WO2006131773A1 - Process for the preparation of s-(-)-amlodipine - Google Patents
Process for the preparation of s-(-)-amlodipine Download PDFInfo
- Publication number
- WO2006131773A1 WO2006131773A1 PCT/HU2006/000050 HU2006000050W WO2006131773A1 WO 2006131773 A1 WO2006131773 A1 WO 2006131773A1 HU 2006000050 W HU2006000050 W HU 2006000050W WO 2006131773 A1 WO2006131773 A1 WO 2006131773A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- amlodipine
- hemitartrate
- tartaric acid
- solvate
- dimethylformamide
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 23
- 238000002360 preparation method Methods 0.000 title claims abstract description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims abstract description 51
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims abstract description 21
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims abstract description 19
- 239000012453 solvate Substances 0.000 claims abstract description 18
- 239000001358 L(+)-tartaric acid Substances 0.000 claims abstract description 16
- 235000011002 L(+)-tartaric acid Nutrition 0.000 claims abstract description 16
- FEWJPZIEWOKRBE-LWMBPPNESA-N L-(+)-Tartaric acid Natural products OC(=O)[C@@H](O)[C@H](O)C(O)=O FEWJPZIEWOKRBE-LWMBPPNESA-N 0.000 claims abstract description 16
- 150000003839 salts Chemical class 0.000 claims abstract description 13
- 229960000528 amlodipine Drugs 0.000 claims abstract description 12
- 239000002904 solvent Substances 0.000 claims abstract description 11
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 7
- 239000012442 inert solvent Substances 0.000 claims abstract description 4
- 239000000126 substance Substances 0.000 abstract description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000000926 separation method Methods 0.000 description 5
- 239000012153 distilled water Substances 0.000 description 4
- AUONNNVJUCSETH-UHFFFAOYSA-N icosanoyl icosanoate Chemical compound CCCCCCCCCCCCCCCCCCCC(=O)OC(=O)CCCCCCCCCCCCCCCCCCC AUONNNVJUCSETH-UHFFFAOYSA-N 0.000 description 4
- 239000012452 mother liquor Substances 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- HTIQEAQVCYTUBX-UHFFFAOYSA-N amlodipine Chemical compound CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1Cl HTIQEAQVCYTUBX-UHFFFAOYSA-N 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 238000001556 precipitation Methods 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- KMPWYEUPVWOPIM-KODHJQJWSA-N cinchonidine Chemical compound C1=CC=C2C([C@H]([C@H]3[N@]4CC[C@H]([C@H](C4)C=C)C3)O)=CC=NC2=C1 KMPWYEUPVWOPIM-KODHJQJWSA-N 0.000 description 2
- KMPWYEUPVWOPIM-UHFFFAOYSA-N cinchonidine Natural products C1=CC=C2C(C(C3N4CCC(C(C4)C=C)C3)O)=CC=NC2=C1 KMPWYEUPVWOPIM-UHFFFAOYSA-N 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000010899 nucleation Methods 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 230000005526 G1 to G0 transition Effects 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical class O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 206010047139 Vasoconstriction Diseases 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 208000011775 arteriosclerosis disease Diseases 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000000480 calcium channel blocker Substances 0.000 description 1
- 230000008061 calcium-channel-blocking effect Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- PVNIIMVLHYAWGP-UHFFFAOYSA-N nicotinic acid Natural products OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 230000015590 smooth muscle cell migration Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 210000004509 vascular smooth muscle cell Anatomy 0.000 description 1
- 230000025033 vasoconstriction Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
- C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
Definitions
- the invention relates to a novel process for the preparation of S-(-)-amlodipine (chemical name: S-(-)-2-(2-aminoethoxy)-methyl-4-(2-chlorophenyl)-3 -ethoxycarbonil-5- methoxycarbonyl-6-methyl-l,4-dihydropiridine) of the formula I
- the invention provides S-(-)-amlodipine-L(+)-hemitartrate dimethylformarnide solvate synthetic intermediate being useful for the preparation of S-(-)-amlodipine.
- Amlodipine and the salts thereof were reported first in the European Patent Specification No. 89 167 are calcium channel blocking agents of long duration of action, and because of their activity they are useful in the treatment of cardiovascular disease, hypertension, angina pectoris, ischemic heart disease.
- (R,S)-amlodipine or salts thereof are used mostly in pharmaceutical compositions.
- the two types of enantiomers of amlodipine and salts thereof have different pharmacological properties (see: J. Med. Chem., (1986) 29, 1696-1702), S-(-)-amlodipine is twice as active as the enantiomeric mixture regarding their calcium channel blocking activity.
- R-(+)-amlodipine is a potent inhibitor of vascular smooth muscle cell migration therefore it can be used in the treatment of arteriosclerosis and vasoconstriction.
- dimethylacetamide is used as solvent and also D-(-)-tartaric acid is necessary for obtaining S-(-)-amlodipine.
- Dimethylacetamide like the DMSO used in the previous process plays a double role as well: as solvent and as associate in the diastereomeric salt formation.
- L-(+)-tartaric acid is used during the resolution, but it is used for isolation of the R-(+) isomer.
- the S-(-) enantiomer is isolated from the mother liquor by seeding or precipitation by adding solvent.
- (+)-amlodipine-L-(+)-hemitartrate DMSO solvate is precipitated from (R,S)-amlodipine base in DMSO solvent with L-(+) tartaric acid, then S-(-)-amlodipine-L-(+)-hemitartrate DMSO solvate is isolated from the mother liquor by seeding.
- R-(+)-amlodipine could be obtained by a process similar to the above- mentioned one, where D-(-)-tartaric acid was used instead of L-(+)-tartaric acid.
- S-(-)-enantiomeric product can be obtained directly by using the natural L-(+)-tartaric acid; the manufacturing process becomes easier and more economical and gives the product in high purity.
- the object of the invention is a process for the preparation of S-(-)-amlodipine (chemical name: S-(-)-2-(2-aminoethoxy)-methyl-4-(2-chlorophenyl)-3 -ethoxycarbonil-5- methoxycarbonyl-6-methyl-l,4-dihydropiridine) of the formula I starting from (R 5 S)- amlodipine by diastereomeric salt formation, in which the (R,S)-amlodipine is reacted with 0.5-1.5 mol of L-(+)-tartaric acid in dimethylformamide solvent and the forming S-(-)- amlodipine-L(+)-hemitartrate dimethylformamide solvate of the formula II is reacted with base in inert solvent.
- S-(-)-amlodipine chemical name: S-(-)-2-(2-aminoethoxy)-methyl-4-(2-chlorophenyl)-3 -eth
- the another object of the invention is the novel S-(-)-amlodipine derivative of the formula II S-(-)-amlodipine L(+)-hemitartrate dimethylfomamide solvate.
- Example 1 S-(-)-amlodipine-L(+)-hemitartrate dimethylfomamide solvate 2.0 g (0,005 mol) of (R,S)-amlodipine base is dissolved in 36 ml (0.46 mol) of dimethylformamide at ambient temperature during stirring and to this mixture a solution of 1.12 g (0,0075 mol) (1.5 eq.) of L-(+)-tartaric acid in 36 ml (0.46 mol) of dimethylformamide is added during continuous stirring.
- Example 2 1.0 g (0.005 mol) of crystalline S-(-)-amlodipine-L(+)-hemitartrate dimethylformamide solvate as described in Example 1 is dissolved in a mixture of about 30 ml of dichloromethane and 30 ml of 2 M NaOH, the layers are separated, the aqueous layer is extracted with 30 ml of dichloromethane. The organic layers are collected, dried on magnesium sulfate, filtered and the filtrate is evaporated.
- Example 3 S-( ⁇ )-amlodipine-L-(+)-tartrate (starting from the diastereomeric salt) 0.6 g (0.57 mmol) of S-(-)-amlodipine-L-(+)-hemitartrate dimethylformamide solvate as described in Example 1 is suspended in 12 ml of water, at ambient temperature, by excluding of the air. 0.1 g (0.66 mmol) of L-(+)-tartaric acid is added to this suspension.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
The object of the invention relates is a process for the preparation of S-(-) amlodipine (chemical name: S-(-)-2-(2-aminoethoxy)-methyl-4-(2-chlorophenyl)-3-ethoxycarbonil-5-methoxy-carbonyl-6-methyl-1,4-dihydropiridine) of the formula (I): starting from (R,S)-amlodipine by diastereomeric salt formation, in which the (R,S)-amlodipine is reacted with 0.5-1.5 mol L-(+)-tartaric acid in dimethylformamide solvent and the forming S-(-)-amlodipine-L(+)-hemitartrate dimethylformamide solvate of the formula (II): is reacted with base in inert solvent. Another object of the invention is the novel S-(-)-amlodipine-L(+)-hemitartrate dimethylfomamide solvate.
Description
PROCESS FOR THE PREPARATION OF S-(-)-AMLODIPINE
The invention relates to a novel process for the preparation of S-(-)-amlodipine (chemical name: S-(-)-2-(2-aminoethoxy)-methyl-4-(2-chlorophenyl)-3 -ethoxycarbonil-5- methoxycarbonyl-6-methyl-l,4-dihydropiridine) of the formula I
I starting from (R,S)-amlodipine by diastereomeric salt formation, in which the (R5S)- amlodipine is reacted with 0.5-1.5 mol L-(+)-tartaric acid in dimethylformarnide solvent and the forming S-(-)-amlodipine-L(+)-hemitartrate dimethylforrnamide solvate of the formula II
II is reacted with base in inert solvent.
Further the invention provides S-(-)-amlodipine-L(+)-hemitartrate dimethylformarnide solvate synthetic intermediate being useful for the preparation of S-(-)-amlodipine.
Amlodipine and the salts thereof were reported first in the European Patent Specification No. 89 167 are calcium channel blocking agents of long duration of action, and because of their activity they are useful in the treatment of cardiovascular disease, hypertension, angina pectoris, ischemic heart disease. At the present time (R,S)-amlodipine or salts thereof are used mostly in pharmaceutical compositions.
The two types of enantiomers of amlodipine and salts thereof have different pharmacological properties (see: J. Med. Chem., (1986) 29, 1696-1702), S-(-)-amlodipine is twice as active as the enantiomeric mixture regarding their calcium channel blocking activity.
According to EP 754 043 European patent specification R-(+)-amlodipine is a potent inhibitor of vascular smooth muscle cell migration therefore it can be used in the treatment of arteriosclerosis and vasoconstriction.
Although both enantiomers have pharmacological activity, S-(-)-amlodipine has greater therapeutical relevance, so we studied the synthesis of this enantiomer.
A resolution method is disclosed in EP 331 315 European patent specification, namely the 2-(2-azidoethoxymethyl)-4-(2-chlorophenyl)-5-methoxycarbonyl-6-methyl-l,4-dihydro- pyridine-3-carboxylic acid is fractionated by cinchonidine. However this process can not be used on industrial scale because of the low yield and the toxicity of cinchonidine.
The absolute configuration of the enantiomers was determined by X-ray diffraction (see: J. Med. Chem. 1992, 35, 3341-3344). According to this study S-(-) and R-(+) enantiomers could have been identified. The separation of two enantiomers was carried out by separation of diastereomeric amine formed with (lS)-camphanic acid using column chromatography. Obviously this separation has only theoretical meaning it can not be used as an industrial scale process.
For the separation of the enantiomers several processes are known. In the first group of the processes non-natural D-(-)-tartaric acid is used for the separation of S-(-)-amlodipine which is far more expensive than the L-(+)-tartaric acid. Such process is disclosed in HU 214 720 Hungarian patent specification, where S-(-)-amlodiρine is produced in dimethyl sulfoxide (DMSO) solvent and the resolution is carried out by D-(-)- tartaric acid. DMSO plays double role: on the one hand it is a solvent and on the other hand it takes part as associate in the diastereomeric salt formation.
Similar process is disclosed in WO 03/035623 published international patent application, in this case dimethylacetamide is used as solvent and also D-(-)-tartaric acid is necessary for obtaining S-(-)-amlodipine. Dimethylacetamide, like the DMSO used in the previous process plays a double role as well: as solvent and as associate in the diastereomeric salt formation.
In the second group of the manufacturing processes L-(+)-tartaric acid is used during the resolution, but it is used for isolation of the R-(+) isomer. The S-(-) enantiomer is isolated from the mother liquor by seeding or precipitation by adding solvent.
Such processes are disclosed in US 2003/176706 published American patent application and in EP 1 348 697 published European patent application. In such processes R-
(+)-amlodipine-L-(+)-hemitartrate DMSO solvate is precipitated from (R,S)-amlodipine base in DMSO solvent with L-(+) tartaric acid, then S-(-)-amlodipine-L-(+)-hemitartrate DMSO solvate is isolated from the mother liquor by seeding.
The process which is disclosed in WO 04/024689 published international patent application is very similar to the above mentioned process: S-(-)~amlodipine-L-(+)- hemitartrate DMSO solvate is isolated from the mother liquor of R-(+)-amlodipine-L-(+)- hemitartrate DMSO solvate by L-(+)-tartaric acid by precipitation with methylene chloride.
AU three of the mentioned processes have common disadvantage: S-(-) enantiomer is obtained indirectly, from the mother liquor. Therefore the enantiomeric purity (hereafter ee) of S-(-)-amlodiρine is only 90-97 %.
Our aim was to provide such process lacking the disadvantages of the previous processes, i.e. to precipitate the S-(-)-amlodipine-L-(+)-hemitartrate from the enantiomeric mixture in one step, so S-(-)-amlodipine can be produced in higher purity.
In the course of our experiments when the reaction of (R5S)- amlodipine base and L- (+)-tartaric acid is performed in dimethylformamide solvent during continuous stirring, we have surprisingly found that the S-(-)-amlodipine-L-(+)-hemitartrate dimethylformamide solvate of the formula II is precipitated as primary product. The diastereomeric salt was washed, filtrated and dissolved in a mixture of dichloromethane and aqueous NaOH solution.
The layers were separated and the organic layer was evaporated. Accordingly the purity of the product obtained was 99.0-99.8 % ee. Further it has been found that S-(-)-amlodipine L-(+)- tartrate was obtained from the S-(-)-amlodipine-L-(+)-hemitartrate dimethylformamide solvate of the formula II by adding of further amount of L-(+)-tartaric acid, in aqueous medium and by excluding of the air. Further it has been also found that any pharmaceutically acceptable salts of S-(-)-amlodipine of formula III could be produced by reacting the S-(-)- amlodipine base with the suitable acid.
III
Further R-(+)-amlodipine could be obtained by a process similar to the above- mentioned one, where D-(-)-tartaric acid was used instead of L-(+)-tartaric acid.
Advantages of the process according to this invention are as follows: S-(-)-enantiomeric product can be obtained directly by using the natural L-(+)-tartaric acid; the manufacturing process becomes easier and more economical and gives the product in high purity.
The object of the invention is a process for the preparation of S-(-)-amlodipine (chemical name: S-(-)-2-(2-aminoethoxy)-methyl-4-(2-chlorophenyl)-3 -ethoxycarbonil-5- methoxycarbonyl-6-methyl-l,4-dihydropiridine) of the formula I starting from (R5S)- amlodipine by diastereomeric salt formation, in which the (R,S)-amlodipine is reacted with 0.5-1.5 mol of L-(+)-tartaric acid in dimethylformamide solvent and the forming S-(-)- amlodipine-L(+)-hemitartrate dimethylformamide solvate of the formula II is reacted with base in inert solvent.
The another object of the invention is the novel S-(-)-amlodipine derivative of the formula II S-(-)-amlodipine L(+)-hemitartrate dimethylfomamide solvate.
The invention is illustrated by following non-limiting Examples.
Example 1: S-(-)-amlodipine-L(+)-hemitartrate dimethylfomamide solvate 2.0 g (0,005 mol) of (R,S)-amlodipine base is dissolved in 36 ml (0.46 mol) of dimethylformamide at ambient temperature during stirring and to this mixture a solution of 1.12 g (0,0075 mol) (1.5 eq.) of L-(+)-tartaric acid in 36 ml (0.46 mol) of dimethylformamide is added during continuous stirring. After the precipitation of the diastereomeric salt precipitates soon, stirring is continued for 20 hours, crystals are filtered washed with methyl tert-buthyl ether to yield 1.0 g of S-(-)-amlodipine-L-(+)-hemitartrate dimethylformamide solvate.
Yield: 76 % Mp: 132-135 °C [α]D : -16.6° (c=1.0 in methanol) ee>99.0 (HPLC) Composition: amlodipine : tartaric acid : dimethylformamide = 2:1:2
(1H NMR3 SOO MHZ5 GC)
Example 2: S-(-)-amlodipine
1.0 g (0.005 mol) of crystalline S-(-)-amlodipine-L(+)-hemitartrate dimethylformamide solvate as described in Example 1 is dissolved in a mixture of about 30 ml of dichloromethane and 30 ml of 2 M NaOH, the layers are separated, the aqueous layer is extracted with 30 ml of dichloromethane. The organic layers are collected, dried on magnesium sulfate, filtered and the filtrate is evaporated. The crude product (0.81 g) is recrystallized from about 20 ml of n-hexane, filtered and washed with about 5 ml of n-hexane to yield 0.60 g of crystalline S-(-)-amlodipine base. Yield: 79 % Mp: 109-112 °C [α]D : -32.3° (c=1.0 in methanol) ee>99.5 (HPLC)
The enantiomeric purity was determined by HPLC as follows:
Column: Chiral-AGP 100-4.6mm 5μm
Chiral stationary phase with α-glycopeptide-modified silica packing Eluent:
A: 0.05 M ammonium acetate buffer ρH=4.5 B: methanol t/min A%
0 100 45 80
Flow rate: 0-9 ml/min Detection: 250 nm
Temperature: ambient temperature Elution rank of the enantiomers: R, S
Example 3: S-(~)-amlodipine-L-(+)-tartrate (starting from the diastereomeric salt) 0.6 g (0.57 mmol) of S-(-)-amlodipine-L-(+)-hemitartrate dimethylformamide solvate as described in Example 1 is suspended in 12 ml of water, at ambient temperature, by excluding of the air. 0.1 g (0.66 mmol) of L-(+)-tartaric acid is added to this suspension. The mixture is heated at 50 °C for 10 min., cooled down by ice-cool water, filtered and washed with small amount of water to yield 0.47 g of S-(-)-amlodipine-L-(+)-tartrate. Yield: 73 %
Mp: 198-202 °C
Example 4; S-(-)-amlodipine L-(+)-tartrate (direct salt-forming)
0.41 g (1 mmol) of S-(-)-amlodipine base is suspended in 2 ml of distilled water at ambient temperature and 0.15 g (1 mmol) of L-(+)-tartaric acid solved in 2 ml of distilled water is added to this suspension. After dissolution S-(-)-amlodipine-L-(+)-tartrate precipitates, which is filtered and washed with water to yield 0.4 g of S-(-)-amlodipine-L-(+)- tartrate.
Yield: 71 % Mp: 198-202 °C
Example 5: S-(-)-amlodipine-L-(+)-hemitartrate (direct salt-forming)
0.41 g (1 mmol) of S-(-)-amlodipine base is suspended in 2 ml of distilled water at ambient temperature and 0.08 g (0.5 mmol) of L-(+)-tartaric acid solved in 2 ml of distilled water is added to this suspension. After dissolution S-(-)-amlodipine-L-(+)-hemitartrate precipitates, which is cooled by ice-cool water, filtered and washed with water to yield 0.4 g of amorphous form of S-(-)-amlodipine-L-(+)-hemitartrate, which does not have narrow melting point.
Yield 82 %
Claims
1. Process for the preparation of S-(-)-amlodipine of formula I,
I starting from (R,S)-amlodipine by diastereomeric salt formation, characterized in that the (R,S)-amlodipine is reacted with 0.5-1.5 mol L-(+)-tartaric acid in dimethylformamide solvent and the forming S-(-)-amlodipine-L(+)-hemitartrate dimethylformamide solvate of the formula (II)
II is reacted with base in inert solvent.
2. S-(-)-amlodipine L-(+)-hemitartrate dimethylformamide solvate.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU0500570A HUP0500570A3 (en) | 2005-06-08 | 2005-06-08 | Process for the preparation of (s)-(-)-amlodipine |
| HUP0500570 | 2005-06-08 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2006131773A1 true WO2006131773A1 (en) | 2006-12-14 |
Family
ID=89986074
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/HU2006/000050 WO2006131773A1 (en) | 2005-06-08 | 2006-06-06 | Process for the preparation of s-(-)-amlodipine |
Country Status (2)
| Country | Link |
|---|---|
| HU (1) | HUP0500570A3 (en) |
| WO (1) | WO2006131773A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008100023A1 (en) * | 2007-02-14 | 2008-08-21 | Hanmi Pharm. Co., Ltd. | Method of preparing s-(-)-amlodipine or a salt thereof and an intermediate used therein |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0331315A2 (en) * | 1988-02-27 | 1989-09-06 | Pfizer Limited | Preparation of R- and S-amlodipine |
| WO1995025722A1 (en) * | 1994-03-24 | 1995-09-28 | Pfizer Limited | Separation of the enantiomers of amlodipine via their diastereomeric tartrates |
| WO2003035623A1 (en) * | 2001-10-24 | 2003-05-01 | Sepracor, Inc. | Method of resolving amlodipine racemate |
| EP1348697A1 (en) * | 2002-03-28 | 2003-10-01 | Council Of Scientific & Industrial Research | Process for the preparation of S(-)-amlodipine-L(+)-hemitartrate |
| WO2006043148A1 (en) * | 2004-10-20 | 2006-04-27 | Emcure Pharmaceuticals Limited | Process for producing enantiomer of amlodipine in high optical purity |
-
2005
- 2005-06-08 HU HU0500570A patent/HUP0500570A3/en unknown
-
2006
- 2006-06-06 WO PCT/HU2006/000050 patent/WO2006131773A1/en active Application Filing
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0331315A2 (en) * | 1988-02-27 | 1989-09-06 | Pfizer Limited | Preparation of R- and S-amlodipine |
| WO1995025722A1 (en) * | 1994-03-24 | 1995-09-28 | Pfizer Limited | Separation of the enantiomers of amlodipine via their diastereomeric tartrates |
| WO2003035623A1 (en) * | 2001-10-24 | 2003-05-01 | Sepracor, Inc. | Method of resolving amlodipine racemate |
| EP1348697A1 (en) * | 2002-03-28 | 2003-10-01 | Council Of Scientific & Industrial Research | Process for the preparation of S(-)-amlodipine-L(+)-hemitartrate |
| WO2006043148A1 (en) * | 2004-10-20 | 2006-04-27 | Emcure Pharmaceuticals Limited | Process for producing enantiomer of amlodipine in high optical purity |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008100023A1 (en) * | 2007-02-14 | 2008-08-21 | Hanmi Pharm. Co., Ltd. | Method of preparing s-(-)-amlodipine or a salt thereof and an intermediate used therein |
Also Published As
| Publication number | Publication date |
|---|---|
| HUP0500570A3 (en) | 2008-03-28 |
| HU0500570D0 (en) | 2005-08-29 |
| HUP0500570A2 (en) | 2007-03-28 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP5503546B2 (en) | Separation of 4,5-dimethoxy-1- (methylaminomethyl) -benzocyclobutane | |
| US20060014793A1 (en) | Process and diastereomeric salts useful for the optical resolution of racemic alpha-(4-(1, 1-dimethylethyl) phenyl] -4- (hydroxydiphenylmethyl) -1-piperidinebutanol and derivative compounds | |
| WO2008062460A2 (en) | Crystalline forms of pregabalin | |
| KR20080020613A (en) | A process for the dynamic resolution of (substituted) (r)- or (s)-mandelic acid | |
| IL175488A (en) | Process for resolving optionally substituted mandelic acids by salt formation with a chiral base cyclic amide | |
| EP1831166B1 (en) | Optical resolution method of amlodipine | |
| WO2006131773A1 (en) | Process for the preparation of s-(-)-amlodipine | |
| JP2004511476A (en) | Method for producing R (+) α-lipoic acid | |
| JP5226000B2 (en) | Method for separating S-(-)-amlodipine from racemic amlodipine | |
| KR101125123B1 (en) | Method of preparing S---amlodipine with high optical purity and intermediate compound produced during the same | |
| CZ282068B6 (en) | 3-methoxy-4-£1-methyl-5-)2-methyl-4,4,4-trifluorobutylcarbamoyl(indol- -3-ylmethyl|-n-)2-methylphenylsulfonyl)benzamide, its pharmaceutically acceptable salts, process of their preparation and pharmaceutical compositions containing thereof | |
| JP5635905B2 (en) | Preparation method of mirtazapine | |
| KR900002342B1 (en) | Process for preparing dextrorotatory optical isomer of diastereomer a of ym-09730 | |
| KR100834967B1 (en) | Process for the high yield production of clopidogrel by racemization of residual liquid | |
| WO2010068049A2 (en) | Process for preparing (r)-(+)-lansoprazole and intermediate used therein | |
| KR20060104761A (en) | Process for preparing lercanidipine hydrochloride | |
| IE47017B1 (en) | 3-(4-bromophenyl)-3-(3-pyridyl)-3-hydroxy-prop-1-ene and its use to prepare pharmaceutically active compounds | |
| EP0842179A1 (en) | Production of optically active benzothiepin salts | |
| KR20090053058A (en) | New chiral resolving agents and method for isolating chiral isomer using same | |
| JPH07247275A (en) | Production of single diastereomer of oxazolidinone derivative and fumarate of single diastereomer of urethane compound | |
| KR20030016288A (en) | Enantiomer separation of piperidone derivatives with simultaneous in situ racemization of the unwanted enantiomer | |
| JPH0374665B2 (en) |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
| NENP | Non-entry into the national phase |
Ref country code: DE |
|
| WWW | Wipo information: withdrawn in national office |
Country of ref document: DE |
|
| 122 | Ep: pct application non-entry in european phase |
Ref document number: 06744404 Country of ref document: EP Kind code of ref document: A1 |