CA1048061A - Process for the preparation of a therapeutically active dihalogenoaminobenzylamine - Google Patents
Process for the preparation of a therapeutically active dihalogenoaminobenzylamineInfo
- Publication number
- CA1048061A CA1048061A CA209,447A CA209447A CA1048061A CA 1048061 A CA1048061 A CA 1048061A CA 209447 A CA209447 A CA 209447A CA 1048061 A CA1048061 A CA 1048061A
- Authority
- CA
- Canada
- Prior art keywords
- acid
- methyl
- cyclohexyl
- dibromo
- amino
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
A B S T R A C T
A process for the preparation of N-cyclohexyl-N-methyl-(2-amino-3,5-dibromobenzyl)-amine which has the formula and acid addition salts thereof, comprising reacting 2,4-dibromo-6-[(N-methyl-N-cyclohexyl)-aminomethyl]-benzoic acid, which has the formula
A process for the preparation of N-cyclohexyl-N-methyl-(2-amino-3,5-dibromobenzyl)-amine which has the formula and acid addition salts thereof, comprising reacting 2,4-dibromo-6-[(N-methyl-N-cyclohexyl)-aminomethyl]-benzoic acid, which has the formula
Description
The present invention relates to a new process for preparing N-cyclohexyl-N-methyl-(2-amino-3,5-dibromobenzyl)-amine or bromhexine, which has the formula Br / CH3 ~ CH2-N ~ (I) Br NH2 and its acid addition salts, especially the hydrochloride.
Bromhexine is a bronchospasmodic agent, which has an extremely strong cough relieving effect, the dosage and toxicity being extremely low.
The preparation of bromhexine has earlier been described in for example the Finnish patents 40,631, 40,803, 40,804, and 41,9620 The present invention concerns a new process for the preparation of bromhexine, which completely differs from the methods described in the above mentioned patents. 2,4-dibromo-6-rN-methyl-N-cyclohexyl)-amino-methy ~-benzoic acid, which is a new agent and has the formula B ~ / CH3 ~ H2-N ~ (II) Br COOH
is used as one of the reactants which is reacted with hydrazoic acid (HN3) in the presence of a strong acid which changes the carboxyl group in the bromhexine to an amino group. This reaction has not before been applied to the preparation of a substance of this kind. The reaction succeeds unexpect-edly well (yield 40-60%) and it has to be considered as extremely surprising in view of the extreme steric hindrance of the carboxyl group even in good yields.
According to the present invention, there is provided a process for the preparation of N-cyclshexyl-N-methyl-(2-amino-3,5-dibromobenzyl)-amine which has the formula ~,i 1~4~6~
Br / CH3 ~ O ~--CH2-N
Br NH2 ~
and acid addition salts thereof, comprising reacting 2,4-dibromo-6- C(N-methyl-N-cyclohexyl)-aminomethyl] -benzoic acid, which has the formula Br /~H3 ~ 2 Br COOH ~
with hydrazoic acid (~N3) which reacts in statu nascendi by the addition of a salt of hydrazoic acid to a solution of an inert organic solvent, a strong acid and said 2,4-dibromo-6- ~(N-methyl-N-cyclohexyl)-aminomethylJ -benzoic acid at a temperature of 35-100C to thereby form N-cyclohexyl-N-methyl-(2-amino-3,5-dibromobenzyl)-amine.
In the process of the invention the strong acid is preferably con-centrated sulphurlc acid but also polyphosphoric acid and other strong acids can be used. As the free hydrazoic acid is instable, very poisonous and volatile, sodium azide, is gradually added to a solvent, which contains a strong acid, thus forming hydrazoic acid in statu nascendi. An inert organic solvent, for example chloroform, can be used as solvent. The temperature is preferably between 35-100 C, at which temperature the reaction is fast. The formed base is converted to acid addition salts by usual methods.
The reactant II may be prepared starting from 2,4-dibromo-6-methyl-benzoic acid (m.p. 162-164 ), the methyl group of which is then brominated, and the reaction product thereof is then, without isolation of the brominated product, reacted with methylcyclohyexylamine to form 2~4-dibromo-6-[ (N-methyl-N-cyclohexyl)-aminomethyl~ -benzoic acid, which is a new substance and has the melting point 277-280~.
The following example illustrates the invention:
6~
Example:
20,25 g of 2,4-dibromo-6-~N-methyl-N-cyclohexyl)-aminomethy~ -benzoic acid, 100 ml of concentrated sulphuric acid and 200 ml of chloroform are stirred at 35C and 10 g sodium azide is added at this te~,perature during one hour. After this the mixture is refluxed for 3 hours, cooled and poured on ice. The reaction product is extracted with heptane and the heptane eva-porated. The residue is dissolved in sulphuric acid and hydrochloric acid is added to precipitate N-cyclohexyl-N-methyl-(?2-amino-3,5-dibromobenzyl)-amine hydrochloride. The yield is 11,3 g (55~ of theor. amount), m.p. 240-242C.
~.1
Bromhexine is a bronchospasmodic agent, which has an extremely strong cough relieving effect, the dosage and toxicity being extremely low.
The preparation of bromhexine has earlier been described in for example the Finnish patents 40,631, 40,803, 40,804, and 41,9620 The present invention concerns a new process for the preparation of bromhexine, which completely differs from the methods described in the above mentioned patents. 2,4-dibromo-6-rN-methyl-N-cyclohexyl)-amino-methy ~-benzoic acid, which is a new agent and has the formula B ~ / CH3 ~ H2-N ~ (II) Br COOH
is used as one of the reactants which is reacted with hydrazoic acid (HN3) in the presence of a strong acid which changes the carboxyl group in the bromhexine to an amino group. This reaction has not before been applied to the preparation of a substance of this kind. The reaction succeeds unexpect-edly well (yield 40-60%) and it has to be considered as extremely surprising in view of the extreme steric hindrance of the carboxyl group even in good yields.
According to the present invention, there is provided a process for the preparation of N-cyclshexyl-N-methyl-(2-amino-3,5-dibromobenzyl)-amine which has the formula ~,i 1~4~6~
Br / CH3 ~ O ~--CH2-N
Br NH2 ~
and acid addition salts thereof, comprising reacting 2,4-dibromo-6- C(N-methyl-N-cyclohexyl)-aminomethyl] -benzoic acid, which has the formula Br /~H3 ~ 2 Br COOH ~
with hydrazoic acid (~N3) which reacts in statu nascendi by the addition of a salt of hydrazoic acid to a solution of an inert organic solvent, a strong acid and said 2,4-dibromo-6- ~(N-methyl-N-cyclohexyl)-aminomethylJ -benzoic acid at a temperature of 35-100C to thereby form N-cyclohexyl-N-methyl-(2-amino-3,5-dibromobenzyl)-amine.
In the process of the invention the strong acid is preferably con-centrated sulphurlc acid but also polyphosphoric acid and other strong acids can be used. As the free hydrazoic acid is instable, very poisonous and volatile, sodium azide, is gradually added to a solvent, which contains a strong acid, thus forming hydrazoic acid in statu nascendi. An inert organic solvent, for example chloroform, can be used as solvent. The temperature is preferably between 35-100 C, at which temperature the reaction is fast. The formed base is converted to acid addition salts by usual methods.
The reactant II may be prepared starting from 2,4-dibromo-6-methyl-benzoic acid (m.p. 162-164 ), the methyl group of which is then brominated, and the reaction product thereof is then, without isolation of the brominated product, reacted with methylcyclohyexylamine to form 2~4-dibromo-6-[ (N-methyl-N-cyclohexyl)-aminomethyl~ -benzoic acid, which is a new substance and has the melting point 277-280~.
The following example illustrates the invention:
6~
Example:
20,25 g of 2,4-dibromo-6-~N-methyl-N-cyclohexyl)-aminomethy~ -benzoic acid, 100 ml of concentrated sulphuric acid and 200 ml of chloroform are stirred at 35C and 10 g sodium azide is added at this te~,perature during one hour. After this the mixture is refluxed for 3 hours, cooled and poured on ice. The reaction product is extracted with heptane and the heptane eva-porated. The residue is dissolved in sulphuric acid and hydrochloric acid is added to precipitate N-cyclohexyl-N-methyl-(?2-amino-3,5-dibromobenzyl)-amine hydrochloride. The yield is 11,3 g (55~ of theor. amount), m.p. 240-242C.
~.1
Claims (7)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of N-cyclohexyl-N-methyl-(2-amino-3,5-dibromobenzyl)-amine which has the formula and acid addition salts thereof, comprising reacting 2,4-dibromo-6[N-methyl-N-cyclohexyl)-aminomethyl]-benzoic acid, which has the formula with hydrazoic acid (HN3) which reacts in statu nascendi by the addition of a salt of hydrazoic acid to a solution of an inert organic solvent, a strong acid and said 2,4-dibromo-6-[N-methyl-N-cyclohexyl)-aminomethyl]-benzoic acid at a temperature of 35-100°C to thereby form N-cyclohexyl-N-methyl-(2-amino-3,5-dibromobenzyl)-amine.
2. A process according to claim 1 wherein the strong acid is con-centrated sulphuric acid.
3. A process according to claim 1 wherein the strong acid is poly-phosphoric acid.
4. A process according to claim 1, 3 or 4 wherein the salt of hydrazoic acid is sodium azide.
5. A process according to claim 1 wherein the inert organic solvent is chloroform.
6. A process according to claim 1 further comprising the step of dis-solving the reaction product of claim 1 in sulphuric acid and hydrochloric acid to form N-cyclohexyl-N-methyl-(2-amino-3,5-dibromobenzyl)-amine hydro-chloride.
7. A process according to claim 1 wherein the 2,4-dibromo-6-[(N-methyl-N-cyclohexyl)-amino-methyl]-benzoic acid is formed by bromination of the methyl group of 2,4-dibromo-6-methyl-benzoic acid followed by reaction with methyl-cyclohexylamine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA209,447A CA1048061A (en) | 1974-09-18 | 1974-09-18 | Process for the preparation of a therapeutically active dihalogenoaminobenzylamine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA209,447A CA1048061A (en) | 1974-09-18 | 1974-09-18 | Process for the preparation of a therapeutically active dihalogenoaminobenzylamine |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1048061A true CA1048061A (en) | 1979-02-06 |
Family
ID=4101173
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA209,447A Expired CA1048061A (en) | 1974-09-18 | 1974-09-18 | Process for the preparation of a therapeutically active dihalogenoaminobenzylamine |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1048061A (en) |
-
1974
- 1974-09-18 CA CA209,447A patent/CA1048061A/en not_active Expired
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