Recently, I came across an article, whose authorship and credibility I cannot confirm, but whose contents are rather intriguing. I included a direct copy of the text below. It is essentially a very crude procedural for the synthesis of a compound known as Pipradrol. I have no interest in performing the synthesis personally, but I was really wanting to get some input and opinion on just how valid these procedural claims are. Is it really possible to perform this synthesis reasonably? From what I've gathered, many of these reagents are pretty readily available, barring a platinum/carbon catalyst and a means of performing bomb hydrogenation. I have some knowledge of Organic Synthesis, but I have no experience with Chichibabin aminations or Grignard reagents. So can someone with real organic chem. experience say how valid this whole thing is? Thanks,
Castor
"The Complete Synthesis of Pipradrol from Domestically Available Chemical Intermediates
Pipradrol is a schedule IV controlled stimulant in the United States, whose safety profile and low potential for abuse places it in the same category of substances as dextroamphetamine and methylphenidate. Pipradrol is structurally related to methylphenidate. The compound was released to market in 1954 under the tradename “Meratran”, and was thoroughly studied as a promising treatment for depression, senile dementia, and a form of ADHD which was then referred to as “Childhood Hyperactivity Syndrome”. Relative to amphetamine, pipradrol is associated with a reduced incidence of “come-down” and “hangover” following stimulation. This is likely due to the extended duration of action and biological half-life of pipradrol, its effects lasting between 10-12 hours, allowing for a slow and stable metabolism over the course of the entire day. Pipradrol was associated with less incidence of hypertension and tachycardia compared with amphetamine. Pipradrol was found to exacerbate preexisting anxiety, frustration, and obsession, and was contraindicated in people with these conditions. Pipradrol was associated with insomnia when taken late in the day. Pipradrol has not seen any appreciable renewal in its production and marketing since it was scheduled in 1972, with its predecessor compound, methylphenidate, dominating most all its previous uses. The current paper discusses a potential renewal of the production of this compound, using intermediates which are readily available on both an industrial and consumer market.
The potential procedure would contain twelve steps of synthesis, assuming access to regents is highly limited and simplistic.
1. Sodium metal is produced by the reductive thermal decomposition of Sodium Hydroxide and Magnesium metal ribbon under low oxygen conditions. The sodium/magnesium oxide amalgam formed is then processed by workup with Dioxane to isolate and coalesce molten sodium metal droplets into useful and storable spheres. Sodium must be produced in bulk, for production of Sodamide and the future drying of solvents.
2. Sodamide is produced by the amination of sodium metal using anhydrous ammonia gas at between 320-350°C. The resulting Sodamide must be cooled quickly under desiccation and immediately covered submerged in mineral oil once cooled to workable temperatures. Oxidative destruction of Sodamide strongly reduces yield and requires further synthesis.
3. Pyridine is prepared via the decarboxylation of Niacin in the presence of a Basic Copper Carbonate catalyst.
4. 2-aminopyridine is produced by the Chichibabin mono-α-amination of pyridine using an aprotic solvent such as Diethyl ether, dried thoroughly using sodium metal. Glass wear must be heat treated in an oven to completely dry the entire apparatus. A KOH layer may be used for air intake at an addition funnel to further reduce water vapor contamination.
5. 2-Bromopyridine is produced by the Brom-displacment of 2-aminopyridine using ~48% HBr and Bromine gas injection.
6. Bromo-benzene is prepared by the reaction of benzene with bromine gas in the presence of an elemental iron catalyst. Bromo-benzene is produced in bulk for multiple future steps.
7. Benzonitrile is produced by performing a Rosenmund–von Braun synthesis from bromobenzene at ~350-400°C in the presence of Copper Cyanide. Sodium Cyanide/DMSO can be used as a stand in.
8. The Grignard reagent 2-Bromomagnesium-pyridine is prepared from 2-bromopryidine under highly aprotic conditions, similar to those used during Chichibabin amination.
9. Benzonitrile is reacted with 2-Bromomagnesium-pyridine to form 2-benzoylpyridine during an initial Grignard substitution followed by solvent hydration.
10. The Grignard reagent Phenyl Magnesium Bromide is prepared from bromobenzene.
11. 2-benzoylpyridine is reacted with Phenyl Magnesium Bromide to produce diphenyl-pyridinylmethanol.
12. Pipradrol is produced by the reductive hydrogenation of di-phenyl-pyridinylmethanol in the presence of hydrogen and a platinum on carbon catalyst.
Castor
"The Complete Synthesis of Pipradrol from Domestically Available Chemical Intermediates
Pipradrol is a schedule IV controlled stimulant in the United States, whose safety profile and low potential for abuse places it in the same category of substances as dextroamphetamine and methylphenidate. Pipradrol is structurally related to methylphenidate. The compound was released to market in 1954 under the tradename “Meratran”, and was thoroughly studied as a promising treatment for depression, senile dementia, and a form of ADHD which was then referred to as “Childhood Hyperactivity Syndrome”. Relative to amphetamine, pipradrol is associated with a reduced incidence of “come-down” and “hangover” following stimulation. This is likely due to the extended duration of action and biological half-life of pipradrol, its effects lasting between 10-12 hours, allowing for a slow and stable metabolism over the course of the entire day. Pipradrol was associated with less incidence of hypertension and tachycardia compared with amphetamine. Pipradrol was found to exacerbate preexisting anxiety, frustration, and obsession, and was contraindicated in people with these conditions. Pipradrol was associated with insomnia when taken late in the day. Pipradrol has not seen any appreciable renewal in its production and marketing since it was scheduled in 1972, with its predecessor compound, methylphenidate, dominating most all its previous uses. The current paper discusses a potential renewal of the production of this compound, using intermediates which are readily available on both an industrial and consumer market.
The potential procedure would contain twelve steps of synthesis, assuming access to regents is highly limited and simplistic.
1. Sodium metal is produced by the reductive thermal decomposition of Sodium Hydroxide and Magnesium metal ribbon under low oxygen conditions. The sodium/magnesium oxide amalgam formed is then processed by workup with Dioxane to isolate and coalesce molten sodium metal droplets into useful and storable spheres. Sodium must be produced in bulk, for production of Sodamide and the future drying of solvents.
2. Sodamide is produced by the amination of sodium metal using anhydrous ammonia gas at between 320-350°C. The resulting Sodamide must be cooled quickly under desiccation and immediately covered submerged in mineral oil once cooled to workable temperatures. Oxidative destruction of Sodamide strongly reduces yield and requires further synthesis.
3. Pyridine is prepared via the decarboxylation of Niacin in the presence of a Basic Copper Carbonate catalyst.
4. 2-aminopyridine is produced by the Chichibabin mono-α-amination of pyridine using an aprotic solvent such as Diethyl ether, dried thoroughly using sodium metal. Glass wear must be heat treated in an oven to completely dry the entire apparatus. A KOH layer may be used for air intake at an addition funnel to further reduce water vapor contamination.
5. 2-Bromopyridine is produced by the Brom-displacment of 2-aminopyridine using ~48% HBr and Bromine gas injection.
6. Bromo-benzene is prepared by the reaction of benzene with bromine gas in the presence of an elemental iron catalyst. Bromo-benzene is produced in bulk for multiple future steps.
7. Benzonitrile is produced by performing a Rosenmund–von Braun synthesis from bromobenzene at ~350-400°C in the presence of Copper Cyanide. Sodium Cyanide/DMSO can be used as a stand in.
8. The Grignard reagent 2-Bromomagnesium-pyridine is prepared from 2-bromopryidine under highly aprotic conditions, similar to those used during Chichibabin amination.
9. Benzonitrile is reacted with 2-Bromomagnesium-pyridine to form 2-benzoylpyridine during an initial Grignard substitution followed by solvent hydration.
10. The Grignard reagent Phenyl Magnesium Bromide is prepared from bromobenzene.
11. 2-benzoylpyridine is reacted with Phenyl Magnesium Bromide to produce diphenyl-pyridinylmethanol.
12. Pipradrol is produced by the reductive hydrogenation of di-phenyl-pyridinylmethanol in the presence of hydrogen and a platinum on carbon catalyst.
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