09-05-02 15:38
No 352997
      Ritalin synthesis.
(Rated as: excellent)

Ritalin (methylphenidate).

threo-Methyl a-phenyl-a-(2-piperidyl)acetate

Its CNS stimulant and it has some of the effects of cocaine (in blocking dopamine uptake).

I think only one problem is in this synthesis - high pressure at hydrogenating.

Quoting from: Yahontov, Sintez khimiko-farmatsevticheskih preparatov, pp 149-153.

Synth. Overview:
2-chloropyridine react with benzylcyanid (with presence of lithium hydride) to produce alfa-phenyl-alfa-(pyridil-2)-acetonitrile, which hydrolysis (in solution of potassium hydroxide) to potassium-alfa-phenyl-alfa-(pypidil-2)-acetate.
Potassium-alfa-phenyl-alfa-(pyridil-2)-acetate is hydrogenated over Raney-nickel at 70C and 50atm to reduce pyridilic cycle to piperidilic.
Products of hydrogenation are heated in strong-alkali solution, which partially bring to obtain of threo-forms from erithro of product and threo-alfa-phenyl-alfa-(2-piperidyl)acetic acid is precipitated with following acidification.
Finely threo-alfa-phenyl-alfa-(2-piperidyl)acetic acid is esterificated with methanol (with presence of  sulfuric acid) to threo-Methyl-alfa-phenyl-alfa-(2-piperidyl)acetate.
Extracting of hydrochloride salt of product gives only one diastereomer - threo-Methyl-alfa-phenyl-alfa-(2-piperidyl)acetate hydrochloride.


1. Alfa-phenyl-alfa-(pyridil-2)-acetonitrile.
To boiling mixture of 120g of lithium hydride (diameter of particles is 0,2-0,3mm) and 2,6l of toluene was added 568g of 2-chloropyridine and 910g of benzylcyanid in 750ml of toluene during 3 hours. Mixture was refluxed 7h, chilled till 20-25C and 1l of methanol was added. Then mixture was refluxed one more hour, chilled till 20-25C and 3,5l of water was added. Toluene layer separated, water layer was extraction with toluene 3x1l. Combined toluenic extractions were evaporated, residue distilled in vacuo. Fraction with Bp = 150-160 at 3-4mmHg was collected. Yield was 88,4% of product with Mp = 89C.

2. Ritalin.
Solution of 190g of alfa-phenyl-alfa-(pyridil-2)-acetonitrile and 380g of potassium hydroxide in 4l of 50% aqueous solution of methanol was refluxed over 7 hours. Methanol and part of water was evaporated till mixture volume became 2l. Ph of mixture was leaded till 8 with added of conc. Hydrochloric acid, and 200g of Nickel-Raney was added. Mixture was hydrogenated at 70C and 50atm. Catalyst was filtered off, washed with water and collateral product (2-benzylpiperidin, 19,5g) was extracted from mixture with 3x200ml chloroform. To the water solution 400g of potassium hydroxide was added and water was evaporated till mixture volume became 1,6l during 3 hours (in process of evaporating threo-forms of product is partially obtained), afterward mixture was chilled till 20-25C and conc. Hydrochloric acid was added till pH = 6,0. Precipitated threo-alfa-phenyl-alfa-(2-piperidyl)acetic acid was filtered off. Mother waters was evaporated, residuums of water were distilled with benzene like azeotrope and 1l of methanol and 150ml of conc. Sulfuric acid were added. Mixture was refluxed 6 hours, chilled, basificated  with 50% solution of potassium carbonate and 44g of erithro-Methyl-alfa-phenyl-alfa-(2-piperidyl)acetate (with presence of threo-isomer) were extracted with chloroform. Chloroform was evaporated and to residue 44g of potassium hydroxide in 100ml of water were added. Mixture was refluxed 5 hours, chilled till 20C and acidificated with conc. Hydrochloric acid till pH = 5. Precipitated product was filtered off. To mother waters were added 80g of potassium hydroxide in 100ml of water. Mixture was refluxed 5 hours and acidify till pH = 6. Product of threo-acid were separated. All separated portions of threo-acid were combined. To product were added 1l of methanol and 150ml of conc. Sulfuric acid, and mixture was refluxed 6 hours, chilled till 2-5C and at this temperature basificated with 50% aqueous solution of potassium carbonate. threo-Methyl-alfa-phenyl-alfa-(2-piperidyl)acetate was extracted with chloroform 3x500ml. Extractions were combined and dried over potassium carbonate and chloroform was evaporated. Residue was distilled in 400ml of diethyl ether, decolourized with active carbon and acidify with ethanolic solution of hydrogen chloride. Precipitated product was recrystallized  from isopropanol. Yield of Ritalin 83g (31,4% for Alfa-phenyl-alfa-(pyridil-2)-acetonitrile). Admixtures of erithro-forms in products are absent.

Wanna make laugh the GOD? - Tell him about your plans.
(Distinctive Doe)
09-05-02 17:45
No 353023
      This could bee interesting  Bookmark   

To bad its not on espacenet  :o(
Brazillian Bees?

Process for the preparation of methylphenidate and its derivatives.
Dias, Luiz Carlos. 
(Universidade Estadual de Campinas- Unicamp, Brazil).    Braz. Pedido PI  (2001),    
BR  9903436  A  20010313  Patent  written in Portuguese. 
Patent BR9903436

A high-yield process for the prepn. of methylphenidate and its 4-substituted Ph derivs. is presented.

Those who give up essential liberties for temporary safety deserve neither liberty nor safety