotermic rxn) and filtered hot.The sodium salt is allowed to crystallize from the filtrate. It is filtered off and recryst from water, yielding the corresponding 4-piperidinecarboxylic acid, sodium salt
here the other patent adds HCL to above to yield free acid (im switching to the other patent here)
The reaction mixture was poured into 1L of ice-water and made acidic to pH 6-6.5 with concentrated hydrochloric acid during which a tan solid precipitated out. The solid was filtered and washed with cold water. The solid was suspended in benzene and water was removed by azeotropic distillation. The mixture was cooled and filtered to yield (IV) (piperidinecarboxylic acid)
5. Methylation (i would add some oleum to this step if I tried it)
Concentrated sulfuric acid (60 mL) was added slowly to a stirred suspension of 132g of (IV) in 570 mL of anhydrous methanol. The resulting solution was refluxed for a total of 73 hours. The reaction mixture was cooled and poured into 2 L of icewater, upon which a gummy brown solid precipitated out. The mixture was made basic to pH 7.4 with dilute sodium hydroxide solution and extracted with methylene chloride. The extracts were dried over magnesium sulfate and evaporated to givecrude product which was recrystallized from N-hexane to give (V) (methyl ester)
6. A mixture of 11g (V) and 80 g Acetic anhydride was heated to reflux for 6 hours. Most of the propionic anhydride was then removed by distillation under reduced pressure. The residue was slurried in about 100 mL of ice-water and made alkaline to pH 8 with ammonium hydroxide. The mixture was extracted with chloroform and the extracts dried over magnesium sulfate and evaporated under reduced pressure. The residue, was dissolved in 50 mL of isopropanol and treated with a solution of 3.8 g (0.03 mole) of oxalic acid dissolved in 50 mL of isopropanol. The product was allowed to crystallize out overnight at room temperature. When filtered and dried, there was obtained dihydroxy acetyl seco carfentanil oxalate.