To a solution of 392 grams of cyclohexanone and 15.6 grams of ammonium acetate in 200 mL benzene, there was added dropwise 340 grams (4.0 mol) of acetyl cyanide. With completion of the addition of acetyl cyanide, the reaction mixture was distilled over 5 hours until all water was removed. The remaining cyclohexenylacetonitrile was distilled slowly under vacuum at a pressure of 50-70 mmHg, at a temperature of 130-140 degrees Celsius.

The distillate is placed in ether, followed by washing with cold water. After evaporation of the ether is complete, the Cyclohexen-1-yl-acetonitrile formed crystals, mp. 90-93 C, mass 380g (77% yield).

METHOD A: Reduction with LiAlH4

To a solution of 42 grams of Lithium Aluminum Hydride in 2000 mL of dry ether in an atmosphere of nitrogen, there was added dropwise 121 grams of Cyclohexen-1-yl-acetonitrile. Once the addition was completed, the mixture was kept at 0 C and stirred for 2 hours.

After decomposition of the excess LiAlH4 with water and conc. NaOH, the final clarified reaction product, cyclohexen-1-yl-ethylamine, was obtained in the amount of 89.5 g (74% yield).

125 grams of cyclohexen-1-yl-ethylamine in 250 mL benzene was added slowly, with continutius stirring, to a soln. of 85 grams of Phenyl acetyl chloride in 170 mL benzene. During the addition, the system was chilled using an ice-bath.

Upon completion of the addition of the cyclohexenylethylamine, the mixture was allowed to stand for 30 minutes, followed by gradual heating on a steam bath. The cyclohexenyl-acetyl-ethylamide hydrochloride was washed with sodium carbonate and the remaining benzene was distilled off, yielding 123 g of crystals of N-(cyclohex-1-en-1-ylmethyl)-2-phenylacetamide.

243 grams (1 mol) of N-(cyclohex-1-en-1-ylmethyl)-2-phenylacetamide was added to a solution of 730 grams of Phosphorous pentoxide in 1200 mL benzene. The reaction mixture was heated for 45 minutes and then allowed to stand at room temperature for 2 hours. The reaction mixture was subsequently transferred, with ice cooling, to a separatory funnel. The mixture was shaken with solid KOH and dried with ether. All the while, a temperature of 0 C was maintained.

178 grams of a bright yellow oil remained. This was placed into 80 mL dry acetone. The oil-acetone mixture was then added to a solution of 200 grams of methylbromide in 300 mL dry acetone. This mixture was subsequently allowed to stand at room temperature for 12 hours.

The residue that remained after distillation in vacuo of acetone was washed with cold water and removed with ether. The aqueous solution of the quaternary salt was reduced after supplementation with a concentrated solution of 56 grams of potassium hydroxide in methanol with Raney Nickel under vacuum at 50 mmHg.

When the reduction had been completed, the product was treated with MeOH and distilled in vacuo with benzene, yielding 85.8 grams of 1-benzyl-2-methyl-1,2,3,4,5,6,7,8-octahydroisoquinoline, mp. 106-108 C. (HCl 195 C).

25 grams of 1-benzyl-2-methyl-1,2,3,4,5,6,7,8-octahydroisoquinoline was heated in 125 mL of phosphoric acid for 72 hours at 130 C (this process is known as Grewe Cyclization).. Thus, the racemic N-methyl-morphinan was obtained, [freebase mp. 110 C, phosphate salt mp. 141-145 C.]

For synthesis of 3-hydroxy-alkyl derivatives of the parent N-methyl-morphinan, the substitution of para-Methoxyphenyl acetyl chloride for Phenyl acetyl chloride in the intermediate synthesis of the cyclohexenyl amide yields the desired target compounds. Equimolar quantities of aforementioned reactants/reagents/catalysts are employed, with only slight modification in the overall procedure required to achieve the desired results.

Xylene is the preferred solvent in 3-hydroxy-alkyl derivative synthesis, whereby the cyclohexen-1-yl-ethylamine intermediate is reacted with p-Methoxyphenyl acetyl chloride, achieving condensation to the desired acetamide intermediate, in this case being N-(cyclohex-1-en-1-ylmethyl)-2-(p-Methoxyphenyl)acetamide.

The substitution of phosphoryl chloride for phorphorous pentoxide in the next stage of the synthesis (toward the isoquinoline) results in the formation of 1-(p-methoxybenzyl)-3,4,5,6,7,8-hexahydroisoquinoline, which may then be further converted to 1-(p-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline follwing reduction with Raney Nickel in the presence of a methylated halogen. This facilitates the formation of the 9, 10 alpha-carbon-nitrogen double cross-bridge in the structure of the molecule.

The 1-(p-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline is then placed in an solution of 40% buffered formaldehyde in methanol and allowed to stand for 2 hours, followed by purification from the Raney Nickel catalyst, yielding 1-(p-methoxybenzyl)-2-methyl-1,2,3,4,5,6,7,8-octahydroisoquinoline.

After purification/recrystallization, the 1-(p-methoxybenzyl)-2-methyl-1,2,3,4,5,6,7,8-octahydroisoquinoline is cyclized to the desired 3-hydroxymorphinan by heating at temperatures of 130-140 C for 60-80 hours with 100% phosphoric acid and buffered 48% hydrobromic acid.

This results in 3-hydroxy-N-methylmorphinan hydrobromide, [mp. 251-253 C], molecular formula: C17H23NO (freebase), mp. 202-203 C. or racemorphanol [DXO/LVO].
liquid
Treatment of 3-hydroxy-N-methylmorphinan with either diazomethane or phenyltrimethylammonium hydroxide yields 3-Methoxy-N-methylmorphinan,
otherwise known as racemethorphan [DXM/LVM].

The enantiomers can then be separated by column chromatography or high-performance liquid chromatography (HPLC) using a chiral mobile phase or a chiral stationary phase.[1]

Dextromethorphan has been synthesized from a benzylisoquinoline (with a planar structure) by a process known as Grewe's cyclization (from the 1950's) to give the corresponding morphinan (with a three dimensional structure). The isoquinoline is 1,2,3,4,5,6,7,8-octahydro-1-(4-methoxybenzyl)isoquinoline (there is just one residual double bond at the fusion position of the two rings of the isoquinoline) is converted into the N-formyl derivative, cyclized to the N- formyl normorphinan, and the formyl group reduced to an N-methyl group, to give 3-methoxy-17-methylmorphinan, or Racemethorphan.

Racemethorphan is a mixture of equal amounts of the (+)-isomer (Dextromethorphan) and the (-)-isomer (Levomethorphan) and this must be resolved into its two separate isomers. The racemic mixture (Racemethorphan) and the (-)-isomer (Levomethorphan) are both Schedule II drugs under the Controlled Substances Act, but the (+)-isomer (Dextromethorphan) has been exempted from scheduling (see 21 U.S.C. 812 (g)(2)). If an appropriate optical isomer of the octahydroisoquinoline is used, the illegal intermediate can be avoided.[2]

^ Feitsma, Karla G. "Chromatographic Separation of Enantiomers." Pharmacy World & Science. 10.1 (1998): 1-11. http://www.springerlink.com/index/V76138801536P090.pdf ^ Dr. Shulgin. "DXM (Dextromethorphan) Synthesis" 5 June 2004. http://brainmeta.com/forum/index.php?showtopic=5964