DESC:FIELD OF THE INVENTION

The present invention relates to synthesis of a- (N-methyl-N-benzyl-amino)-3-hydroxyacetophenone hydrochloride. More particularly, the present invention relates to a highly improved and efficient one pot synthesis of a-(N-methyl-N-benzylamino)-3-hydroxyacetophenone hydrochloride.

BACKGROUND OF THE INVENTION

a- (N- methyl -N- benzyl-amino) -3-hydroxyacetophenone hydrochloride is an important intermediate for phenylephrine which in turn is an 1-adrenergic receptor agonist of the phenethylamine class, and is primarily used as a decongestant for bronchiectasis and vascular contraction nasal mucosa. It can reduce nasal and sinus congestion relieve nasal mucosal hyperemia or swelling, and may also relieve symptoms of nasal congestion. This supplement can also be used to treat shock and supraventricular tachycardia, or used to maintain blood pressure during anaesthesia and mydriatic check.

Various synthesis studies and findings regarding phenylephrine have been reported for example US6187956; (2001) but only a few are of industrial value. (R)-phenylephrine hydrochloride (figure 1) is the common form of phenylephrine in the pharmaceutical industry. a-(N-methyl-N-benzylamino)-3-hydroxy acetophenone hydrochloride (b) is a key intermediate to accomplish the synthesis of (R)-phenylephrine hydrochloride.

One such method of synthesis of a-(N-methyl-N-benzylamino)-3-hydroxy acetophenone hydrochloride involves bromination of hydroxy acetophenone after protection of phenolic hydroxyl group by benzoylation to give 3-Benzoloxy-w-bromoacetopheone. The resultant was condensed with N-methyl benzylamine and after debenzoylation step produced a-(N-methyl-N-benzylamino)-3-hydroxy acetophenone hydrochloride. However, this process involves 4 steps and overall yield reported is only 46 % w.r.t. 3-Hydroxyacetophenone.

In another method for preparation of a-(N-methyl-N-benzylamino)-3-hydroxy acetophenone hydrochloride it is prepared via O-acyl protection of phenolic -OH group followed by bromination and reaction with N-Methyl benzylamine in large amount of water and solvent. This process has drawback as it generate large volumes of waste water which needed treatment for its disposal. De-protection also gives acetic acid and in turn sodium acetate disposal problem.

Thus, the contemporary process of preparation of a-(N-methyl-N-benzylamino)-3-hydroxy acetophenone hydrochloride involves a complex multicomponent multistage process. Moreover, such processes are difficult on a commercial scale, involve use of expensive reagents, or generate undesirable by-products.

It is therefore, a need to develop a process which not only overcomes the disadvantages of the prior art but also be economical, operationally simple and industrially applicable.

The present invention overcomes the above-discussed limitations as it provides an eco-friendly, cost effective and a novel one pot synthesis of a-(N-methyl-N-benzylamino)-3-hydroxy acetophenone hydrochloride avoiding multistep synthetic methods. The novel process of the present invention is of immense importance in the area of new drug development. There was a need of process for the preparation of said compound as there exist no such process for the said compound in the literature which can be operable industrially.

OBJECTS OF THE INVENTION

It is therefore an object of the present invention to provide a highly improved and efficient one pot synthesis of a-(N-methyl-N-benzylamino)-3-hydroxy acetophenone hydrochloride.

Another object of the present invention is to provide a process which gives a-(N-methyl-N-benzylamino)-3-hydroxy acetophenone hydrochloride with high purity.

Another object of the present invention is to provide a process which is simple and easy to handle at an industrial scale.

Another object of the present invention is to provide a-(N-methyl-N-benzylamino)-3-hydroxy acetophenone hydrochloride in good yield.

Another object of the present invention is to provide an improved one pot synthesis process comprising the two reaction step which can be carried out in the single reactor without isolation of stage I intermediate.

Yet another object of the present invention is to provide a novel one pot synthesis of a-(N-methyl-N-benzylamino)-3-hydroxy acetophenone hydrochloride that can be carried out in the existing manufacturing facilities without incurring any additional or substantial costs.

A further object of the present invention is to provide a process which generates very less amount of waste water which is easily treatable and disposable.

SUMMARY OF THE INVENTION

Accordingly, present invention provides an improved process of preparation of one pot synthesis of a-(N-methyl-N-benzylamino)-3-hydroxy acetophenone hydrochloride represented by Formula I:
.
(Formula 1)

The compound represented by Formula 1 is prepared via one pot process using 3-hydroxy acetophenone. The process involves allylic chlorination and in situ reaction of N-methyl benzylamine with suitable organic / inorganic base in the presence of one or more suitable solvent/s as per the reaction scheme illustrated in Fig. 2.

DETAILED DESCRIPTION OF THE INVENTION

An improved process for one pot synthesis of a-(N-methyl-N-benzylamino)-3-hydroxy acetophenone hydrochloride is provided as per the reaction scheme illustrated in Figure 2:

Fig. 2

The described process involves two steps in which 3-hydroxy acetophenone represented by Formula 2 is reacted with sulfuryl chloride in the presence of suitable solvent /solvent mixtures and after completion of reaction, the solvents are removed by general work up process and the residual intermediate represented by Formula 3 after solvent removal is further reacted in the next step with N-methylbenzylamine represented by Formula 4 in the presence of suitable base and catalyst.

After completion of reaction, the mass is filtered and the filtrate after treatment with HCl solution in isopropyl alcohol gives the desired product represented by Formula 1 in good yield and quality.

The process of allylic chlorination involves the use of sulfuryl chloride with mixed solvent system containing, not being limited to, one at least from C1 to C6 alcohol which includes methanol, Isopropyl alcohol, butanol, n-hexanol, cyclohexanol, methylene chloride, dichloroethane etc and partner solvents which includes aliphatic esters like ethyl acetate, di-isopropyl acetate, butyl acetate etc., chlorinated solvents like methylene chloride, dichloroethane and aromatic solvents like toluene, xylene etc.

The chlorination reaction was carried in the temperature range of 0 to 45 deg C more specifically at 25 to 30 deg C. The reaction time is generally 5 to 10 hrs depends on chlorination reagent addition time.

The N-methyl benzylation process include use of inorganic bases, not being limited to, like sodium carbonate, potassium carbonate, magnesium carbonate, calcium carbonate, barium carbonate and other alkali and alkaline earth metal carbonates. The process utilises the catalysts which are generally phase transfer catalyst , not being limited to, such as tetra butyl ammonium bromide, benzyl triethylmonium chloride etc. The solvent used in the amination stage include C1-to C6 alcohols which includes methanol, Isopropyl alcohol, butanol, n-hexanol, cyclohexanol, methylene chloride, dichloroethane etc. and aromatic solvents such as toluene, xylene etc.

N-methyl benzylation reaction temperature ranges from ambient to 90 deg C and even more than it depending upon the solvent used for the reaction. N-methyl benzylamine used in mole ratio in the range of 0.9 to 1.5 moles with respect to ketone but is not limited to this range and can use more than 1.5 moles. Hydrochloride salt is prepared by using either conc. Hydrochloric acid or HCl gas dissolved in methanol, isopropyl alcohol etc.

The improved process of preparation of one pot synthesis of a-(N-methyl-N-benzylamino)-3-hydroxy acetophenone hydrochloride has numerous advantages in that the process operate with minimum usages of water in order to reduce waste water generation. Also the reagent used is very limited so as to avoid its recovery and recycle as mentioned in the processes described in the prior art.

The novel process is free of protection and de-protection methods and hence has high environmental and economical benefits.

The two step reaction chemistry is carried out in single reactor without isolation of stage I compound. The yield obtained is higher than the processes of the prior arts.

Having generally described this invention, a further understanding can be obtained by reference to certain specific examples which are provided herein for purposes of illustration only and are not intended to be limiting unless otherwise specified.

EXAMPLE 1

Step I – Preparation of 2-Chloro-1-(3-hydroxyphenyl) ethan-1-one

Sulfuryl chloride (134.97 g, 1.0 mole) was slowly dropped into a solution of 3-hydroxyacetophenone (136.14 g, 1.0 mole) in Di-Isopropylacetate (450 ml ) and methanol (75mL) in a 1000 mL flask at ambient temperature, under stirring. The reaction mixture was stirred for 1 hour and put in an ice-water bath. Then, 10 % sodium bicarbonate solution ( 250 ml) was dropped into the solution slowly. After stirring for another 1 hour in the ice-water bath. The resulting mixture was allowed to settle and aqueous layer was separated and extracted with Di-isopropylacetate. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to produce d as a crude product of dark brown oil (180 g, >100%). The product was confirmed by 1H NMR.

Step II : Preparation of a-(N-methyl-N-benzylamino)-3-hydroxy acetophenone hydrochloride

To the solution of 2-Chloro-1-(3-hydroxyphenyl) ethan-1-one (180 g) obtained in from above step in isopropyl alcohol (700 mL) in the same reactor, Na2CO3 (212 gm, 2 mole) was successively dropped, then the CH3NHBn (115.4 mg, 1.25 mole) was dropped into the solution. The reaction mixture was stirred for 1 hour at room temperature and then warmed to 60 deg C. After the completion of reaction as seen by HPLC, the resulting mixture was filtered and the mother liquor was treated with HCl gas dissolved in isopropyl alcohol. The acidic mixture was heated up to 40 ~ 45?, then the temperature was kept for 2 hours, and cooled to the temperature of 0?. The product was precipitated as a white solid, after recrystallization in acetone obtained the pure product, (230 g, 79 %).

Example 2

Step I – Preparation of 2-Chloro-1-(3-hydroxyphenyl) ethan-1-one

Sulfuryl chloride (134.97 g, 1.0 mole) was slowly dropped into a solution of 3-hydroxyacetophenone (136.14 g, 1.0 mole) in Toluene ( 500 ml ) and methanol (100 mL) in a 1000 mL flask at ambient temperature, under stirring. The reaction mixture was stirred for 1 hour and put in an ice-water bath. Then, 10 % sodium bicarbonate solution (250 ml) was dropped into the solution slowly. After stirring for another 1 hour in the ice-water bath the resulting mixture was allowed to settle and aqueous layer was separated and extracted with Toluene. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to produce desired product as a crude product of dark brown oil (185 g, >100%).

Step II : Preparation of a-(N-methyl-N-benzylamino)-3-hydroxy acetophenone hydrochloride

To the solution of 2-Chloro-1-(3-hydroxyphenyl) ethan-1-one (180 g) in toluene (700 mL), Na2CO3 (212 gm, 2 mole) was successively dropped, then the CH3NHBn (115.4 mg, 1.25 mole) was dropped into the solution. The reaction mixture was stirred for 1 hour at room temperature and then warmed to 60 Deg C. After the completion of reaction as seen by HPLC, the resulting mixture was filtered and the mother liquor was treated with 35 % HCl solution. The acidic mixture was heated up to 40 ~ 45?, then the temperature was kept for 2 hours, and cooled to the temperature of 0?. The product was precipitated as a white solid, after recrystallization in acetone obtained the pure product, (240 g, 82.4 %).

1H-NMR spectrum appended below confirms the structure.
,CLAIMS:WE CLAIM:

1. A one pot synthesis of a compound represented by Formula 1 comprising the steps of:
reacting a compound represented by Formula 2 with sulfuryl chloride in the presence of suitable solvent/solvent mixtures to yield an intermediate compound represented by Formula 3; reacting the said intermediate compound represented by Formula 3 with a compound of Formula 4 in the presence of suitable base and catalyst resulting into the compound of Formula 1.

2. The process as claimed in claim 1, wherein the compound of Formula 1 is:

3. The process as claimed in claim 1, wherein the compound of Formula 2 is:

4. The process as claimed in claim 1, wherein the compound of Formula 3 is:

5. The process as claimed in claim 1, wherein the compound of Formula 4 is:

5. The process as claimed in claim 1, wherein the suitable solvent/solvent mixtures, not being limited to, include C1 to C6 alcohol such as methanol, Isopropyl alcohol, butanol, n-hexanol, cyclohexanol, methylene chloride, dichloroethane etc. and partner solvents including aliphatic esters like ethyl acetate, di-isopropyl acetate, butyl acetate etc., chlorinated solvents like methylene chloride, dichloroethane and aromatic solvents like toluene, xylene etc.

6. The process as claimed in claim 1, wherein the suitable bases, not being limited to, include sodium carbonate, potassium carbonate, magnesium carbonate, calcium carbonate, barium carbonate and other alkali and alkaline earth metal carbonates.

7. The process as claimed in claim 1, wherein the suitable catalysts, not being limited to, include tetra butyl ammonium bromide, benzyl triethylmonium chloride etc.

Dated this 26th day of April, 2016.