FORM 2
THE PATENTS ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
"A PROCESS FOR THE PREPARATION OF AMBROXOL"
2. APPLICANT:
(a) NAME: AMI LIFESCIENCES PVT. LTD.
(b) NATIONALITY: Indian
(c) ADDRESS: 2nd Floor, Prestige Plaza, 40, Urmi Society, Urmi Char Rasta,
Productivity Road, Baroda-390 020, Gujarat, India.
3. PREAMBLE TO THE DESCRIPTION:
The following specification describes the invention and the manner in which it is to be performed.

FIELD OF THE INVENTION:
The present invention relates to an improved and economic process for preparing Ambroxol and its hydrochloride salt with high yield and purity.
BACKGROUND OF THE INVENTION:
Ambroxol is a secretolytic agent used in the treatment of respiratory diseases associated with viscid or excessive mucus. Ambroxol acts as a mucoactive drug with several properties including secretolytic and secretomotoric actions that restore the physiological clearance mechanisms of the respiratory tract, which play an important role in the body's natural defence mechanisms.
Chemically, Ambroxol is known as trans-4-(2-Amino-3,5-dibromobenzylamino)-cyclohexanol of formula (I).

A number of processes are known in the literature for preparing Ambroxol and its salts. US patent no. 3536713 and GB1420976 disclose preparation of Ambroxol by the bromination of N-(trans-p-hydroxy-cyclohexyl)-2-(2-amino-benzyl)-amine as depicted in Scheme-1. However, the yield of bromination is very low.

EP130224 discloses preparation of Ambroxol from Methyl anthranilate via bromination, hydrazinolysis, mesylation, condensation with cyclohexanolamine, and Schiff base reduction steps as depicted in Scheme-2. The process is tedious, involves number of reaction steps and hence, the overall yield is low.


Scheme-2
ES526526 discloses preparation of Ambroxol using reaction of 2,4-dibromo-6-(chloromethyl)benzenamine with O-protected trans-4-hydroxy cyclohexylamine and subsequent deprotection. The 2,4-dibromo-6-(chloromethyl)benzenamine is prepared from Methyl anthranilate via bromination and reduction with L1AIH4 followed by reaction with thionyl chloride. The process involves use of hazardous reactants viz. LiAlH4and thionyl chloride. Further, synthesis of commercially unavailable O-protected trans-4-hydroxy cyclohexylamine raw material adds to the process steps making the process cumbersome and non-feasible at commercial scale. The synthetic route is depicted in Scheme-3.


ES544291 describes preparation of Ambroxol from 2-nitrobenzoic acid by the amide formation with trans-4-hydroxy cyclohexylamine in presence of DCC to give 2-amino-3,5-dibromo-N-(trans-4-hydroxycyclohexyl)benzamide followed by reduction with LiAIH4 and subsequent bromination. ES549316 discloses preparation of Ambroxol starting from reaction of 3,5-dibromo-anthranoyl chloride with 4-aminocyclohexanol (1:2, cis/trans) to give mixture of cis- and trans-amide. The obtained mixture of cis- and trans-amide is recrystallized from chloroform to give 62% of trans-amide which accounts in lowering of the overall yield. The synthetic route is depicted in Scheme-4.


CN101337897 discloses use of sodium borohydride in presence of transition metal salts such as TiCl4 for the efficient reduction of 2-amino-3,5-dibrorno-N-(trans-4-hydroxycyclohexyl)benzamide as depicted in Scheme-5.

CN102050748 provides a one-pot process for the prepn. of Ambroxol, which comprises reaction of 2-nitrobenzaldehyde with trans 4-aminocyclohexanol to obtain Schiff base, followed by hydrogenation of the double bond in the presence of transition metal catalyst and subsequent reduction of the nitro group. CN102351720 describes process for the preparation of ambroxol from 2-nitrobenzaldehyde via reduction with Fe/HCl to obtain 2-aminobenzaldehyde, followed by bromination with bromine, condensation with trans-4-aminocyclohexanol, and reduction with sodium borohydride as depicted in Scheme-6. The processes involve use of expensive 2-nitrobenzaldehyde as raw material.


Also, number of approaches for the synthesis of Ambroxol is known in the art employing 2-aminobenzaldehyde or its derivatives as a starting material. CA1003441 describes preparation of Ambroxol comprising formation of imine intermediate from 2-Aminobenzaldehyde and trans-4-aminocyclohexanol, which is reduced to Ambroxol. The process uses benzene for the imine formation reaction. Benzene being a class-I solvent is not suitable for reaction from a regulatory compliance point of view.
CA996109 discloses reductive animation reaction of 2-Aminobenzaldehyde and trans-4-aminocyclohexanol in presence of formic acid. The process involves reaction at higher temperature and the water formed during the reaction has to be distilled out continuously.
A cursory review of the above literature reveals that there are many disadvantages involved in adopting the methods known in the art viz.,
1) Use of expensive raw materials viz. 2-Nitrobenzaldehyde, 2-Nitrobenzoic acid or
2-Aminobenzaldehyde
2) Use of expensive and/or corrosive reagents viz. SOCl2, p-TSA, TiCl4 etc.
3) Use of LiAIH4 as a reducing agent is hazardous and LiAIH4 is very expensive as
compared to other reducing agents such as NaBH4. Handling of LiAIH4 in bulk at
plant level is not safe and quenching LiAIH4 can lead to large volumes of pasty
aluminate solids that present serious filtration issues.

4) Lengthy and tedious reaction procedures.
5) Lower yield.
6) Higher Impurity levels.
In view of the above, there is a need in the art to provide an efficient and cost-effective process for preparation of Ambroxol. Therefore, the objective of the instant invention is to provide an efficient and economic process for preparation of Ambroxol which is devoid of hazardous and expensive corrosive agents that can be industrially scalable.
SUMMARY OF THE INVENTION:
In accordance with the above, the invention provides a process for preparation of Ambroxol which comprises:
a. Reducing 3,5-Dibromomethyl anthranilate with sodium borohydride in presence
of methanol in a suitable solvent to obtain 3,5-Dibromo-2-aminobenzyl alcohol;
b. Oxidizing the 3,5-Dibromo-2-aminobenzyl alcohol with manganese dioxide in an
inert hydrocarbon solvent to obtain 3,5-Dibromo-2-aminobenzaldehyde;
c. Reacting 3,5-Dibromo-2-aminobenzaldehyde with Trans-4-aminocyclohexanol in
an inert hydrocarbon solvent to obtain Trans-4-(2-amino-3,5-
dibromobenzylideneamino)cycIohexanol and
d. Reducing Trans-4-(2-amino-3,5-dibromobenzylideneamino)cyclohexanol with
sodium borohydride to obtain Ambroxol.
In another aspect, the Ambroxol obtained according to the invention is converted into its hydrochloride salt by treating with a source of HC1. The source of HC1 according to the invention is IPA- HCl.
In another embodiment, the invention provides efficient reduction of ester (II) to alcohol (III) with higher yield and purity using NaBH4 as a reducing agent in presence of methanol in an ether solvent.
In another embodiment, the invention provides efficient reduction of ester (II) to alcohol (III) with higher yield and purity using NaBH4 as a reducing agent in presence of methanol in THF.

In another embodiment, the invention provides an improved and efficient conversion of alcohol (III) to aldehyde (IV) using manganese dioxide in an inert hydrocarbon solvent such as toluene.
In another embodiment, the invention provides an improved process for the preparation of Ambroxol with an overall yield of 78-80%.
In yet another embodiment, the invention provides Ambroxol and its hydrochloride salt having a purity of more than 99.9%.
In still another embodiment, the invention provides Ambroxol and its hydrochloride salt having impurity content below 0.1% as per specified regulatory limit.
The reaction process for preparation of Ambroxol hydrochloride is depicted in Scheme 7.
DETAILED DESCRIPTION OF THE INVENTION:
The invention will now be described in detail in connection with certain embodiments, so that various aspects thereof may be more fully understood and appreciated. However, any skilled person will appreciate the extent to which such embodiments could be extrapolated in practice.
Accordingly, in one embodiment, 3,5-Dibromo-2-aminobenzyl alcohol (III) is prepared by reducing 3,5-Dibromomethyl anthranilate (II), with sodium borohydride as cost-effective and non-hazardous reducing agent, in presence of methanol in an ether solvent. The suitable ethers include but not limited to, acyclic ethers such as diethyl ether or cyclic ethers such THF. In an embodiment, the reduction is carried out using NaBH4 in presence of methanol in THF. The use of NaBH4 as a reducing agent in presence of methanol in THF proceeds with efficient reduction of ester (II) to alcohol (III) smoothly and gives higher yield and purity.
The reaction mass was stirred at 40-45°C and methanol was added during the period of 8-10 h. The reaction was monitored by HPLC and upon completion of the reaction, the solvent was distilled out and purified water and 1 N HC1 solution were added to the reaction mass with stirring for 30-40 minutes and filtered to obtain 3,5-Dibromo-2-

aminobenzyl alcohol (III), which may be washed with purified water prior to subjecting to oxidation.
3,5-Dibromo-2-aminobenzyl alcohol (III) thus obtained was taken in an inert hydrocarbon solvent, toluene; manganese dioxide was added slowly and the reaction mass was heated at 75-85°C. The reaction was monitored by HPLC and upon completion of the reaction, the reaction mass was filtered and the filtrate was collected to obtain 3,5-Dibromo-2-aminobenzaldehyde (IV) with good yield and purity. Thus, in one aspect of the invention, the invention provides improved conversion of alcohol (III) to aldehyde (IV) using manganese dioxide in an inert hydrocarbon solvent such as toluene.
To the filtrate containing 3,5-Dibromo-2-aminobenzaldehyde (IV) obtained in the preceding step, Trans-4-aminocyclohexanol was added and the reaction mass was heated at 85-110°C with stirring. The reaction was monitored by HPLC and upon completion of the reaction, the reaction mass was cooled, filtered and washed with water to obtain Trans-4-(2-amino-3,5-dibromobenzylideneamino)cyclohexanol (V).
Trans-4-(2-amino-3,5-dibromobenzylideneamino)cyclohexanol (V) thus obtained was charged in methanol. The reaction mass was cooled to 15-20°C and sodium borohydride was added in small portions during 3 to 4 hrs with continuous stirring. The reaction mass was stirred at 40-45°C. The reaction was monitored by HPLC. Upon completion of the reaction, methanol was distilled out and the reaction mass was cooled, filtered, washed with water, and vacuum dried to obtain Ambroxol.
In another aspect, the invention provides a process for preparation of Ambroxol Hydrochloride, wherein Ambroxol is dissolved in isopropyl alcohol, followed by addition of hydrochloric acid in small portions with continuous stirring during 20-30 minutes. The reaction mass was stirred at 40-45°C for 40-45 minutes. The reaction mass was cooled, filtered, washed with isopropyl alcohol, and the precipitate was vacuum dried to obtain Ambroxol Hydrochloride.
The process steps as detailed above are shown in scheme 7 as depicted below.


Examples:
Some typical examples illustrating the embodiments of the present invention are provided; however, these are exemplary only and should not be regarded as limitations of the present invention.
Example-1
Preparation of 3,5-Dibromomethyl anthranilate
To a 500 mL round bottomed flask equipped with mechanical stirrer, Methyl anthranilate (50.0 g) was dissolved in methanol (150 mL). The solution was cooled, bromine (60 g) was added slowly during the period of I hour with continuous stirring. To this reaction mixture, hydrogen peroxide (20 g) was added slowly and stirring was continued. The

reaction was monitored by HPLC. Upon completion of the reaction, the solvent was distilled out. Ammonia gas was purged into the reaction mass and the solid obtained was filtered. The obtained 3,5-Dibromomethyl anthranilate was washed with methanol. Yield: 97.5% Purity. 99.9% (By HPLC)
Example-2
Preparation of 3,5-Dibromo-2-aminobenzyl alcohol
To a 500 mL round bottomed flask equipped with mechanical stirrer, 3,5-Dibromomethyl
anthranilate (50.0 g) was dissolved in THF (70 mL). To this solution, sodium borohydride
(8.2 g) was added in small portions during the period of 10 minutes. The reaction mass
was stirred at 40-45°C and methanol (10 mL) was added during the period of 8-10 h. The
reaction was monitored by HPLC. Upon completion of the reaction, the solvent was
distilled out. Purified water (200 mL) and 1 N HCl solution were added, reaction mass
was stirred for 30-40 minutes and filtered. The obtained 3,5-Dibromo-2-aminobenzyl
alcohol was washed with purified water.
Yield: 98%
Purity: 99.9% (By HPLC)
Example-3
Preparation of Ambroxol
To a 500 mL four-necked round bottomed flask equipped with mechanical stirrer, thermo pocket, reflux condenser and water bath, toluene (100 mL) and 3,5-Dibromo-2-aminobenzyl alcohol (45 g) were charged. To this reaction mixture, manganese dioxide (37 g) was added slowly. The reaction mass was heated at 75-85°C. The reaction was monitored by HPLC. Upon completion of the reaction, the reaction mass was filtered and the filtrate was collected.
The filtrate was transferred to a clean assembly and cooled to 30-40°C. Then, Trans-4-aminocyclohexanol (14.09 g) was added. The reaction mass was heated at 85-110°C with stirring. The reaction was monitored by HPLC. Upon completion of the reaction, the reaction mass was cooled, filtered and washed with water to give Trans-4-(2-amino-3,5-dibromobenzylideneamino)cyclohexanol.

To a four-necked round bottomed flask equipped with mechanical stirrer, thermo pocket,
reflux condenser and water bath, Trans-4-(2-amino-3,5-
dibromobenzylideneamino)cyclohexanol obtained as shown above was charged with 150 mL methanol. The reaction mass was cooled to 15-20°C and sodium borohydride (5.3 g) was added in small portions during 3-4 h with continuous stirring. The reaction mass was stirred at 40-45°C. The reaction was monitored by HPLC. Upon completion of the reaction, methanol was distilled out. The reaction mass was cooled, filtered, washed with water, and vacuum dried to obtain Ambroxol. Yield: 80% Purity: 99.9% (By HPLC)
Example-4
Preparation of Ambroxol Hydrochloride
To a four-necked round bottomed flask equipped with mechanical stirrer, thermo pocket,
reflux condenser and water bath, Ambroxol (50 g) in isopropyl alcohol (120 mL) was
charged. To this solution, hydrochloric acid (12 g) was added in small portions with
continuous stirring during 20-30 minutes. The reaction mass was stirred at 40-45°C for
40-45 minutes. The reaction mass was cooled, filtered, washed with isopropyl alcohol,
and vacuum dried to obtain Ambroxol Hydrochloride.
Yield: 98.5%
Purity: 99.9% (By HPLC)
Industrial advantages of the present invention:
1) Use of cheap and easily available Methyl anthranilate (I) as a starting raw material.
2) Use of NaBH4 as cost-effective and non-hazardous reducing agent as compared to other agents such as LiAIH4.
3) Use of NaBH4/MeOH/THF system for efficient reduction of ester (II) to alcohol (III) giving 98% yield and higher purity of 99.9%.

3) Avoids use of hazardous reactants such as SOCl2, LiAlH4.
4) Efficient conversion of alcohol (III) to aldehyde (IV) using manganese dioxide in toluene.
5) Higher overall yield (78-80%) and purity (99.9%).
6) Formation of pharmacopial impurities below 0.1% as per specified regulatory limit.

We claim,
1. A process for preparation of Ambroxol comprising:
a. reducing 3,5-Dibromomethyl anthranilate with sodium borohydride in
presence of methanol in a suitable solvent to obtain 3,5-Dibromo-2-
aminobenzyl alcohol;
b. oxidizing 3,5-Dibromo-2-aminobenzyl alcohol with manganese dioxide in an
inert hydrocarbon solvent to obtain 3,5-Dibromo-2-aminobenzaldehyde;
c. reacting 3,5-Dibromo-2-aminobenzaldehyde with Trans-4-aminocyclohexanoI
in an inert hydrocarbon solvent to obtain Trans-4-(2-amino-3,5-
dibromobenzylideneamino)cyclohexanol and
d. reducing Trans-4-(2-amino-3,5-dibrornobenzylidenearnino) cyclohexanol with
sodium borohydride to obtain Ambroxol.
2. The process according to claim 1, wherein, the solvent used in preparation of 3,5-Dibromo-2-aminobenzyl alcohol is acyclic or cyclic ether.
3. The process according to claim 2, wherein, the solvent used in preparation of 3,5-Dibromo-2-aminobenzyl alcohol isTHF.
4. The process according to claim 1, wherein, the reduction of 3,5-Dibromomethyl anthranilate is carried out at a temperature of 40-45°C.
5. The process according to claim 1, wherein, the inert hydrocarbon solvent used is toluene.
6. The process according to claim 1, wherein, the oxidation of 3,5-Dibromo-2-aminobenzyl alcohol is carried out at a temperature of 75-85°C.
7. The process according to claim 1, wherein, the reaction of 3,5-Dibromo-2-aminobenzaldehyde with Trans-4-aminocyclohexanol is carried out at a temperature of 85- 110°C.

8. The process according to claim 1, wherein, the reduction of Trans-4-(2-amino-3,5-dibromobenzylideneamino)cyclohexanol is carried out at a temperature of 40-45°C.
9. The process according to claim 1, wherein, the Ambroxol is optionally converted into Ambroxol hydrochloride salt by treating Ambroxol with 1PA-HC1 at a temperature of 40-45°C.
10. The process according to claim 1, wherein, the process for the reduction of 3,5-dibromomethyl anthranilate to 3,5-Dibromo-2-aminobenzyl alcohol comprises the steps of:
a. treating a solution of 3,5-dibromomethyl anthranilate in THF with sodium
borohydride;
b. adding methanol to the reaction mixture portion wise and stirring the reaction
mixture at a temperature of 40-45°C;
c. adding hydrochloric acid solution to the reaction mixture and
d. isolating the obtained 3,5-Dibromo-2-aminobenzyl alcohol.