Claims:We claim:
1. A process for the synthesis of levo free (+)-3-methoxymorphinan hydrochloride (IV), comprises the steps of:
(i) reacting 3-methoxymorphinan comprising 2% levo form (I), with hydrochloric acid in a solvent;
(ii) recrystallizing with acetone to obtain the hydrochloride salt of 3-methoxymorphinan comprising about 0.2% levo form (II);
(iii) dissolution of (II) in demineralized water, adjusting the pH to a range of 10 – 12 using a base, followed by the addition of toluene to separate the organic layer comprising (+)-3-methoxymorphinan comprising about 0.2% levo form (III);
(iv) reacting (III) with hydrochloric acid in a solvent; and
(v) recrystallizing using acetone.

2. The process according to claim 1, wherein the solvent employed in steps (i) and (iv) may be selected from alcohols, ketonic solvents, hydrocarbons, esters, ethers, and the like.

3. The process according to claims 1 and 2, wherein the solvent employed in steps (i) and (iv) may be selected from alcohols such as methanol, ethanol, isopropyl alcohol, butanol and the like; ketonic solvents such as acetone, methyl isobutyl ketone, methyl ethyl ketone, and the like; hydrocarbons such as benzene, toluene, heptane, and the like; esters such as ethyl acetate, butyl acetate and the like; and ethers such as tetrahydrofuran, diisopropyl ether, and the like.

4. The process according to claim 1, wherein the base used in step (ii) may be selected from caustic lye, sodium hydroxide, potassium hydroxide, ammonia, and the like.

5. The process according to claim 1, wherein the molar ratio of 3-methoxymorphinan and hydrochloric acid is 1:0.8 to 1:1.2. , Description:FIELD OF THE INVENTION

The present invention relates to a process for the synthesis of 3-methoxymorphinan hydrochloride that is free of levo isomer.

BACKGROUND OF THE INVENTION

Morphines are well-known narcotic analgesics. 3-Methoxymorphinan is the penultimate intermediate of dextromethorphan hydrobromide which is an anti-tussive agent. 3-Methoxymorphinan which belongs to the morphinan class of compounds, is a levomethorphan metabolite that has been shown to produce local anesthetic effects. Morphinans are generally prepared from isoquinolines by cyclization. Initially, the racemic forms were used as such. However, as the levo and dextro isomers differed in their actions, resolution of the isomers has become important. In particular, the dextro isomer of 3-methoxy-N-methyl morphinan, commonly known as dextromethorphan, is known to be of more utility than its levo isomer as an effective and safe antitussive drug. Dextromethorphan is non-opioid while levomethorphan is opioid/narcotic (having addictive properties). Hence, dextromethorphan without the presence of levomethorphan is desired as a final product, and methods for preparing the dextromethorphan have gained more commercial importance.

Some of the commonly used resolving agents include hydrogen chloride, tartaric acid and its derivatives, malic acid, mandelic acid, N-acetyl-2-phenylglycine, naproxen, Leucine derivatives, phenylalanine, and gluconic acid and its derivatives.

US4202982A discloses the preparation of the hydrochloride salt of crude (+-)-N-cyclobutylmethyl-14ß-hydroxy-3-methoxymorphinan by dissolution in acetone and treatment with dry hydrogen chloride in ether. CN102731399B discloses the preparation of 3-methoxymorphinan hydrochloride derivative using methanol, hydrochloric acid, and acetone. However, there was no disclosure about the optical purity in these patents.

US3682925A and US3855227A disclose resolution of racemic (+-)-3-methoxymorphinan using (-)-di-O-isopropylidene-2-keto-L-gulonic acid as the resolving agent and benzene as the solvent and then recrystallized using benzene-hexane (1:1). US3914234A discloses resolution of (+-)-2-methoxymorphinan using 1-tartaric acid in methanol followed by recrystallization from methanol. However, there was no disclosure about the preparation of the hydrogen chloride (HCl) derivative in these patents.

US3910919A discloses the preparation of the HCl derivative of 3-methoxymorphinan using dry ether followed by recrystallization from methanol-acetone.

Though there is prior art disclosing the preparation of the HCl derivative of 3-methoxymorphinan or the resolution of its racemic mixture, none of the above prior art has disclosed the absence or extent of levo form present in the final HCl derivative of 3-methoxymorphinan.

OBJECTIVE OF THE PRESENT INVENTION

The principal object of the present invention is to provide a process for the synthesis of pure dextro 3-methoxymorphinan hydrochloride by the resolution of a racemic mixture of 3-methoxymorphinan.

SUMMARY OF THE PRESENT INVENTION

The present invention relates to a process for the synthesis of 3-methoxymorphinan hydrochloride that is free of levo isomer (pure dextro 3-methoxymorphinan hydrochloride). The advantages of the process are that the process is a high yield process, easy to perform, scalable and hence industrially viable apart from the usage of commercially available raw materials. The advantage of having 3-methoxymorphinan in the hydrochloride form is that the hydrochloride salt which is a crystalline solid is easy to handle and store in comparison with 3-methoxymorphinan which is a thick liquid.

The process for the synthesis of 3-methoxymorphinan that is free of levo isomer (IV) comprises of:
(i) reacting 3-methoxymorphinan comprising 2% levo form (I), with hydrochloric acid in a solvent;
(ii) recrystallizing with acetone to obtain the hydrochloride salt of 3-methoxymorphinan comprising about 0.2% levo form (II);
(iii) dissolution of (II) in demineralized water, adjusting the pH to a range of 10 – 12 using a base, followed by the addition of toluene to separate the organic layer comprising (+)-3-methoxymorphinan comprising 0.2% levo form (III);
(iv) reacting 3-methoxymorphinan comprising 0.2% levo form (III), with hydrochloric acid in a solvent; and
(v) recrystallizing using acetone.

BRIEF DESCRIPTION OF THE PRESENT INVENTION

Fig. 1 shows the schematic representation of the process for the synthesis of 3-methoxymorphinan with levo form in undetectable levels, of the present invention.
Fig. 2 shows the structure of the final product 3-methoxymorphinan of the present invention which has no trace of the levo form.
Fig. 3(a) shows the chiral High-performance liquid chromatography (HPLC) graph of 3-methoxymorphinan before the start of the reaction.
Fig. 3(b) shows the chiral High-performance liquid chromatography (HPLC) graph of the end product 3-methoxymorphinan.HCl after purification.

DESCRIPTION OF THE PRESENT INVENTION

The present invention relates to a process for the synthesis of 3-methoxymorphinan hydrochloride with no trace of levo form.

According to an embodiment of the invention, the process for the synthesis of 3-methoxymorphinan that is free of levo isomer (IV) comprises of:
(i) reacting 3-methoxymorphinan comprising 2% levo form (I), with hydrochloric acid in a solvent;
(ii) recrystallizing with acetone to obtain the hydrochloride salt of 3-methoxymorphinan comprising about 0.2% levo form (II);
(iii) dissolution of (II) in demineralized water, adjusting the pH to a range of 10 – 12 using a base, followed by the addition of toluene to separate the organic layer comprising (+)-3-methoxymorphinan comprising 0.2% levo form (III);
(iv) reacting (III) with hydrochloric acid in a solvent; and
(v) recrystallizing using acetone.

According to another embodiment of the invention, the process for the synthesis of 3-methoxymorphinan that is free of levo isomer (IV) comprises of:
(i) reacting 3-methoxymorphinan comprising 2% levo form (I), with hydrochloric acid in a solvent selected from an alcohol, ether, ketone, hydrocarbon and the like;
(ii) recrystallizing with acetone to obtain the hydrochloride salt of 3-methoxymorphinan comprising about 0.2% levo form (II);
(iii) dissolution of (II) in demineralized water, adjusting the pH to a range of 10 – 12 using a base, followed by the addition of toluene to separate the organic layer comprising (+)-3-methoxymorphinan comprising 0.2% levo form (III);
(iv) reacting (III) with hydrochloric acid in a solvent selected from an alcohol, ether, ketone, hydrocarbon and the like; and
(v) recrystallizing using acetone.

The organic solvent used in steps (i) and (iv) may be selected from alcohols such as methanol, ethanol, isopropyl alcohol, butanol and the like; ketonic solvents such as acetone, methyl isobutyl ketone, methyl ethyl ketone, and the like; hydrocarbons such as benzene, toluene, heptane, and the like; esters such as ethyl acetate, butyl acetate, and the like; and ethers such as tetrahydrofuran, diisopropyl ether, and the like.

The base used in step (ii) may be selected from caustic lye, sodium hydroxide, potassium hydroxide, ammonia, and the like.

According to a preferred embodiment of the present invention, the process for the synthesis of 3-methoxymorphinan that is free of levo isomer (IV) comprises of:
(i) reacting 3-methoxymorphinan comprising of approximately 2% levo form (I), with hydrochloric acid in methanol; and
(ii) recrystallizing with acetone to obtain the hydrochloride salt of 3-methoxymorphinan comprising about 0.2% levo form (II);
(iii) dissolution of (II) in demineralized water, adjusting the pH to a range of 10 – 12 using caustic lye followed by the addition of toluene to separate the organic layer comprising (+)-3-methoxymorphinan comprising 0.2% levo form (III);
(iv) reacting (III) with hydrochloric acid in methanol; and
(v) recrystallizing using acetone.

The organic solvent used in steps (i) and (iv) is preferably methanol. The base used in step (ii) is preferably caustic lye due to its low cost and easy availability.

The following examples and experimental studies are provided for illustrative purposes only and are not limiting to this disclosure in any way. Various modifications of the invention, in addition to those shown and described herein, will become apparent to those skilled in the art from the following examples and the foregoing description. Such modifications are also intended to fall within the scope of the appended claims.

EXPERIMENTAL STUDY

The process for the synthesis of 3-methoxymorphinan hydrochloride that is free of levo form (IV) disclosed in the present invention, is a convenient, economical and commercially viable high yield process.

The present invention is illustrated further by the following examples in which the structure and purity of the product was confirmed by at least one of the following techniques: Infrared (IR) spectrometry, proton nuclear magnetic resonance (NMR) spectrometry; with the proton NMR spectrometry being determined at 300 MHz using the indicated solvent. The presence or absence of the levo form at the start, during the course of the experiments and at the end of the experiments, was checked and confirmed by chiral High-performance liquid chromatography (HPLC).

The chemical symbols have their usual meaning and the following abbreviations, L (liter(s)), ml (milliliter(s)), g (gram(s)), ºC (degrees Celsius), mm (millimetre), µm (micrometre), v/v (volume/volume), RT (retention time), RRT (relative retention time), and BDL (below detectable level), have also been used.

EXAMPLES

Example 1
1L of methanol was charged in a 3L four-necked round-bottomed flask at room temperature followed by 200g of (+)-3-methoxymorphinan of chiral purity 98.0% comprising 2% levo isomer (I). It was stirred for 15 to 20 minutes for complete dissolution. 89g of hydrochloric acid was charged into the reaction mass slowly at 25 ± 5°C. Upon completion of the addition, the reaction mass was refluxed at a temperature of 70 ± 5°C and the mass was maintained for 7 hours. The mass was then distilled out in methanol. The reaction mass was then cooled to a temperature of 25 ± 5°C. Crude 3-methoxymorphinan hydrochloride comprising 0.2% of the levo form was obtained. This was checked by Chiral HPLC. To this, 1L of acetone was charged and stirred at a temperature of 25-30°C for 10 to 15 minutes and then heated to 50-55°C. The reaction was maintained at a temperature of 50-55°C for 2 hours. The reaction mass was cooled to 20-25°C and maintained at 20-25°C for 3 hours. Thus obtained crude (+)-3-methoxymorphinan hydrochloride (II) was centrifuged and washed with 200ml acetone. The crude (+)-3-methoxymorphinan hydrochloride was unloaded and weighed. It was found to be 206g.

Crude (+)-3-methoxymorphinan hydrochloride (II) was charged into a 3L four-necked round-bottomed flask to which 412ml of demineralized (DM) water was added and stirred for 10 to 15 minutes for dissolution. The pH of the reaction mass was adjusted to 11 ± 1 using 60.5g of caustic soda (CS) lye. 412ml of toluene was charged into the reaction mixture and stirred for 1 hour. It was allowed to settle for 30 minutes. The organic layer was separated and kept aside. The aqueous layer was charged into a round-bottomed flask along with 206ml of toluene. It was stirred for 1 hour and allowed to settle for 30 minutes. The organic layer was separated and the aqueous layer was discarded. The combined organic layer was charged into a round-bottomed flask along with 206ml of DM water. It was stirred for 1 hour and allowed to settle for 30 minutes. The organic layer containing the product was separated. The organic layer was completely distilled out at 70 ± 5 °C under vacuum of about 650mm Hg. The mass was cooled to 45 ± 5 °C and the mass of (+)-3-methoxymorphinan (III) was unloaded and weighed. It was found to be 178g.

1L of methanol was charged into a 3L four-necked round-bottomed flask at room temperature. 178g of (+)-3-methoxymorphinan (III) was charged into the round-bottomed flask and stirred for 15 to 20 minutes for complete dissolution. 79g of hydrochloric acid was charged slowly into the reaction mass at 25 ± 5 °C. Upon completion of the addition, the reaction mass was refluxed at 70 ± 5 °C and was maintained for 7 hours. Methanol was then distilled out. The reaction mass was cooled to 25 ± 5 °C and 890ml of acetone was charged into the reaction mass. It was stirred at 25-30 °C for 10 to 15 minutes and then heated to 50-55 °C. The reaction was maintained at 50-55°C for 1 hour. The reaction mass was cooled to 10-15 °C and maintained for 2 hours at 10-15 °C. Thus obtained pure (+)-3-methoxymorphinan hydrochloride was centrifuged and washed with 178ml of acetone. It was spin dried for 1 hour. The pure (+)-3-methoxymorphinan hydrochloride (IV) was unloaded and weighed. The wet weight was found to be 203gm. Thus obtained (+)-3-methoxymorphinan hydrochloride (IV) was dried at 50-55 °C for 4 to 5 hours. This material was cooled to 25±5 °C, unloaded and weighed. It was found to be 193gm.

The purity of the final product 3-methoxymorphinan hydrochloride (IV) was checked and confirmed by chiral HPLC. The absence of the levo form is interpreted by the absence of the peak associated with the levo isomer in the purified end product (IV). Typical chiral HPLC graphs of 3-methoxymorphinan (I) at the start of the reaction and 3-methoxymorphinan hydrochloride (IV) after purification are presented in Fig. 3(a) and Fig. 3(b) respectively.

The chiral HPLC conditions are as follows:
Name of the Instrument: HPLC with UV/PDA detector
Column : Chirobiotic V2 (250 x 4.6mm, 5µm)
Flow rate : 0.8 ml/min
Wave length : 225 nm
Injection volume : 20 µl
Run time : 70 minutes
Diluent : Water:Acetonitrile::75:25 (v/v)
Column temperature: 25°C
Mobile Phase - Buffer [pH 4.2]: Methanol (80:920, v/v)
System suitability criteria:
The resolution between (+) 3-methoxymorphinan HCl and (-) 3-methoxymorphinan HCl (L-isomer) peaks should not be less than 2.0.
RTs and RRTs:
(+) 3-Methoxymorphinan.HCl: RT (min) 34; RRT 1
(-) 3-Methoxymorphinan.HCl: RT (min) 41; RRT 1.2

The final product was characterized using IR Spectrum, Proton NMR spectrum, and Mass spectrum. The Specific Optical Rotation was also checked.

The IR spectrum of (+)-3-methoxymorphinan hydrochloride was recorded in a KBr pellet using Shimadzu (Make), IR-Affinity-S FTIR spectrometer. The results are presented in Table 1.

The proton NMR spectrum of (+)-3-methoxymorphinan hydrochloride was recorded in BRUKER-400MHZ using solvent DMSO. The structure of the final product is presented in Fig. 2. The results are presented in Table 2.

The Mass spectrum m/z 258.1 corresponds to the [M+1]+ ion of the (+)-3-methoxymorphinan, and the range of Specific Optical Rotation was between (+) 21° and (+) 28° [c=1 in methanol].

Example 2
Experiments were conducted as specified in Example 1 but (+)-3-methoxymorphinan hydrochloride was recrystallized using toluene instead of acetone. The levo isomer content in the final product was assessed in a manner similar to Example 1.

Example 3
Experiments were conducted as specified in Example 1 but (+)-3-methoxymorphinan hydrochloride was recrystallized using isopropyl alcohol instead of acetone. The levo isomer content in the final product was assessed in a manner similar to Example 1.

A comparative study to assess the amounts of levo isomer present in the final product (+)-3-methoxymorphinan hydrochloride (IV) while using acetone, toluene, and isopropyl alcohol is presented in Table 3. The comparison of the results from Examples 1, 2 and 3, indicated that acetone was a more effective recrystallization agent for obtaining the desired levo free (+)-3-methoxymorphinan hydrochloride.

Easy availability in sufficient quantity and the low cost make methanol a preferable solvent in steps (i) and (iv). The base used in step (ii) is preferably caustic lye due to its low cost and easy availability. Acetone is used in steps (ii) and (v) to obtain the required purity of the hydrochloride salt of 3-methoxymorphinan with minimum yield loss unlike other solvents such as methanol which result in loss of material and low yield, while isopropyl alcohol or toluene do not render the desired high purity.

The advantages of the process of the present invention are that it is a high yield process, easy to perform, scalable, and hence industrially viable apart from the usage of commercially available raw materials.

While this invention has been described with reference to illustrative embodiments, this description is not intended to be construed in a limiting sense. Various modifications of the illustrative embodiments, as well as other embodiments of the invention, will be apparent to persons skilled in the art upon reference to this description. It is therefore contemplated that the appended claims will cover any such modifications or embodiments as fall within the true scope of the invention.