CS219406B1 - Method of making the 2-chlor-3-cyan-4-methoxymethyl-6-methyl-5-nitropyridine - Google Patents
Method of making the 2-chlor-3-cyan-4-methoxymethyl-6-methyl-5-nitropyridine Download PDFInfo
- Publication number
- CS219406B1 CS219406B1 CS580862A CS580862A CS219406B1 CS 219406 B1 CS219406 B1 CS 219406B1 CS 580862 A CS580862 A CS 580862A CS 580862 A CS580862 A CS 580862A CS 219406 B1 CS219406 B1 CS 219406B1
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- Czechoslovakia
- Prior art keywords
- methoxymethyl
- methyl
- nitropyridine
- cyano
- chlor
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- KGHLPTCKXVCLBS-UHFFFAOYSA-N 2-chloro-4-(methoxymethyl)-6-methyl-5-nitropyridine-3-carbonitrile Chemical compound COCC1=C(C#N)C(Cl)=NC(C)=C1[N+]([O-])=O KGHLPTCKXVCLBS-UHFFFAOYSA-N 0.000 title claims description 4
- 238000004519 manufacturing process Methods 0.000 title description 2
- 238000000034 method Methods 0.000 claims description 7
- 238000005660 chlorination reaction Methods 0.000 claims description 6
- FDZPYSHPLURJEA-UHFFFAOYSA-N 4-(methoxymethyl)-6-methyl-5-nitro-2-oxo-1h-pyridine-3-carbonitrile Chemical compound COCC1=C(C#N)C(=O)NC(C)=C1[N+]([O-])=O FDZPYSHPLURJEA-UHFFFAOYSA-N 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 150000001408 amides Chemical class 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 18
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 239000012320 chlorinating reagent Substances 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- FPTYZBDNBMVYCL-UHFFFAOYSA-N 3-methyl-5-nitro-1h-pyridin-2-one Chemical compound CC1=CC([N+]([O-])=O)=CN=C1O FPTYZBDNBMVYCL-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 1
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 1
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- -1 chlorobenzene-thionyl chloride Chemical compound 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000000994 depressogenic effect Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
Landscapes
- Pyridine Compounds (AREA)
Description
Vynález se týká způsobu výroby 2-chlor-3-kyan-4-methoxymethyl-6-methyl-5-nitropyridinu, základního meziproduktu HarrisFolkersovy syntézy vitaminu Be (J. Ara. Chem. Soc. 61, 1045, 1939; BIOS 7,66, 159). V průmyslovém měřítku se vyrábí chlorací ’3-kyan-4-metho-xymethyl-6-<methyl-5-nitro-2-pyridonu různými chloračními činidly, především oxychloridem fosforečným a chloridem fosforečným, popřípadě v přítomnosti různých terciárních aminů, jako dimethylanilinu, pyridinu apod., nebo směsí chloridu fosforečného- s oxychloridem fosforečným (J. Frágner -a kol., Vitaminy 2, str. 1009; Těsta, Vecchi, Gaz. Chim. ital. 87, 467, 1957; Cuiban, Cilianu, Revista de Chimie č. 2, 74, 1959). Nevýhodou uvedených postupů je to, že delším zahříváním reakční směsi na vyšší teplotu (120 až 130 °C) doohází více či méně k destrukci žádaného· produktu, zatímco při nižší teplotě reakce buď neprobíhá, nebo· poskytuje nízké výtěžky, jak tomu je například v případě chlorace thionylchloridem (Těsta, Vecchi, l.c.).The invention relates to a process for the preparation of 2-chloro-3-cyano-4-methoxymethyl-6-methyl-5-nitropyridine, a basic intermediate of the HarrisFolkers synthesis of vitamin Be (J. Ara. Chem. Soc. 61, 1045, 1939; BIOS 7.66) , 159). It is produced on an industrial scale by chlorination of 3-cyano-4-methoxymethyl-6- (methyl-5-nitro-2-pyridone) with various chlorinating agents, in particular phosphorus oxychloride and phosphorus pentachloride, optionally in the presence of various tertiary amines such as dimethylaniline, pyridine and the like, or a mixture of phosphorus pentachloride with phosphorus oxychloride (J. Fragner et al., Vitamins 2, p. 1009; Dough, Vecchi, Gaz. Chim. ital. 87, 467, 1957; Cuiban, Cilianu, Revista de Chimie No. 2, 74, 1959). A disadvantage of these processes is that prolonged heating of the reaction mixture to a higher temperature (120 to 130 ° C) results in more or less destruction of the desired product, while at lower temperature the reaction either does not proceed or provides low yields, as in e.g. in the case of chlorination with thionyl chloride (Dough, Vecchi, lc).
Bylo zjištěno, že uvedené nevýhody lze odstranit způsobem výroby 2-chlor-3-kyan-4-methoxymethyl-6-methyl-5-nitropyridinu chlorací 3-kyan-4-methoxymethyl-6-me;thyl-5-nitro-2-pyridonu podle vynálezu, jehož podstata spočívá v tom, že se chlorace pro2 vádí v přítomnosti substituovaného amidu obecného vzorce:It has been found that these disadvantages can be overcome by a process for preparing 2-chloro-3-cyano-4-methoxymethyl-6-methyl-5-nitropyridine by chlorination of 3-cyano-4-methoxymethyl-6-me ; The compound of the present invention is characterized in that chlorination is carried out in the presence of a substituted amide of the formula:
RiRi
ZOF
R.CONR.CON
Rl ve kterémRl in which
R značí vodík, alkyl -s 1 — 4 atomy uhlíku nebo- fenyl aR is hydrogen, alkyl of 1-4 carbon atoms or phenyl and
Ri jsou alkyly s 1 — 4 atomy uhlíku, jako katalyzátoru.R 1 is C 1-4 alkyl as a catalyst.
Při provedení způsobu podle vynálezu lze používat obvyklých chloračních činidel, thionylchloridu, fosgenu, chloridu a oxychloridu fosforečného apod., a reakci provádět buď v přebytku chloračníhoi činidla, které se po skončené reakci oddestiluje, nebo v přítomnosti rozpouštědla. Jako rozpouštědla lze s výhodou používat chlorovaných alifatických nebo aromatických uhlovodíků, jako dichlo-rethanu, chlorbenzenu apod.In the process of the invention, conventional chlorinating agents, thionyl chloride, phosgene, chloride and phosphorus oxychloride and the like can be used, and the reaction can be carried out either in excess of the chlorinating agent, which is distilled off after the reaction, or in the presence of a solvent. As the solvent, chlorinated aliphatic or aromatic hydrocarbons such as dichloromethane, chlorobenzene and the like can be advantageously used.
Proti doposud známým způsobům má způsob podle vynálezu tyto výhody: nižší reakční teplotu, kratší reakční dobu, vyšší výtěžky a čistý surový produkt. Provedení je jednoduché, snadno proveditelné v běžném zařízení.Compared to the known processes, the process of the invention has the following advantages: lower reaction temperature, shorter reaction time, higher yields and pure crude product. The design is simple, easy to perform in a conventional device.
Uvedené příklady provedení způsob p-odle vynálezu toliko ilustrují, ale nijak neomezují.These examples illustrate the process according to the invention but are not intended to limit it.
Příklady provedeníExamples
Příklad 1Example 1
Směs 4,46 g jemně rozetřeného· 3-kyan-4-methoxymethyl-6-methyl-5-nitro-2-pyridonu, 15 ml chlorbenzenu, 14,5 ml thionylchloridu a 0,2 ml dimethylformamidu se za míchání pod zpětným chladičem zahřívá 1 hodinu na £0 °'C. Potom se ve vakuu oddestiluje směs chlorbenzenu -a thionylchloridu (23 ml), odparek se rozpustí v 60 ml benzenu (2X po 3i0 ml), benzenový roztok: se vytřepe vodou, zfiltruje s karborafinem a ve vakuu odpaří. Světle hnědý odparek ochlazením okamžitě ztuhne v krystalickou látku s t. t. 69 až 71 °C. Výtěžek 4,6 g, tj, 95,9 % teorie.A mixture of 4.46 g of finely divided 3-cyano-4-methoxymethyl-6-methyl-5-nitro-2-pyridone, 15 ml of chlorobenzene, 14.5 ml of thionyl chloride and 0.2 ml of dimethylformamide is heated to reflux with stirring. 1 hour at £ 0 ° C. The mixture of chlorobenzene-thionyl chloride (23 ml) was distilled off in vacuo, the residue was dissolved in 60 ml of benzene (2 x 30 ml), the benzene solution was shaken with water, filtered with carboraffin and evaporated in vacuo. The light brown residue solidified upon cooling to a crystalline solid, m.p. 69-71 ° C. Yield 4.6 g, i.e., 95.9% of theory.
Příklad 2Example 2
Směs 2,23 g jemně rozetřeného 3-kyan-4-methoxyměthyl-6-methyl-5-nitro-2-pyridonu, 7,25 ml thionylchloridu a 0,1 ml dimethylformamidu se zahřívá za míchání 1 hodinu na 65 °C. Potom se za normálního tlaku oddestiluje přebytečný thionylchlorid (teplota lázně 85 °C, regenerováno' 5 ml) a zbytek se rozpustí v 60 ml benzenu. Benzenový roztok se protřepe vodou, zfiltruje s karborafinem a benzen se oddestiluje ve vakuu. Olejovitý odparek ochlazením ztuhne v krystalickou látku s t. t. 67 až 70 °C, výtěžek 2,2 gramů, tj. 91,3 % teorie.A mixture of 2.23 g of finely triturated 3-cyano-4-methoxymethyl-6-methyl-5-nitro-2-pyridone, 7.25 ml of thionyl chloride and 0.1 ml of dimethylformamide was heated to 65 ° C with stirring for 1 hour. Excess thionyl chloride is then distilled off under normal pressure (bath temperature 85 ° C, regenerated with 5 ml) and the residue is dissolved in 60 ml of benzene. The benzene solution is shaken with water, filtered with carboraffin and the benzene is distilled off in vacuo. The oily residue solidified on cooling to give a crystalline solid having a melting point of 67-70 ° C, yield 2.2 g, i.e. 91.3% of theory.
Příklad 3Example 3
Směs 4,46 jemně rozetřeného 3-.kya.n-4-me’thoxyrnethyl-6-methyl-5-nitro-2-pyrid0nu, 1,45 ml thionylchloridu, 0,2 ml dimethylformamidu a 15 ml chlorbenzenu se zahřívá za míchání 3 hodiny na 95 QC. Po skončeném zahřívání se nerozpuštěná látka odsaje, promyje malým množstvím benzenu a vysuší. Získá se 2,2 g látky s t. t. 214 až 2!17 QC, nedávající depresi s výchozím 3-kyan-4-methoxymethyl-6-methyl-5-nitro-2-py.ridonem. Filtrát se rozloží 70 ml vody a vzniklá směs se vytřepe petroletherem. Petroletherový výtřep se zfiltruje s karborafinem, petrolether s chlorbenzenem se odpaří ve vakuu a ochlazením odparku se získá žlutá krystalická látka s t. t. 69 až 71 °C. Výtěžek 2,1 g, tj.A mixture of 4.46 gently triturated 3-cyano-4-methoxymethyl-6-methyl-5-nitro-2-pyridine, 1.45 ml thionyl chloride, 0.2 ml dimethylformamide and 15 ml chlorobenzene is heated with stirring After 3 hours at 95 DEG C. After complete heating, the insoluble matter is filtered off with suction, washed with a small amount of benzene and dried. 2.2 g of solid, mp 214-2! 17 Q C oblivious depressed starting with 3-cyano-4-methoxymethyl-6-methyl-5-nitro-2-py.ridonem. The filtrate is quenched with 70 ml of water and the mixture is shaken with petroleum ether. The petroleum ether shake was filtered with carboraffin, the petroleum ether with chlorobenzene was evaporated in vacuo and the residue was cooled to give a yellow crystalline solid, mp 69-71 ° C. Yield 2.1 g.
86,5 % teorie, počítáno na zreagovaný 3-kyan-4rmethoxymethyl-6-methyl-5-imtro-2npyridon.86.5% of theory, calculated on the converted 3-cyano-4-methoxymethyl-6-methyl-5-nitro-2-pyridone.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS580862A CS219406B1 (en) | 1962-10-12 | 1962-10-12 | Method of making the 2-chlor-3-cyan-4-methoxymethyl-6-methyl-5-nitropyridine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS580862A CS219406B1 (en) | 1962-10-12 | 1962-10-12 | Method of making the 2-chlor-3-cyan-4-methoxymethyl-6-methyl-5-nitropyridine |
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| Publication Number | Publication Date |
|---|---|
| CS219406B1 true CS219406B1 (en) | 1983-03-25 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CS580862A CS219406B1 (en) | 1962-10-12 | 1962-10-12 | Method of making the 2-chlor-3-cyan-4-methoxymethyl-6-methyl-5-nitropyridine |
Country Status (1)
| Country | Link |
|---|---|
| CS (1) | CS219406B1 (en) |
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1962
- 1962-10-12 CS CS580862A patent/CS219406B1/en unknown
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