EP0922031A1 - Ein verfahren zur herstellung von dihydroyridinen - Google Patents
Ein verfahren zur herstellung von dihydroyridinenInfo
- Publication number
- EP0922031A1 EP0922031A1 EP97935558A EP97935558A EP0922031A1 EP 0922031 A1 EP0922031 A1 EP 0922031A1 EP 97935558 A EP97935558 A EP 97935558A EP 97935558 A EP97935558 A EP 97935558A EP 0922031 A1 EP0922031 A1 EP 0922031A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- solvent
- alanine
- catalyst
- water
- different
- 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.)
- Withdrawn
Links
- 238000000034 method Methods 0.000 title claims abstract description 19
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- 125000004925 dihydropyridyl group Chemical group N1(CC=CC=C1)* 0.000 title claims abstract description 6
- UCMIRNVEIXFBKS-UHFFFAOYSA-N beta-alanine Chemical compound NCCC(O)=O UCMIRNVEIXFBKS-UHFFFAOYSA-N 0.000 claims abstract description 26
- -1 benzylidene acetoacetic ester Chemical compound 0.000 claims abstract description 14
- 239000003054 catalyst Substances 0.000 claims abstract description 13
- 229940000635 beta-alanine Drugs 0.000 claims abstract description 12
- 150000002148 esters Chemical class 0.000 claims abstract description 11
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 8
- 238000006000 Knoevenagel condensation reaction Methods 0.000 claims abstract description 6
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 claims abstract description 5
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 claims abstract description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 3
- 239000002904 solvent Substances 0.000 claims description 12
- 238000006243 chemical reaction Methods 0.000 claims description 11
- 239000000203 mixture Substances 0.000 claims description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- 150000001875 compounds Chemical class 0.000 claims description 6
- 125000000649 benzylidene group Chemical group [H]C(=[*])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 3
- 239000011877 solvent mixture Substances 0.000 claims description 2
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 claims 3
- 238000009835 boiling Methods 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 description 16
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 239000006227 byproduct Substances 0.000 description 11
- 238000003786 synthesis reaction Methods 0.000 description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- RZTAMFZIAATZDJ-HNNXBMFYSA-N 5-o-ethyl 3-o-methyl (4s)-4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Chemical group CCOC(=O)C1=C(C)NC(C)=C(C(=O)OC)[C@@H]1C1=CC=CC(Cl)=C1Cl RZTAMFZIAATZDJ-HNNXBMFYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 229960003580 felodipine Drugs 0.000 description 6
- 239000000543 intermediate Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- LLMLNAVBOAMOEE-UHFFFAOYSA-N 2,3-dichlorobenzaldehyde Chemical compound ClC1=CC=CC(C=O)=C1Cl LLMLNAVBOAMOEE-UHFFFAOYSA-N 0.000 description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 239000012467 final product Substances 0.000 description 4
- RAIYODFGMLZUDF-UHFFFAOYSA-N piperidin-1-ium;acetate Chemical compound CC([O-])=O.C1CC[NH2+]CC1 RAIYODFGMLZUDF-UHFFFAOYSA-N 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 238000003445 Hantzsch reaction Methods 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000012299 nitrogen atmosphere Substances 0.000 description 3
- 239000003586 protic polar solvent Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical compound C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- WRQNANDWMGAFTP-UHFFFAOYSA-N Methylacetoacetic acid Chemical compound COC(=O)CC(C)=O WRQNANDWMGAFTP-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- YPMPTULBFPFSEQ-PLNGDYQASA-N ethyl (z)-3-aminobut-2-enoate Chemical compound CCOC(=O)\C=C(\C)N YPMPTULBFPFSEQ-PLNGDYQASA-N 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 238000010626 work up procedure Methods 0.000 description 2
- PVHUJELLJLJGLN-INIZCTEOSA-N (S)-nitrendipine Chemical group CCOC(=O)C1=C(C)NC(C)=C(C(=O)OC)[C@@H]1C1=CC=CC([N+]([O-])=O)=C1 PVHUJELLJLJGLN-INIZCTEOSA-N 0.000 description 1
- IEDIKTABXQYWBL-UHFFFAOYSA-N 3-aminopropanoic acid Chemical compound NCCC(O)=O.NCCC(O)=O IEDIKTABXQYWBL-UHFFFAOYSA-N 0.000 description 1
- UIAGMCDKSXEBJQ-IBGZPJMESA-N 3-o-(2-methoxyethyl) 5-o-propan-2-yl (4s)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate Chemical group COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)[C@H]1C1=CC=CC([N+]([O-])=O)=C1 UIAGMCDKSXEBJQ-IBGZPJMESA-N 0.000 description 1
- WDYVUKGVKRZQNM-UHFFFAOYSA-N 6-phosphonohexylphosphonic acid Chemical compound OP(O)(=O)CCCCCCP(O)(O)=O WDYVUKGVKRZQNM-UHFFFAOYSA-N 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 1
- 229910000831 Steel Inorganic materials 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 150000005690 diesters Chemical class 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 239000000383 hazardous chemical Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- SRJOCJYGOFTFLH-UHFFFAOYSA-N isonipecotic acid Chemical compound OC(=O)C1CCNCC1 SRJOCJYGOFTFLH-UHFFFAOYSA-N 0.000 description 1
- OJURWUUOVGOHJZ-UHFFFAOYSA-N methyl 2-[(2-acetyloxyphenyl)methyl-[2-[(2-acetyloxyphenyl)methyl-(2-methoxy-2-oxoethyl)amino]ethyl]amino]acetate Chemical compound C=1C=CC=C(OC(C)=O)C=1CN(CC(=O)OC)CCN(CC(=O)OC)CC1=CC=CC=C1OC(C)=O OJURWUUOVGOHJZ-UHFFFAOYSA-N 0.000 description 1
- VKQFCGNPDRICFG-UHFFFAOYSA-N methyl 2-methylpropyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate Chemical group COC(=O)C1=C(C)NC(C)=C(C(=O)OCC(C)C)C1C1=CC=CC=C1[N+]([O-])=O VKQFCGNPDRICFG-UHFFFAOYSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 229960000715 nimodipine Drugs 0.000 description 1
- 229960000227 nisoldipine Drugs 0.000 description 1
- 229960005425 nitrendipine Drugs 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000010959 steel Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 231100000721 toxic potential Toxicity 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity 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 present invention relates to a novel process for the preparation of dihydropyridines .
- a number of 4-aryl-l , 4-dihydro-2 , 6-dimethyl-3 , 5- pyridinedicarboxylic acid (V) asymmetric diesters are well known active principles used in the treatment of cardiovascular conditions (see US 3932645, DE 2117573, US 4154839, DE 3222367, EP 7293).
- EP 124743 discloses the synthesis of benzylidene intermediates of high purity, in order to avoid the formation of by-products in the second step, starting from ordinary raw materials (appropriate benzaldehyde and acetoacetic esters), in a low molecular alcohol as the solvent, and with piperidine acetate as the catalyst.
- the main drawback of this synthesis resides actually in the use of a catalyst prepared starting from acetic acid and piperidine, which products obviously involve handling problems due to their characteristics of toxicity, corrosivity and inflammability.
- JP 78 53638 ( CA 89:179714) also discloses, although not in connection with dihydropyridines synthesis, similar reaction conditions in the synthesis of benzylidene acetoacetic esters.
- EP 534520 describes the inhibition of the formation of by-products during the cyclocondensation (second step, scheme 2), by means of a short thermal reaction between a benzylidene acetoacetic ester and an amino crotonic ester in a water-miscible solvent (preferably a low molecular alcohol), combined with, or followed by, the addition of a strong acid to the reaction mixture.
- a water-miscible solvent preferably a low molecular alcohol
- the present invention avoids the formation of byproducts in the Hantzsch synthesis of dihydropyridines (in two steps), thanks to a process which makes use of: a) less expensive and less environmentally risky conditions in the Knoevenagel condensation (first step, scheme 2), which allow to obtain extremely pure intermediate benzylidene acetoacetic esters in a good yield; b) mild reaction conditions (anyhow inhibiting any side-reactions) in the second step (scheme 2), which allow to obtain an extremely pure final product in a high yield, by means of a very simple work up.
- the process of the invention is carried out in an alcohol medium, at temperatures from 20 * C to 60*C, in the presence of ⁇ -alanine ( 3-aminopropanoic acid) as the catalyst.
- ⁇ -alanine exerts its catalytic activity in rather low catalyst/aldehyde molar ratios (3%), thus permitting, for example in the preparation of Felodipine intermediate, a ⁇ -alanine/2, 3-dichlorobenzaldehyde 1.5% weight ratio, compared with a piperidine acetate/2, 3-dichlorobenzaldehyde 5.2% weight ratio stated in example 3 of EP 124743.
- ⁇ -Alanine is also preferable to piperidine acetate for environmental reasons, and it also involves the remarkable advantage of replacing two toxic potential impurities (acetic acid and piperidine) of the final dihydropyridine product with only one ordinary potential impurity ( ⁇ -alanine), as it turns out from the comparison between the data inferable from the Registry of Toxic Effects of Chemical Substances (for the definitions of toxic and ordinary impurities see USP XIII, page 1922) .
- the process of the present invention being free from risks of formation of by-products, advantageously yields a final dihydropyridine product of high purity, moreover allowing very simple, versatile reaction conditions, which are also advantageous from the environment and costs point of views.
- the following example further illustrates the process of the invention.
- the mixture is then slowly cooled to room temperature (20 * -25 * C), again with stirring and under nitrogen atmosphere, keeping these conditions for 12 hours.
- the reaction product precipitates (optionally by seeding with some methyl 2 , 3-dichlorobenzylidene acetoacetate crystals), the mixture is cooled at 0 * C and left at this temperature for at least 3 hours.
- the solvent is refluxed for 8-12 hours, then the mixture is slowly cooled to room temperature (20°-25 ⁇ C), with stirring. After about 12 hours, the mixture contains the solid reaction product (as in the above example, in case of a supersaturated solution, seed crystals can be made use of).
- Lichrosorb Merck mobile phase: acetonitrile/water 1/1): felodipine: 99.8% (area); dimethyl ester: 0.07% (area); diethyl ester: 0.02% (area).
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Hydrogenated Pyridines (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pyridine Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ITMI961780 | 1996-08-23 | ||
| IT96MI001780A IT1283793B1 (it) | 1996-08-23 | 1996-08-23 | Processo per la preparazione di diidropiridine |
| PCT/EP1997/004172 WO1998007698A1 (en) | 1996-08-23 | 1997-07-31 | A process for the preparation of dihydropyridines |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP0922031A1 true EP0922031A1 (de) | 1999-06-16 |
Family
ID=11374816
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP97935558A Withdrawn EP0922031A1 (de) | 1996-08-23 | 1997-07-31 | Ein verfahren zur herstellung von dihydroyridinen |
Country Status (6)
| Country | Link |
|---|---|
| EP (1) | EP0922031A1 (de) |
| JP (1) | JP2000515855A (de) |
| AU (1) | AU3850597A (de) |
| CA (1) | CA2263601A1 (de) |
| IT (1) | IT1283793B1 (de) |
| WO (1) | WO1998007698A1 (de) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2161156C1 (ru) * | 1999-06-01 | 2000-12-27 | Джи.Б.Кемикалс Энд Фармасьютикалс Лтд | Способ получения 3-этил-5-метиловый эфир 2-[2-(n-фталимидо)-этоксиметил]-4-(2-хлорфенил)-1,4-дигидро-6-метил-3,5- пиридиндикарбоновой кислоты |
| CA2425561C (en) | 2003-04-14 | 2007-09-18 | Brantford Chemicals Inc. | Process to prepare 1,4-dihydropyridine intermediates and derivatives thereof |
| CN103467369B (zh) * | 2013-09-30 | 2015-11-04 | 山东新华制药股份有限公司 | 尼莫地平杂质ⅰ的制备方法 |
| CN104177286A (zh) * | 2014-08-11 | 2014-12-03 | 广东东阳光药业有限公司 | 一种地平类药物的制备方法 |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2117573C3 (de) * | 1971-04-10 | 1978-07-27 | Bayer Ag, 5090 Leverkusen | Verfahren zur Herstellung von unsymmetrischen l,4-Dihydropyridin-3,5dicarbonsäureestern, sowie ihre Verwendung als Arzneimittel |
| US3932645A (en) * | 1971-04-10 | 1976-01-13 | Farbenfabriken Bayer Ag | Pharmaceutical compositions containing unsymmetrical esters of 1,4-dihydropyridine 3,5-dicarboxylic acid |
| GB1409865A (en) * | 1973-02-13 | 1975-10-15 | Science Union & Cie | Dihydropyridines derivatives their preparation and pharmaceu tical compositions containing them |
| SE429652B (sv) * | 1978-06-30 | 1983-09-19 | Haessle Ab | 2.6-dimetyl-4-(2.3-diklorfenyl)-1.4-dihydropyridin-3.5-dikarboxylsyra-3-metylester-5-etylester |
| DE3208628A1 (de) * | 1982-03-10 | 1983-09-22 | Bayer Ag, 5090 Leverkusen | Neue verbindungen, verfahren zu ihrer herstellung sowie ihre verwendung als arzneimittel |
| ATE20064T1 (de) * | 1982-07-22 | 1986-06-15 | Pfizer | Anti-ischaemische und antihypertensive dihydropyridin-derivate. |
| DE3312283A1 (de) * | 1983-04-05 | 1984-10-18 | Bayer Ag, 5090 Leverkusen | Verfahren zur herstellung von unsymmetrischen 1,4-dihydropyridincarbonsaeureestern |
| DE3741540A1 (de) * | 1987-12-08 | 1989-06-22 | Bayer Ag | Verfahren zur herstellung von unsymmetrischen dihydropyridinen |
| WO1993006082A1 (en) * | 1991-09-13 | 1993-04-01 | Merck & Co., Inc. | Process for the preparation of 4-substituted-1,4-dihydropyridines |
-
1996
- 1996-08-23 IT IT96MI001780A patent/IT1283793B1/it active IP Right Grant
-
1997
- 1997-07-31 EP EP97935558A patent/EP0922031A1/de not_active Withdrawn
- 1997-07-31 JP JP10505637A patent/JP2000515855A/ja not_active Ceased
- 1997-07-31 CA CA002263601A patent/CA2263601A1/en not_active Abandoned
- 1997-07-31 AU AU38505/97A patent/AU3850597A/en not_active Abandoned
- 1997-07-31 WO PCT/EP1997/004172 patent/WO1998007698A1/en not_active Ceased
Non-Patent Citations (1)
| Title |
|---|
| See references of WO9807698A1 * |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2000515855A (ja) | 2000-11-28 |
| ITMI961780A0 (de) | 1996-08-23 |
| CA2263601A1 (en) | 1998-02-26 |
| ITMI961780A1 (it) | 1998-02-23 |
| IT1283793B1 (it) | 1998-04-30 |
| WO1998007698A1 (en) | 1998-02-26 |
| AU3850597A (en) | 1998-03-06 |
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