IES64896B2 - Process for the resolution of racemic 3-(2-pyridyl)-3-phenyl-N,N-dimethylpropylamines - Google Patents
Process for the resolution of racemic 3-(2-pyridyl)-3-phenyl-N,N-dimethylpropylaminesInfo
- Publication number
- IES64896B2 IES64896B2 IES950207A IES64896B2 IE S64896 B2 IES64896 B2 IE S64896B2 IE S950207 A IES950207 A IE S950207A IE S64896 B2 IES64896 B2 IE S64896B2
- Authority
- IE
- Ireland
- Prior art keywords
- compound
- pyridyl
- formula
- acid
- pharmaceutically acceptable
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 19
- IJHNSHDBIRRJRN-UHFFFAOYSA-N N,N-dimethyl-3-phenyl-3-(2-pyridinyl)-1-propanamine Chemical class C=1C=CC=NC=1C(CCN(C)C)C1=CC=CC=C1 IJHNSHDBIRRJRN-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 19
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 12
- 150000003839 salts Chemical class 0.000 claims abstract description 10
- 239000002253 acid Substances 0.000 claims abstract description 8
- 238000004519 manufacturing process Methods 0.000 claims abstract description 5
- -1 3,5-disubstituted benzoic acid Chemical class 0.000 claims abstract description 3
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 3
- 239000000460 chlorine Substances 0.000 claims abstract description 3
- 125000001309 chloro group Chemical group Cl* 0.000 claims abstract description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- 238000006243 chemical reaction Methods 0.000 claims description 5
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- VYWYYJYRVSBHJQ-UHFFFAOYSA-N 3,5-dinitrobenzoic acid Chemical group OC(=O)C1=CC([N+]([O-])=O)=CC([N+]([O-])=O)=C1 VYWYYJYRVSBHJQ-UHFFFAOYSA-N 0.000 claims description 3
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 2
- 230000003197 catalytic effect Effects 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims description 2
- 239000011976 maleic acid Substances 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 abstract description 2
- 230000001387 anti-histamine Effects 0.000 abstract description 2
- 239000000739 antihistaminic agent Substances 0.000 abstract description 2
- 230000000694 effects Effects 0.000 abstract description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- VYWYYJYRVSBHJQ-UHFFFAOYSA-M 3,5-dinitrobenzoate Chemical compound [O-]C(=O)C1=CC([N+]([O-])=O)=CC([N+]([O-])=O)=C1 VYWYYJYRVSBHJQ-UHFFFAOYSA-M 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000012452 mother liquor Substances 0.000 description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 150000001558 benzoic acid derivatives Chemical class 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
- 238000010899 nucleation Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 229910052736 halogen Chemical group 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 150000003512 tertiary amines Chemical group 0.000 description 1
Landscapes
- Pyridine Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A process for preparing in essentially pure form the d-isomer of a compound of the formula I wherein X is chlorine and n is 0 or 1, or a pharmaceutically acceptable addition salt thereof, comprises reacting the dl-form of a compound formula I with a 3,5-disubstituted benzoic acid as resolving agent and, if desired, converting the compound thus obtained into a pharmaceutically acceptable acid addition salt thereof. These compounds have strong anti-histamine activity.
Description
APPLICATION Nc...............—«
Process for the Resolution of Racemic 3-(2-Pvridvl)-3-phenvl-N.IV-
dimethvlpropvlamines.
This invention relates to a process for the resolution of racemic 3-(2-pyridyl)-3-phenylΝ,Ν-dimethylpropylamines. In particular, it relates to a process for the preparation of the tZ-isomers of compounds of the formula I
wherein X is chlorine, and n is 0 or 1, and salts thereof.
These compounds are well known and have strong anti-histamine activity.
U.S. Patent Specification No. 3,061,517 describes a process for the separation of the disomers of phenyl-(2-pyridyl)-alkyl substituted tertiary amines and halogen substituted derivatives thereof from a racemic mixture of same. However, the resolving agent, dphenylsuccinic acid is difficult to manufacture and is therefore expensive. The process must be carried out in an organic solvent. Furthermore, successive purification steps by multiple recrystallisation are required with consequent low yields and high costs of the desired products.
It is the object of the invention to provide a superior process for preparing the rf-isomer of a compound of the formula I as defined above.
According to the invention there is provided a process for preparing, in essentially pure form, the d-isomer of a compound of the formula I wherein X and n are as already defined, or a pharmaceutically acceptable addition salt thereof, which process comprises reacting the (//-form of a compound of the formula I with a 3,5-disubstituted benzoic acid
-2and, if desired, converting the compound thus obtained into a pharmaceutically acceptable acid addition salt thereof.
The {/-isomers obtained according to the process of the invention are essentially optically pure and can be reacted with suitable mineral and organic acids to form pharmaceutically ¢:
acceptable acid addition salts thereof. Examples of suitable acids are hydrochloric acid, hydrobromic acid, tartaric acid, citric acid, succinic acid, maleic acid and fumaric acid. »
The substituents on the benzene radical of the resolving agent may be methyl, bromo or nitro. Preferably, the resolving agent is 3,S-dinitrobenzoic acid.
The separation of the {/and /-isomers of the compound of the formula I is accomplished in a continuous cyclic process using the achiral disubstituted benzoic acid as the resolving agent. The process is designed on the basis that addition salts of the compound of the formula I with the disubstituted benzoic acid crystallise in a form in which individual crystals are comprised entirely of pure {/- or pure /-isomer. Seeding a saturated solution, for example, with pure {/-isomer affords a crop greatly enriched in that isomer. The /isomer is then obtained by appropriate seeding of the mother liquor. The balance of the mother liquor is restored after each cycle by the addition of the appropriate quantities of racemate and resolving agent.
The reaction of the dl-form of a compound of the formula I with the resolving agent is preferably carried out in water in the presence of a mineral acid, preferably hydrochloric acid. The undesired /-isomer, after conversion back to the {//-form, and the resolving agent are cycled back into the process.
The mole ratio of racemate to resolving agent is not critical but is preferably in the range of from 2:1 to 3 :1.
Following the reaction between the racemate and resolving agent, the product can be removed and washed with water. Following extraction of the resulting product into a ,.
V solvent, the pure {/-isomer of the formula I can be obtained by distillation of the solvent.
-3The reaction is typically performed at a temperature of 20 to 90°C, the preferred temperature being 60 to 80°C.
The invention is illustrated by the following Example.
EXAMPLE (a) d'-3-(2-Pyridyl)-3-(p-chJorophenyl)-NJV-dimethyIpropylamine
A mixture of 105 g of d, /-3-(2-pyridyl)-3-(p-chlorophenyl)-N,N-dimethylpropylamine, 31 g of /-3-(2-pyridyl)-3-(p-chIorophenyl)-N,N-dimethylpropyIamine 3,5-dinitrobenzoate, 11 g of 3,5-dinitrobenzoic acid, 26.5 mi of concentrated hydrochloric acid and 200 ml of water is agitated at a temperature or about 70° C for about 12 hours. The precipitated /-3(2-pyridyl)-3-(p-chlorophenyl)-N,N-dimethylpropylaniine 3,5-dinitrobenzoate is removed by filtration at about 20°C.
To the mother liquor is added 25 g of 4/-3-(2-pyridyl)-3-(p-chlorophenyl)-N,N-dimethyIpropylamine, and 28 g of 3,5-dinitrobenzoic add (alternately the 3,5-dinitrobenzoate salt of the cff-form may be used) and the mixture is agitated at a temperature of about 70° C for about 12 hours. The predpitated
The 23* +49° to +53° (cone., 5% in dimethylformamide). The yield from each cycle is about 33% but overall is essentially quantitative.
-4The /-3-(2-pyridyl)-3-(p-chlorophenyl)-N,N-dimethylpropylamine 3,5-dinitrobenzoate, isolated on alternate cycles of the process, is converted back to the d7-form by heating in aqueous hydrochloric add in the presence of a catalytic amount Of maleic add. The d7-3(2-pyridyl)-3-(p-chlorophenyl)-N,N-dimethylpropylamine 3,5-dinitrobenzoate so obtained is recycled back into the process.
(b) d-3-(2-Pyridyl>3-(p-chIorophenyl)-N,N-
Fifty grams of the above base, ef-3-(2-pyridyl)-3-(p-chlorophenyl)-N,N-
The d-3-(2-pyridyl)-3-(p-chlorophenyl)-N,N-dimethylpropylamine maleate so obtained is filtered, washed with ethyl acetate and dried.
M.P. 112-115°, [ajo25’ +39.5 to +43.0® (cone., 5% in dimethylformamide).
Claims (5)
1. A process for preparing in essentially pure form the rf-isomer of a compound of the formula I wherein X is chlorine and n is 0 or 1, or a pharmaceutically acceptable addition salt thereof, which process comprises reacting the d/-form of a compound of formula I with a 3,5-disubstituted benzoic acid as resolving agent and, if desired, converting the compound thus obtained into a pharmaceutically acceptable acid addition salt thereof.
2. A process according to claim 1, wherein the resolving agent is 3,5-dinitrobenzoic acid, and the reaction is carried out in water.
3. A process according to claim 1 or 2 wherein the /-form of the compound of formula I, obtained in alternate cycles of the process, is converted back to the d/-form by heating in aqueous hydrochloric acid in the presence of a catalytic amount of maleic acid.
4. A process according to any preceding claim, wherein the compound prepared is d-3-(2-pyridyl)-3-(p-chlorophenyl)-N,N-dimethylpropylamine or d-3-(2-pyridyl)-3-phenyl-N,N-dimethylpropylamine or a pharmaceutically acceptable acid addition salt thereof.
5. A pharmaceutical composition containing a compound prepared by a process claimed in any preceding claim.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IES950207 IES64896B2 (en) | 1995-03-23 | 1995-03-23 | Process for the resolution of racemic 3-(2-pyridyl)-3-phenyl-N,N-dimethylpropylamines |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IES950207 IES64896B2 (en) | 1995-03-23 | 1995-03-23 | Process for the resolution of racemic 3-(2-pyridyl)-3-phenyl-N,N-dimethylpropylamines |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IES950207A2 IES950207A2 (en) | 1995-09-20 |
| IES64896B2 true IES64896B2 (en) | 1995-09-20 |
Family
ID=11040690
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IES950207 IES64896B2 (en) | 1995-03-23 | 1995-03-23 | Process for the resolution of racemic 3-(2-pyridyl)-3-phenyl-N,N-dimethylpropylamines |
Country Status (1)
| Country | Link |
|---|---|
| IE (1) | IES64896B2 (en) |
-
1995
- 1995-03-23 IE IES950207 patent/IES64896B2/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| IES950207A2 (en) | 1995-09-20 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MM4A | Patent lapsed |