Title of Invention

AN IMPROVED PROCESS FOR MANUFACTURE OF 2-AMINO-3,5-DIBROMO-N-CYCLOHEXYL-N-METHYLBENZENEMETHANAMINE HYDROCHLORIDE (BROMHEXINE HYDROCHLORIDE)

Abstract Disclosed herein is a process for preparation of Bromhexine Hydrochloride which comprises bromination of o-nitro toluene and subsequent alkylation of o-nitrobenzyl bromide using N-methyl cyclohexylamine to from N-(2-nitrobenzyl)-N-methylcyclohexyl amine; reduction of N-(2-aminobenzyl)-N-methylcyclohexylamine followed by bromination to obtain Bromhexine and isolated as Bromhexine Hydrochloride salt.
Full Text FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION (See section 10 and rulel3) 1. TITLE OF THE INVENTION:
"An improved process for manufacture of 2-amino-3,5-dibromo-N-cyclohexyl-N-methylbenzenemethanamine Hydrochloride (Bromhexine Hydrochloride)"
2. APPLICANT (S)
(a) NAME: FDC Ltd.
(b)NATIONALITY: Indian company incorporated under the Companies
Act 1956
(c) ADDRESS: 142-48, S.V. Road, Jogeshwari (West) Mumbai - 400 102, Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed.

Field of invention:
The present invention pertains to an improved process for manufacture of 2-amino-3,5-dibromo-N-cyclohexyl-N-methylbenzenemethanamine Hydrochloride (Bromhexine Hydrochloride) of formula I.
Br H3C , v
Br NH2 HCI
(Formula -I)
Bromhexine Hydrochloride is used in the treatment of suppressing coughs, and producing secretion in warm-blooded animals. The compound efficiently detaches and removes mucus from the respiratory tract and has, therefore, gained wide use in the preparation of anti-tussive medicines.
Discussion of related art:
DE 1169939 describes preparation of Bromhexine Hydrochloride by bromination of N-(2-aminobenzyl)camphidine in an organic solvent, preferably in halogenated hydrocarbon or glacial acetic acid. Also described an alternative method, which comprises, reduction of N-(2 or 4-nitrobenzyl-3,5-dihalobenzyl)camphidine by catalytic reduction with hydrogen in presence of precious metal catalyst such as Palladium and Platinum or by reduction with hydrazine hydrate and Raney Nickel in an organic solvent. Further, the amine derivative was transformed by known methods into their pharmaceutically accepted salts.
US Patent 3336308 teaches the preparation of Bromhexine Hydrochloride by reaction of bromination of amino-benzylamine derivatives. The Hydrochloride or Hydrobromide salts of amino-benzylamine derivatives were isolated and purified by crystallization. In an alternative method, which describes the reaction of 3,5-dihalo-diacetylamino-benzyl) halide in an organic solvent with an amine to obtain 3,5-dihalo diacetyl amino benzyl
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amine, followed by its deacylation to obtain N-(2-amino 3,5-dihalo benzyl) amine. More importantly, it narrates reduction of halo-nitro- benzylamines with noble metal catalyst or Raney Nickel hydrazine hydrate procedure. It also narrates reduction by iron, zinc or tin and mineral acid.
DE 2412119 narrates preparation of Bromhexine Hydrochloride by reaction of 2-aminobenzyl alcohol derivatives with N-methylcyclohexylamine. The free base is converted into its acid addition salt.
DE 2365624 describes preparation of Bromhexine Hydrochloride by condensation of 2-acetylamino-5-halobenzyl alcohol with N-alkylcyclohexyl amine. The resultant amides were deacylated and treated with acid to form acid addition salts.
DE 2443712 describes procedure for production of Bromhexine Hydrochloride from 2,4-dibromo-6-[(N-methyl-N-cyclohexyl)aminomethyl] benzoic acid which reacts with hydrozoic acid (HN3) in presence of strong acid, whereby the group carboxylic is converted into an amino group in an organic solvent like chloroform at 35°-100°C and isolated as its acid addition salt. The invention also relates to a process for the preparation of Benzylamine derivatives and acid salts thereof by reacting aminobenzyl halide with amine derivatives. Also process of aminating reactive derivative of the benzyl alcohol to benzylamine derivatives is narrated.
US 4191780 describe manufacture of Bromhexine derivatives, in particular Glycol, Glycolic acid derivatives.
DE 2633518 teaches the preparation of Bromhexine Hydrochloride using 3-bromo-2-nitrobenzyl bromide as a starting substance and is reacted with N-methylcyclohexylamine in the presence of an acid acceptor. The nitro group of the resultant N-cyclohexyl-N-methyl-2-nitro-3-bromobenzylamine is then reduced and the resulting N-cyclohexyl-N-methyl-2-amino-3-bromobenzylamine is brominated. The compound has excellent bronchosecretolytic action.
The prior art process employ essentially o-Nitrobenzyl bromide, traditionally prepared by procedure involving bromination using N-bromo succinimide as brominating agent and
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benzoyl peroxide as radical initiator in Carbon Tetrachloride as solvent of choice. (Ref. JOC, 1954,19,1571).
It is now a known fact that Carbon Tetrachloride is a carcinogenic solvent and more importantly has been classified as ozone depleting substance class-I (ODS). This fact warrants for suitable substitution of Carbon Tetrachloride.
The reduction procedure employed in most of the prior art patents and publications involves use of costly noble metal catalysts of palladium and platinum. These catalysts are expensive and hence, not economically viable. Some of the patents also narrate use of iron, zinc or tin hydrochloride as reagent of choice, for reduction of nitro groups. The use of these reagents leads to formation of huge amount of sludge, thus increasing environmental load of effluent. The prior art processes are thus difficult to carry out, industrially hazardous and have lead to huge amount of industrial waste.
Objects of the invention:
a) The object of the invention is to provide an efficient green process for preparation of 2-amino - 3,5 - dibromo - N - cyclohexyl - N - methylbenzenemethanamine Hydrochloride (Bromhexine Hydrochloride), which eliminates formation of hazardous waste, gives high yields and is efficient and economical.
b) Another object of the invention is to provide a process for preparation of 2-amino-3,5-dibromo- N - cyclohexyl - N - methylbenzenemethanamine Hydrochloride (Bromhexine Hydrochloride), which employs less number of reaction steps and is less time consuming, easy and convenient to carry out.
c) Another object of the invention is to provide a process for preparation of 2-amino-3,5-dibromo-N-cyclohexyl-N-methylbenzenemethanamine Hydrochloride (Bromhexine Hydrochloride), which employs cheaper and easily available
raw materials.
d) Another objective of the invention is to provide a process for preparation of 2-
amino-3,5 -dibromo-N-cyclohexyl-N-methylbenzenemethanamine Hydrochloride
(Bromhexine Hydrochloride), wherein the solvent and catalyst employed in
reduction process are routinely recycled and reused.
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e) Another objective of the invention is to provide a process for the preparation of 2-amino-3,5-dibromo-N-cyclohexyl-N-methylbenzenemethanamine Hydrochloride (Bromhexine Hydrochloride), which is suitable for industrial scale-up. The present invention thus offers the advantage of developing an efficient and green synthesis of Bromhexine Hydrochloride. It further provides an environmental advantage in that chemical waste is substantially reduced.
f) An other objective of the invention is to provide a process for the 2-amino-3, 5-dibromo-N-cyclohexyl-N-methylbenzenemethanamine Hydrochloride (Bromhexine Hydrochloride), wherein the brominating agent for o-Nitrotoluene is 3,5-dibromodimethylhydantoin using Azoisobutyronitrile (AIBN) as radical initiator in a suitable solvent which can be routinely recovered and recycled.
Summary of the Invention:
The present invention discloses a process for preparation of 2-amino-3,5-dibromo-N-cyclohexyl-N-methylbenzenemethanamine Hydrochloride (Bromhexine Hydrochloride) of formula I, wherein said process comprises the following steps of:
a) brominating o-nitro toluene using 3,5-dibromo dimethyl hydantoin in an organic solvent and subsequent alkylation of the o-nitro benzylbromide using N-methyl cyclohexylamine at 20°-100°C to form N-(2-nitrobenzyl)-N-methylcyclohexyl amine of formula-II;
b) reducing the compound of formula II with Raney Nickel in an organic solvent at 20° - 70°C and 5.0 - 55.0 psi gauge pressure to form N-(2-aminobenzyl)-N-methylcyclohexylamine of formula-Ill;
c) brominating the compound of formula III using Bromine in an organic solvent to yield Bromhexine and isolating the Bromhexine as its Hydrochloride salt.
Detailed description of invention:
Making Active Pharmaceutical Ingredients (APIs) requires long chain of chemical reactions and a large quantity of solvent, in order to achieve overall process efficiency. It is mandatory to involve reactions, which are more efficient, and more environment friendly. Pharmaceutical companies do produce huge amounts of hazardous waste, per year. Green manufacturing programmes, undertaken in many industries, center around efficient waste management and making the entire process green from the start.
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According to the invention, there is provided a process for preparation of 2-amino-3, 5-dibromo-N-cyclohexyl-N-methylbenzenemethanamine Hydrochloride (Bromhexine Hydrochloride), of formula-I, comprising sequential bromination and alkylation of o-Nitrotoluene. o-Nitrotoluene is brominated using 3,5-dibromo dimethyl hydantoin in an organic solvent, followed by alkylation with N-methyl cyclohexylamine at 20°-100°C to form N-(2-nitrobenzyl)-N-methylcyclohexyl amine of formula-II. The organic solvent used in bromination and subsequent alkylation may be selected from monochlorobenzene, dichlorobenzene, trichlorobenzene, ethylene chloride, or combination thereof, preferably monochlorobenzene.

The compound of formula-II is then reduced with noble metal catalyst in an organic solvent at 20° - 70°C and 5.0 - 55.0 psi gauge pressure to form N-(2-aminobenzyl)-N-methylcyclohexylamine of formula-Ill. The noble metal catalyst used for hydrogenation may be selected from Raney Nickel, Palladium, Platinum or Platinum Oxide, more preferably Raney Nickel. The organic solvent used in hydrogenation of compound of formula-II may be selected from methanol, ethanol, tetrahydrofuran, acetic acid, or combination thereof, preferably methanol or ethanol, or methanol-ethanol mixture. Preferably, hydrogenation is carried out at 20° - 70°C and 25 - 50 psi gauge pressure.

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The compound of formula-Ill is further brominated using liquid bromine in an organic solvent to yield Bromhexine, which is isolated as its hydrochloric salt. The organic solvent used in bromination of compound of formula-Ill, may be selected from methanol, ethanol or acetic acid, or combination thereof, preferably methanol or ethanol or methanol-ethanol mixture.
The process of the invention eliminates formation of by-products and gives high yield of the product. It employs cheaper and easily available raw materials and eliminates use of hazardous reagents. It is, therefore, efficient, economical and safe to carry out. It comprises of only three steps and is, therefore, less time consuming and is easy and convenient to carry out. For the above reasons, it is also suitable for industrial scale-up. The following examples are illustrative of the invention, but not limitative of the scope thereof.
Examples:
Example 1:
Preparation of N-(2-nitrobenzyl)-N-methyl cyclohexylamine :
315.0 Kg o-Nitrotoluene was mixed with 1000 Lit Monochlorobenzene. To this mixture 275.0 Kg 3,5- Dibromo dimethylhydantoin & 26.0 Kg Azoisobutyronitrile (AIBN) was charged. The reaction mixture was digested for 10 hr at 60°C. After cooling, sodium carbonate solution (10%) charged to adjust pH 9.5. 175.0 Kg N-methylcyclohexylamine was added to the reaction mixture and the reaction mixture was digested for 8 hr at 85°C. Organic and aqueous layers were separated. Organic layer was charged with dilute hydrochloric acid solution. Monocholorobenzene layer was separated after complete formation of hydrochloride salt of the product. The aqueous acidic layer was then basified with caustic lye to yield 350.0 Kg of N-(2-nitrobenzyl)-N-methylcyclohexylamine of formula II. Organic layer was steam distilled to recover Monochlorobenzene, which is recycled in next batch.
Example 2:
Preparation of N-(2-amino-3,5-dibromobenzyl)-N-methylcyclohexylamine
Hydrobromide:
2.0 Kg Raney Nickel catalyst was added to solution of 70.0 Kg N-(2-nitrobenzyl)-N-methylcyclohexylamine (II) in 380.0 Lit Methanol or Ethanol. Reaction mass was purged
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with hydrogen at 5.0-50.0 psi gauge pressure at 70°C. After exothermic reaction, the reaction mass was allowed to settle for 30-45 mins. Raney Nickel catalyst settled in hydrogenator was recycled for three consecutive batches and clear reaction mass was every time siphoned from top. 340.0 Kg Liquid Bromine was added slowly to the filtered reaction mass. Resulting reaction mass was digested for 3 hr and filtered to yield 310.0Kg N-(2-amino-3,5-dibromobenzyl)-N-methylcyclohexylamineHydrobromide.
Example 3:
Preparation of N-(2-amino-3,5-dibromobenzyl)-N-methylcyclohexylamine
Hydrochloride:
150.0 KgN- (2-amino-3,5-dibromobenzyl)-N-methylcyclohexylamine Hydrobromide
was dissolved in 400.0 Lit Toluene and was neutralized with sodium carbonate solution
(10%) to pH 9.5. Organic and aqueous layers were separated. N- (2-amino-3,5-
dibromobenzyl)-N-methylcyclohexylamine was liberated as free base in Toluene.
Organic layer was concentrated under vacuum to yield residue which was dissolved in
1200.0 Lit Ethanol. 60.0 Lit HC1 was added to yield 105.0 Kg N -(2-amino-3,5-
dibromobenzyl)-N-methylcyclohexylamine Hydrochloride.
It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative examples and that the present invention may be embodied in other specific forms without departing from the essential attributes thereof, and it is therefore desired that the present embodiments and examples be considered in all respects as illustrative and not restrictive, reference being made to the appended claims, rather than to the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.
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We claim,
A process for preparation of 2-amino-3,5-dibromo-N-cyclohexyl-N-
methylbenzenemethanamine Hydrochloride (Bromhexine Hydrochloride) of
formula-I comprising the steps of:
Br H3C

Formula I a) brominating o-nitro toluene using 3,5-dibromo dimethyl hydantoin in an organic solvent and subsequent alkylation of the o-nitrobenzyl bromide using N-methyl cyclohexylamine at 20°-100°C to form N-(2-nitrobenzyl)-N-methylcyclohexyl amine of formula-II;
H3C

N02
Formula II b) reducing the compound of formula II with a hydrogenation catalyst in an organic solvent at 20° - 70°C and 5.0 - 55.0 psi gauge pressure to form N-(2-aminobenzyl)-N-methylcyclohexylamine of formula-Ill;
H3C

Formula III c) brominating the compound of formula III using bromine in an organic solvent to yield Bromhexine and isolating the Bromhexine as its Hydrochloride salt.
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2. The process, as claimed in claim 1, wherein the solvent used in step a) and step b) is selected from monochlorobenzene, dichlorobenzene, trichlorobenzene, ethylene chloride, or combination thereof, preferably monochlorobenzene.
3. The process, as claimed in claim 1, wherein the hydrogenation catalyst is selected from Raney Nickel, Palladium, Platinum or Platinum Oxide, more preferably Raney Nickel.
4. The process, as claimed in claims 1 and 3, wherein the hydrogenation catalyst, Raney nickel, is recycled and reused for minimum three times.
5. The process, as claimed in claim 1, wherein step b) is carried out at 20° - 70°C and 25.0 - 50.0 psi gauge pressure.
6. The process as claimed in claim 1, wherein the solvent used for hydrogenation reaction of formula II is selected from methanol, ethanol, tetrahydrofuran, acetic acid, or combination thereof, preferably methanol or ethanol or mixture thereof.
7. The process, as claimed in claim 1, wherein the solvent used for the bromination of compound of formula III is selected from methanol, ethanol and acetic Acid, or combination thereof, preferably methanol or ethanol or mixture thereof.
8. The process, as claimed in claim 1, wherein the bromination of the compound of formula III is carried out using liquid bromine.
9. The process for preparation of 2-amino-3,5-dibromo-N-cyclohexyl-N-methylbenzenemethanamine Hydrochloride (Bromhexine Hydrochloride) of formula-I as substantially described herein with reference to the foregoing examples lto 3.
Dated this 22nd day of May 2006
Dr. Gopakumar G. Nair Agent for the Applicant
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ABSTRACT


Disclosed herein is a process for preparation of Bromhexine Hydrochloride which comprises bromination of o-nitro toluene and subsequent alkylation of o-nitrobenzyl bromide using N-methyl cyclohexylamine to form N-(2-nitrobenzyl)-N-methylcyclohexyl amine; reduction of N-(2-nitrobenzyl)-N-methylcyclohexyl amine with a hydrogenation catalyst to obtain N-(2-aminobenzyl)-N-methylcyclohexylamine followed by bromination to obtain Bromhexine and isolated as Bromhexine Hydrochloride salt.
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Documents:

770-MUM-2006-ABSTRACT 20-6-2008.pdf

770-mum-2006-abstract(granted)-(7-4-2010).pdf

770-mum-2006-abstract.doc

770-mum-2006-abstract.pdf

770-mum-2006-cancelled pages(15-2-2010).pdf

770-mum-2006-cancelled pages(20-6-2008).pdf

770-MUM-2006-CLAIMS 20-6-2008.pdf

770-MUM-2006-CLAIMS(AMENDED)-(15-2-2010).pdf

770-mum-2006-claims(granted)-(7-4-2010).pdf

770-mum-2006-claims.doc

770-mum-2006-claims.pdf

770-mum-2006-correspondance-received-ver-010606.pdf

770-mum-2006-correspondance-received-ver-040606.pdf

770-mum-2006-correspondance-received-ver-220506.pdf

770-MUM-2006-CORRESPONDENCE 20-6-2008.pdf

770-mum-2006-correspondence(22-3-2007).pdf

770-mum-2006-correspondence(ipo)-(8-4-2010).pdf

770-mum-2006-description (complete).pdf

770-MUM-2006-DESCRIPTION(COMPLETE) 20-6-2008.pdf

770-mum-2006-description(granted)-(7-4-2010).pdf

770-MUM-2006-FORM 1 20-6-2008.pdf

770-mum-2006-form 1(1-6-2006).pdf

770-mum-2006-form 1(22-5-2006).pdf

770-mum-2006-form 18(22-3-2007).pdf

770-mum-2006-form 2 20-6-2008.pdf

770-mum-2006-form 2(granted)-(7-4-2010).pdf

770-MUM-2006-FORM 2(TITLE PAGE) 20-6-2008.pdf

770-mum-2006-form 2(title page)-(granted)-(7-4-2010).pdf

770-mum-2006-form 26(22-5-2006).pdf

770-MUM-2006-FORM 3 20-6-2008.pdf

770-mum-2006-form-2.doc

770-mum-2006-form-2.pdf

770-mum-2006-form-9.pdf

770-mum-2006-marked copy(15-2-2010).pdf

770-MUM-2006-REPLY TO HEARING(15-2-2010).pdf


Patent Number 239903
Indian Patent Application Number 770/MUM/2006
PG Journal Number 15/2010
Publication Date 09-Apr-2010
Grant Date 07-Apr-2010
Date of Filing 22-May-2006
Name of Patentee FDC LIMITED
Applicant Address 142-48, S.V. ROAD, JOGESHWARI (W), MUMBAI.
Inventors:
# Inventor's Name Inventor's Address
1 JOSHI SHREERANG VIDHYADHAR 142-48, S.V. ROAD, JOGESHWARI (W), MUMBAI 400102.
2 KHARAT AVINASH ANANDRAO 142-48, S.V. ROAD, JOGESHWARI (W), MUMBAI 400102.
3 CHINDARKAR SUNIL SUBHASHCHANDRA 142-48, S.V. ROAD, JOGESHWARI (W), MUMBAI 400102.
4 BHORGAY DILIP BABURAO 142-48, S.V. ROAD, JOGESHWARI (W), MUMBAI 400102.
5 CHANDAVARKAR MOHAN ANAND 142-48, S.V. ROAD, JOGESHWARI (W), MUMBAI 400102.
PCT International Classification Number A61K9/00, C07D213/38
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA