IES61604B2 - A process for producing pharmaceutical compounds - Google Patents
A process for producing pharmaceutical compoundsInfo
- Publication number
- IES61604B2 IES61604B2 IES940271A IES61604B2 IE S61604 B2 IES61604 B2 IE S61604B2 IE S940271 A IES940271 A IE S940271A IE S61604 B2 IES61604 B2 IE S61604B2
- Authority
- IE
- Ireland
- Prior art keywords
- selegiline
- phenylisopropylamine
- added
- solvent
- pharmaceutical compounds
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 13
- 150000001875 compounds Chemical class 0.000 title abstract description 7
- MEZLKOACVSPNER-GFCCVEGCSA-N selegiline Chemical compound C#CCN(C)[C@H](C)CC1=CC=CC=C1 MEZLKOACVSPNER-GFCCVEGCSA-N 0.000 claims abstract description 15
- 229960003946 selegiline Drugs 0.000 claims abstract description 15
- FRCFWPVMFJMNDP-UHFFFAOYSA-N n-propan-2-ylaniline Chemical class CC(C)NC1=CC=CC=C1 FRCFWPVMFJMNDP-UHFFFAOYSA-N 0.000 claims abstract description 14
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 13
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000002904 solvent Substances 0.000 claims abstract description 5
- 150000003512 tertiary amines Chemical class 0.000 claims abstract description 5
- YORCIIVHUBAYBQ-UHFFFAOYSA-N propargyl bromide Chemical compound BrCC#C YORCIIVHUBAYBQ-UHFFFAOYSA-N 0.000 claims abstract description 4
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 claims abstract description 3
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 claims abstract description 3
- 229960001252 methamphetamine Drugs 0.000 claims abstract description 3
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 239000007858 starting material Substances 0.000 claims description 4
- 239000012044 organic layer Substances 0.000 claims description 3
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical class Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims 1
- 150000001412 amines Chemical class 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 229940123685 Monoamine oxidase inhibitor Drugs 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- SWLQAGBBUFCESY-UHFFFAOYSA-N ethyl-di(propan-2-yl)azanium;bromide Chemical compound Br.CCN(C(C)C)C(C)C SWLQAGBBUFCESY-UHFFFAOYSA-N 0.000 description 2
- 239000002899 monoamine oxidase inhibitor Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 239000002830 appetite depressant Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000003218 coronary vasodilator agent Substances 0.000 description 1
- 230000003001 depressive effect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 229940093499 ethyl acetate Drugs 0.000 description 1
- 235000019439 ethyl acetate Nutrition 0.000 description 1
- 230000003400 hallucinatory effect Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical class CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- MYWUZJCMWCOHBA-SECBINFHSA-N levmetamfetamine Chemical compound CN[C@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-SECBINFHSA-N 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- IYETZZCWLLUHIJ-UHFFFAOYSA-N methyl-(1-phenylpropan-2-yl)-prop-2-ynylazanium;chloride Chemical compound Cl.C#CCN(C)C(C)CC1=CC=CC=C1 IYETZZCWLLUHIJ-UHFFFAOYSA-N 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229960003678 selegiline hydrochloride Drugs 0.000 description 1
- 239000003204 tranquilizing agent Substances 0.000 description 1
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.
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. v
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
CH3
I
C6H5CHZ-CH-N-CH2-C=CH. HC1 i
ch3
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;-
4
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 10 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, 15 the desired phenylisopropylamine derivative is Selegiline.
Preferably, HC1 is added to form Selegiline HC1.
The invention also provides a phenylisopropylamine derivative, especially Selegiline or Selegiline.HC1 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 mis of diisopropylethylamine were mixed at room temperature. To that clear solution 533.4 mis propargylbromide (80% solution in toluene) was added and diisopropylethylamine-hydrobromid salt precipitated. The temperature rose to 59°C. 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 HC1 gas was added until Selegiline HC1 was crystallised. After recrystallisation in ethylacetate and methanol 410.5 grs of Selegiline HC1 were obtained.
Melting Point: 142.5 - 147°C 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 diisopropvlethylamine.
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 4 hereinbefore described which may be varied in detail.
Claims (5)
1' A process for preparing a phenylisopropylamine derivative, especially Selegiline, 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 tertiary 10 amine base is diisopropylethylamine, preferably the starting material is methamphetamine, preferably the solvent is toluene.
3. A process as claimed in claim 1 or 2 wherein propargylbromide is added and diisopropvlethylamine- 15 hydrobromid salt is precipitated, preferably the organic layer formed is concentrated and the desired phenylisopropylamine derivative is isolated, preferably HC1 is added to form Selegiline.HC1.
4. A process substantially as hereinbefore described 20 with reference to the Example.
5. A phenylisopropylamine derivative, especially Selegiline or Selegiline.HC1 whenever prepared by a process as claimed in any of claims 1 to 4.
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IE027194A IES940271A2 (en) | 1993-12-16 | 1994-03-29 | "A process for producing pharmaceutical compounds" |
| IE940543A IE940543A1 (en) | 1993-12-16 | 1994-07-04 | A process for producing pharmaceutical compounds |
| GB9413847A GB2284810B (en) | 1993-12-16 | 1994-07-08 | A process for producing Selegiline |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IE930972 | 1993-12-16 | ||
| IE027194A IES940271A2 (en) | 1993-12-16 | 1994-03-29 | "A process for producing pharmaceutical compounds" |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IES61604B2 true IES61604B2 (en) | 1994-11-16 |
| IES940271A2 IES940271A2 (en) | 1994-11-16 |
Family
ID=26319672
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE027194A IES940271A2 (en) | 1993-12-16 | 1994-03-29 | "A process for producing pharmaceutical compounds" |
| IE940543A IE940543A1 (en) | 1993-12-16 | 1994-07-04 | A process for producing pharmaceutical compounds |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE940543A IE940543A1 (en) | 1993-12-16 | 1994-07-04 | A process for producing pharmaceutical compounds |
Country Status (2)
| Country | Link |
|---|---|
| GB (1) | GB2284810B (en) |
| IE (2) | IES940271A2 (en) |
Family Cites Families (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 |
| DE1802297C3 (en) * | 1967-10-25 | 1974-10-17 | Chinoin Gyogyszer Es Vegyeszeti Termekek Gyara Rt, Budapest | Isopropylamine derivatives and processes for their preparation |
| HU187775B (en) * | 1982-07-14 | 1986-02-28 | Chinoin Gyogyszer Es Vegyeszeti Termekek Gyara Rt,Hu | New process for producing propargile-amines of pharmaceutical activity |
| HU207282B (en) * | 1984-05-31 | 1993-03-29 | Chinoin Gyogyszer Es Vegyeszet | Process for producing phenyl-alkyl-amine derivatives and pharmaceutical compositions containing them |
-
1994
- 1994-03-29 IE IE027194A patent/IES940271A2/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
Also Published As
| Publication number | Publication date |
|---|---|
| GB2284810B (en) | 1998-07-08 |
| IES940271A2 (en) | 1994-11-16 |
| GB9413847D0 (en) | 1994-08-24 |
| IE940543A1 (en) | 1995-06-28 |
| GB2284810A (en) | 1995-06-21 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MK9A | Patent expired |