Title of Invention

AN IMPROVED AND NOVEL PROCESS FOR THE PREPARATION OF N-METHYL-1-NAPHTHALENEMETHANAMINE

Abstract

The present invention discloses an improved and impurity-free process for the preparation of N-methyl-1-naphthalenemethanamine of formula I starting from 1-chloromethylnaphthalene of formula III. N-methylformamide is reacted with a strong base in N,N-dimethylformamide and/or non-polar solvent to get its anion and this anion is reacted with 1-chloromethylnaphthalene to get the formamide derivative of formula VI. Alternatively, N-methylformamide (without generating the anion separately) and 1-chloromethylnaphthalene can be reacted together in the presence of a mild base and a phase transfer catalyst in N,N-dimethylformamide and/or a non-polar solvent to get the required formamide of formula VI. The compound of formula VI on acid or base hydrolysis gave the required compound of formula I. The main advantages of the present invention are it involves simple, economical, and easy to adopt process on a commercial scale. No tertiary-amine impurity is formed in this process. Compound of formula I is a key intermediate used in the synthesis of anti-fungal drug, terbinafine of formula II.

Full Text

INTRODUCTION Present invention relates to an improved process for the preparation of N-methyl-1-naphthalenemethanamine. N-methyl-1-naphthalenemethanamine prepared by the process of the present invention having formula I given below is an intermediate used in the synthesis of (E)-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-l-naphthalenemethan-amine of formula II (also known as terbinafme). Terbinafine is a fungistatic antimycotic. Terbinafme blocks ergosterol synthesis by squalene epoxidase inhibition, effects fungicidally upon dermatophytes, yeasts, dimorphous fungi and micromycetes. It has a very good passage into adipose tissue (skin and nails). The invention also relates to a novel intermediate and a process for its preparation BACKGROUND OF INVENTION In the literature only four processes are known for the preparation of compound of formula I. In the first procedure reported in J. Am. Chem. Soc, 1943, 65, 1984-92, 1-chloromethylnaphthalene is reacted with methylamine in a conventional maimer to get the required compound of formula I. No details about yield, conditions, and quality are given in this publication. In the second procedure reported in J. Chem. Soc, 1966, page 1573-9, 1 -chloromethylnaphthalene is reacted with a large excess of methylamine in benzene in a closed flask to get the required compound of formula I (shown in Scheme-I). The related bis-alkylated impurity of formula IV formed in the reaction was removed by hydrochloride salt formation and repeated extraction into ether. No yield and purity data for the required product was given in this publication. Such a process needs to be thoroughly studied before utilizing it for commercial production. Also, the level of related impurity may be very critical in certain cases. In the third procedure which is reported in J. Med. Chem. 1981, —, 141, a process for the preparation of compound of formula I is described starting from naphthalene-1-carboxaldehyde (shown in Scheme-II). In this process Naphthalene-1-carboxaldehyde is reacted with methylamine in the presence of platinum-on-carbon under hydrogenation conditions to get the compound of formula I. The main drawback in this process is the preparation of naphthalene-1-carboxaldehyde. Naphthalene-1 -carboxaldehyde is prepared in a five-step process starting from naphthalene (scheme-II). Naphthalene is reacted with formaldehyde and hydrochloric acid to get 1-chloromethylnaphthalene. 1-Chloromethylnaphthalene is reacted with hexamine and hydrolyzed to get crude naphthalene-1-carboxaldehyde. This crude compound is treated with sodium bisulfite to get the bisulfite adduct of naphthalene-1-carboxaldehyde. Isolated bisulfite adduct is hydrolyzed with acid or base to get the purified naphthalene-1-carboxaldehyde, which is further purified by high vaccum distillation. Therefore such a lengthy process for the preparation of compound of formula I is not economically viable on a commercial scale. Another disadvantage of the process is it involves high-pressure hydrogenation with platinum-on-carbon. Handling of hydrogen gas and special equipment like high-pressure hydrogenator is always risky on a commercial scale. Such process needs to be avoided wherever it is possible. In the fourth procedure, which is disclosed in the US pat. 4,282,251, l-chloromethyl-naphthalene is reacted with ethanolic methylamine to get the required compound of formula I. The basic chemistry involved in this process is similar to the one given in the second procedure given above. Therefore establishing the process on commercial scale is not easy and the drawbacks are the same as discussed earlier. In this patent no yield and quality of the required product has been mentioned. Keeping in view of the difficulties in commercialization of the above-mentioned processes for the preparation of compound of formula I, and recognizing the importance of this compound as an important intermediate in the synthesis of terbinafine, we aimed to develop a simple and economical process for the preparation of the compound of formula I. We observed that a simple and economical process for the preparation of compound of formula I may be by (a) avoiding the usage of costly raw material like naphthalene-1-carboxaldehyde, (b) avoiding formation of by-products, (c) using readily and easily available raw materials (d) developing a process, which can be suitable for any scale of manufacture and (e) avoiding the usage of hydrogenation chemistry which requires special handling and costly reagents. We felt that such an approach would meet the requirements of the costs, safety, and ecology in the process for the preparation of compound of formula I Accordingly we developed an improved process for the preparation of compound of formula I, which is illustrated in the Scheme-Ill given below: Accordingly, the present invention provides an improved process for the preparation of N-methyl-1-naphthalenemethanamine of formula I, useful for the preparation of antifungal terbinafme of formula II, which comprises : i) Generating the anion of N-methylformamide with a strong base in N,N-dimethylformamide and/or a non-polar solvent and reacting this anion with 1-chloromethylnaphthalene of the formula III, ii) Hydrolyzing the resulting formamide derivative of formula VI using an acid or base to get the crude corresponding secondary amine of the formula I, iii) Purifying the resulting crude N-methyl-1-naphthalenemethanamine of formula I by acid / base treatment, iv) Extracting the purified base into a solvent and distilling the solvent to get the purified compound of formula I. Generating the anion of N-methylformamide and reacting this anion with an alkyl halide is novel and applied for the first time for the preparation of compound of formula I. Alternatively, the compound of formula VI can be prepared by reacting N-methylformamide (without generating the anion separately) and 1-chloromethyl-naphthalene together in the presence of a mild base and a phase transfer catalyst to get the required tertiary amide of formula VI. The 1-chloromethylnaphthalene of formula III can be readily prepared from naphthalene by following the known procedure (Org. Synth. Coll. Vol. IV, pl95). The amide of formula VI can be easily hydrolyzed by acid or base to get the compound of formula I free from a tertiary amine. In a preferred embodiment compound of formula III is reacted with the anion of N-methylformamide (generated by using a strong base) in the presence of a non-polar solvent at an ambient or elevated temperature to get the formamide of formula VI. The strong base used to generate the anion can be butyl lithium, lithium diisopropylamide, sodium amide, lithium amide, sodium hydride, potassium t-butoxide, etc. The mild base used in the direct reaction can be selected from sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, sodium methoxide, etc. The reaction can be done at a temperature in the range of 20-80°C. The phase transfer catalyst used in the process can be a quatemary ammonium salt like, tetra-n-butylammonium bromide or iodide, benzyltrimethylammonium chloride, bromide, or iodide, etc. The non-polar solvent used in the process can be selected from benzene, toluene, xylene, cyclohexane, heptane, etc. The hydrolysis of compound of formula VI can be done either with an acid or with a base. For the acid hydrolysis method aqueous sulfuric acid with or without acetic acid may be used. For the alkaline hydrolysis, base can be sodium hydroxide, potassium hydroxide and the medium of the reaction can be water or aqueous alcoholic solvent like methanol, ethanol, isopropanol, etc. The required product of formula I can be purified by acid/base workup and later on by high vaccum distillation. The invention also provides novel compound of formula VI and novel processes for its preparation. Accordingly the present invention provides a process for the preparation of novel compound of formula VI, which comprises: Generating the anion of N-methylformamide with a strong base in N,N-dimethylformamide and/or a non-polar solvent and reacting this anion with 1-chloromethylnaphthalene of formula III, Alternatively, the compound of the formula VI can be prepared by reacting N-methylformamide (without generating the anion separately) and 1 -chloromethylnaphthalene together in the presence of a mild base and a phase transfer catalyst to get the required tertiary amide of the formula VI. The invention is described in detail in the Examples given below which are provided only by way of illustration and therefore should not be construed to limit the scope of the invention further illustrated by the following example. Example 1 Preparation of N-methyl-1-naphthalenemethanamine: a) Preparation of N-methyl-N-(l-methylnaphthyl)-formamide: Into a IL three-necked RB flask was charged 200ml of dry N,N-dimethyiformamide and 32gr (as 50% in paraffin oil) of sodium hydride under nitrogen atmosphere. The reaction mixture was cooled to 20°C and a solution of 50gr of N-methylformamide in 50ml of N,N-dimethylformamide was added at 20-25°C over a period of L5-2.0hr. After the addition is over, reaction mixture is maintained at 25-30°C for Ihr. A solution of 100gr of 1-Chloromethylnaphthalene in 100ml of toluene was slowly added to the reaction mixture and maintained at 40-45°C for Ihr before quenching into water. The product was extracted into toluene (2 x 250ml) and the solvent distilled off to get 160gr of the crude N-methyl-N-(l-naphthylmethyl)-formamide. This was directly used in the next step. b) Base hydrolysis of N-methyl-N-(l-methylnaphthyl)-formamide: The crude N-methyl-N-(l-naphthylmethyl)-formamide prepared according to the step (a) above was suspended in 300ml of 20% aqueous sodium hydroxide and heated at 60-70°C for a period of 7hr. The reaction mixture was cooled to 25°C and extracted with toluene (2 x 200ml). The toluene layer was extracted with 3N hydrochloric acid (2 x 300ml). The aqueous layer was decolorized with activated carbon and basified to pH 10.0 with 20% aqueous sodium hydroxide. The liberated base was extracted into toluene and the toluene layer distilled off to get 86gr of the crude product. This was distilled under high vaccum to get 82gr (85%) of pure N-methyl-1-naphthalene-methaneamine. Example-2 Preparation of N-methyl-l-naphthalenemethanamine: a) Preparation of N-methyl-N-(l-niethylnaphthyl)-formamide: Into a IL three-necked RB flask was charged 200ml of dry N,N-dimethylformamide and 32gr (as 50% in paraffin oil) of sodium hydride under nitrogen atmosphere. The reaction mixture was cooled to 2°C and a solution of 50gr of N-methylformamide in 50ml of N,N-dimethylformamide was added at 20-25°C over a period of 1.5-2.0hr. After the addition is over, reaction mixture is maintained at 25-30°C for Ihr. A solution of 100gr of 1-Chloromethylnaphthalene in 100ml of toluene was slowly added to the reaction mixture and maintained at 40-45°C for Ihr before quenching into water. Product was extracted into toluene (2 x 250ml) and the solvent distilled off to get 160gr of the crude N-methyl-N-(l-naphthylmethyl)-formamide. This was directly used in the next step. b) Acid hydrolysis of N-methyl-N-(l-methylnaphthyl)-formainide: The crude N-methyl-N-(l-naphthylmethyl)-formamide prepared according to the step (a) described above was suspended in 1000ml of 10% aqueous sulfuric acid and heated to reflux temperature and maintained for 4hr at this temperature. The reaction mixture was cooled to 25°C and extracted with toluene (2 x 200ml). The aqueous layer was treated with active carbon and filtered. The filtrate was basified to pH 10.0 with sodium hydroxide. The liberated base was extracted into toluene and the toluene layer distilled off to get 82gr of the crude product. This was distilled under high vaccum to get 79gr (82%) of pure N-methyl-1-naphthalene-methaneamine. Example 3 Preparation of N-methyl-1-naphthalenemethanamine: a) Preparation of N-methyl-N-(l-metliyInaphthyI)-formamide: Into a IL three-necked RB flask was charged 100gr of 1-chloromethylnaphthlene, 120gr of N-methylformamide, and 5gr of tetra-n-butylammonium bromide. The reaction mixture was cooled to 5°C and 50gr of powdered potassium hydroxide was added in lots keeping the internal temperature below 5°C. After maintaining for 4hrs at this temperature, reaction mixture was heated to 25°C and diluted with water (200ml) and toluene (200ml). Aqueous layer was extracted with toluene (200ml) and the combined toluene layer was dried with sodium sulfate and solvent distilled off to get 120gr of the crude N-methyl-N-(l-naphthylmethyl)-formamide. This was directly used in the next step. b) Acid hydrolysis of N-methyl-N-(l-methylnaphthyl)-formamide: The crude N-methyl-N-( 1 -naphthylmethyl)-formamide prepared by the process described in step(a) above was suspended in 800ml of 10% aqueous sulfuric acid and heated to reflux temperature and maintained for 4hr at this temperature. The reaction mixture was cooled to 25°C and extracted with toluene (2 x 150ml). The aqueous layer was treated with active carbon and filtered. The filtrate was basified to pH 10.0 with sodium hydroxide. The liberated base was extracted into toluene and the toluene layer distilled off to get 45gr of the crude product.This was distilled under high vaccum to get 39gr (41%) of pure N-methyl-1-naphthaienemethanamine. Advantages of the present invention: 1. Process is simple and can be done easily on any commercial scale. 2. The compound of formula I prepared by this process is free from bis-alkylated impurity of formula IV. 3. The process is economical, as it does not involve use of expensive Pt/C reagent, and naphthalene-1-carboxaldehyde. Also it does not involve special equipment like hydrogenator. 4. The chemistry involved in the process is simple and easy to handle on a commercial scale. All the raw materials are cheap and readily available. Overall yield is high (up to 85%). 5. The process can also be applied to prepare any similar secondary amines of formula I. We claim: 1, An improved process for the preparation of N-methyl-1-naphthalenemethanamine of formula I, useful for the preparation of anti-ftmgal terbinafme of formula II, i) Generating the anion of N-methylformamide with a strong base in N,N-dimethylformamide {and / or a non-polar solvent} and reacting the resulting anion with 1-chloromethylnaphthalene of formula III, to get the novel corresponding formamide derivative of formula VI, I ii) Hydrolyzing the resulting formamide derivative of formula VI using an acid or base to get the crude corresponding secondary amine of formula I, iii) Purifying the resulting crude N-methyl-1-naphthalenemethanamine of formula I by acid / base treatment and iv) Extracting the purified base into a solvent and distilling the solvent to get the purified compound of formula I. 2. An improved process as claimed in claim 1 wherein the reaction in step (i) is effected in the presence of a non polar solvent selected from benzene, toluene, xylene, cyclohexane, heptane and the like, preferably, toluene or heptane. 3. An improved process as claimed in claims 1 & 2 wherein the strong base used in step (i) is selected from butyl lithium, lithium diisopropylamide, sodium amide, lithium amide, sodium hydride, potassium t-butoxide, etc., preferably sodium amide or sodium hydride 4. An improved process as claimed in claims 1 to 3 wherein the temperature of the reaction can be in the range of 0-80®C, preferably between 0-30°C. 5. An improved process for the preparation of N-methyl-1-naphthalenemethanamine of formula I, useful for the preparation of anti-fungal terbinafine of formula II, which comprises: i) Reacting N-methylformamide (without generating the anion separately) and 1- chloromethylnaphthalene together in the presence of a mild base and a phase transfer catalyst in N,N-dimethylformamide and/or a non-polar solvent to get the required tertiary amide of formula VI. (ii) Hydrolyzing the resulting formamide derivative of formula VI using an acid or base to get the crude corresponding secondary amine of formula I, iii) Purifying the resulting crude N-methyI-1-naphthalenemethanamine of formula I by acid / base treatment and iv) Extracting the purified base into a solvent and distilling the solvent to get the purified compound of formula I. 6. An improved process as claimed in claim 5 step (i) wherein the mild base used in the reaction can be selected from sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, sodium methoxide, etc., preferably sodium hydroxide or potassium hydroxide. 7. An improved process as claimed in claim 5, step (ii) wherein the acid used in the acid hydrolysis step is aqueous sulfuric acid with or without acetic acid as a solvent, preferably without acetic acid. 8. An improved process as claimed in claim 5, step (ii) wherein the base used in the base hydrolysis is aqueous sodium or potassium hydroxide. 9. An improved process as claimed in claim 5, step (ii) wherein the solvent used in basic hydrolysis is water with or without alcoholic solvents like, methanol, ethanol, isopropanol, etc. 10. An improved process as claimed in claim 5, step (iii) wherein the solvent used for extraction of purified compound of formula I is selected from benzene, toluene, xylene, cyclohexane, heptane, etc., preferably toluene or heptane. 11. A Novel compound of formula VL 12. A process for the preparation of novel compound of formula VI, Which comprises: (i) Generating the anion of N-methylformamide with a strong base in N,N-dimethylformamide and/or a non-polar solvent and reacting the resultant anion with 1-chloromethylnaphthalene of formula III, to get the corresponding novel formamide derivative of formula VI. 13. A process as claimed in claim 12 wherein the strong base used in step (i) is selected from butyl lithium, lithium diisopropylamide, sodium amide, lithium amide, sodium hydride, potassium t-butoxide, etc., preferably sodium amide or sodiimi hydride. 14. A process for the preparation of novel compound of formula VI, Which comprises: (i) Reacting N-methylformamide (without generating the anion separately) and 1-chloromethylnaphthalene together in the presence of a mild base and a phase transfer catalyst in N,N-dimethylformamide and/or a non-polar solvent to get the required tertiary amide of formula VI. 15. An improved process as claimed in claim 14, step (i) wherein the mild base used is selected from sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, sodium methoxide, etc., preferably potassium hydroxide, sodium hydroxide. 16. A process as claimed in claims 14 and 15 wherein the non-polar solvent used in step (i) is selected from benzene, toluene, xylene, cyclohexane, heptane, etc., preferably toluene or heptane. 17. A process as claimed in claims 14 to 16 wherein the temperature of the reaction is in the range of 0-80°C, preferably between 0-30°C. 18. A process as claimed in claims 14 to 17 wherein the phase transfer catalyst used is selected from tetra-n-butylammonium bromide, tetra-n-butylammonium iodide, tetra-n-butylammonium hydrogensulfate, N-benzyltrimethyl-ammonium chloride, etc, preferable tetra-n-butylammonium bromide. 19. An improved process for the preparation of compound of formula I substantially as described with particular reference to Examples 1-3. 20. A process for the preparation of novel compound of the formula VI substantially as described with particular reference to the step (a) of the Examples 1-3.

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