IES65748B2 - Process for the separation of the optical antipodes of racemic phenyl-(2-Pyridyl)-dimethylpropylamines - Google Patents
Process for the separation of the optical antipodes of racemic phenyl-(2-Pyridyl)-dimethylpropylaminesInfo
- Publication number
- IES65748B2 IES65748B2 IES950206A IES65748B2 IE S65748 B2 IES65748 B2 IE S65748B2 IE S950206 A IES950206 A IE S950206A IE S65748 B2 IES65748 B2 IE S65748B2
- Authority
- IE
- Ireland
- Prior art keywords
- compound
- pyridyl
- salt
- formula
- acid
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 16
- 230000003287 optical effect Effects 0.000 title description 4
- 238000000926 separation method Methods 0.000 title description 4
- NSAGKCVHEKTUFT-UHFFFAOYSA-N N,N-dimethyl-1-phenyl-1-pyridin-2-ylpropan-1-amine Chemical class C1(=CC=CC=C1)C(CC)(N(C)C)C1=NC=CC=C1 NSAGKCVHEKTUFT-UHFFFAOYSA-N 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 20
- 150000003839 salts Chemical class 0.000 claims abstract description 16
- 239000002253 acid Substances 0.000 claims abstract description 15
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 13
- 235000003704 aspartic acid Nutrition 0.000 claims abstract description 7
- -1 benzenesulphonyl aspartic acid Chemical class 0.000 claims abstract description 7
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 claims abstract description 5
- 125000001309 chloro group Chemical group Cl* 0.000 claims abstract description 4
- 238000004519 manufacturing process Methods 0.000 claims abstract description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims abstract description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims abstract description 3
- 229910052794 bromium Chemical group 0.000 claims abstract description 3
- 239000000460 chlorine Substances 0.000 claims abstract description 3
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 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 5
- 159000000000 sodium salts Chemical class 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- 230000001387 anti-histamine Effects 0.000 abstract description 2
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000000243 solution Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 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
- 238000000746 purification Methods 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000011976 maleic acid Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 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
- 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
- 125000000217 alkyl group Chemical group 0.000 description 1
- 150000001510 aspartic acids Chemical class 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000012452 mother liquor Substances 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
- 239000002244 precipitate Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
Landscapes
- Pyridine Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A process for preparing in substantially pure form the d-isor of a compound of the formula I wherein X is chlorine or bromine and n is 0 or 1, or a pharmaceutically acceptable acid addition salt thereof, comprises reacting the d1-form of a compound of the formula I with a D-substituted benzenesulphonyl aspartic acid or a salt thereof as resolving agent and, if desired, converting the compound thus obtained into a pharmaceutically acceptable acid addition salt thereof. These compounds have strong anti-histaminic activity.
Description
PROCESS FOR THE SEPARATION OF THE OPTICAL ANTIPODES OP RACEMIC PHENYL-(2-PYRIDYL)-DIMETHYLPROPYLAMINES
This invention relates to a process for the separation ί of the optical antipodes of racemic phenyl-(2-pyridyl)dimethylpropylamines. In particular, it relates to a process for the preparation of the d-isomers of compounds of the formula I
wherein X is chlorine or bromine, and n is 0 or 1, and salts thereof.
These compounds are well known and have strong anti-histaminic activity.
U.S. Patent Specification No. 3,061,517 describes a process for the separation of the d-isomers of phenyl-(2-pyridyl)-alkyl substituted tertiary amines and certain halogen-substituted derivatives thereof from a racemic mixture of- same. However, the resolving agent, d-phenylsuccinic acid, used in this process is difficult to prepare and therefore expensive. The reaction must also be carried out in an organic solvent. Furthermore, successive purification steps by recrystallisation are required with consequent low yields of the end products.
- 2 S65748
It is an object of the invention to provide an improved process for preparing the d-isomer of a compound of the formula I as defined above.
According to the invention there is provided a process for preparing, in substantially pure form, the d-isomer of a compound of the formula I
wherein X and n are as already defined, or a pharmaceutically acceptable acid addition salt thereof, which process comprises reacting the dl-form of a compound of the formula I with a D-substituted benzenesulphonyl aspartic acid or a salt thereof as resolving agent and, if desired, converting the compound thus obtained into a pharmaceutically acceptable acid addition salt thereof.
The d-isomers obtained according to the process of the invention are substantially free of their optical antipodes and can be reacted with suitable mineral and organic acids to form the corresponding pharmaceutically acceptable acid addition salts thereof. Examples of suitable acids are hydrochloric acid, hydrobromic acid, tartaric acid, citric acid, succinic acid and maleic acid.
The substituent on the benzenesulphonyl radical of the resolving agent may be, for example, C^_4 alkyl, nitro, bromo or chloro. Preferably, the resolving agent is
D-tosylaspartic acid or a salt thereof, preferably the ** sodium salt thereof.
1 Prior to the reaction with the resolving agent, the dl-form of the compound of the formula I is preferably treated with an L-substituted benzenesulphonyl aspartic acid or a salt thereof, in order to remove a large proportion of the undesired 1-isomer of the compound of the formula I. This step eliminates the requirement for subsequent successive purification steps by recrystalisation, thus improving the efficiency of the process and the yield of the end product.
D- and L-substituted benzenesulphonyl aspartic acids can be readily obtained in conventional manner in high yield from the commercially available aspartic acids and without the use of any organic solvents.
The reaction of the dl-form of a compound of the formula I with the resolving agent is preferably carried out in water. The volume of water required is far less than the volume of solvent required in the process described in U.S. Patent Specification No. 3,061,517. The resolving agent in aqueous solution can be readily cycled back into the process without the need for isolation or purification.
The mole ratio of racemate to resolving agent is not critical but is preferably in the range of from about
1:1 to 2:1.
f
Following the reaction between the racemate and resolving agent, the product can be removed by filtration and washed with solvent, preferably water.
Following extraction of the resulting product into a solvent, the pure d-isomer of the compound of formula I can be obtained by distillation of the solvent. M.
The reaction is typically performed at a temperature of f
to 50°C, the preferred temperature being 20 to 30°C.
The invention is illustrated by the following Example.
EXAMPLE io (a) d-3-(2-Pyridyl)-3-p-bromophenyl-N,N-dimethylpropylamine
Sixty-five grams of racemic 3-(2-pyridyl)-3-p15 bromophenyl-N,N-dimethylpropylamine are combined with an aqueous solution of sodium L-tosylaspartate (equivalent to about 50 g of L-tosylarpartic acid). The pH is adjusted to about 4 with concentrated hydrochloric acid, and the undesired 2-3-(2-pyridyl)-3-p-bromophenylΝ,Ν-dimethyl-propylamine L-tosy.laspartate salt which precipitates is removed by filtration.
The mother liquor, now greatly enriched in the desired d-isomer, is made strongly alkaline with
40% aqueous sodium hydroxide, and the liberated base is extracted into toluene. The toluene solution is extracted with 170 ml of dilute (10%) hydrochloric acid. The resultant solution (containing about 39 g of crude d-3-(2-pyridyl)3-p-bromophenyl-N,N-dimethylpropylamine) is treated with 120 ml of an aqueous solution of sodium D-tosylaspartate (equivalent to about 33 g of D-tosylaspartic acid). The pH is adjusted to about 4.5 with hydrochloric acid, and the mixture is stirred for about 10 hours. Hydrocholoric acid is used to partially neutralise the racemic 3-(2-pyridyl)-3-p-bromopheny1-N,N-dimethylpropy1amine, thus reducing the requirement for a full equivalent of the tosylaspartic acids. The precipitated product is filtered and washed with water. The wet product is dispersed in about one volume of water, the solution is made alkaline with 40% aqueous sodium hydroxide, and the liberated base is extracted into toluene. The solution is washed with water and the toluene is removed by distillation.
The d-3-(2-pyridyl)-3-p-bromophenyl-N,N-dimethylpropylamine so obtained is a mobile oil; [a]D25° + 73 to + 76° (cone., 10% in toluene). The yield is 80%.
d-3-(2-Pyridyl)-3-p-bromophenyl-N,N-dimethylpropylamine maleate
Fifteen grams of the above base, d-3-(2-pyridyl)3-p-bromophenyl-N,N-dimethylpropylamine, and 5.3 g of maleic acid are dissolved in 100 ml of ethyl acetate and heated to about 65° to 70°C. The solution is cooled and stirred for ca. 3 hours.
The d-3-(2-pyridyl)-3-p-bromophenyl-N,N-dimethylpropylamine maleate so obtained is filtered, washed with ethyl acetate and dried.
M.P. 105-113°C, [a]D25° + 35.0 to + 38.5° (cone.,
% in dimethylformamide).
Claims (5)
1. A process for preparing in substantially pure form the d-isomer of a compound of the formula I f wherein X is chlorine or bromine and n is 0 or 1, or a pharmaceutically acceptable acid addition salt thereof, which process comprises reacting the dl-form of a compound of the formula I with a D-substituted benzenesulphonyl aspartic acid or a salt thereof 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 D-tosylaspartic acid or a salt thereof, preferably the sodium salt thereof, and the reaction is carried out in water.
3. A process according to claim 1 or 2 wherein the dl-form of the compound of the formula I is treated with an L-substituted benzenesulphonyl aspartic acid or a salt thereof, preferably L-tosylaspartic acid or the sodium salt thereof, prior to the reaction with the resolving agent.
4. A process according to any preceding claim, wherein the compound prepared is d-3-(2-pyridyl)-3-pchlorophenyl-N,N-dimethylpropylamine, d-3(2-pyridyl)-3-p-bromophenyl-N,N-dimethylpropylamine maleate or d-3-(2-pyridyl)-3-phenyl-N,N-dimethylpropylamine .
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 |
|---|---|---|---|
| IES950206 IES65748B2 (en) | 1995-03-23 | 1995-03-23 | Process for the separation of the optical antipodes of racemic phenyl-(2-Pyridyl)-dimethylpropylamines |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IES950206 IES65748B2 (en) | 1995-03-23 | 1995-03-23 | Process for the separation of the optical antipodes of racemic phenyl-(2-Pyridyl)-dimethylpropylamines |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IES950206A2 IES950206A2 (en) | 1995-11-01 |
| IES65748B2 true IES65748B2 (en) | 1995-11-01 |
Family
ID=11040689
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IES950206 IES65748B2 (en) | 1995-03-23 | 1995-03-23 | Process for the separation of the optical antipodes of racemic phenyl-(2-Pyridyl)-dimethylpropylamines |
Country Status (1)
| Country | Link |
|---|---|
| IE (1) | IES65748B2 (en) |
-
1995
- 1995-03-23 IE IES950206 patent/IES65748B2/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| IES950206A2 (en) | 1995-11-01 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MM4A | Patent lapsed |