WO2021176381A1

WO2021176381A1 - A method for preparation of diastereomeric lactate salts of 1-(1-naphthyl)ethyl amine and pure enantiomers of 1-(1-naphthyl)ethyl amine

Info

Publication number: WO2021176381A1
Application number: PCT/IB2021/051789
Authority: WO
Inventors: Gollapudy Subrahmanyam; Sunil V JOSHI; Nilesh Liladhar Bonde; Pravin Jotiba MOHITE
Original assignee: Embio Limited
Priority date: 2020-03-04
Filing date: 2021-03-04
Publication date: 2021-09-10

Abstract

The invention relates to method for preparation of pure enantiomers of 1-(1-naphthyl)ethyl amine by preparing lactate salt with chiral lactic acid as resolving agent. The method comprises reaction of L-lactic acid or D-lactic acid with racemic 1-(1-naphthyl)ethyl amine to form diastereomeric salts of (R/S)-1-(1-naphthyl)ethyl amine-(D/L)-lactate from which pure enantiomer is isolated. The invention also comprises method for preparation of compound with enriched enantiomers of 1-(1-naphthyl)ethyl amine from the mother liquor separated from the diastereomeric lactate salt. The enriched enantiomer is reacted with pure enantiomers of mandelic acid or lactic acid, preferably D-mandelic acid or L-mandelic acid and converted to diastereomeric mandelate salt. Pure (R)- or (S)-1-(1-naphthyl)ethyl amine is obtained from the diastereomeric mandelate salt. The chiral purity of pure enantiomer obtained is between 99% and 100%.

Description

TITLE OF THE INVENTION

A method for preparation of diastereomeric lactate salts of 1-(1- naphthyl)ethyl amine and pure enantiomers of 1-(1-naphthyl)ethyl amine

DESCRIPTION OF THE INVENTION Technical field of the invention

[0001] The present invention relates to a method for preparation of pure enantiomers of 1-(1-naphthyl)ethyl amine by forming its salt with resolving agents. The method also relates to isolation of pure enantiomers of 1-(1- naphthyl)ethyl amine from the enantiomeric ally enriched fractions of 1-(1- naphthyl)ethyl amine obtained from the mother liquors of the corresponding salts.

[0002] Background of the invention

[0003] (R)-1-(1-naphthyl)ethyl amine is an important starting material for preparation of the drug cinacalcet. Cinacalcet is a secondary amino compound that is (1R)-1-(naphthalen-1-yl) ethanamine in which one of the hydrogens attached to the nitrogen is substituted by a 3-[3-(trifluoromethyl)phenyl]propyl group. The drug mimics the action of calcium on tissues.

[0004] Cinacalcet is widely used to treat elevated levels of parathyroid hormone in patients undergoing dialysis due to long term kidney diseases. The drug controls the release of parathyroid hormone and lowers the parathyroid hormone levels within a short time. It is also used to treat the increased calcium levels in people with a hormonal disorder or cancer of parathyroid gland.

[0005] It is imperative to ensure the removal of all undesirable impurities from cinacalcet to accomplish its best pharmacological effect. To achieve this, it is necessary to use enantiomeric ally pure (R)-1-(1-naphthyl)ethyl amine in the preparation of cinacalcet. There are very few methods available for resolution of enantiomers of 1-(1-naphthyl)ethyl amine from its racemic mixture.

[0006] The Patent Application CN101735070A entitled “ Resolution method of R- (+)-1-(1-naphthyl) ethylamine ” discloses a process for resolution of racemic amine by using D-tartaric acid as a chiral resolving agent to obtain the enantiomer salt and separating the salts based on difference in solubility followed by alkalization and dissociation. The enantiomeric excess value achieved using the method is significantly high. Even though the disclosed method is cost effective and convenience in operation, the process yields only (R)-naphthyl ethyl amine having enanatiomeric excess of 96%, which is far removed from the pure enantiomer with 100% purity.

[0007] The Patent Application US 2996545 entitled “ Optical resolution ofalpha- ( alpha-naphthyl) ethylamine ” describes a method of resolution of 1-(1- naphthyl)ethyl amine using D-tartaric acid in the presence of warm methanol followed by cooling the solution when the corresponding tartrate salt crystallizes out. The tartrate salt is separated and purified by fractional crystallization to obtain crystalline and optically pure (R)-1-(1-naphthyl)ethyl amine. The disclosed method overcomes the use of known expensive resolving agents such as L-malic acid and D-camphoric acid however the problems such as difficulty in recovery of resolving agents and loss of material are not addressed by the disclosed method. Another important drawback of this method is that crystallization steps need to be repeated several times until a constant optical rotation and the desired optical purity is obtained. Considering the industrial application of the method, it is difficult to carry out repeated crystallizations during industrial production which implies enhanced cost, increased time for production and also material loss of product. Further, the patent document does not mention the formation of optically pure (S) form of the salt.

[0008] The research publication entitled “A Publication of reliable methods for the preparation of organic compounds " in Organic Syntheses, 6, 826 (1988), Submitted by E. Mohacsi and W. Leimgruber, discloses the process for resolution of (S)-isomer of 1-(1-naphthyl)ethyl amine using (-)-2,3:4,6-di-O-isopropylidene- 2-keto-L-gulonic acid hydrate in acetone. The disclosed process is useful for the isolation of both (R) and (S) isomers since the document mentions the recovery of (R) -enantiomer from the filtrate. However, the process is not economically advantageous because gluonic acid derivative is used as the resolving agent in the process is very expensive.

[0009] The publication in Chirality 21,331 (2009) entitled “ Optical resolution of 1-(1-naphthyl)ethylamine by its dicarboxylic acid derivatives: Structural features of the oxalic acid derivative diastereomeric salt pair " discloses a process for resolution of (S)-naphthyl ethyl amine using succinyl derivative of (R)-N-[1-(1- Naphthyl)ethylamine. The (R)-isomer is precipitated out from mother liquor, after filtration of diastereomeric salt of succinyl derivative with (S)-amine. The disclosed process results in preparation of the enriched (R)-isomer. Although the said process gives enriched (R)-isomer, the chiral auxiliary namely succinyl derivative of (R)-N-[1-(1-naphthyl)ethyl amine may tedious to prepare and not economically viable.

[0010] The European patent application EP2403823 entitled “ Process for the preparation of cinacalcet and salts thereof and intermediates for use in the process ” discloses a process for resolution of racemic amine using D-mandelic acid. The racemic amine is reacted with D-mandelic acid in ethanol as solvent to obtain the salt of (R) isomer and with isopropyl alcohol or acetone as solvent to obtain the salt of (S) isomer. The disadvantage of the disclosed process is the use of different solvents to resolve the racemic amine which complicates the process.

[0011] It is obvious from the above-mentioned prior arts that there is no single method to obtain pure enantiomers of chiral amines with chiral purity greater than 99%. Further, all the methods mentioned in the prior arts either require multiple separation and purification steps or involve the use of very costly chiral resolving agents. [0012] Therefore, there is a need for a method for preparation and isolation of pure enantiomers of 1-(1-naphthyl) ethyl amine with best chiral purity and with commercial feasibility.

Summary of the invention

[0013] The invention relates to a method for preparation of enantiomeric ally pure (R)-1-(1-naphthyl)ethyl amine or (S)-1-(1-naphthyl)ethyl amine by resolving a racemic mixture of 1-(1-naphthyl)ethyl amine using a-hydroxy acid as resolving agent, particularly chiral enantiomers of lactic acid and converting it into the lactate salt.

[0014] The invention is a method of preparation of diastereomeric lactate salts by reacting racemic 1-(1-naphthyl)ethyl amine with pure enantiomers of D- or L- lactic acid to obtain any one of the diastereomeric lactate salt including (S)-1-(1- naphthyl)ethyl amine L-lactate, (R)-1-(1-naphthyl)ethyl amine D-lactate, distereomerically enriched (R)-1-(1-naphthyl)ethyl amine L-lactate or distereomerically enriched (S)-1-(1-naphthyl)ethyl amine D-lactate.

[0015] The method for preparation of pure enantiomers of 1-(1-naphthyl)ethyl amine includes the preparation of diastereomeric lactate salt of racemic 1-(1- naphthyl)ethyl amine with D-lactic acid or L-lactic acid and separating the lactate salt form the mother liquor. The pure enantiomer is isolated from lactate salt by dissolving it in water, followed by addition of a base preferably ammonia, extracting in an organic solvent preferably ethyl acetate and drying the organic layer over sodium sulfate under reduced pressure to obtain pure (R)-1-(1- naphthyl)ethyl amine or (S)-1-(1-naphthyl)ethyl amine, which has a chiral purity between 99% and 100%.

[0016] The method for preparation of pure enantiomers of 1-(1-naphthyl)ethyl amine further includes the isolation of enantiomerically enriched 1-(1- naphthyl)ethyl amine from the separated mother liquor, reacting enantiomerically enriched 1-(1-naphthyl)ethyl amine with pure enantiomers of mandelic acid or lactic acid, preferably D-mandelic acid or L-mandelic acid to obtain diastereomeric mandelate salt with Formula 5, 6, 7 and 8 and isolating pure enantiomers of 1-(1-naphthyl)ethyl amine from the mandelate salts.

[0017] The pure enantiomers of 1-(1-naphthyl)ethyl amine are obtained from the diastereomeric mandelate salt by dissolving it in an organic solvent preferably toluene to obtain a reaction mass, adding a base preferably ammonium hydroxide to the reaction mass with stirring, separation of organic layer and the aqueous layer, extraction of aqueous layer with organic solvent, washing and drying of the separated organic layer and concentrating the organic layer under reduced pressure to obtain pure enantiomers of (R)-1-(1-naphthyl)ethyl amine or (S)-1-(1- naphthyl)ethyl amine, which has chiral purity between 99% and 100%.

Brief description of the drawings

[0018] The foregoing and other features of embodiments will become more apparent from the following detailed description of embodiments when read in conjunction with the accompanying drawings.

[0019] Figure 1 is a schematic representation of the method of preparation of enantiomerically pure (R)-1-(1-naphthyl)ethyl amine or (S)-1-(1-naphthyl) ethyl amine.

[0020] Figure 2 is a flowchart representing the method of preparation of pure enantiomers of (R)-1-(1-naphthyl)ethyl amine or (S)-1-(1-naphthyl)ethyl amine from racemic 1-(1-naphthyl)ethyl amine. [0021] Figure 3 represents the preparation of diastereomeric lactate salt from racemic 1-(1-naphthyl)ethyl amine.

[0022] Figure 4 illustrates the preparation of enantiomerically pure (R)-1-(1- naphthyl)ethyl amine or (S)-1-(1-naphthyl)ethyl amine from diastereomeric lactate salts.

[0023] Figure 5 is a flowchart for preparation of enriched enantiomer of (R)-1-(1- naphthyl)ethyl amine or (S)-1-(1-naphthyl)ethyl amine from the mother liquor separated from the lactate salt.

[0024] Figure 6 represents the preparation of diastereomeric mandelate salt from enriched enantiomer.

[0025] Figure 7 is a flowchart representing the preparation of pure enantiomer of (R)-1-(1-naphthyl)ethyl amine or (S)-1-(1-naphthyl)ethyl amine from the diastereomeric mandelate salt.

Detailed description of the invention

[0026] Reference will now be made in detail to the description of the present subject matter, one or more examples of which are shown in figures. Each example is provided to explain the subject matter and not a limitation. Various changes and modifications obvious to one skilled in the art to which the invention pertains are deemed to be within the spirit, scope and contemplation of the invention.

[0027] In order to make the matter of the invention clear and concise, the following definitions are provided for specific terms used in the following description.

[0028] The term “ Enantiomers ” refers to optical isomers what are mirror images of each other which are non-superimposable. [0029] The term “ Diastereomers ” refers to stereoisomers that are not mirror images of one another. These isomers are non-superimposable on one another and possess two or more stereocenters.

[0030] The invention relates to a method for preparation of pure enantiomers of 1- (1-naphthyl)ethyl amine using pure enantiomers of a-hydroxy acids particularly lactic acid as resolving agent and converting racemic mixture of amine to lactate salt.

[0031] The method for preparation of pure enantiomers of 1-(1-naphthyl)ethyl amine includes the preparation of diastereomeric lactate salt from racemic 1-(1- naphthyl)ethyl amine with D-lactic acid or L-lactic acid, separating the lactate salt from the mother liquor and isolating the pure enantiomer from lactate salt. The method includes steps for isolation of enantiomerically enriched fractions of 1-(1- naphthyl)ethyl amine obtained from the mother liquor of the corresponding lactate salts, converting it to diastereomeric mandelate salts with pure enantiomers of mandelic acid or lactic acid and converting the diastereomeric mandelate salts of the enantiomerically enriched fraction to pure enantiomers of 1-(1-naphthyl)ethyl amine.

[0032] Figure 1 illustrates a schematic representation of the method of preparation of enantiomerically pure (R)-1-(1-naphthyl)ethyl amine and (S)-1-(1- naphthyl) ethyl amine. As represented in the Figure 1, the racemic mixture of 1- (1-naphthyl)ethyl amine obtained by addition of hydroxylamine hydrochloride to 1-acetyl naphthalene followed by catalytic reduction using Raney nickel in presence of hydrogen. The racemic amine is treated with pure enantiomer of lactic acid in the presence of ethyl acetate to obtain the lactate salt as crystals. The crystalline lactate salt is separated from the mother liquor. Pure enantiomer of 1- (1-naphthyl)ethyl amine is produced by reacting the lactate salt with ammonia followed by extraction in toluene. The separated mother liquor is treated with aqueous ammonia to obtain enriched enantiomer of 1-(1-naphthyl)ethyl amine which are converted to mandelate salt on reaction with pure enantiomers of mandelic acid. Pure enantiomers of 1-(1-naphthyl)ethyl amine are obtained from the mandelate salt by reacting it with ammonia in the presence of toluene.

[0033] Figure 2 is a flowchart for the method of preparation of enantiomeric ally pure (R)-1-(1-naphthyl)ethyl amine or (S)-1-(1-naphthyl)ethyl amine from racemic 1-(1-naphthyl)ethyl amine. The method (200) for the preparation of pure enantiomers of 1-(1-naphthyl)ethyl amine comprises the step (201) of preparing crystalline diastereomeric lactate salt of Formula A by reacting equimolar quantities of racemic 1-(1-naphthyl)ethyl amine with any one of L-lactic acid or D-lactic acid. At step (202), the crystalline diastereomeric lactate salt of Formula A is separated from mother liquor. At step (203), pure enantiomers of 1-(1- naphthyl)ethyl amine is isolated from the separated crystalline diastereomeric lactate salt. At step (204), enantiomerically enriched 1-(1-naphthyl)ethyl amine is isolated from mother liquor separated at step (202). At step (205), diastereomeric mandelate salt is obtained by reacting equimolar quantities of the enantiomerically enriched 1-(1-naphthyl)ethyl amine with D-mandelic acid or L-mandelic acid. At step (206), the diastereomeric mandelate salt obtained is converted to pure enantiomers of 1-(1-naphthyl)ethyl amine.

[0034] Figure 3 represents the preparation of diastereomeric lactate salt from racemic 1-(1-naphthyl)ethyl amine. The method for the preparation of pure enantiomer (200) comprises the step (201) of preparation of diastereomeric lactate salt which further comprises the step (201 a) of dissolving racemic 1-(1- naphthyl)ethyl amine in a solvent medium to obtain a solution. At step (201 b), D- lactic acid or L-lactic acid is added to the solution between 10 and 15 minutes at room temperature to obtain a reaction mixture. In the next step (201c), the reaction mixture is stirred for 3 hours at ambient temperature to obtain white crystalline diastereomeric lactate salt of Formula A. The solvent media for the reaction used in step (201 a) is selected from a group of solvents such as hydrocarbon, aromatic hydrocarbon, alkyl/aryl ethers, alkyl alcohols, ketones and esters. The preferred solvent for reaction is ethyl acetate and butyl acetate and more preferred organic solvent is ethyl acetate. The diastereomeric lactate salt obtained by the method is any one of (S)-1-(1-naphthyl)ethyl amine L-lactate, (R)-1-(1-naphthyl)ethyl amine D-lactate.. [0035] One embodiment of the invention is a method for preparation of diastereomeric lactate salt of (S)-1-(1-naphthyl)ethyl amine which comprises the steps of reacting equimolar quantities of L-lactic acid with racemic 1-(1- naphthyl)ethyl amine in ethyl acetate resulting in the formation of (S)-1-(1- naphthyl)ethyl amine L-lactate with [Formula 3].

[0036] Another embodiment of the invention is a method for preparation of diastereomeric lactate salt of (R)-1-(1-naphthyl)ethyl amine which comprises the steps of reacting equimolar quantities of D-lactic acid with racemic 1-(1- naphthyl)ethyl amine in ethyl acetate resulting in the formation of (R)-1-(1- naphthyl)ethyl amine D-lactate with [Formula 4] .

[0037] According to the method (200) of the invention, the step (203) is for the isolation of pure enantiomer from the lactate salt. As illustrated in Figure 4, step (203) for isolation of pure enantiomer further comprises the step (203 a) of dissolving the separated crystalline diastereomeric lactate salt of Formula A in water to obtain a reaction mixture. At step (203 b), a base is added to the reaction mixture with stirring to obtain a solution which at step (203 c) is extracted with an organic solvent to obtain an organic layer. At step (203 d), the organic layer is separated and the separated organic layer is dried at step (203 e) under reduced pressure to obtain pure enantiomer of (R)-1-(1-naphthyl)ethyl amine or (S)-1-(1- naphthyl)ethyl amine. The chiral purity of the pure enantiomer obtained in step (203 e) is between 99% and 100%. The base added to the reaction mixture in step (203 b) is selected from a group comprising alkali or alkaline earth metal hydroxide or aqueous ammonia, preferably aqueous ammonia. The organic solvent for extraction at step (203 c) is selected from a group comprising toluene, methylene chloride, ethylene chloride and ethyl acetate, particularly ethyl acetate.

[0038] The method for the preparation of pure enantiomers of 1-(1-naphthyl)ethyl amine according to the invention comprises the step (204) of isolating enantiomerically enriched 1-(1-naphthyl)ethyl amine from the mother liquor separated from the lactate salt in step (202). Figure 5 is a flowchart for preparation of enriched enantiomer of (R)-1-(1-naphthyl)ethyl amine or (S)-1-(1- naphthyl)ethyl amine from the mother liquor separated from the lactate salt. As illustrated in Figure 5, the step (204) further comprises step (204 a) of treating mother liquor separated from lactate salt with a base preferably aqueous ammonia to obtain a first organic layer and aqueous layer. At step (204 b), the first organic layer and the aqueous layer are separated, and the separated aqueous layer is extracted with an organic solvent at step (204 c), the preferable organic solvent being ethyl acetate, to obtain a second organic layer. At step (204 d), the second organic solvent layer is separated from the aqueous layer and combined with the first organic layer to form the combined organic layer at step (204 e). This is followed by washing and drying the combined organic layer over sodium sulphate at step (204 f). In step (204 g) the dried organic layer is concentrated under reduced pressure to obtain enriched enantiomers. The base used for treating the mother liquor in step (204 a) is an organic or inorganic base, preferably an inorganic base selected from a group comprising alkali or alkaline earth metal hydroxide or aqueous ammonia, more preferably aqueous ammonia. The chiral purity of enriched enantiomer obtained in step (204 g) is between 75%-80%.

[0039] The invention is a method for preparing pure enantiomer of 1-(1- naphthyl)ethyl amine in step (206) which is accomplished by the conversion of enriched enantiomer obtained from the mother liquor of lactate salt to the diastereomeric mandelate salt in step (205). Figure 6 represents the preparation of diastereomeric mandelate salt from enriched enantiomer which further comprises of the step (205 a) of dissolving enriched enantiomer in a solvent to obtain a solution. At step (205 b), D-mandelic acid or L-mandelic acid is added to the solution, with stirring, at ambient temperature to obtain a reaction mass. The reaction mass is raised to the temperature of 65°C -70°C and at step (205 c) which is followed by cooling the reaction mass to room temperature to obtain crystals of the diastereomeric mandelate salt at step (205 d). The mandelate salt obtained in step (205 d) is any one of (R)-1-(1-naphthyl)ethyl amine-(R)-mandelate, (S)-1-(1- naphthyl)ethyl amine (S)-mandelate.

[0040] According to the invention, the step (206) of converting diastereomeric mandelate salt obtained from enriched enantiomer to pure enantiomers of 1-(1- naaphthyl) ethyl amine further comprises of steps depicted in Figure 7 which includes the step (206 a) of dissolving the diastereomeric mandelate salt in an organic solvent, preferably toluene to obtain a reaction mass. The reaction mass is cooled at step (206 b) followed by addition of a base at step (206 c) with stirring to obtain a first organic layer and aqueous layer. The base added in step (206 c) is selected from a group comprising alkali or alkaline earth metal hydroxide and ammonium hydroxide, preferably ammonium hydroxide. At step (206 d) the first organic layer and aqueous layer are separated, and the aqueous layer is extracted with toluene at step (206 e) to obtain the second organic layer. In step (206 f), the second organic layer is separated and combined with first organic layer to obtain a combined organic layer. The combined organic layer is washed and dried at step (206 g). At step (206 h), the washed and dried combined organic layer is concentrated under reduced pressure to obtain pure enantiomers of (R)-1-(1- naphthyl)ethyl amine or (S)-1-(1-naphthyl)ethyl amine. The organic solvents used for dissolving the mandelate salt at step (206 a) and extracting the aqueous layer at step (206 e) is selected from a group comprising toluene, hexane, ethyl acetate and methylene chloride. The preferred organic solvent is toluene. The chiral purity of the pure enantiomers of (R)-1-(1-naphthyl)ethyl amine or (S)-1-(1- naphthyl)ethyl amine is between 99% and 100%.

[0041] The following examples are offered to illustrate various aspects of the invention. However, the examples are not intended to limit or define the scope of the invention in any manner.

Example 1: Method for preparation of (S)-1-(1-naphthyl)ethyl amine (L)-lactate

[0042] 100g of racemic 1-(1-naphthyl)ethyl amine (584 mmol) is dissolved in 600 mL of ethyl acetate followed by addition of 59.19g (assay 89.3%) of L-Lactic acid 584mmol, in 10-15 minutes at room temperature. The reaction mixture is stirred at ambient temperature for 3 hours. The solid diastereomeric salt formed is filtered off to give white crystalline solid and mother liquor is separated. The yield of the lactate salt is 53.42g and the percentage molar yield is 35%. The purity of (S)-1-(1-naphthyl)ethyl amine (L)-Lactate obtained is 99%

Example 2: Method for preparation of (S)-1-(1-naphthyl)ethyl amine

[0043] 50 g of the diastereomeric salt of example 1 (155mmol) is dissolved in 25mL of water. 25mL of aqueous ammonia is added to the solution, with continuous stirring. The solution is stirred and extracted twice with ethyl acetate at a volume of 100mL. The organic layer obtained is dried over sodium sulfate and concentrated under reduced pressure. 25g of light-yellow liquid of (S)-1-(1- naphthyl)ethyl amine is obtained and the percentage molar yield of the reaction is 94.4%. The chiral purity of the (S)-1-(1-naphthyl)ethyl amine obtained is 99%.

Example 3: Method for preparation of enriched (R)-1-(1-naphthyl)ethyl amine

[0044] 600mL of mother liquor of example 1 is treated with 85mL of aqueous ammonia and the organic layer is separated. The aqueous layer is back extracted with ethyl acetate. The total organic layer is combined and washed with water, followed by drying over sodium sulfate. The organic layer is then concentrated under reduced pressure to obtain 64 g of enriched enantiomer of (R)-1-(1- naphthyl)ethyl amine with a chiral purity of 75% and the percentage molar yield of the reaction is 64%.

Example 4: Method for preparation of (R)-1-(1-naphthyl)ethyl amine (R)- mandelate

[0045] 64 g of the enriched isomer of (R)-1-(1-naphthyl)ethyl amine obtained in example 3 (374mmol) is dissolved in ethanol (384mL) and stirred at ambient temperature. 57g of (R)-mandelic acid (375 mmol) is added to the reacting solution. The resulting clear solution is stirred and temperature is raised to 65°C - 70°C. The reaction mass is cooled gradually to room temperature. During the cooling cycle, the (R)-1-(1-naphthyl)ethyl amine (R)-mandelate crystallizes out. The crystals of (R)-1-(1-naphthyl)ethyl amine (R)-mandelate formed is filtered off to obtain 77g of the (R)-1-(1-naphthyl)ethyl amine (R)-mandelate and the percentage molar yield of the reaction is 85%.

Example 5: Method for preparation of (R)-1-(1-naphthyl)ethyl amine

[0046] 75g of (R)-1-(1-naphthyl)ethyl amine (R)-mandelate of example 4 (232mmol) is stirred in 225mL of toluene. The reaction mass is cooled followed by addition of 56mL of aqueous ammonia. The resulting biphasic layer is stirred and the organic layer is separated. The aqueous layer is back extracted with toluene. The total organic layer is washed with water and concentrated under reduced pressure to obtain 72 g of (R)-1-(1-naphthyl)ethyl amine with chiral purity of 99.96% and the percentage molar yield of the reaction is 96%.

Example 6: Method for preparation of (R)-1-(1-naphthyl)ethyl amine (D)-lactate

[0047] 100 g of racemic 1-(1-naphthyl)ethyl amine (584mmol) is dissolved in 600mL of ethyl acetate followed by addition of 58.53g (assay 90%) of (D)-Lactic acid at room temperature and stirring at ambient temperature for 3 hours. During stirring, the (R)-1-(1-naphthyl)ethyl amine (D)-lactate precipitates out as white solid, which is filtered off and the mother liquor is separated. The yield of the lactate salt is 53.42g and the percentage molar yield is 35%. The purity of (R)-1- (1-naphthyl)ethyl amine (D)-lactate obtained is 99.2% as assessed by high performance liquid chromatography.

Example 7: Method for preparation of (R)-1-(1-naphthyl)ethyl amine

[0048] 50 g of the diastereomeric salt of example 6 (155mmol) is dissolved in 25mL of water. 25mL of aqueous ammonia is added to the solution, with continuous stirring. The solution is stirred and extracted with 2x100 mL of ethyl acetate. The organic layer obtained is dried over sodium sulfate and concentrated under reduced pressure. 25 g of a light yellow liquid of (R)-1-(1-naphthyl)ethyl amine is obtained with a chiral purity of greater than 99%. The percentage molar yield of the reaction is 94.4%.

Example 8: Method for preparation of enriched (S)-1-(1-naphthyl)ethyl amine

[0049] 600 mL of the mother liquor of example 6 is treated with 85mL of aqueous ammonia and the organic layer is separated. The aqueous layer is back extracted with ethyl acetate. The total organic layer is combined and washed with water, followed by drying over sodium sulfate. The organic layer is concentrated under reduced pressure to obtain 64g of enriched enantiomer of (S)-1-(1-naphthyl)ethyl amine with chiral purity of 75% and wherein the percentage molar yield of the reaction is 64%. Example 9: Method for preparation of (S)-1-(1-naphthyl)ethyl amine (S)- mandelate

[0050] 64 g of enriched isomer of (S)-1-(1-naphthyl)ethyl amine (374mmol) obtained in example 8 is dissolved in 385mL of ethanol and stirred at ambient temperature. 57g of (S)-mandelic acid (375 mmol) is added to the clear solution. The resulting clear solution is continuously stirred and the temperature is raised to 65°C -70°C. The reaction mass is cooled gradually to room temperature. During the cooling cycle, the (S)-1-(1-naphthyl)ethyl amine (S)-mandelate crystallizes out. The (S)-1-(1-naphthyl)ethyl amine (S)-mandelate formed is filtered off to give 77g of the (S)-1-(1-Naphthyl)ethyl amine (S)-mandelate and the percentage molar yield of the reaction is 85%.

Example 10: Method for preparation of (S)-1-(1-naphthyl)ethyl amine [0051] 75g of (S)-1-(1-naphthyl)ethyl amine (S)-mandelate of example 9

(232mmol) is stirred in 225mL toluene. The reaction mass is cooled followed by addition of 56mL of aqueous ammonia. The resulting biphasic layer is continuously stirred and the organic layer is separated. The aqueous layer is back extracted with toluene. The total organic layer is washed with water and concentrated under reduced pressure to obtain 72 g of (R)-1-(1-naphthyl)ethyl amine with chiral purity of 99.96%. The percentage molar yield of the reaction is 96%.

[0052] The method of the invention results in obtaining both the (R) and (S) enatiomers of 1-(1-naphthyl)ethyl amine, which exhibits high degree of chiral purity in the range between 99% and 100%. The greatest advantage of the method is that it involves less cumbersome steps. Further, the resolving agents, bases and organic solvents used in the method are easily available and are of low cost.

Claims

Claims We claim:

1. A method (200) for preparation of pure enantiomers of 1-(1- naphthyl)ethyl amine, the method comprising the steps of: a. preparing crystalline diastereomeric lactate salt of Formula A by reacting racemic 1-(1-naphthyl)ethyl amine with any one of L- lactic acid or D-lactic acid (201),

b. separating the crystalline diastereomeric lactate salt of Formula A from mother liquor (202); c. isolating pure enantiomers of 1-(1-naphthyl)ethyl amine from the separated crystalline diastereomeric lactate salt of Formula A

(203); d. isolating enantiomerically enriched 1-(1-naphthyl)ethyl amine from the mother liquor (204) which separated in step (202); e. obtaining diastereomeric mandelate salt of enriched enantiomers (205) by reacting the isolated enantiomerically enriched 1-(1- naphthyl)ethyl amine with any one of D-mandelic acid or L- mandelic acid, wherein the mandelate salt obtained is one of (R)-1- (1-naphthyl)ethyl amine-(R)-mandelate, (S)-1-(1-naphthyl)ethyl amine-(R)-mandelate, (R)-1-(1-naphthyl)ethyl amine-(S)- mandelate, (S)-1-(1-Naphthyl)ethyl amine (S) -mandelate; and f. converting diastereomeric mandelate salt to pure enantiomers of 1- (1-naphthyl)ethyl amine (206).

2. The method as claimed in claim 1, wherein preparing diastereomeric lactate salt from racemic 1-(1-naphthyl)ethyl amine (201) further comprises the steps of: a. dissolving racemic 1-(1-naphthyl)ethyl amine in a solvent and obtaining a solution (201 a), wherein the solvent is selected from a group comprising hydrocarbon, aromatic hydrocarbon, alkyl or aryl ethers, alkyl alcohols, ketones and esters, preferably esters and more preferably ethyl acetate; b. adding D-lactic acid or L-lactic acid to the solution (201 b), wherein the lactic acid is added, at room temperature, within a time interval of 10 to 15 minutes of forming the solution, and obtaining a reaction mixture (201 b); c. stirring the reaction mixture at ambient temperature for 3 hours and obtaining white crystalline diastereomeric lactate salt of Formula A

(201 c).

3. The method as claimed in claim 1, wherein isolating pure enantiomers of 1-(1-naphthyl)ethyl amine from the separated crystalline diastereomeric salt of Formula A (203) further comprises the steps of: i. dissolving the separated crystalline diastereomeric lactate salt of Formula A in water (203 a) and obtaining a reaction mixture; ii. adding a base to the reaction mixture with stirring and obtaining a solution (203 b), wherein the base is selected from a group comprising alkali or alkaline earth metal hydroxide or aqueous ammonia, preferably aqueous ammonia; iii. extracting the obtained solution with organic solvent (203 c), wherein the organic solvent is selected from a group comprising toluene, methylene chloride, ethylene chloride and ethyl acetate, preferably ethyl acetate; iv. separating the organic layer (203 d); and v. drying the organic layer under reduced pressure and obtaining pure enantiomer of (R)-1-(1-naphthyl)ethyl amine or (S)-1-(1- naphthyl)ethyl amine (203 e), wherein the chiral purity of pure enantiomer of 1-(1-Naphthyl)ethyl amine obtained is between 99% and 100%.

4. The method as claimed in claim 1, wherein isolating enantiomerically enriched 1-(1-naphthyl)ethyl amine from the mother liquor separated from the lactate salt (204) further comprises the steps of: i. treating mother liquor with aqueous ammonia and obtaining a first organic layer and aqueous layer (204 a); ii. separating the first organic layer and the aqueous layer (204 b); iii. extracting the aqueous layer with an organic solvent, preferably ethyl acetate and obtaining a second organic layer (204 c); iv. separating the second organic solvent layer from the aqueous layer (204 d); v. combining the separated second organic layer with first organic layer to form combined organic layer (204 e); vi. washing the combined organic layer and drying the washed combined organic layer over sodium sulphate (204 f); and vii. concentrating the dried organic layer under reduced pressure and obtaining enriched enantiomer (204 g), wherein the chiral purity of enriched enantiomer is between 75% and 80%.

5. The method as claimed in claim 1, wherein obtaining diastereomeric mandelate salt of enriched enantiomers (205) further comprises the steps of: i. dissolving enriched enantiomer in a solvent and forming a solution (205a), wherein the solvent is selected from a group comprising alcohol, ethers and esters, preferably linear or branched chain alcohols and more preferably ethanol; ii. adding a chiral a-hydroxy acetic acid to the formed solution with stirring, at ambient temperature and obtaining a reaction mass (205 b), wherein the a-hydroxy acetic acid is preferably lactic acid or mandelic acid, more preferably mandelic acid; iii. raising the temperature of reaction mass between 65°C and 70°C (205 c); and iv. cooling the reaction mass to room temperature and obtaining crystals of the diastereomeric mandelate salt (205 d).

6. The method as claimed in claim 1, wherein converting diastereomeric mandelate salt of the enriched enantiomer to pure enantiomers of 1-(1- naphthyl)ethyl amine (206) further comprises the steps of: i. dissolving the diastereomeric mandelate salt in an organic solvent and obtaining a reaction mass (206 a), wherein the organic solvent is selected from a group comprising toluene, hexane, ethyl acetate and methylene chloride, preferably toluene; ii. cooling the reaction mass (206 b); iii. adding a base to the reaction mass with stirring and obtaining a first organic layer and aqueous layer (206 c), wherein the base is selected from a group comprising aqueous solution of alkali or alkaline earth metal hydroxide and ammonium hydroxide, preferably ammonium hydroxide; iv. separating the first organic layer and aqueous layer (206 d); v. extracting the aqueous layer with toluene and obtaining a second organic layer (206 e); vi. separating the second organic layer and combining it with first organic layer forming a combined organic layer (206 f); vii. washing and drying the combined organic layer (206 g); and viii. concentrating the combined organic layer under reduced pressure and obtaining pure enantiomers of (R)-1-(1- naphthyl)ethyl amine or (S)-1-(1-naphthyl)ethyl amine (206 h), wherein the chiral purity of pure enantiomer of 1-(1- Naphthyl)ethyl amine obtained is between 99% and 100%. 7. A diastereomeric lactate salt of Formula A obtained using the method claimed in claim 2 wherein the chiral purity of the diastereomeric salt is between 99% and 100% and wherein the lactate salt is of any one of (S)-1-(1-naphthyl)ethyl amine L-lactate, (R)-1-(1-naphthyl)ethyl amine D-lactate.

8. A pure enantiomer (R)-1-(1-naphthyl)ethyl amine of Formula 1 obtained using method claimed in claim 3 or claim 6, wherein the chiral purity of the enantiomer is between 99% and 100%.

9. A pure enantiomer (S)-1-(1-naphthyl)ethyl amine of Formula 2 obtained using method claimed in claim 3 or claim 6, wherein the having chiral purity of the enantiomer is between 99% and 100%.