DESCRIPTION

The present invention provides an improved process for the preparation of intermediates of Dextromethorphan, N-[2-(1-cyclohexen-1-yl)ethyl]-2-(4-methoxyphenyl)acetamide and N-Formyl morphinan.

Dextromethorphan hydrobromide of Formula I is chemically known as morphinan,3-methoxy-17-methyl-(9α, 13α, 14α) hydrobromide monohydrate

Formula I

Dextromethorphan (DXM or DM) is an antitussive or cough suppressant drug. It is one of the active ingredients used to prevent coughs in many over-the-counter cold and cough medicines, such as Robitussin, Vicks 44, Coricidin, NyQuil, Dimetapp, and Delsym, among others.

U.S. Patent No. 2,676,177 describes Dextromethorphan. The U.S. Food and Drug Administration (FDA) approved Dextromethorphan for over-the-counter sale as a cough suppressant in 1958.

US. Patent No. 2,634,273 and British patent no. 685,748 describe a process for the preparation of N-[2-(1-cyclohexen-1-yl)ethyl]-2-(4-methoxyphenyl)acetamide and its converstion to Dextromethorphan.

US 3,634,429 discloses a process for the preparation of (+)-3-methoxy-N-formylmorphinan by cyclization of (+)-1-(p-methoxybenzyl)–2-formyl-l ,2,3,4,5,6,7,8-octahydroisoquinoline in the presence of phosphoric acid and and sulfuric acid at 70 °C.

Present inventors found one or the other problems while developing intermediates of dextromethorphan and their conversions to dextromethorphan as per the processes of prior art. The inventors suffered especially with the low yield, purity of intermediates and use of lengthy maintenance of the reaction, which effected overall yield and purity of Dextromethorphan or salt thereof. Long reaction time and low overall yields makes prior art process very expensive and less productive.

Therefore, there is a need to develop an improved process for the intermediates of Dextromethorphan. Inventors of the present invention found that the use of a catalyst improves yield of N-[2-(1-cyclohexen-1-yl)ethyl]-2-(4-methoxyphenyl)acetamide of Formula II. Furher, it has now been surprisingly found that, when the cyclization reaction is performed in presence of lower quantity of sulfuric acid results higher yield to form Formula A and it reduces the maintainance time of reaction.

The present invention provides a simple and convenient processes for the preparation of compound of Formula II, compound of Formula A and conversion of Formula A to dextromethorphan of Formula I, which are amenable to a large scale production.

In one aspect, the present invention provides a process for the preparation of N-[2-(1-cyclohexen-1-yl)ethyl]-2-(4-methoxyphenyl)acetamide of Formula II
,
Formula II
which comprises reaction of p-methoxy phenyl acetic acid of Formula III or salt thereof
Formula III
with cyclohexenyl ethyl amine of Formula IV or salt thereof

Formula IV
by using a catalyst in presence of organic solvent.

The catalyst used for conducting the reaction is selected from boric acid, boron trifluoride etherate, alkyl or aryl sulfonate salt and the like. It activates the reaction and reduces the time period for completion of the reaction. The molar equivalent of catalyst may range from about 0.005 to about 0.5 or about 0.01 to about 0.1 per molar equivalent of compount of Formula III.

Compounds III and IV may be used as a salt for coducting the reaction. Salt can be formed from an acid includes inorganic acid or organic acid. Inorganic acids may be selected from hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid and the like; organic acid may be selected from acetic acid, formic acid, succinic acid, tartaric acid, citric acid, and the like.

Suitable organic solvent or mixtures thereof used for performing the reaction includes but not limited to hydrocarbon such as hexane, heptane, cyclohexane, toluene, petroleum ether and the like; halogenated solvent such as dichloromethane, carbon tetrachloride, chloroform, chlorobenzene and the like.

Suitable temperatures for conducting the reaction range from about 50 to about 100 °C or from about 80 to about 90 °C. The reaction may be carried out for a certain period of time, for example, from about 5 to about 10 hours.

The yield of N-[2-(1-cyclohexen-1-yl)ethyl]-2-(4-methoxyphenyl)acetamide of Formula II is greater than or equal to 95% and above.

N-[2-(1-cyclohexen-1-yl)ethyl]-2-(4-methoxyphenyl)acetamide of Formula II may have the purity greater than or equal to 95 % determined by the gas chromatography (GC).

The intermeidate of Formula II obtianed from the present invention is converted to intermediate of Formula B and dextromethorphan by the processes known in the prior art, for example, US 2,634,273 patent.

In another aspect of the present invention provides an improved process for the preparation of 3-methoxy-N-formylmorphinan of Formula A

Formula A
which comprises cyclization of N-formyl octabase of Formula B

Formula B
in presence of phosphoric acid and less than or equal to 0.35 molar equivalents of sulfuric acid.

The quantity of sulfuric acid used for cyclization is less than or equal to 0.35 molar equivalent or about 0.05 molar equivalents per molar equivalent of compound of formula B to improve the yield of 3-methoxy-N-formylmorphinan of Formula A.

The reaction may be performed in presence or absence of solvent. The solvent may be selected from alcohol such as methanol, ethanol, isopropanol, and the like; hydrocarbon such as hexane, heptane, cyclohexane, toluene and the like; ketone such as cetone, ethyl methyl ketone, methyl isobutyl ketone and the like; nitriles such as acetonitrile, propionitrile and the like; halogenated hydrocarbons such as dichloromethane, ethylene dichloride, chloroform and the like; or their combinations with water.

Suitable temperature for conducting the reaction may range from about 50 to about 80 °C or about 60 to about 65 °C. Suitable time for the completion of the reaction range from about 15 to about 35 hours or about 20 to about 30 hours.

After completion of the reaction, the reaction mixture is diluted with water and organic solvnet and then subjected for separation of two layers. The resultant organic layer may be utilized for further reaction to provide dextromethorphan or it may be subjected for isolation of solid by using suitable techniques such as recrystallization, anti-solvent technique, and the like. Suitable organic solvent is selected from alcohol, halogenated solvent, ketone, nitrile, hydrocarbon, and the like.

The resultant 3-methoxy-N-formylmorphinan of Formula A obtained from the present invention may have the yield greater than about 99 %.

The intermeidate of 3-methoxy-N-formylmorphinan of Formula A is substantially utilized for the preparation of Dextromethorphan or salt thereof by the processes known in the prior art such as Indian Journal of Heterocyclic Chemistry, 14(2), 167-168; 2004 or US 2,634,273 patent.

The present invention is further illustrated by the following example, which does not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present application.

EXAMPLES
Example -1
Preparation of N-[2-(1-cyclohexen-1-yl)ethyl]-2-(4-methoxyphenyl)acetamide of Formula II

To a solution of p-methoxy phenyl acetic acid (750 g) in toluene (450 ml) was added Boric acid (0.7 g). The reaction mass was heated to a temperature of 80-90 oC and then added cyclohexenyl ethylamine (565 g). The reaction mixture was heated up to reflux temperature for 8-10 hrs and water was separated through dean stark azeotropic. The reaction mixture was distilled under atmospheric pressure to afford the compound of Formula II.
Yield: 99%
Purity: 99%

Example –2:
Cyclization reaction of N-Formyl octabase to N-Formyl morphinan

To dry phosphoric acid (800 g, m/c below 0.5%) was added sulfuric acid (2.0gm) and the mixture was stirred for 15 minutes. To this stirred mixture was added N-Formyl octa base of Formula B (120 g) and the resulting reaction mixture was stirred at 60-65 oC for 30 hrs and reaction monitored by HPLC for completion of reaction. After reaction completion, the reaction mixture was poured in to a chilled mixture of water and toluene. The organic layer was separated and concentrated completely to afford titled compound.
Yield: 90%
Purity: 86%

We Claim:

1. An improved process for the preparation of N-[2-(1-cyclohexen-1-yl)ethyl]-2-(4-methoxyphenyl)acetamide of Formula II
,
Formula II
which comprises reaction of p-methoxy phenyl acetic acid of Formula III or salt thereof

with cyclohexenyl ethyl amine of Formula IV or salt thereof

Formula IV
by using a catalyst in presence of organic solvent.

2. The process according to claim 1, wherein the said salt of compounds III and IV is selected from inorganic acid or organic acid.

3. The process according to claim 1, wherein the said catalyst is boric acid, boron trifluoride etherate, alkyl or aryl sulfonate salt and the like.

4. The process according to claim 1, wherein the said organic solvent is selected from hydrocarbon, halogenated solvent.

5. The process according to claim 1, wherein the compound of Formula II is further converted to compound of Formula A.

6. An improved process for the preparation of 3-methoxy-N-formylmorphinan of Formula A

Formula A
which comprises cyclization of N-formyl octabase of Formula B

Formula B
in presence of phosphoric acid and less than or equal to 0.35 molar equivalents of sulfuric acid.

7. The process according to claim 6, wherein the said molar equivalent of sulfuric acid is 0.05 per equivalent of compound of Formula B.

8. The process according to claim 6, wherein the compound of Formula A is further converted to Dextromethorphan.