GB2284810A - Alkenylation and alkynylation of phenylisopropylamine derivatives with tertiary amine base - Google Patents
Alkenylation and alkynylation of phenylisopropylamine derivatives with tertiary amine base Download PDFInfo
- Publication number
- GB2284810A GB2284810A GB9413847A GB9413847A GB2284810A GB 2284810 A GB2284810 A GB 2284810A GB 9413847 A GB9413847 A GB 9413847A GB 9413847 A GB9413847 A GB 9413847A GB 2284810 A GB2284810 A GB 2284810A
- Authority
- GB
- United Kingdom
- Prior art keywords
- selegiline
- phenylisopropylamine
- tertiary amine
- amine base
- hcl
- 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.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/04—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups
- C07C209/06—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups by substitution of halogen atoms
- C07C209/08—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups by substitution of halogen atoms with formation of amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Phenylisopropylamine derivatives are prepared by introducing a propargyl or 2-halo-propenyl radical into a suitable compound in the presence of a solvent and a tertiary amine base. Thus selegiline (I) is prepared from methamphetamine (II) and propargyl bromide in the presence of toluene and diisopropylethylamine. <IMAGE>
Description
"A process for producing pharmaceutical compounds The invention relates to an industrial process for producing pharmaceutical compounds and in particular to a process for producing phenylisopropylamine derivatives.
Phenylisopropylamine derivatives have been known since 1965. British Patent Specification No. 1,153,578 describes the Monoamine Oxidase inhibitor (MAO-inhibitor) activities of several phenylisopropylamine derivatives.
Selegiline was found to be the most active compound.
Selegiline hydrochloride is the compound of the formula
It is used, especially in the (-)-Form in the treatment of
Parkinsons disease and as a coronary dilator, hallucinogenic and depressive agent and also as a tranquilliser, analgesic and an appetite suppressant.
The processes for preparing phenylisopropylamine derivatives described in UK 1,153,579 are not generally economically viable.
The present invention is directed towards providing an improved process for the production of phenylisopropylamine derivatives, particularly Selegiline.
According to the invention there is provided a process for preparing a phenylisopropylamine derivative including the steps of:
mixing an appropriate starting material, a solvent
and a tertiary amine base, and
introducing a propargyl or 2-halogeno-propenyl
radical.
In a preferred embodiment of the invention, the tertiary amine base is diisopropylethylamine.
In one embodiment of the invention, the starting material is methamphetamine. Typically, the solvent is toluene.
Preferably, propargylbromide is added and diisopropylethylamine-hydrobromid salt is precipitated.
In one embodiment, the organic layer formed is concentrated and the desired phenylisopropylamine derivative is isolated.
In a particularly preferred embodiment of the invention, the desired phenylisopropylamine derivative is Selegiline.
Preferably, HCl is added to form Selegiline HCl.
The invention also provides a phenylisopropylamine derivative, especially Selegiline or Selegiline.HCl whenever prepared by the process of the invention.
The invention will be more clearly understood from the following description thereof given by way of example only.
EXAMPLE 605.4 grs (-) Methamphetamine, 1.7 litres toluene and 1123 mls of diisopropylethylamine were mixed at room temperature. To that clear solution 533.4 mls propargylbromide (80% solution in toluene) was added and diisopropylethylamine-hydrobromid salt precipitated. The temperature rose to 590C. After 6 hours the reaction was completed and 1.5 litres of water were added.
The water layer was separated, the organic layer concentrated under vacuum and Selegiline base was isolated. The base was dissolved in acetone and HCl gas was added until Selegiline HCl was crystallised. After recrystallisation in ethylacetate and methanol 410.5 grs of Selegiline HCl were obtained.
Melting Point: 142.5 - 1470C
Optical Rotation: - 11.4 (10% in water)
The compound prepared in accordance with the example may be converted into pharmaceutically acceptable acid addition salts. Salt formation may be accomplished by using mineral acids or organic acids.
The process of the invention allows a single pot reaction to be carried out in one phase. A good yield is achieved in a relatively short time. It is believed that the key to such a successful process is the creation of very strong basic conditions using a tertiary amine, especially diisopropylethylamine.
It will be appreciated that while the invention has been described with reference to a process for preparing the particular phenylisopropylamine Selegiline, the process may also be applied to preparing other isopropylamine derivatives.
The invention is not limited to the embodiments hereinbefore described which may be varied in detail.
Claims (11)
1. A process for preparing a phenylisopropylamine
derivative including the steps of:
mixing an appropriate starting material, a
solvent and a tertiary amine base, and
introducing a propargyl or 2-halogeno-propenyl
radical.
2. A process as claimed in claim 1 wherein the
phenylisopropylamine derivative is selegiline.
3. A process as claimed in claim 1 or 2 wherein the
tertiary amine base is diisopropylethylamine.
4. A process as claimed in claim 3 wherein the starting
material is methamphetamine.
5. A process as claimed in any preceding claim wherein
the solvent is toluene.
6. A process as claimed in any preceding claim wherein
propargylbromide is added and diisopropylethylamine
hydrobromid salt is precipitated.
7. A process as claimed in claim 6 wherein the organic
layer formed is concentrated and the desired
phenylisopropylamine derivative is isolated.
8. A process as claimed in claim 7 wherein HCl is added
to form Selegiline.HCl.
9. A process substantially as hereinbefore described
with reference to the example.
10. A phenylisopropylamine derivative whenever prepared
by a process as claimed in any of claims 1 to 9.
11. Selegiline or Selegiline.HCl whenever prepared by a
process as claimed in any of claims 1 to 9.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IE930972 | 1993-12-16 | ||
| IE027194 IES61604B2 (en) | 1993-12-16 | 1994-03-29 | A process for producing pharmaceutical compounds |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| GB9413847D0 GB9413847D0 (en) | 1994-08-24 |
| GB2284810A true GB2284810A (en) | 1995-06-21 |
| GB2284810B GB2284810B (en) | 1998-07-08 |
Family
ID=26319672
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB9413847A Expired - Fee Related GB2284810B (en) | 1993-12-16 | 1994-07-08 | A process for producing Selegiline |
Country Status (2)
| Country | Link |
|---|---|
| GB (1) | GB2284810B (en) |
| IE (2) | IES61604B2 (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1031425A (en) * | 1962-03-30 | 1966-06-02 | Chinoin Gyogyszer Es Vegyeszet | New aralkylamines and their preparation |
| GB1242109A (en) * | 1967-10-25 | 1971-08-11 | Chinoin Gyogyszer Es Vegyeszet | New isopropylamine derivatives and process for the preparation thereof |
| EP0099302A2 (en) * | 1982-07-14 | 1984-01-25 | CHINOIN Gyogyszer és Vegyészeti Termékek Gyára RT. | New process for the preparation of propargyl amines |
| WO1985005617A1 (en) * | 1984-05-31 | 1985-12-19 | Chinoin Gyógyszer és Vegyészeti Termékek Gyára Rt. | Phenylisopropylamine derivative and its preparation |
-
1994
- 1994-03-29 IE IE027194 patent/IES61604B2/en not_active IP Right Cessation
- 1994-07-04 IE IE940543A patent/IE940543A1/en not_active IP Right Cessation
- 1994-07-08 GB GB9413847A patent/GB2284810B/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1031425A (en) * | 1962-03-30 | 1966-06-02 | Chinoin Gyogyszer Es Vegyeszet | New aralkylamines and their preparation |
| GB1242109A (en) * | 1967-10-25 | 1971-08-11 | Chinoin Gyogyszer Es Vegyeszet | New isopropylamine derivatives and process for the preparation thereof |
| EP0099302A2 (en) * | 1982-07-14 | 1984-01-25 | CHINOIN Gyogyszer és Vegyészeti Termékek Gyára RT. | New process for the preparation of propargyl amines |
| WO1985005617A1 (en) * | 1984-05-31 | 1985-12-19 | Chinoin Gyógyszer és Vegyészeti Termékek Gyára Rt. | Phenylisopropylamine derivative and its preparation |
Also Published As
| Publication number | Publication date |
|---|---|
| GB9413847D0 (en) | 1994-08-24 |
| GB2284810B (en) | 1998-07-08 |
| IE940543A1 (en) | 1995-06-28 |
| IES940271A2 (en) | 1994-11-16 |
| IES61604B2 (en) | 1994-11-16 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PCNP | Patent ceased through non-payment of renewal fee |
Effective date: 20070708 |