EP1506156A1 - Method for preparing 2-alkoxyphenoxyethanamines from 2-alkoxyphenoxyethylacetamides - Google Patents
Method for preparing 2-alkoxyphenoxyethanamines from 2-alkoxyphenoxyethylacetamidesInfo
- Publication number
- EP1506156A1 EP1506156A1 EP02750895A EP02750895A EP1506156A1 EP 1506156 A1 EP1506156 A1 EP 1506156A1 EP 02750895 A EP02750895 A EP 02750895A EP 02750895 A EP02750895 A EP 02750895A EP 1506156 A1 EP1506156 A1 EP 1506156A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- acetamide
- alkoxyphenoxyethanamines
- ethyl
- substituted phenol
- alkyloxazoline
- 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.)
- Withdrawn
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/02—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
- C07C233/08—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to acyclic carbon atoms of a saturated carbon skeleton containing rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C217/06—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted
- C07C217/14—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring
- C07C217/18—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted
- C07C217/20—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted by halogen atoms, by trihalomethyl, nitro or nitroso groups, or by singly-bound oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/14—Preparation of carboxylic acid amides by formation of carboxamide groups together with reactions not involving the carboxamide groups
Definitions
- the present invention relates to a method for preparing 2- Alkoxyphenoxyethanamines and more particularly relates to the preparation of 2-Alkoxyphenoxyethylacetamides to be used in the method for preparing 2-Alkoxyphenoxyethanamines.
- 2-Alkoxyphenoxyethanamines are known compounds. They are used among others as starting material for the synthesis of pharmaceutical active substances like for example Carvedilol as described in US 4,503,067 and Tamsulosin as described in US 4,731 ,478.
- CH 383 998 discloses a synthesis of 2-Alkoxyphenoxyethanamines in which liquid ammonia is reacted with 2-Methoxyphenoxyethylbromide in methanol. The mixture is heated for ten hours in an autoclave. This method often leads to di- and tri-substituted amines as side products. Unsatisfying yields, complicated isolation procedure and the use of liquid ammonia makes this process very costly.
- the object of the present invention is therefore to provide a process for the.., industrial production of 2-Alkoxyphenoxyethanamines which is cheap and easy to operate.
- the present invention provides the new chemical entity 2-Alkoxyphenoxyethylacetamide as the only intermediate in the process for producing a 2-Alkoxyphenoxyethanamine.
- 2- Alkoxyphenoxyethylacetamide as an easily available intermediate, the number of process steps is reduced with advantage and the raw material employed is easy to obtain and to handle.
- the 2-Alkoxyphenoxyethylacetamide has to be produced by a process, using the reaction of an ortho substituted phenol with a 2-Alkyloxazoline. This reaction only comprises the use of cheap, harmless and easily available raw materials and makes the process for producing 2- Alkoxyphenoxyethanamine suitable for production in industrial scale.
- R ' is selected from the group consisting of methyl or ethyl.
- Alkoxyphenoxyethylacetamide which is a new chemical entity.
- the acetamide can be easily isolated by pouring the reaction mixture into water and collecting the solid residue.
- the acetamide has the formular
- R and R ' are each selected from the group consisting of methyl or ethyl.
- the second step comprises hydrolyzation of the acetamide with water and is obtained in the presence of organic or mineralic acids such as hydrochloric acid or sulfuric acid to give a 2-Alkoxyphenoxyethanamine.
- organic or mineralic acids such as hydrochloric acid or sulfuric acid
- cleavage at the ether oxygen or aromatic ring substitution does not appear, if hydrolysis of the acetamide is performed in the presence of hydrochloric acid.
- the use of phosphoric acid would lead to process water containing phosphate salts. For reasons of environmental protection, these phosphate salts have to be removed from the process water, which again causes costs.
- the reactions may be conducted under atmospheric pressure. Another advantage of the present invention is the absence of a catalyst, as was necessary in one of the methods described in the state of the art.
- the present invention comprises the new chemical entity 2- Methoxyphenoxyethylacetamide, in particular as intermediate compound in the process for production of 2-Alkoxyphenoxyethanamine. It also comprises the use of an ortho substituted phenol for the reaction with an 2-Alkyloxazoline to give the acetamide. It further comprises the use of the 2-Alkyloxazoline for the reaction with the ortho substituted phenol to give the acetamide intermediate and the use of the acetamide intermediate in a hydrolysis reaction to give a 2-Alkoxyphenoxyethanamine.
- Example 2 The procedure of Example 2 is followed except that 223 g of N-[2-(2- Ethoxy-phenoxy)-ethyl]-acetamide are employed. About 126 g of 2-(2- Ethoxy-phenoxy)-ethylamine (70%) are obtained. The 2-(2-Ethoxy- phenoxy)-ethylamine has a boiling point of 94-96°C at 1 Torr.
Abstract
The present invention relates to a method for preparing 2-Alkoxyphenoxyethanamines and more particularly relates to the preparation of the new chemical entity 2-Alkoxyphenoxyethylacetamides, in particular as intermediates in said method. An industrial process for the synthesis of 2-Alkoxyphenoxyethanamines which is cheap and easy to perform, is a long felt need for those skilled in the art. The object of the present invention is therefore to provide a process for the industrial production of phenoxyethanamine which is cheap and easy to perform. This object is solved by the new chemical entity 2-Alkoxyphenoxyacetamide which is prepared by reacting an ortho substituted phenol with a 2-Alkyloxazoline. By hydrolysis of the acetamide with water in the presence of organic or mineral acids such as hydrochloric acid and/or sulfuric acid, the 2-Alkylphenoxyethanamine is obtained.
Description
METHOD FOR PREPARING 2-ALKOXYPHENOXYETHANAMINES FROM 2-ALKOXYPHENOXYETHYLACETAMIDES
Description
The present invention relates to a method for preparing 2- Alkoxyphenoxyethanamines and more particularly relates to the preparation of 2-Alkoxyphenoxyethylacetamides to be used in the method for preparing 2-Alkoxyphenoxyethanamines.
2-Alkoxyphenoxyethanamines are known compounds. They are used among others as starting material for the synthesis of pharmaceutical active substances like for example Carvedilol as described in US 4,503,067 and Tamsulosin as described in US 4,731 ,478.
CH 383 998 discloses a synthesis of 2-Alkoxyphenoxyethanamines in which liquid ammonia is reacted with 2-Methoxyphenoxyethylbromide in methanol. The mixture is heated for ten hours in an autoclave. This method often leads to di- and tri-substituted amines as side products. Unsatisfying yields, complicated isolation procedure and the use of liquid ammonia makes this process very costly.
US 3,474,134 discloses a synthesis of 2-Alkoxyphenoxyethanamines in which three steps are involved. In addition, halogenated substances as well as the toxic, corrosive and inflammable substance hydrazin are employed. This makes the synthesis not convenient for production in larger scale.
US 3,412,154 discloses a two-step synthesis of 2- Alkoxyphenoxyethanamines in which the harmful substance chloroacetonitrile is used and a pressurised catalytic hydrogenation by raney cobalt catalyst is required. This makes the synthesis dangerous and costly as well.
An industrial process for the synthesis of 2-Alkoxyphenoxyethanamines which is cheap and easy to operate, is a long felt need for those skilled in the art.
The object of the present invention is therefore to provide a process for the.., industrial production of 2-Alkoxyphenoxyethanamines which is cheap and easy to operate.
In carrying out this object, the present invention provides the new chemical entity 2-Alkoxyphenoxyethylacetamide as the only intermediate in the process for producing a 2-Alkoxyphenoxyethanamine. By employing 2- Alkoxyphenoxyethylacetamide as an easily available intermediate, the number of process steps is reduced with advantage and the raw material employed is easy to obtain and to handle.
In the present invention, to produce 2-Alkoxyphenoxyethanamine, first the 2-Alkoxyphenoxyethylacetamide has to be produced by a process, using the reaction of an ortho substituted phenol with a 2-Alkyloxazoline. This reaction only comprises the use of cheap, harmless and easily available raw materials and makes the process for producing 2- Alkoxyphenoxyethanamine suitable for production in industrial scale.
The process to synthesize 2-Alkoxyphenoxyethylacetamide uses an ortho substituted phenol which has the formular
where R is selected from the group consisting of methyl or ethyl. As a convenient second educt for the process, 2-Alkyloxazoline, which has the formular
is used. R' is selected from the group consisting of methyl or ethyl.
In a preferred embodiement of the invention, it was found that the reaction of these two educts can be carried out either without solvents at 130- 200°C or in high boiling solvents. The possibility of the performing this reaction either without solvents or with solvents easy to handle is clearly an advantage of the present invention and reduces the costs of an industrial production process.
The reaction of the two educts leads to the 2-
Alkoxyphenoxyethylacetamide, which is a new chemical entity. The acetamide can be easily isolated by pouring the reaction mixture into water and collecting the solid residue. The acetamide has the formular
where R and R'are each selected from the group consisting of methyl or ethyl. By using the before mentioned educts, surprisingly no further purification of the obtained 2-Alkoxyphenoxyethylacetamide is necessary. This acetamide is than used further in the present inventive process.
The second step comprises hydrolyzation of the acetamide with water and is obtained in the presence of organic or mineralic acids such as hydrochloric acid or sulfuric acid to give a 2-Alkoxyphenoxyethanamine. Surprisingly, cleavage at the ether oxygen or aromatic ring substitution does not appear, if hydrolysis of the acetamide is performed in the presence of hydrochloric acid. The use of phosphoric acid would lead to process water containing phosphate salts. For reasons of environmental protection, these phosphate salts have to be removed from the process water, which again causes costs. In contrast to one , of the methods of the state of the art, the reactions may be conducted under atmospheric pressure. Another advantage of the present invention is the absence of a catalyst, as was necessary in one of the methods described in the state of the art.
The present invention comprises the new chemical entity 2- Methoxyphenoxyethylacetamide, in particular as intermediate compound in the process for production of 2-Alkoxyphenoxyethanamine. It also comprises the use of an ortho substituted phenol for the reaction with an 2-Alkyloxazoline to give the acetamide. It further comprises the use of the 2-Alkyloxazoline for the reaction with the ortho substituted phenol to give the acetamide intermediate and the use of the acetamide intermediate in a hydrolysis reaction to give a 2-Alkoxyphenoxyethanamine.
The invention will be further illustrated by the following examples which are provided for further understanding and not to limit the scope of the invention.
EXAMPLE 1
Preparation of N-[2-(2-Methoxy-phenoxy)-ethyl]-acetamide
A mixture of 372 g (3 Mol) Guaiacol and 255 g (3 Mol) of 2- Methyloxazoline are heated at 160°C for 20h in a three-necked flask equipped with a stirrer, condenser and thermometer. After cooling to 90°C the reaction mixture is poured into water and the solid residue obtained is collected, washed with water and dried. The yield amounts to 480 g (76%), the obtained N-[2-(2-Methoxy-phenoxy)-ethyl]-acetamide has a melting point of 57-59°C. The N-[2-(2-Methoxy-phenoxy)-ethyl]-acetamide is used for the next step without further purification.
EXAMPLE 2
Preparation of 2-(2-Methoxy-phenoxy)-ethylamine
209 g (1 mol) of N-[2-(2-Methoxy-phenoxy)-ethyl]-acetamide are refluxed in 400 ml HCI (5n) for 4h. The pH of the reaction mixture is adjusted to 8-9 with 30% NaOH solution and the oily layer is taken up in toluene, which is evapurated afterwards. The 2-(2-Methoxy-phenoxy)^ethylamine is purified by distillation under vacuum. The yield is 125 g 2-(2-Methoxy-phenoxy)- ethylamine (74,8%), the boiling point is 1 10-115°C at 2Torr.
EXAMPLE 3
Preparation of N-[2-(2-Ethoxy-phenoxy)-ethyl]-acetamide
A mixture of 414 g (3 Mol) of guaethol and 255 g (3 Mol) of 2- Methyloxazoline are treated in the same manner as described in Example 1. About 501 g of N-[2-(2-Ethoxy-phenoxy)-ethyl]-acetamide (72%) is obtained. The N-[2-(2-Ethoxy-phenoxy)-ethyl]-acetamide has a melting point of 77-79X and is used for the next step without further purification.
EXAMPLE 4
Preparation of 2-(2-Ethoxy-phenoxy)-ethylamine
The procedure of Example 2 is followed except that 223 g of N-[2-(2- Ethoxy-phenoxy)-ethyl]-acetamide are employed. About 126 g of 2-(2- Ethoxy-phenoxy)-ethylamine (70%) are obtained. The 2-(2-Ethoxy- phenoxy)-ethylamine has a boiling point of 94-96°C at 1 Torr.
Claims
2-Alkoxyphenoxyethylacetamide of the formular
where R and R'are each selected from the group consisting of methyl or ethyl.
Process for producing a 2-Alkoxyphenoxyethylacetamide, in particular as an intermediate in the process for producing a 2- Alkoxyphenoxyethanamine, comprising the step of: reacting an ortho substituted phenol with a 2-Alkyloxazoline to produce the acetamide as mentioned in claim 1.
3. Process according to claim 2 where the ortho substituted phenol has the formular
' where R is selected from the group consisting of methyl or ethyl.
4. Process according to claim 2 or 3 where the 2-Alkyloxazoline has the formular
where R' is selected from the group consisting of methyl or ethyl.
5. Process according to claim 2, 3 or 4, where the acetamide has the formular
where R and R' are each selected from the group consisting of methyl or ethyl.
6. Process according to one of the claims 2 to 5 comprising the step of: hydrolyzing the 2-Alkoxyphenoxyethylacetamide as claimed in claim 1 with water in the presence of organic or mineral acids such as hydrochloric acid and/or sulfuric acid to produce the 2-
Alkoxyphenoxyethanamine.
7. Use of the ortho substituted phenol in the reaction with the 2- Alkyloxyzoline to produce the acetamide intermediate.
8. Use of the 2-Alkyloxazoline in the reaction with the ortho substituted phenol to produce the acetamide intermediate.
9. Use of the acetamide intermediate in a hydrolysis reaction to produce a 2-Alkoxyphenoxyethanamine
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/EP2002/005021 WO2003095416A1 (en) | 2002-05-07 | 2002-05-07 | Method for preparing 2-alkoxyphenoxyethanamines from 2-alkoxyphenoxyethylacetamides |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP1506156A1 true EP1506156A1 (en) | 2005-02-16 |
Family
ID=29414643
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP02750895A Withdrawn EP1506156A1 (en) | 2002-05-07 | 2002-05-07 | Method for preparing 2-alkoxyphenoxyethanamines from 2-alkoxyphenoxyethylacetamides |
Country Status (3)
| Country | Link |
|---|---|
| EP (1) | EP1506156A1 (en) |
| AU (1) | AU2002367923A1 (en) |
| WO (1) | WO2003095416A1 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP6865754B2 (en) | 2016-01-22 | 2021-04-28 | シェブロン・オロナイト・カンパニー・エルエルシー | Synthetic lubricating oil composition containing a mixture of an olefin copolymer dispersant type viscosity improver and an amine compound |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH383998A (en) * | 1959-08-05 | 1964-11-15 | Ciba Geigy | Process for the preparation of new secondary amines |
| CH378343A (en) * | 1959-08-05 | 1964-06-15 | Ciba Geigy | Process for the preparation of new secondary amines |
| US3474134A (en) * | 1960-03-03 | 1969-10-21 | Burroughs Wellcome Co | Phenoxyethyl-guanidines and the salts thereof |
| US3412154A (en) * | 1964-08-12 | 1968-11-19 | Parke Davis & Co | Amino-substituted phenone compounds |
-
2002
- 2002-05-07 WO PCT/EP2002/005021 patent/WO2003095416A1/en not_active Application Discontinuation
- 2002-05-07 AU AU2002367923A patent/AU2002367923A1/en not_active Abandoned
- 2002-05-07 EP EP02750895A patent/EP1506156A1/en not_active Withdrawn
Non-Patent Citations (1)
| Title |
|---|
| See references of WO03095416A1 * |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2003095416A1 (en) | 2003-11-20 |
| AU2002367923A1 (en) | 2003-11-11 |
| AU2002367923A8 (en) | 2003-11-11 |
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