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WO2004080945A1 - Process for the preparation of n-methyl-1-naphthalenemethanamine - Google Patents

Process for the preparation of n-methyl-1-naphthalenemethanamine Download PDF

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WO2004080945A1
WO2004080945A1 PCT/IN2004/000051 IN2004000051W WO2004080945A1 WO 2004080945 A1 WO2004080945 A1 WO 2004080945A1 IN 2004000051 W IN2004000051 W IN 2004000051W WO 2004080945 A1 WO2004080945 A1 WO 2004080945A1
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base
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Muddasani Pulla Reddy
Peddi Rajashekhara Reddy
Kagitha Radharani
Nannapaneni Venkaiah Chowdary
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Natco Pharma Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
    • C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
    • C07C211/30—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring the six-membered aromatic ring being part of a condensed ring system formed by two rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/04—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups
    • C07C209/06—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups by substitution of halogen atoms
    • C07C209/08—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups by substitution of halogen atoms with formation of amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/02—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • C07C233/03—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to hydrogen atoms

Definitions

  • N-methyl-1-naphmalenemethanamine 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- 1 -naphthalenemethan- amine of formula II (also known as terbinafme).
  • Terbinafine is a fungistatic antimycotic. Terbinafine blocks ergosterol synthesis by squalene epoxidase inhibition,
  • II Terbinafine (II) 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
  • 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.
  • 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.
  • the present invention provides 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,
  • the compound of 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 formula VI.
  • the 1-chloromethylnaphthalene of formula III can be readily prepared from naphthalene by following the known procedure (Org. Synth. Coll. Vol. IV, pi 95).
  • 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.
  • 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 quaternary 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.
  • aqueous sulfuric acid with or without acetic acid may be used.
  • 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.
  • 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,
  • 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 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 -methyl-1-naphthalene-methaneamine.
  • 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.
  • N-methyl-l-naphthalenemethanamine a) Preparation of N-methyI-N-(l-methylnaphthyl)-formamide: Into a IL three-necked RB flask was charged lOOgr 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.
  • the crude N-methyl-N-(l-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-naphthalenemethanamine.
  • the compound of formula I prepared by this process is free from bis-alkylated impurity of formula IV.
  • 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.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

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).

Description

PROCESS FOR THE PREPARATION OF N-METHYL-1-NAPHTHALENEMETHANAMINE
Present invention relates to an improved process for the preparation of N-methyl-1- naphthalenemethanamine. N-methyl-1-naphmalenemethanamine 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- 1 -naphthalenemethan- amine of formula II (also known as terbinafme). Terbinafine is a fungistatic antimycotic. Terbinafine blocks ergosterol synthesis by squalene epoxidase inhibition,
Figure imgf000003_0001
I Terbinafine (II) 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 rnethylamine in a conventional manner 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 rnethylamine 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.
IE I IV
Scheme-I 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 rnethylamine in the presence of platinum-on-carbon under hydrogenation conditions to get the compound of formula I.
Figure imgf000004_0002
V
Scheme-II
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, 1-chloromethylnaphthalene is reacted with ethanolic rnethylamine 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:
Figure imgf000006_0001
πι VI
Scheme-Ill
Accordingly, the present invention provides 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,
Figure imgf000006_0002
Terbinafine (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,
Figure imgf000007_0001
III o get the novel corresponding formamide derivative of formula VI,
Figure imgf000007_0002
VI ii) Hydro lyzing the resulting formamide derivative of formula VI using an acid or base to get the crude corresponding secondary amine of the formula I,
Figure imgf000007_0003
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-chloromethylnaphthalene 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, pi 95). 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 quaternary 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,
Figure imgf000009_0001
πι to get the novel corresponding formamide derivative of formula VI,
Figure imgf000009_0002
VI
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-l-naphthalenemethanamine: a) Preparation of N-methyl-N-(l-i-iethylnaphthyl)-formamide:
Into a 1L 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 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 1.5-2.0hr. After the addition is over, reaction mixture is maintained at 25-30°C for lhr. A solution of lOOgr of 1-Chloromethylnaphthalene in 100ml of toluene was slowly added to the reaction mixture and maintained at 40-45°C for lhr 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-methyI-N-(l-methylnaphthy_)-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 -methyl-1-naphthalene-methaneamine.
Exampk-2
Preparation of N-methyl-l-naphthalenemethanamine: a) Preparation of N-methyl-N-(l-methylnaphthyl)-forma ide:
Into a 1L 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 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 1.5-2.0hr. After the addition is over, reaction mixture is maintained at 25-30°C for lhr. A solution of lOOgr of 1-Chloromethylnaphthalene in 100ml of toluene was slowly added to the reaction mixture and maintained at 40-45°C for lhr 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-methyInaphthyl)-formamide:
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-l-naphthalenemethanamine: a) Preparation of N-methyI-N-(l-methylnaphthyl)-formamide: Into a IL three-necked RB flask was charged lOOgr 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-(l-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-naphthalenemethanamine.
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.

Claims

We claim:
1. 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, .
Figure imgf000013_0001
I Terbinafine (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 the resulting anion with 1-chloromethylnaphthalene of formula III,
Figure imgf000013_0002
III to get the novel corresponding formamide derivative of formula VI,
Figure imgf000013_0003
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,
Figure imgf000014_0001
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,
Figure imgf000014_0002
I Terbinafine (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.
Figure imgf000015_0001
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,
Figure imgf000015_0002
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.
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 VI.
Figure imgf000016_0001
VI
12. A process for the preparation of novel compound of formula VI,
Figure imgf000016_0002
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,
Figure imgf000016_0003
III to get the corresponding novel formamide derivative of formula VI.
Figure imgf000017_0001
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 sodium hydride.
14. A process for the preparation of novel compound of formula VI,
Figure imgf000017_0002
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.
Figure imgf000017_0003
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.
PCT/IN2004/000051 2003-03-12 2004-03-01 Process for the preparation of n-methyl-1-naphthalenemethanamine Ceased WO2004080945A1 (en)

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ES2311426A1 (en) * 2005-04-27 2009-02-01 Cadila Pharmaceuticals Limited A process for the preparation of rupatadine
CN101885667B (en) * 2009-05-14 2013-02-13 上海宝钢化工有限公司 Synthesis method of 1-chloromethyl naphthalene, catalyst thereof and application of non-cationic surfactant

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2311426A1 (en) * 2005-04-27 2009-02-01 Cadila Pharmaceuticals Limited A process for the preparation of rupatadine
ES2311426B1 (en) * 2005-04-27 2009-12-22 Cadila Pharmaceuticals Limited A PROCEDURE FOR THE PREPARATION OF RUPATADINA AND ITS SALTS.
CN101885667B (en) * 2009-05-14 2013-02-13 上海宝钢化工有限公司 Synthesis method of 1-chloromethyl naphthalene, catalyst thereof and application of non-cationic surfactant

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