IT201800002408A1 - PREPARATION OF AN ATYPIC ANTIDEPRESSANT - Google Patents

Description

Description of the patent for industrial invention entitled:

"PREPARATION OF AN ATYPIC ANTIDEPRESSANT"

FIELD OF THE INVENTION

The present invention relates to a new method of preparation of 1- (3-chlorophenyl) -2 - [(1,1-dimethylethyl) amino] -1-propanone (Bupropion) and its intermediates.

STATE OF THE TECHNIQUE

Bupropion, 1- (3-chlorophenyl) -2 - [(1,1-dimethylethyl) amino] -1-propanone of formula (I),

is an oral antidepressant of the aminoketone class developed by Glaxo Wellcome. Its hydrochloride salt of formula (Ia)

it was approved by the Food and Drug Administration (FDA) on December 30, 1985 and was then marketed under the name Wellbutrin®. Subsequently, it was discovered that bupropion is also particularly effective in smoking cessation therapy.

The compound is known from US 3,819,706 granted on June 25, 1974. US 3,819,706 also describes a process for obtaining bupropion comprising the bromination of 3-chloro-propiophenone of formula (II) and the subsequent conversion of 2-bromine-1- (3- chloro-phenyl) -propan-1-one of formula (III) thus obtained in bupropion with tert-butylamine:

Molecular bromine is widely used for the bromination of 3-chloro-propiophenone, but due to its reactivity it is not particularly selective and various impurities are formed during the reaction, including α-bis-bromopropiophenone. In addition, in addition to having a high cost per se, the use of molecular bromine requires high precautions and controls due to its direct danger, since bromine is caustic to the skin and lungs. Finally, it also presents problems related to the generation of stoichiometric quantities of gaseous hydrobromic acid during the process, which is why the use of appropriate abatement mechanisms is required.

CN 105 968 023 describes a bromination process of 3-chloro-propiophenone with hydrobromic acid in the presence of hydrogen peroxide as oxidant. Therefore CN 105 968 023 describes a process that allows to avoid the use of molecular bromine, however the procedures described in the Chinese application use acetonitrile or dichloromethane as solvents, which according to the ICH guidelines (ICH Harmonized Tripartite Guideline - Impurities: Guideline for Residual Solvents Q3C (R5)) are part of the class 2 solvents, i.e. they are toxic solvents that should be avoided. The Chinese application also includes a procedure that uses the less toxic acetone: however, it is generally known that hydrogen peroxide in acetone and in the presence of an acid easily leads to a highly explosive mixture and therefore a procedure that uses these conditions is absolutely inadvisable.

Another disadvantage of the processes described by CN 105 968 023 concerns the isolation of the product: the procedures with hydrogen peroxide lead to a reaction mixture, where the product must be separated by distillation. The inventors of the present invention by repeating this procedure have noticed that, in addition to the fact that the distillation requires a considerable energy consumption, the 2-bromo-1- (3-chloro-phenyl) -propan-1-one of formula (III) has a limited stability at high temperatures and during the distillation process undergoes partial degradation.

There is therefore the need to have an improved process for the preparation 2-bromo-1- (3-chloro-phenyl) -propan-1-one of formula (III), which overcomes all the disadvantages of the processes known in the art. and which can be easily used on an industrial scale in the synthesis of bupropion, in particular as its hydrochloride salt of formula (Ia).

Not only should this process not envisage the use of molecular bromine, but this new process should in particular envisage the use of efficient, economical and operationally simple reaction conditions in order to obtain 2-bromo-1- (3-chlorine -phenyl) -propan-1-one of formula (III) in an advantageous way, in particular on an industrial scale and in high yield and purity, without having to resort to a separation by distillation. In addition, this process should not use toxic organic solvents.

SUMMARY OF THE INVENTION

The object of the invention is a process for obtaining 2-bromo-1- (3-chloro-phenyl) -propan-1-one of formula (III), comprising the bromination of 3-chloro-propiophenone of formula (II) with hydrobromic acid or a salt thereof in the presence of sodium hypochlorite as an oxidant.

This procedure not only allows to avoid the use of molecular bromine, but allows to obtain 2-bromo-1- (3-chloro-phenyl) -propan-1-one of formula (III) without having to resort to a step of distillation, and therefore to obtain in safe conditions a product with a high degree of purity, so as to satisfy the regulatory requirements required for APIs.

DETAILED DESCRIPTION OF THE INVENTION

The invention provides, as a first object, a process for obtaining 2-bromo-1- (3-chloro-phenyl) -propan-1-one of formula (III)

comprising:

- the reaction of 3-chloro-propiophenone of formula (II)

with hydrobromic acid or a salt thereof in the presence of sodium hypochlorite.

Preferably the bromination of 3-chloro-propiophenone of formula (II) is carried out with hydrobromic acid in aqueous solution.

Preferably, the bromination of 3-chloro-propiophenone of formula (II) is carried out using sodium hypochlorite in aqueous solution.

The invention provides as a further preferred object a process for obtaining 2-bromo-1- (3-chloro-phenyl) -propan-1-one of formula (III)

comprising:

- the reaction of 3-chloro-propiophenone of formula (II)

with hydrobromic acid or a salt thereof in the presence of sodium hypochlorite in aqueous solution as oxidant;

- the formation of a biphasic reaction mixture; And

- the isolation of 2-bromo-1- (3-chloro-phenyl) -propan-1-one of formula (III) from the aqueous solution.

The invention provides as a further preferred object a process for obtaining 2-bromo-1- (3-chloro-phenyl) -propan-1-one of formula (III) as defined above without the use of organic solvents.

The invention provides as a further preferred object a process for obtaining 2-bromo-1- (3-chloro-phenyl) -propan-1-one of formula (III) as defined above without having to resort to a distillation step.

The term "comprising" also includes the terms "consistent" and "consisting essentially of".

The 3-chloro-propiophenone of formula (II) is a known compound and is commercially available.

The aqueous solution of hydrobromic acid can be a saturated solution (68.85% HBr in water (w / w) at room temperature) or more diluted. For example, the solution may be about 48% HBr in water (w / w).

Its salts, for example the alkaline earth or alkaline salts, for example sodium bromide, lithium bromide or potassium bromide, can be used as technical equivalents of hydrobromic acid.

The aqueous sodium hypochlorite solution used as an oxidant can be a solution at a concentration of up to about 30%, typically at a concentration between about 3% and about 25%. For example, the aqueous solution of sodium hypochlorite can have a concentration of about 10-25%, for example 12% or 15%, therefore concentrations at which hypochlorite is commonly used as a whitener and disinfectant.

Preferably, the reaction of 3-chloro-propiophenone of formula (II) with hydrobromic acid is carried out without the use of an organic solvent. In this case, 3-chloro-propiophenone of formula (II) can be simply suspended in aqueous solution of hydrobromic acid and sodium hypochlorite.

The reaction of 3-chloro-propiophenone of formula (II) with hydrobromic acid can be carried out at a temperature between about 0 ° C and the reflux temperature, preferably at a temperature between 0 ° C and 80 ° C. More preferably, the reaction can be carried out at temperatures equal to or lower than 60 ° C, for example at 5 ° C, 10 ° C, 20 ° C, 25 ° C, or at 50 ° C.

The bromination reaction can be advantageously carried out using from about 2 to about 1 moles of hydrobromic acid per mole of 3-chloropropiophenone of formula (II), preferably from about 1.5 to about 1.1 moles, more preferably about 1.3 moles.

The bromination reaction can be advantageously carried out using from about 2 to about 0.8 moles of sodium hypochlorite per mole of 3-chloro-propiophenone of formula (II), preferably from about 1.5 to about 0.8 moles, plus preferably between about 1.0 and 1.1 moles.

The reaction of 3-chloro-propiophenone of formula (II) with hydrobromic acid in the presence of sodium hypochlorite in aqueous solution leads to a biphasic mixture, which can possibly also be filtered on perlite. The aqueous phase is then discarded. The oily phase containing 2-bromo-1- (3-chloro-phenyl) -propan-1-one of formula (III) can be anhydrified by drying or by freezing at temperatures below 0 ° C, or it can be used in the next step as such.

Drying can be carried out by drying with a dehydrating agent, for example sodium sulfate (Na2SO4), magnesium sulfate (MgSO4), sodium carbonate (Na2CO3), potassium carbonate (K2CO3), soda flakes (NaOH) or anhydrous calcium chloride (CaCl2), preferably sodium sulfate (Na2SO4).

Operating under these conditions, the bromination reaction according to the present invention proceeds with a conversion with molar yields of 2-bromo-1- (3-chloro-phenyl) -propan-1-one of formula (III) greater than 90% , typically greater than / equal to 93%, and with a residue of 3-chloropropiophenone of formula (II) ≤ 5%.

The 2-bromo-1- (3-chloro-phenyl) -propan-1-one of formula (III) thus obtained can be converted into bupropion of formula (I), as defined above, by reaction with tert-butylamine, and if desired converted into a pharmaceutically acceptable salt thereof, in particular the hydrochloride salt of formula (Ia),

The reaction of 2-bromo-1- (3-chloro-phenyl) -propan-1-one of formula (III) with tert-butylamine can be carried out in a solvent, for example DMF, preferably at a temperature between about 10 ° C and 50 ° C, for example at about 30 ° C or at about 35 ° C.

The conversion of bupropion into a pharmaceutically acceptable salt thereof, in particular into the hydrochloride salt of formula (Ia), can be carried out in a solvent, for example in an alcohol.

The following example further illustrates the invention.

Example - Preparation of 2-bromo-1- (3-chloro-phenyl) -propan-1-one of formula (III)

100 g (0.593 moles) of 3-chloro-propiophenone and 90 mL of hydrobromic acid (48%, 0.80 moles) are loaded into a reactor and the suspension is stirred and brought to 20 ° C. Then 342 mL of sodium hypochlorite (12%, 0.610 moles) are dropped, maintaining the temperature below 30 ° C in 2-3 hours. The biphasic mixture is stirred at 20-25 ° C for 1 hour, then the end of the reaction occurs. At the end of the reaction, the stirring is stopped and the organic phase comprising 2-bromo-1- (3-chloro-phenyl) -propan-1-one of formula (III) is separated from the aqueous solution. <1> H-NMR (300 MHz, CDCl3) δ: 8.03-7.41 (4 H, m), 5.22 (1H, q), 1.93 (3H, d).

Claims (10)

CLAIMS 1. A process for obtaining 2-bromo-1- (3-chloro-phenyl) -propan-1-one of formula (III) comprising: - the reaction of 3-chloro-propiophenone of formula (II) with hydrobromic acid or a salt thereof in the presence of sodium hypochlorite. 2. A process according to claim 1, where the hydrobromic acid is in aqueous solution. 3. A process according to claims 1 or 2, where sodium hypochlorite is in aqueous solution. 4. A process according to claims 1-3, comprising: - the reaction of 3-chloro-propiophenone of formula (II) with hydrobromic acid or a salt thereof in the presence of sodium hypochlorite in aqueous solution as oxidant; - the formation of a biphasic reaction mixture; And - the isolation of 2-bromo-1- (3-chloro-phenyl) -propan-1-one of formula (III) from the aqueous solution. 5. A process according to claims 1-4, where the reaction of 3-chloro-propiophenone of formula (II) with hydrobromic acid is carried out without the use of organic solvents. 6. A process according to claims 1-5, wherein the reaction of 3-chloro-propiophenone of formula (II) with hydrobromic acid is carried out without having to resort to a distillation step. 7. A process according to claims 1-6, where the reaction of 3-chloro-propiophenone of formula (II) with hydrobromic acid is carried out at a temperature between about 0 ° C and the reflux temperature. 8. A process according to claims 1-7, wherein the reaction of 3-chloro-propiophenone of formula (II) with hydrobromic acid is carried out using from about 2 to about 1 mol of hydrobromic acid per mol of 3-chloropropiophenone of formula (II). 9. A process according to claims 1-8, wherein the reaction of 3-chloro-propiophenone of formula (II) with hydrobromic acid is carried out using from about 2 to about 0.8 moles of sodium hypochlorite per mole of 3- chloro-propiophenone of formula (II). 10. A process according to claims 1-9, where 2-bromo-1- (3-chloro-phenyl) -propan-1-one of formula (III) thus obtained is converted into bupropion of formula (I) by reaction with tert-butylamine, and if desired converted into a pharmaceutically acceptable salt thereof, in particular in the hydrochloride salt of formula (Ia),