CS248547B1 - Method of hydrochloride 2-piperidinoethylchloride production - Google Patents
Method of hydrochloride 2-piperidinoethylchloride production Download PDFInfo
- Publication number
- CS248547B1 CS248547B1 CS742285A CS742285A CS248547B1 CS 248547 B1 CS248547 B1 CS 248547B1 CS 742285 A CS742285 A CS 742285A CS 742285 A CS742285 A CS 742285A CS 248547 B1 CS248547 B1 CS 248547B1
- Authority
- CS
- Czechoslovakia
- Prior art keywords
- hydrochloride
- piperidine
- reaction mixture
- reaction
- thionyl chloride
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 9
- VFLQQZCRHPIGJU-UHFFFAOYSA-N 1-(2-chloroethyl)piperidine;hydron;chloride Chemical compound Cl.ClCCN1CCCCC1 VFLQQZCRHPIGJU-UHFFFAOYSA-N 0.000 title claims abstract description 6
- 238000004519 manufacturing process Methods 0.000 title abstract description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 21
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims abstract description 14
- 238000006243 chemical reaction Methods 0.000 claims abstract description 8
- 239000011541 reaction mixture Substances 0.000 claims abstract description 8
- SZIFAVKTNFCBPC-UHFFFAOYSA-N 2-chloroethanol Chemical compound OCCCl SZIFAVKTNFCBPC-UHFFFAOYSA-N 0.000 claims abstract description 4
- 238000002360 preparation method Methods 0.000 claims abstract description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 16
- KZTWONRVIPPDKH-UHFFFAOYSA-N 2-(piperidin-1-yl)ethanol Chemical compound OCCN1CCCCC1 KZTWONRVIPPDKH-UHFFFAOYSA-N 0.000 claims description 8
- 238000009835 boiling Methods 0.000 claims description 3
- 238000005660 chlorination reaction Methods 0.000 claims description 3
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- 239000012442 inert solvent Substances 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 125000001340 2-chloroethyl group Chemical group [H]C([H])(Cl)C([H])([H])* 0.000 abstract 1
- 238000002425 crystallisation Methods 0.000 abstract 1
- 230000008025 crystallization Effects 0.000 abstract 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- -1 2-piperidinoethylene chloride hydrochloride Chemical compound 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 125000003870 2-(1-piperidinyl)ethoxy group Chemical group [*]OC([H])([H])C([H])([H])N1C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 1
- PMAHPMMCPXYARU-UHFFFAOYSA-N 4-(1-methylpiperidin-1-ium-1-yl)-2,2-diphenylbutanamide;bromide Chemical compound [Br-].C=1C=CC=CC=1C(C(N)=O)(C=1C=CC=CC=1)CC[N+]1(C)CCCCC1 PMAHPMMCPXYARU-UHFFFAOYSA-N 0.000 description 1
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 125000002603 chloroethyl group Chemical group [H]C([*])([H])C([H])([H])Cl 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229950005166 fenpiverinium bromide Drugs 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- MZDGXTXYHXDWIM-UHFFFAOYSA-N methyl benzoate;hydrochloride Chemical compound Cl.COC(=O)C1=CC=CC=C1 MZDGXTXYHXDWIM-UHFFFAOYSA-N 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229950008096 pitofenone Drugs 0.000 description 1
- NZHMAQSCHUSSSJ-UHFFFAOYSA-N pitofenone Chemical compound COC(=O)C1=CC=CC=C1C(=O)C(C=C1)=CC=C1OCCN1CCCCC1 NZHMAQSCHUSSSJ-UHFFFAOYSA-N 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000002048 spasmolytic effect Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
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- Hydrogenated Pyridines (AREA)
Abstract
Vynález se týká způsobu výroby hydrochloridu 2-piperidinoethylchloridu. Podstatou výroby je reakce piperidinu s ethylenchlorhydrinem na 2-piperidinoetbanol a jeho převedeni na odpovídajici 2-chlorethylderivát v jednom reakcnim stupni v prostředí toluenu. 2-piperidinoethylchloridhydrochlorid vykrystalizuje z reakční směsi a přečistí se krystalizací.The invention relates to a process for the preparation of the hydrochloride 2-piperidinoethyl chloride. The essence of the production is the reaction of piperidine with ethylene chlorohydrin to 2-piperidinoetbanol and its transfer to the corresponding 2-chloroethyl derivative in one reaction step in toluene. 2-piperidinoethyl chloride hydrochloride crystallizes from the reaction mixture and purified by crystallization.
Description
Vynález se týké způsobu výroby hydrochloridu 2-piperidinoethylohloridu vzorceThe invention relates to a process for the preparation of 2-piperidinoethylene chloride hydrochloride of the formula
HNCHOCHOC1 / 2 2 +HNCH O O CH C1 / 2 + 2
Cl' klíčového meziproduktu syntézy mnoha léčiv, například klinicky používaných spasmolytik pitofenonhydrochloridu a fenpiveriniumbromidu (hydrochlorid methylesteru kyseliny 2-/4-/2-(l-piperidinyl)ethoxy/benzoyl/benzoové a l-(4-amino-4-oxo-3,3-difenylbutyl)-1-methylpiperidiniumbromid)·C1 'a key intermediate for the synthesis of many drugs, such as the clinically used spasmolytics pitofenone hydrochloride and fenpiverinium bromide (2- / 4- / 2- (1-piperidinyl) ethoxy / benzoyl) benzoic acid methyl ester hydrochloride and 1- (4-amino-4-oxo-3) (3-diphenylbutyl) -1-methylpiperidinium bromide) ·
Podle literatury se titulní sloučenina připravuje ve dvou stupních, a to tak, že se piperidin nejprve převede na 2-hydroxyethylderivát, který se izoluje a Čistí destilací, a v dalším stupni potom reakcí a thionylchloridem poskytne žádaný chlorethylderivát. (P.S.Wadia se sp., Chem.Abstr. 52,15547g, 1958$ NSR pat. spis Č.881 655)· Byla též popsána jednostupňová syntéza v prostředí chloroformu, avšak s výtěžkem pouze 28 % (T.Bany, Acta Bol. Pharm. 12,223.1955, Chem.Abstr. 50,12O42e,1956). Jak je patrno, jsou popsané způsoby výroby technologicky nevýhodné.According to the literature, the title compound is prepared in two steps by first converting the piperidine to the 2-hydroxyethyl derivative, which is isolated and purified by distillation, followed by reaction with thionyl chloride to give the desired chloroethyl derivative. (PSWadia se sp., Chem.Abstr. 52,15547g, 1958 $ NSR Pat. No. 881,655) · A one-step synthesis in chloroform was also described, but with a yield of only 28% (T.Bany, Acta Bol. Pharm., 12,223, 1955, Chem. As can be seen, the production methods described are technologically disadvantageous.
Nyní byl nalezen způsob výroby hydrochloridu 2-piperidinoethylchloridu, který je technicky, preparativně i ekonomicky podstatně jednodušší a výhodnější.We have now found a process for the preparation of 2-piperidinoethyl chloride hydrochloride which is technically, preparatively and economically substantially simpler and more advantageous.
Tento způsob, který je předmětem vynálezu, vychází z reakce piperidinu s ethylenchlorhydrinem a chlorace vzniklého hydroxyethylpiperidinu thionylchloridem v prostředí netečného rozpouštědla, jako aromatického uhlovodíku, například toluenu, za teplot 70°C až teploty varu reakční směsi. Jeho podstata spočívá v tom, že se po ukončené hydroxyethylaci piperidinu a po zředění reakcní směsi použitým rozpouštědlem v množství 0,4 až 0,6 jejího objemu provádí v jednom reakčním stupni chlorace vzniklého hydroxyethyl248 547 piperidinu thionylchloridem při teplotě 70 až 85°C a vyloučený produkt se po ochlazení reakční směsi izoluje.This process is based on the reaction of piperidine with ethylene chlorohydrin and the chlorination of the resulting hydroxyethyl piperidine with thionyl chloride in an inert solvent such as an aromatic hydrocarbon such as toluene at 70 ° C to the boiling point of the reaction mixture. It is based on the fact that after complete hydroxyethylation of piperidine and dilution of the reaction mixture with 0.4 to 0.6 volume of solvent used in one reaction stage, the chlorination of the resulting hydroxyethyl 2448 piperidine with thionyl chloride is carried out at 70 to 85 ° C and precipitated the product is isolated after cooling the reaction mixture.
Provedení způsobu podle vynálezu je velmi jednoduché. Způsob lze realizovat v jedné reakční nádobě, produkt první reakce, t^. hydroxyethylpiperidin, se neizoluje, nýbrž v přiměřeně zředěné reakční směsi se přímo chloruje thionylchloridem. Proti literárním údajům stačí v tomto případě lOx nižší přebytek thionylchloridu a výtěžky jsou průměrně o 20 % teorie vyšší. -Z uvedeného jsou zřejmé výhody způsobu podle vynálezu, jehož bližší podrobnosti vyplývají z příkladu provedení, který tento způsob pouze iluetruje, ale nijak neomezuje.The process according to the invention is very simple to carry out. The process may be carried out in a single reaction vessel, the product of the first reaction, i. hydroxyethylpiperidine is not isolated but is directly chlorinated with thionyl chloride in an appropriately diluted reaction mixture. In comparison to the literature data, a 10x lower excess of thionyl chloride is sufficient in this case and the yields are on average 20% higher. From the foregoing, the advantages of the process according to the invention are obvious, the details of which are apparent from an exemplary embodiment, which is not only illustrative but not limiting.
K roztoku 5,8 litru piperidinu v 5 litrech toluenu se přidá 4,16 litru ethylenchlorhydrinu, směs se zahřeje k varu a při teplo tě varu se udržuje 3 h. Po odstranění vyhřívací lázně se přidá 7 litrů toluenu a přikape se roztok 4,53 litru thionylchloridu v 1,25 litru toluenu. Potom se reakční směs za míchání udržuje při teplotě 78 až 80°C ještě 4 h. Nechá se stát přes noc, vyloučený krystalický produkt se odsaje a promyje toluenem. Získá se 9,4 kg surového produktu, který po krystalizaci z 2-propanolu poskytneTo a solution of 5.8 liters of piperidine in 5 liters of toluene was added 4.16 liters of ethylene chlorohydrin, the mixture was heated to boiling and maintained at reflux for 3 hours. After removal of the heating bath, 7 liters of toluene were added and the solution added 4.53 liter of thionyl chloride in 1.25 liter of toluene. Thereafter, the reaction mixture is kept under stirring at 78-80 ° C for a further 4 hours. It is left to stand overnight, the precipitated crystalline product is filtered off with suction and washed with toluene. 9.4 kg of crude product are obtained, which is crystallized from 2-propanol
6,3 kg (58 % teorie) čisté látky. Zpracováním matečných louhů se získá další podíl, kterým se celkový výtěžek hydrochloridu 2-piperidinoethylchloridu zvýší o 10 % teorie.6.3 kg (58% of theory) of pure substance. Working up the mother liquors yielded an additional portion, which increased the overall yield of 2-piperidinoethyl chloride hydrochloride by 10% of theory.
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS742285A CS248547B1 (en) | 1985-10-18 | 1985-10-18 | Method of hydrochloride 2-piperidinoethylchloride production |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS742285A CS248547B1 (en) | 1985-10-18 | 1985-10-18 | Method of hydrochloride 2-piperidinoethylchloride production |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CS248547B1 true CS248547B1 (en) | 1987-02-12 |
Family
ID=5423318
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CS742285A CS248547B1 (en) | 1985-10-18 | 1985-10-18 | Method of hydrochloride 2-piperidinoethylchloride production |
Country Status (1)
| Country | Link |
|---|---|
| CS (1) | CS248547B1 (en) |
-
1985
- 1985-10-18 CS CS742285A patent/CS248547B1/en unknown
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