MXPA00006128A - A NOVEL PHOSPHATE SALT OF ISOPROPYL-METHYL-[2-(3-n-PROPOXYPHENOXY)ETHYL]AMINE - Google Patents
A NOVEL PHOSPHATE SALT OF ISOPROPYL-METHYL-[2-(3-n-PROPOXYPHENOXY)ETHYL]AMINEInfo
- Publication number
- MXPA00006128A MXPA00006128A MXPA/A/2000/006128A MXPA00006128A MXPA00006128A MX PA00006128 A MXPA00006128 A MX PA00006128A MX PA00006128 A MXPA00006128 A MX PA00006128A MX PA00006128 A MXPA00006128 A MX PA00006128A
- Authority
- MX
- Mexico
- Prior art keywords
- propoxyphenoxy
- amine
- ethyl
- methyl
- isopropyl
- Prior art date
Links
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical class OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 title claims description 25
- NUZYBIKIXLKGKN-UHFFFAOYSA-N n-methyl-n-[2-(3-propoxyphenoxy)ethyl]propan-2-amine Chemical compound CCCOC1=CC=CC(OCCN(C)C(C)C)=C1 NUZYBIKIXLKGKN-UHFFFAOYSA-N 0.000 title abstract 3
- -1 monophosphate salt Chemical class 0.000 claims abstract description 52
- 238000000034 method Methods 0.000 claims abstract description 22
- 238000002360 preparation method Methods 0.000 claims abstract description 11
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 7
- 239000003814 drug Substances 0.000 claims abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 31
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 12
- 150000001412 amines Chemical class 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 5
- 239000003085 diluting agent Substances 0.000 claims description 2
- QUPDWYMUPZLYJZ-UHFFFAOYSA-N ethyl Chemical compound C[CH2] QUPDWYMUPZLYJZ-UHFFFAOYSA-N 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims 1
- 229910019142 PO4 Inorganic materials 0.000 claims 1
- 230000001476 alcoholic effect Effects 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims 1
- 239000010452 phosphate Substances 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 235000019439 ethyl acetate Nutrition 0.000 description 10
- 150000001875 compounds Chemical class 0.000 description 7
- 230000003444 anaesthetic effect Effects 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 2
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 description 1
- YYMPIPSWQOGUME-UHFFFAOYSA-N 3-propoxyphenol Chemical compound CCCOC1=CC=CC(O)=C1 YYMPIPSWQOGUME-UHFFFAOYSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 125000006014 bromoethoxy group Chemical group 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- XHFGWHUWQXTGAT-UHFFFAOYSA-N n-methylpropan-2-amine Chemical compound CNC(C)C XHFGWHUWQXTGAT-UHFFFAOYSA-N 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
Abstract
The present invention relates to a novel monophosphate salt of isopropyl-methyl-[2-(3-n-propoxyphenoxy)ethyl]amine. Moreover, the present invention also relates to a process for the preparation of the monophosphate salt of isopropyl-methyl-[2-(3-n-propoxyphenoxy)ethyl]amine as well as a pharmaceutical formulation containing it and its use in medicine.
Description
NEW ISOPROPIL-METHYL- [2- (3-n-PROPOXYPHENOXY) ETHYL] AMINE PHOSPHATE SALT
Field of the Invention The present invention relates to a new phosphate salt of isopropylmethyl- [2- (3-n-propoxyphenoxy) ethyljamine. Additionally, the present invention also relates to a process for the preparation of a phosphate salt of isopropyl-methyl- [2- (3-n-propoxyphenoxy) ethyl] amine as well as a pharmaceutical formulation containing it and its use in medicine. .
BACKGROUND OF THE INVENTION AND PRIOR ART L a i s o p r o p i l-m e t i l - [2 - (3-n -propoxyphenoxy) ethyl] amine is UJI compound with anesthetic properties. Therefore it is useful as an anesthetic compound for the treatment of pain, including localized pain.
WO 9715548 describes isopropyl-methyl- [2- (3-n-propoxyphenoxy) ethyl] amine as well as a process for its preparation. The process comprises a pair of reaction steps that start by reacting 3-n-propoxyphenol with 1,2-dibromoethane, which results in l- (2-bromoethoxy) -3-n-propoxybenzene. In addition, 1- (2- REF.120791 bromoethoxy) -3-n-propoxybenzene is reacted with N-methylisopropylamine in an autoclave. The product, isopropyl-methyl- [2- (3-n-propoxyphenoxy) ethyl] amine, was further purified further by means of vacuum distillation.
Brief Description of the Invention The object of the present invention is to provide a monophosphate salt of isopropylmethyl- [2- (3-n-propoxyphenoxy) ethyl] amine.
According to the invention there is also provided a process for the preparation of the isopropyl-methyl- [2- (3-n-propoxyphenoxy) ethyl] amine monophosphate salt, which comprises treating isopropylmethyl- [2- (3 -n-propoxyphenoxy) ethyl] amine with phosphoric acid in a solvent system.
The isopropyl-methyl- [2- (3-n-propoxyphenoxy) ethyl] amine monophosphate salt is a crystalline and stable salt of isopropyl-methyl- [2- (3-n-propoxyphenoxy) ethyl] amine and therefore has advantageous properties.
Additionally, the crystalline monophosphate salt of isopropyl-methyl- [2- (3-n-propoxyphenoxy) ethyl] ami a can be used to introduce a crystalline intermediate in the process for the preparation of isopropyl-methyl- [2- (3- n-propoxyphenoxy) and il] amine. This introduces a simple and convenient purification step in a reaction sequence where the other intermediates are syrups. In this way, distillation that consumes time and energy used in the process according to the prior art is avoided. The crystallization of the isopropyl-methyl- [2- (3-n-propoxyphenoxy) ethyl] amine monophosphate salt results in an intermediate of high purity which can be further converted to isopropyl-methyl- [2- (3-n) -propoxyphenoxy) ethyl] amine by means of a simple alkalization step.
Preparation In the preparation of the isopropyl-methyl- [2- (3-n-propoxyphenoxy) ethyl] amine monophosphate salt the content of isopropyl-methyl- [2- (3-n-propoxyphenoxy) ethyl] amine in Ethyl acetate is first tested and adjusted to 6-10 ml ethyl acetate per gram of isopropyl-methyl- [2- (3-n-propoxyphenoxy) ethyl] amine. The content of isopropyl-methyl- [2- (3-n-propoxyphenoxy) ethyl] amine in ethyl acetate is preferably 7-9 ml of ethyl acetate per gram of isopropyl-methyl- [2- (3-n- propoxyphenoxy) and il] amine. To the solution of isopropyl-methyl- [2- (3-n-propoxyphenoxy) ethyl] amine in ethyl acetate, methanol and a solution of phosphoric acid in methanol are added. The amount of phosphoric acid should be about 0.9 to 1.0 molar equivalents, preferably 0.95 equivalents. The total amount of methanol added to the tested solution should be adjusted to the amount of phosphoric acid used. The concentration of phosphoric acid in the resulting solution of isopropyl-methyl- [2- (3-n-propoxyphenoxy) ethyl] amine in methanol / ethyl acetate should be about 5-15% by volume, preferably 9-11% in volume. The precipitated salt is collected, for example by filtration or centrifugation, and subsequently washed with ethyl acetate.
The monophosphate salt of isopropyl-methyl- [2- (3-n-p rop ox i f e n i x i) e t i 1 am i a a can be processed further by means of processes known in the art, e.g. convert to its basic form, i.e. isopropyl-methyl- [2- (3-n-propoxyphenoxy) ethyl] amine, by aqueous base treatment.
Medical and Pharmaceutical Usage The isopropyl-methyl- [2- (3-n-propoxyphenoxy) ethyl] amine monophosphate salt is useful because it possesses pharmacological activity and especially for use as an anesthetic compound. Therefore it is indicated as a pharmacist, especially in the treatment of pain, including localized pain.
According to a further aspect of the invention there is thus provided the isopropyl-methyl- [2- (3-n-propoxyphenoxy) ethyl] amine monophosphate salt for use as a pharmacist, especially in the treatment of pain.
Pharmaceutical Formulations The isopropyl-methyl- [2- (3-n-propoxyphenoxy) ethyl] amine monophosphate salt will normally be administered parenterally, especially injected in the form of pharmaceutical formulations containing the active ingredient in a pharmaceutically dosage form. acceptable. The compositions containing the isopropyl-methyl- [2- (3-n-propoxyphenoxy) ethyl] amine monophosphate salt for parenteral administration could include other ingredients commonly used in the parenteral administration of pharmaceutically active compounds.
According to a further aspect of the present invention, there is thus provided a pharmaceutical formulation containing the isopropyl-methyl- [2- (3-n-propoxyphenoxy) ethyl] amine monophosphate salt in admixture with an adjuvant, diluent or carrier pharmaceutically acceptable. Formulations including the isopropyl-methyl- [2- (3-n-propoxyphenoxy) ethyl] amine salt could be prepared by techniques that are known per se. Usually the active substance will constitute between 0.5 and 10% by weight of the preparation, more specifically between 1 and 5% by weight.
According to a further aspect of the present invention, there is provided a method for the treatment of a pain, this method comprises the administration of a therapeutically effective amount of the isopropylmethyl- [2- (3-n- propoxyphenoxy) ethyl] amine to a person who suffers from, or is susceptible to pain.
The present invention is described in more detail in the following non-limiting examples.
Examples Example 1. Preparation of the isopropyl-methyl- [2- (3-n-propoxyphenoxy) ethyl] amine monophosphate salt To a tested solution of isopropyl-methyl- [2- (3-n-propoxyphenoxy) ethyl] Amine (19. or kg, 75.7 mol) in ethyl acetate (8 ml of EtOAc / g of isopropyl-methyl- [2- (3-n-propoxyphenoxy) ethyl] amine) was added MeOH (9.6 L) followed by H3P04 (4.85 L, 72.5 mol) dissolved in MeOH
(19.2 L) for 3 hours at room temperature. The resulting suspension of the title compound is then isolated by filtration and the solid material is washed with
EtOAc. Yield 89% (41.8 kg of wet compound, corresponds to 67.6 mole of dry compound); Mp: 131-134 ° C.
It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.
Claims (13)
1. A salt of isopropyl-methyl- [2- (3-n-propoxyphenoxy) ethyl] amine phosphate.
2. A monophosphate salt of isopropyl-methyl- [2- (3-n-propoxyphenoxy) et il] amine.
3. A process for the preparation of the isopropyl-methyl- [2- (3-n-propoxyphenoxy) et il] amine monophosphate salt, characterized in that it comprises the following steps: i) adding phosphoric acid to a solution of isopropyl-methyl- [2- (3-n-propoxyphenoxy) ethyl] amine in an organic solvent system; ii) let the solution crystallize; iii) isolating the monophosphate salt of isopropyl-methyl- [2- (3-n-propoxyphenoxy) ethyl] amine thus obtained.
4. A process according to claim 3, characterized in that the organic solvent system used in step i) is ethyl acetate.
5. A process according to claim 3, characterized in that the phosphoric acid added in step i) is added as an alcoholic solution of phosphoric acid.
6. A process according to claim 5, characterized in that the alcohol solution is a methanolic solution.
7. A process according to claim 3, characterized in that 0.9-1.0 equivalents of phosphoric acid are used in step i).
8. A process according to claim 3, characterized in that? .95 equivalents of phosphoric acid are used in step i).
9. A process in accordance with the claim 3, characterized in that the concentration of phosphoric acid in the resulting solution after completion of the addition is between 5-15% by weight.
10. A process according to claim 3, characterized in that the concentration of phosphoric acid in the resulting solution after the addition should be between 9-11% by weight.
11. A pharmaceutical formulation, characterized in that it contains the isopropyl-methyl- [2- (3-n-propoxyphenoxy) ethyl] amine monophosphate salt and a pharmaceutically acceptable carrier or diluent.
12. Use of a salt of isopropyl-methyl- [2- (3-n-propoxyphenoxy) -ethyl] amine monophosphate in the manufacture of a medicament for the treatment of pain.
13. The isopropyl-methyl- [2- (3-n-propoxyphenoxy) ethyl] amine phosphate salt prepared by a process according to any of claims 3-10. PROPOXYPHENOXY) ETHYL] AMINE SUMMARY OF THE INVENTION The present invention relates to a new salt of isopropyl-methyl- [2- (3-n-propoxyphenoxy) ethyl] amine monophosphate. In addition, the present invention also relates to a process for the preparation of the isopropyl-methyl- [2- (3-n-propoxyphenoxy) ethyl] amine monophosphate salt as well as to a pharmaceutical formulation containing it, and to its use in medicine.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE9704835-9 | 1997-12-22 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| MXPA00006128A true MXPA00006128A (en) | 2002-03-05 |
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