FI74275B - Foerfarande foer framstaellning av 4- (2'-nitrofenyl)-2,6-dimetyl-3,5-dimetoxikarbonyl-1,4-dihydro-pyridin. - Google Patents
Foerfarande foer framstaellning av 4- (2'-nitrofenyl)-2,6-dimetyl-3,5-dimetoxikarbonyl-1,4-dihydro-pyridin. Download PDFInfo
- Publication number
- FI74275B FI74275B FI822842A FI822842A FI74275B FI 74275 B FI74275 B FI 74275B FI 822842 A FI822842 A FI 822842A FI 822842 A FI822842 A FI 822842A FI 74275 B FI74275 B FI 74275B
- Authority
- FI
- Finland
- Prior art keywords
- nitrophenyl
- dimethyl
- pyridine
- nitrobenzaldehyde
- dimetoxicarbonyl
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- CMWKITSNTDAEDT-UHFFFAOYSA-N 2-nitrobenzaldehyde Chemical compound [O-][N+](=O)C1=CC=CC=C1C=O CMWKITSNTDAEDT-UHFFFAOYSA-N 0.000 claims description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 7
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 6
- HYIMSNHJOBLJNT-UHFFFAOYSA-N nifedipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1[N+]([O-])=O HYIMSNHJOBLJNT-UHFFFAOYSA-N 0.000 claims description 6
- WRQNANDWMGAFTP-UHFFFAOYSA-N Methylacetoacetic acid Chemical compound COC(=O)CC(C)=O WRQNANDWMGAFTP-UHFFFAOYSA-N 0.000 claims description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- 229910021529 ammonia Inorganic materials 0.000 claims description 3
- 239000003960 organic solvent Substances 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- 150000007530 organic bases Chemical class 0.000 claims description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- COLPLFZHPXIFCQ-UHFFFAOYSA-N 1,4-dihydropyridine-3,5-dicarboxylic acid Chemical compound OC(=O)C1=CNC=C(C(O)=O)C1 COLPLFZHPXIFCQ-UHFFFAOYSA-N 0.000 description 1
- PLAZTCDQAHEYBI-UHFFFAOYSA-N 2-nitrotoluene Chemical compound CC1=CC=CC=C1[N+]([O-])=O PLAZTCDQAHEYBI-UHFFFAOYSA-N 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- KRVSOGSZCMJSLX-UHFFFAOYSA-L chromic acid Substances O[Cr](O)(=O)=O KRVSOGSZCMJSLX-UHFFFAOYSA-L 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- AWJWCTOOIBYHON-UHFFFAOYSA-N furo[3,4-b]pyrazine-5,7-dione Chemical compound C1=CN=C2C(=O)OC(=O)C2=N1 AWJWCTOOIBYHON-UHFFFAOYSA-N 0.000 description 1
- 229960001597 nifedipine Drugs 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 150000002927 oxygen compounds Chemical class 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000000304 vasodilatating effect 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Hydrogenated Pyridines (AREA)
Description
1 74275
Menetelmä 4-(21-nitrofenvyli)-2,6-dimetyyli-3,5-dimetoksi-karbonyyli-1,4-dihydropyridiinin valmistamiseksi
Kyseessä oleva keksintö koskee uutta menetelmää, jonka avulla voidaan valmistaa 4-(21-nitrofenyyli)-2,6-dimctyyli-3,5-dimetoksikarbonyyli-1,4-dihydropyridiiniä, jonka kaava on
Cx N02 H 3COOC 3 I I i CH^^N ^CH-H 3 joka tunnetaan yleisellä nimellä Nifedipiini ja joka on koro-naari-vasodilatorisen vaikutuksensa ansiosta arvokas lääke angina pectoriksen hoidossa. 4-(2'-nitrofenyyli)-2,6-dimetyyli-3,5-dimetoksikarbonyyli-1,4-dihydropyridiini on tunnettu yhdiste ja siitä on tehty selkoa ensimmäisen kerran saksalaisessa patentissa 1 670 827. Mainitussa saksalaisessa patentissa selostetun menetelmän mukaan yhdistettä saadaan antamalla 2-nitro-bentsaldehydin, metyyliasetoasetaatin ja ammoniakin reagoida jossakin inertissä orgaanisessa liuotti-messa, esimerkiksi metanolissa. Menetelmä perustuu Hantzsch'in pyridiini-synteesiin, sillä 1,4-dihydropyridiini- 3,5-dikarboksyylihapon mainittu esteri on stabiili välituote, jota valmistetaan synteettisesti tämän menetelmän mukaisesti.
On tunnettua valmistaa tämän synteesin lähtöainetta, so. 2-nitrobentsaldehydiä hapettamalla 2-nitrotolueenia kromihapon avulla ja mukana on rikkihappoa ja asetanhydridiä (Houben-Weyl, Methoden der organischen Chemie, nide VII, osa I, Sauerstoffverbindungen II, 1954, 143). Välituote, 2-nitro-bentsaldehydi-diasylaatti, jonka kaava on 2 74275 CH(OAc) 2
kX
ja joka muodostuu reaktiossa, on stabiili yhdiste, joka voidaan edelleen hydrolysoida, jolloin saadaan 2-nitro-bentsaldehydiä. Tämän synteesin tuotos on noin 60 % teoreettisesta .
Keksinnön mukaisen menetelmän mukaan käytetään reagoivaa ainetta, so. 2-nitrobentsaldehydi-diasylaattia, jonka kaava on II, ensimmäisen kerran 4-(2'-nitrofenyyli)-2,6-dimetyyli- 3,5-dimetoksikarbonyyli-1,4-dihydropyridiinin synteesissä. Täten korvataan kallis lähtömateriaali 2-nitrobentsaldehydi vähemmän kalliilla 2-nitrobentsaldehydi-diasylaatilla, jota voidaan valmistaa kuten edellä on selostettu. Yhdisteen annetaan reagoida metyyliasetoasetaatin ja ammoniakin kanssa siten, että mukana on inertiä orgaanista liuotinta, kuten me-tanolia siten, että mukana on jotakin orgaanista emästä kuten pyridiiniä tai ilman sitä, lämpötilavälillä 20-150°C. Tämä menetelmä, jossa voidaan jättää pois yksi synteesivai-he - koska ei ole tarpeen hydrolysoida alustavasti 2-nitro-bentsaldehydi-diasylaattia, jonka kaava on II vastaavaksi 2-nitrobentsaldehydiksi - edustaa uutta ja yksinkertaistettua Hantzsch'in menetelmää pyridiinien synteesiä varten.
Keksintöä valaistaan, mutta sitä ei rajoiteta seuraavilla esimerkeillä.
Esimerkki 1 2-nitrobentsaldehydi-diasylaattia (0,1 moolia, 25,4 g), metyyliasetoasetaattia (0,2 moolia, 23,2 g) ja NH^OHrta (12 ml) kuumennettiin metanolissa (20 ml) ja mukana oli pyridiiniä, useita (7) tunteja. Jäähdytettiin 15°C:een ja saostunut aine suodatettiin erilleen. Raakatuote kiteytettiin etikkahaposta, ja tuotos oli 4-(2'-nitrofenyyli)-2,6-dime-tyyli-3,5-dimetoksikarbonyyli-1,4-dihydropyridiiniä (21,7 g, 62 l teoreettisesta), sp. 172-174°C.
3 74275
Esimerkki 2 2-nitrobentsaldehydi-diasylaattia (0,1 moolia, 25,4 g), metyyliasetoasetaattia (0,21 moolia, 26 g), NH^OH:ta (12 ml) ja metanolia (45 ml) kuumennettiin paluujäähdyttäen 5 h ajan. Jäähdytettiin 15°C:een ja suodatettiin saostunut tuote erilleen. Raakatuotteen kiteyttäminen etikkahaposta antoi tuotokseksi 4-(2'-nitrofenyyli)-2,6-dimetyyli-3,5-di-metoksikarbonyy1i-1,4-dihydropyridiiniä (19,0 g, 55 % teoreettisesta) , sp. 173-174°C.
Claims (1)
- 74275 Patenttivaatimus Menetelmä, jonka avulla voidaan valmistaa 4-(2'-nitrofenyyli)- 2,6-dimetyyli-3,5-dimetoksikarbonyyli-1,4-dihydro-pyridiiniä, jonka kaava on Stf°2 cooch3 ch3 J H tunnettu siitä, että annetaan 2-nitrobentsaldehydi-diasylaatin, metyyliasetoasetaatin ja ammoniakin reagoida siten, että mukana on jotakin inerttiä orgaanista liuotinta, kuten metanolia, ja että mukana on jotakin orgaanista emästä kuten pyridiiniä tai ilman sitä, lämpötilaväIillä 20-150°C. I.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| YU2005/81A YU41983B (en) | 1981-08-19 | 1981-08-19 | Process for preparing 1,4-dihydro-pyridine derivatives |
| YU200581 | 1981-08-19 |
Publications (4)
| Publication Number | Publication Date |
|---|---|
| FI822842A0 FI822842A0 (fi) | 1982-08-16 |
| FI822842L FI822842L (fi) | 1983-02-20 |
| FI74275B true FI74275B (fi) | 1987-09-30 |
| FI74275C FI74275C (fi) | 1988-01-11 |
Family
ID=25556467
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| FI822842A FI74275C (fi) | 1981-08-19 | 1982-08-16 | Foerfarande foer framstaellning av 4- (2'-nitrofenyl)-2,6-dimetyl-3,5-dimetoxikarbonyl-1,4-dihydro-pyridin. |
Country Status (13)
| Country | Link |
|---|---|
| US (1) | US4467093A (fi) |
| JP (1) | JPS5839663A (fi) |
| AT (1) | AT380876B (fi) |
| CA (1) | CA1185243A (fi) |
| CH (1) | CH651297A5 (fi) |
| DK (1) | DK155734C (fi) |
| ES (1) | ES8306364A1 (fi) |
| FI (1) | FI74275C (fi) |
| NL (1) | NL8203260A (fi) |
| PL (1) | PL131222B1 (fi) |
| SE (1) | SE441743B (fi) |
| SU (1) | SU1099842A3 (fi) |
| YU (1) | YU41983B (fi) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4771057A (en) * | 1986-02-03 | 1988-09-13 | University Of Alberta | Reduced pyridyl derivatives with cardiovascular regulating properties |
| JPH02118009U (fi) * | 1989-03-09 | 1990-09-21 |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1670827C3 (de) * | 1967-03-20 | 1974-10-24 | Bayer Ag, 5090 Leverkusen | 4-(2'-Nitrophenyl)-2,6-dimethyl-3,5-dicarbmethoxy-1,4-dihydropyridin |
| DE2808930A1 (de) * | 1978-03-02 | 1979-09-06 | Bayer Ag | Verfahren zur herstellung von 2-nitrobenzaldehyd |
| JPS554318A (en) * | 1978-06-23 | 1980-01-12 | Asahi Chem Ind Co Ltd | Preparation of 1,4-dihydropyridine |
| JPS5520719A (en) * | 1978-07-31 | 1980-02-14 | Asahi Chem Ind Co Ltd | Preparation of 1,4-dihydropyridine derivative |
| JPS55124760A (en) * | 1979-03-16 | 1980-09-26 | Kanebo Ltd | Preparation of 1,4-dihydropyridine derivative or its salt |
-
1981
- 1981-08-19 YU YU2005/81A patent/YU41983B/xx unknown
-
1982
- 1982-07-27 US US06/402,487 patent/US4467093A/en not_active Expired - Fee Related
- 1982-07-29 CA CA000408333A patent/CA1185243A/en not_active Expired
- 1982-08-11 AT AT0307082A patent/AT380876B/de not_active IP Right Cessation
- 1982-08-11 SE SE8204658A patent/SE441743B/sv not_active IP Right Cessation
- 1982-08-16 FI FI822842A patent/FI74275C/fi not_active IP Right Cessation
- 1982-08-17 PL PL1982237935A patent/PL131222B1/pl unknown
- 1982-08-17 ES ES515063A patent/ES8306364A1/es not_active Expired
- 1982-08-17 CH CH4929/82A patent/CH651297A5/de not_active IP Right Cessation
- 1982-08-18 DK DK370382A patent/DK155734C/da not_active IP Right Cessation
- 1982-08-18 SU SU823482656A patent/SU1099842A3/ru active
- 1982-08-19 JP JP57142768A patent/JPS5839663A/ja active Granted
- 1982-08-19 NL NL8203260A patent/NL8203260A/nl not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| DK155734B (da) | 1989-05-08 |
| JPS6314709B2 (fi) | 1988-04-01 |
| SE8204658L (sv) | 1983-02-20 |
| US4467093A (en) | 1984-08-21 |
| YU200581A (en) | 1984-02-29 |
| JPS5839663A (ja) | 1983-03-08 |
| SE8204658D0 (sv) | 1982-08-11 |
| FI74275C (fi) | 1988-01-11 |
| PL237935A1 (en) | 1983-02-28 |
| ES515063A0 (es) | 1983-06-01 |
| FI822842L (fi) | 1983-02-20 |
| AT380876B (de) | 1986-07-25 |
| NL8203260A (nl) | 1983-03-16 |
| DK155734C (da) | 1989-09-25 |
| PL131222B1 (en) | 1984-10-31 |
| YU41983B (en) | 1988-04-30 |
| ES8306364A1 (es) | 1983-06-01 |
| DK370382A (da) | 1983-02-20 |
| SE441743B (sv) | 1985-11-04 |
| SU1099842A3 (ru) | 1984-06-23 |
| CH651297A5 (de) | 1985-09-13 |
| CA1185243A (en) | 1985-04-09 |
| FI822842A0 (fi) | 1982-08-16 |
| ATA307082A (de) | 1985-12-15 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MM | Patent lapsed |
Owner name: LEK, TOVARNA FARMACEVTSKIH IN KEMICNIH |