Claims:We claim:
1. A process for the synthesis of phenylephrine hydrochloride comprises of:
(i) chlorination of 3-hydroxyacetophenone using sulfuryl chloride in the presence of a solvent to obtain 3'-hydroxy-2-chloroacetophenone (1);
(ii) reacting 3'-hydroxy-2-chloroacetophenone (1) with N-methylbenzylamine in the presence of a solvent to obtain N-benzyl-N-methyl-2-amino-m-hydroxyacetophenone hydrochloride (2);
(iii) hydrogenation of N-benzyl-N-methyl-2-amino-m-hydroxyacetophenone hydrochloride (2) with hydrogen gas and palladium on carbon, to obtain racemic phenylephrine (3);
(iv) resolution of the racemic phenylephrine (3) with a resolving agent in the presence of a solvent to obtain diastereomeric S (4-S) and R (4-R) salts of phenylephrine;
(v) reacting the S-isomer salt (4-S) with aqueous ammonia followed by treatment with acetic anhydride and sulfuric acid, to obtain R-phenylephrine (5);
(vi) reacting the R-isomer salt (4-R) with aqueous ammonia to obtain R-phenylephrine (5); and
(vii) reacting R-phenylephrine (5) obtained from steps (v) and (vi) with isopropyl alcohol hydrochloride, to obtain phenylephrine hydrochloride.

2. The process according to claim 1, wherein the organic solvent used in step (i) may be selected from dichloromethane, chloroform, toluene, ethyl acetate alone or as a mixture with methanol, ethanol, isopropyl alcohol, and the like in varying amounts.

3. The process according to claim 1, wherein the solvent used in step (ii) may be selected from dichloromethane, chloroform, toluene, isopropyl alcohol, and the like or as a mixture with water in varying amounts.

4. The process according to claim 1, wherein the solvent used in step (iv) may be selected from methanol, ethanol, isopropyl alcohol, butanol, cyclohexenol, acetone, cyclohexanone, toluene, cyclohexane, isopropyl ether, tetrahydrofuran or as combinations thereof and optionally containing varying amount of water.

5. The process according to claim 1, wherein the resolving agent of step (iv) may be selected from L-tartaric acid, mandelic acid, camphor sulfonic acid, 1-bromocamphor sulfonic acid, glutamic acid. , Description:FIELD OF THE INVENTION

The present invention relates to a process for the synthesis of phenylephrine hydrochloride from 3-hydroxyacetophenone.

BACKGROUND OF THE INVENTION

Phenylephrine hydrochloride is a decongestant frequently used in over-the-counter formulations to treat cough and cold.

Some of the prior art references disclose the synthesis of phenylephrine from 3-hydroxyacetophenone by chlorination followed by amination and hydrogenation reactions. There are quite a few references that disclose the preparation of phenylephrine using sulfuryl chloride, bromine, N-methylbenzylamine/methylamine, hydrochloric acid and methanol to form an intermediate compound.

IN201621014436A discloses the synthesis of a-(N-methyl-N-benzyl-amino)-3-hydroxyacetophenone hydrochloride from 3-hydroxy acetophenone. The process involves chlorination by sulfuryl chloride in conjunction with sodium hydroxide followed by amination using N-methyl benzylamine in suitable organic/ inorganic solvents. This patent application does not disclose further reduction of the hydrochloride salt and formation of L-phenylephrine hydrochloride.

US8617854B2 discloses the production of phenylephrine, i.e. 3-[(1R)-1-hydroxy-2-methylamino-ethyl]-phenol. One of the two key steps in this patent is the chlorination of 3'-hydroxyacetophenone to 3'-hydroxy-2-chloroacetophenone in the presence of methanol and dichloromethane. The second key step relates to the enantioselective reduction of 3'-hydroxy-2-chloroacetophenone to (R)-3-(2-chloro-1-hydroxyethyl)-phenol, in particular using an enzyme, viz., an alcohol dehydrogenase (ADH). (R)-3-(2-chloro-1-hydroxyethyl)-phenol after reduction with methylamine generates the desired product L-phenylephrine.

US6187956B1 discloses the preparation of L-phenylephrine hydrochloride wherein N-benzyl-N-methyl-2-amino-m-hydroxyacetophenone hydrochloride salt undergoes hydrogenation in the presence of [Rh(COD)Cl]2 and (2R,4R)-4-(dicyclohexylphosphino)-2-(diphenyl-phosphino-methyl)-N-methyl-aminocarbonylpyrrolidine as the catalyst system. N-benzyl-L-phenylephrine obtained in the above step is further hydrogenated, in the presence of activated charcoal and palladium chloride solution to obtain L-phenylephrine hydrochloride.

OBJECTIVE OF THE PRESENT INVENTION

The principal object of the present invention is to provide a process for the synthesis of phenylephrine hydrochloride from 3-hydroxyacetophenone.

SUMMARY OF THE PRESENT INVENTION

The present invention relates to a process for the synthesis of phenylephrine hydrochloride from 3-hydroxyacetophenone. In the present invention, the unwanted S-isomer is converted to the desired R-isomer thus increasing the yield and avoiding wastage of material. Also, the chiral purity of phenylephrine hydrochloride synthesized by the process of the present invention is more than 99%. 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 process for the synthesis of phenylephrine hydrochloride from 3-hydroxyacetophenone comprises of:
(i) chlorination of 3-hydroxyacetophenone using sulfuryl chloride in the presence of a solvent to obtain 3'-hydroxy-2-chloroacetophenone (1);
(ii) reacting 3'-hydroxy-2-chloroacetophenone (1) with N-methylbenzylamine in the presence of a solvent to obtain N-benzyl-N-methyl-2-amino-m-hydroxyacetophenone hydrochloride (2);
(iii) hydrogenation of N-benzyl-N-methyl-2-amino-m-hydroxyacetophenone hydrochloride (2) with hydrogen gas and palladium on carbon, to obtain racemic phenylephrine (3);
(iv) resolution of the racemic phenylephrine (3) with a resolving agent to obtain the diastereomeric S (4-S) and R (4-R) salts of phenylephrine;
(v) reacting the S-isomer salt (4-S) with aqueous ammonia followed by treatment with acetic anhydride and sulfuric acid, to obtain the R-isomer of the free base phenylephrine (5);
(vi) reacting the R-isomer salt (4-R) with aqueous ammonia to obtain the R-isomer of the free base phenylephrine (5); and
(vii) reacting the R-isomer of the free base phenylephrine (5) obtained in steps (v) and (vi) with isopropyl alcohol hydrochloride to obtain phenylephrine hydrochloride.

BRIEF DESCRIPTION OF THE PRESENT INVENTION

Fig. 1 shows the schematic representation of the process of the present invention for the synthesis of phenylephrine hydrochloride.
Fig. 2 depicts the Chiral HPLC chromatograph of Racemic Phenylephrine.
Fig. 3 depicts the Chiral HPLC chromatograph of (R)-Phenylephrine.
Fig. 4 depicts the Chiral HPLC chromatograph of (S)-Phenylephrine.

DESCRIPTION OF THE PRESENT INVENTION

The present invention relates to a process for the synthesis of phenylephrine hydrochloride from 3-hydroxyacetophenone.

According to an embodiment of the invention, the process for the synthesis of phenylephrine hydrochloride comprises of:
(i) chlorination of 3-hydroxyacetophenone using sulfuryl chloride in the presence of a solvent to obtain 3'-hydroxy-2-chloroacetophenone (1);
(ii) reacting 3'-hydroxy-2-chloroacetophenone (1) with N-methylbenzylamine in the presence of a solvent to obtain N-benzyl-N-methyl-2-amino-m-hydroxyacetophenone hydrochloride (2);
(iii) hydrogenation of N-benzyl-N-methyl-2-amino-m-hydroxyacetophenone hydrochloride (2) with hydrogen gas in the presence of palladium on carbon, to obtain racemic phenylephrine (3);
(iv) resolution of the racemic phenylephrine (3) with a resolving agent in the presence of a solvent to obtain diastereomeric S (4-S) and R (4-R) salts;
(v) reacting the S-isomer salt (4-S) with aqueous ammonia followed by treatment with acetic anhydride and sulfuric acid, to obtain the R-isomer of the free base phenylephrine (5);
(vi) reacting the R-isomer salt (4-R) with aqueous ammonia to obtain the R-isomer of the free base phenylephrine (5); and
(vii) reacting the R-isomer of the free base phenylephrine (5) obtained in steps (v) and (vi) with isopropyl alcohol hydrochloride, to obtain phenylephrine hydrochloride.

The organic solvent used in step (i) may be selected from dichloromethane, chloroform, toluene, ethyl acetate alone or as a mixture with methanol, ethanol, isopropyl alcohol, and the like in varying amounts.

The solvent used in step (ii) may be selected from dichloromethane, chloroform, toluene, ethyl acetate, isopropyl alcohol, and the like or as a mixture with water in varying amounts.

The solvent used in step (iv) may be selected from methanol, ethanol, isopropyl alcohol, butanol, cyclohexenol, acetone, cyclohexanone, toluene, cyclohexane, isopropyl ether, tetrahydrofuran or as combinations thereof and optionally containing varying amount of water.

The resolving agent of step (iv) may be selected from L-tartaric acid, mandelic acid, camphor sulfonic acid, 1-bromocamphor sulfonic acid, glutamic acid.

According to a preferred embodiment of the present invention, the process for the synthesis of phenylephrine hydrochloride comprises of:
(i) chlorination of 3-hydroxyacetophenone using sulfuryl chloride in the presence of a solvent to obtain 3'-hydroxy-2-chloroacetophenone (1);
(ii) reacting 3'-hydroxy-2-chloroacetophenone (1) with N-methylbenzylamine in the presence of a solvent to obtain N-benzyl-N-methyl-2-amino-m-hydroxyacetophenone hydrochloride (2);
(iii) hydrogenation of N-benzyl-N-methyl-2-amino-m-hydroxyacetophenone hydrochloride (2) with hydrogen gas and palladium on carbon, to obtain racemic phenylephrine (3);
(iv) resolution of the racemic phenylephrine (3) with L-tartaric acid in the presence of a solvent to obtain diastereomeric S (4-S) and R (4-R) tartrate salts;
(v) reacting the S-isomer salt (4-S) with aqueous ammonia followed by treatment with acetic anhydride and sulfuric acid, to obtain the R-isomer of the free base phenylephrine (5);
(vi) reacting the R-isomer salt (4-R) with aqueous ammonia to obtain R-phenylephrine (5); and
(vii) reacting the R-isomer of the free base R-phenylephrine (5) obtained from steps (v) and (vi) with isopropyl alcohol hydrochloride, to obtain phenylephrine hydrochloride.

The preferable organic solvent used in step (i) is dichloromethane. The preferable organic solvent in step (iv) is isopropyl alcohol.

The chiral purity of phenylephrine hydrochloride was found to be more than 99%, and more specifically more than 99.5% as determined by chiral High-performance Liquid Chromatography (HPLC).

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 phenylephrine hydrochloride from 3-hydroxyacetophenone 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 (H1-NMR) spectrometry being determined at 300 MHz using the indicated solvent. The chiral purity of phenylephrine hydrochloride was checked and confirmed by chiral High-performance Liquid Chromatography (HPLC).

The chemical symbols have their usual meaning and the following abbreviations, ml or mL (milliliter(s)), g (gram(s)), kg (kilogram(s)), ºC (degrees Celsius), mm (millimeter(s)), µm (micrometer(s)), min (minutes), µL (microliter(s)), nm (nanometer(s)), v/v/v (volume/volume/volume), RT (retention time), RRT (relative retention time), have also been used.

EXAMPLES

Example 1
100 g of 3-hydroxyacetophenone was charged into a round-bottomed flask along with 300 ml of dichloromethane. 158 g of sulfuryl chloride was added drop-wise at 0°C over a period of 2 hours. Upon completion of the addition, the reaction mass was stirred for 1 hour and quenched with 300 ml of water. The aqueous layer was extracted with 100 ml of dichloromethane and the separated organic layers were concentrated to obtain compound (1). Thus obtained compound (1) was weighed and found to be 125g with a yield of 100%. The purity of compound (1) was checked by HPLC and found to be 88%. Compound (1) was characterized using proton NMR and Mass chromatography.
H1-NMR data (DMSO d6): d 5.12 (S, 2H), 7.03-7.06 (m, 1H), 7.35-7.30 (m, 2H), 7.41-7.39 (m, 1H), 9.8 (s, 1H).
Mass ESI (-ve) M-2: 168.8

Example 2
125 g of compound (1) obtained in Example 1 was charged into a round-bottomed flask along with 1000 ml of ethyl acetate and 156 g of sodium carbonate. 89 g of N-methylbenzylamine was added to the reaction mass. The reaction mass was stirred for 36 hours at ambient temperature. 300 ml of water was charged into the reaction mass and the organic layer was separated. The organic layer was washed with 500 ml of water. IPA HCl solution was charged into the organic layer and stirred for 1 hour. The solid was filtered and washed with ethyl acetate to obtain compound (2). Thus obtained compound (2) was weighed and found to be 170 g with a yield of 80%. The purity of compound (2) was checked by HPLC and found to be 95%. Compound (2) was characterized using proton NMR and Mass chromatography.
H1-NMR data (DMSO d6): d 2.79 (S, 3H), 4.46 (d, 2H), 5.0 (d, 2H), 7.17 (d, 1H), 7.4-7.34 (m, 6H), 7.6 (d, 2H), 10.2 (s, 1H), 10.6 (S, 1H).
Mass ESI (M-HCl): 255
Example 3
100 g of compound (2) obtained in Example 2 was charged into an autoclave vessel along with 1000 ml of methanol and 5 g of 5% palladium on carbon. The reaction was purged with hydrogen gas four times. 10 kg of hydrogen gas pressure was applied and stirring was continued at 50°C until the reaction completed [as monitored by TLC (solvent system: 20% methanol in dichloromethane). Upon asserting completion of the reaction, the pressure was released and the catalyst was filtered out. The filtered reaction mixture was concentrated under reduced pressure and basified with aqueous ammonia to obtain precipitation of a solid compound. The solid compound was filtered and washed with water. Thus obtained solid compound (3) was weighed and found to be 48 g with a yield of 84%. The purity of compound (3) was checked by HPLC and found to be 97%. Compound (3) was characterized using proton NMR and Mass chromatography.
H1-NMR data (DMSO d6): d 2.29 (S, 3H), 2.54 (m, 2H), 4.5 (m, 1H), 6.6 (d, 1H), 6.7-6.69 (m, 2H), 7.06 (t, 1H)
Mass ES+ (M+H): 168

Example 4
100 g of compound (3) obtained in Example 3 was charged into a round-bottomed flask along with 300 ml of isopropanol. 100 g of L-tartaric acid was charged into the reaction mixture. The reaction mixture was heated to 60-65°C for 1 hour. The reaction mass was then cooled to 25-35°C and stirred for 15 hours. The reaction mass was filtered to obtain a solid material identified to be the S-isomer salt (4-S) of phenylephrine and the filtrate comprising the R-isomer salt (4-R) of phenylephrine [identification of S- and R- isomers was through chiral HPLC]. The solid material S-isomer salt, i.e. (4-S) was weighed and found to be 90 g.

Example 5(a)
The filtrate comprising the R-isomer salt (4-R) obtained in Example 4, was concentrated under reduced pressure and 200 ml of water was added. This was basified with aqueous ammonia until a pH of 9.5 – 9.7 was attained. The solid was filtered, and washed with water to obtain the R-isomer of the free base phenylephrine (5). Thus obtained solid was weighed and found to be 30 g with a yield of 30%.
The purity of the R-isomer of the free base phenylephrine (5) was checked by HPLC and found to be 99% and the chiral purity was also found to be 99%. The R-isomer of the free base phenylephrine (5) was characterized using proton NMR and Mass chromatography.
H1-NMR data (DMSO d6): d 2.29 (S, 3H), 2.54 (m, 2H), 4.5 (m, 1H), 6.6 (d, 1H), 6.7-6.69 (m, 2H), 7.06 (t, 1H).
Mass ES+ (M+H): 168

Example 5(b)
90 g of the solid material (4-S) obtained in Example 4 was dissolved in water and basified with lye solution until a pH of 9.5 - 9.7 was attained. The solid was filtered, and washed with water to obtain the S-isomer of the free base phenylephrine. This S-isomer was charged into a round-bottomed flask and 40 g of acetic anhydride was added followed by 23.4 g of sulfuric acid. The reaction mass was heated to a temperature of 100-105°C and maintained for 10 hours. The reaction mass was distilled off under reduced pressure, and water was added to the reaction mass. The reaction mass was heated for 4 hours at reflux. It was then cooled to room temperature, and aqueous ammonia was added until a pH of up to 9.5 - 9.7 was attained. The solid was filtered, and washed with water to obtain R-isomer of the free base phenylephrine (5). Thus obtained solid was weighed and found to be 30 g with a yield of 30%.
The purity of R-isomer of the free base phenylephrine (5) obtained from Example 5(b) was checked by HPLC and found to be 99% and the chiral purity was found to be 98%. The R-isomer of the free base phenylephrine (5) was characterized using proton NMR and Mass chromatography.
H1-NMR data (DMSO d6): d 2.29 (S, 3H), 2.54 (m, 2H), 4.5 (m, 1H), 6.6 (d, 1H), 6.7-6.69 (m, 2H), 7.06 (t, 1H).
Mass ES+ (M+H): 168

Example 6
100 g of the combined R-isomer of the free base phenylephrine (5) obtained from Example 5(a) and Example 5(b) was charged into a round-bottomed flask along with 1000 ml of methanol. IPA HCl was added until a pH of 0.5 - 1 was attained. The reaction mass was distilled completely under reduced pressure at 50°C. 500 ml of isopropanol was added into the crude solid and stirred for 10 hours at room temperature. The solid was filtered and washed with isopropanol to obtain hydrochloride salt of phenylephrine. Thus obtained phenylephrine hydrochloride was weighed and found to be 108 g with a yield of 90%.
The purity was checked by HPLC and found to be 99.8%, and the chiral purity was checked by chiral HPLC and found to be 99.5%. Phenylephrine hydrochloride obtained in Example 6 was characterized and found to have the following values.
SOR [2% solution in water, 589 nm at 25°C]: -46°
Melting range: 141-145°C
H1-NMR data (DMSO d6): d 9.56 (s, 1H), 8.99 (s, 1H), 7.15 (t, 1H), 6.81 (s, 1H), 6.78 (d, 1H), 6.70 (d, 1H), 6.11 (s, 1H), 4.83 (m, 1H), 3.05 (m, 1H), 2.11 (m, 1H), 2.53 (s, 3H)
Mass ES+ (M+H): 168

The Chiral HPLC conditions considered for the aforementioned examples are as below.
Column: Chiral Pak AD, 250 x 4.6mm, 10µm;
Flow: 1.0 ml/min;
Injection volume: 10µL;
Detector: 270nm;
Column temperature: 25°C;
Run time: 35min;
Mobile Phase: n-Hexane: ethanol: Trifluoroacetic acid (920:80:1.0, v/v/v)
(All volumes were accurately measured and taken in a clean and dry bottle and capped tightly. The ingredients were mixed thoroughly)

Diluent-1: n-Hexane: IPA :: 8: 2 v/v
Blank preparation: Diluent-1: Methanol :: 85:15, v/v

Preparation of System suitability solution:
10 mg of racemic mixture (compound (3)) was taken in a 10 ml volumetric flask, dissolved in 1.5 ml of methanol, then diluted to volume with Diluent-1, and mixed.

Preparation of Test solution:
10 mg of the sample to be examined was taken in a 10ml volumetric flask, dissolved in 1.5 ml of methanol, diluted to volume with Diluent-1, and mixed.

Standard solution:
10 mg of phenylephrine hydrochloride (reference standard) was taken in a 10ml volumetric flask, dissolved in 1.5 ml of methanol, diluted to volume with Diluent-1, and mixed.

Procedure:
The blank preparation, system suitability solution, standard solution and test solutions were injected individually and the peaks were integrated; the presence of R- and S- enantiomers was observed. The chiral purity (% R-isomer) was deduced by area normalization method.

System suitability criteria:
The resolution between (R)-Phenylephrine and (S)-Phenylephrine should not be less than 1.5. The RT and RRT for the R- and S- isomers are as below:

S. No. Name of the compound ~RT (min) ~RRT
1 (R)-Phenylephrine 13.0 1
2 (S)-Phenylephrine 17.5 1.35

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. The phenylephrine hydrochloride produced by the process of the present invention is as per the quality specification criteria of US/ EP/ IP Pharmacopoeias. This process converts the unwanted S-isomer into the desired R-isomer thereby avoiding wastage of material. Also, the chiral purity of the final product is more than 99%.

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.