CS268273B1 - Method of 2,2-diphenyl-4-piperidinobutanoic acid's nitrile production - Google Patents
Method of 2,2-diphenyl-4-piperidinobutanoic acid's nitrile production Download PDFInfo
- Publication number
- CS268273B1 CS268273B1 CS875318A CS531887A CS268273B1 CS 268273 B1 CS268273 B1 CS 268273B1 CS 875318 A CS875318 A CS 875318A CS 531887 A CS531887 A CS 531887A CS 268273 B1 CS268273 B1 CS 268273B1
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- CS
- Czechoslovakia
- Prior art keywords
- alkylation
- toluene
- diphenyl
- reaction
- hydrochloride
- Prior art date
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- 238000000034 method Methods 0.000 title claims abstract description 11
- 238000004519 manufacturing process Methods 0.000 title abstract description 3
- YHMXLMFIXSBDHX-UHFFFAOYSA-N 2,2-diphenyl-4-piperidin-1-ylbutanoic acid Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(C(=O)O)CCN1CCCCC1 YHMXLMFIXSBDHX-UHFFFAOYSA-N 0.000 title abstract 2
- 150000002825 nitriles Chemical class 0.000 title abstract 2
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 45
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 28
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims abstract description 18
- 230000029936 alkylation Effects 0.000 claims abstract description 8
- 238000005804 alkylation reaction Methods 0.000 claims abstract description 8
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 claims abstract description 8
- WNRWEBKEQARBKV-UHFFFAOYSA-N 1-(2-chloroethyl)piperidine Chemical compound ClCCN1CCCCC1 WNRWEBKEQARBKV-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000002904 solvent Substances 0.000 claims abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims abstract description 6
- -1 2-piperidinoethylchloride hydrochloride sodium amide Chemical compound 0.000 claims abstract description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- NEBPTMCRLHKPOB-UHFFFAOYSA-N 2,2-diphenylacetonitrile Chemical compound C=1C=CC=CC=1C(C#N)C1=CC=CC=C1 NEBPTMCRLHKPOB-UHFFFAOYSA-N 0.000 claims description 6
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 239000011541 reaction mixture Substances 0.000 claims description 3
- VFLQQZCRHPIGJU-UHFFFAOYSA-N 1-(2-chloroethyl)piperidine;hydron;chloride Chemical compound Cl.ClCCN1CCCCC1 VFLQQZCRHPIGJU-UHFFFAOYSA-N 0.000 claims description 2
- 238000009835 boiling Methods 0.000 claims description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 abstract description 10
- 239000007795 chemical reaction product Substances 0.000 abstract description 3
- 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 abstract description 2
- 229950005166 fenpiverinium bromide Drugs 0.000 abstract description 2
- 239000012429 reaction media Substances 0.000 abstract description 2
- 230000002048 spasmolytic effect Effects 0.000 abstract 1
- 239000000203 mixture Substances 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 241001432959 Chernes Species 0.000 description 1
- 238000005684 Liebig rearrangement reaction Methods 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 230000002152 alkylating effect Effects 0.000 description 1
- 230000002921 anti-spasmodic effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000000812 cholinergic antagonist Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000002274 desiccant Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000011020 pilot scale process Methods 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000006561 solvent free reaction Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
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- Hydrogenated Pyridines (AREA)
Abstract
Řešeni se týká způsobu výroby nitrilu kyseliny 2,2-dlfenyl-4-piperídinobutanové, který Je meziproduktem známého spasmolytika fenpiveriniumbromidu. Postup, popsaný v literatuře pracuje při alkylaci s bázi 2-piperidinoethylchlorldu a s amidem sodným, reakčnim prostředím Je benzen. Nový způsob používá k alkylaci přímo hydrochlorid 2-piperidinoethylchlorldu, amid sodný Je nahrazen hydroxidem sodným a reakce probíhá bez rozpouštědla při teplotě okolo 100 C. K izolaci reakčniho produktu se používá místo v literatuře popisovaného ethyletheru toluenu v kombinaci s benzinem.The present invention relates to a process for the production of a nitrile 2,2-diphenyl-4-piperidino-butyric acid, which is an intermediate known spasmolytics of fenpiverinium bromide. Procedure, described in the literature works in alkylation with 2-piperidinoethylchloride a with sodium amide, the reaction medium (I) benzene. The new process uses alkylation directly 2-piperidinoethylchloride hydrochloride sodium amide is replaced by hydroxide sodium and the reaction proceeds without solvent at a temperature of about 100 ° C. It is used to isolate the reaction product instead of the ethyl ether described in the literature toluene in combination with gasoline.
Description
Vynález se týká způsobu výroby nitrilu kyseliny 2,2-dlfeny1-4-piperidinobutanové vzorce IThe invention relates to a process for the preparation of 2,2-diphenyl-4-piperidinobutanoic acid nitrile of the formula I.
/1/./ 1 /.
který Je meziproduktem známého spasmolytika fenpiveriniumbromidu. Podle dostupné literatury /Bockmuhl M.: DRP 710 227, 1942; Bockmuhl M. , Ehrhart G.: Justus Liebigs Ann.Chern. 561,52, 1948/ se látka vzorce I připravuje alkylaci difenylacetonitrilu bází 2-piperidinoethylchloridu v prostředí benzenu v přítomnosti amidu sodného. Reakčni produkt se převede na hydrochlorid, který se rozloži hydroxidem sodným a báze se extrahuje ethyletherem. Tento způsob je za uvedených podmínek použitelný v laboratorním měřítku; při převádění už do poloprovozního měřítka se objevuje řada nevýhod. Především je to malá stálost báze 2-piperidinoethylchloridu, která se musi z hydrochloridu uvolnit a čistit destilací a stejně nevýhodná Je práce s amidem sodným, který je nebezpečný a manipulace s ním je nepříjemná. Dále Je to použiti benzenu jako reakčniho prostředí a ethyletheru k extrakci reakčního produktu. Obě tato rozpouštědla jsou pro práci v provozním měřítku málo vhodná.which is an intermediate of the known antispasmodic fenpiverinium bromide. According to available literature / Bockmuhl M .: DRP 710 227, 1942; Bockmuhl M., Ehrhart G .: Justus Liebigs Ann.Chern. 561,52, 1948], a compound of formula I is prepared by alkylation of diphenylacetonitrile with 2-piperidinoethyl chloride base in benzene in the presence of sodium amide. The reaction product is converted into the hydrochloride, which is decomposed with sodium hydroxide and the base is extracted with ethyl ether. This method is applicable on a laboratory scale under the stated conditions; There are a number of disadvantages to converting to pilot scale. In particular, it is the low stability of the 2-piperidinoethyl chloride base that must be released from the hydrochloride and purified by distillation, and it is equally disadvantageous to work with sodium amide, which is dangerous and inconvenient to handle. It is further used benzene as the reaction medium and ethyl ether to extract the reaction product. Both of these solvents are unsuitable for work on a commercial scale.
S ohledem na větší výrobu látky vzorce I bylo nezbytné hledat vhodnější reakčni podmínky, amid sodný nahradit bezpečnějším činidlem, stejně jako benzen a ethylether nahradit rozpouštědly z provozního hlediska přijatelnějšími. Bylo zjištěno, že 2-piperidinoethylchlorid je možné použít ve formě hydrochloridu, amid sodný lze se zcela shodnými výsledky, při nesrovnatelně vyšši bezpečnosti práce, nahradit pevným hydroxidem sodným, reakci provést bez rozpouštědla a ethylether při extrakci nahradit to1uenem.In view of the larger production of the compound of formula I, it was necessary to seek more suitable reaction conditions, to replace sodium amide with a safer reagent, as well as to replace benzene and ethyl ether with more operationally acceptable solvents. It has been found that 2-piperidinoethyl chloride can be used in the form of the hydrochloride, sodium amide can be replaced with solid sodium hydroxide, solvent-free reaction and ethyl ether with toluene during extraction with incomparably higher work safety results.
Tyto nové poznatky vedly k vypracování způsobu výroby nitrilu kyseliny 2,2-difenyl-4-piperidinobutanové, dosud připravované alkylaci difenylacetonitrilu bázi 2-piperidinoethylchloridu v prostředí benzenu v přítomnosti amidu sodného, podle vynálezu, jehož podstata spočívá v tom, že se k alkylaci difenylacetonitrilu používá 2-piperidinoethylchlorid ve formě hydrochloridu, reakce probíhá v přítomnosti hydroxidu sodného bez rozpouštědla při teplotě 90 až 110 °C, po ukončení alkylace se při uvedené teplotě reakčni směs rozpouští v rozpouštědle, nemisitelném s vodou, typu aromatického uhlovodíku s teplotou varu nad 100 °C, např. toluenu, přidáním vodné kyseliny chlorovodíkové o hmotnostní koncentraci 5 až 10 % se báze převede na hydrochlorid, z něhož se znovu uvolni hydroxidem sodným, vyjme se do aromatického uhlovodíku, s výhodou toluenu a z toluenového roztoku se izoluje přidáním benzinu.These new findings have led to the preparation of a process for the preparation of 2,2-diphenyl-4-piperidinobutanoic acid nitrile, hitherto prepared by alkylation of diphenylacetonitrile base 2-piperidinoethyl chloride in benzene in the presence of sodium amide, according to the invention, which consists in alkylating diphenylacetonitrile. 2-piperidinoethyl chloride is used in the form of the hydrochloride, the reaction is carried out in the presence of sodium hydroxide without solvent at a temperature of 90 to 110 ° C, after alkylation, the reaction mixture is dissolved in a water-immiscible solvent of aromatic hydrocarbon boiling above 100 °. C, e.g. toluene, by adding aqueous hydrochloric acid at a concentration of 5 to 10% by weight, the base is converted into the hydrochloride, from which it is liberated again with sodium hydroxide, taken up in an aromatic hydrocarbon, preferably toluene, and isolated from the toluene solution by adding petrol.
Provedeni způsobu podle vynálezu je velmi jednoduché a bezpečné i ve větším měřítku, a technický i ekonomický přinos Je evidentní. Je to především použití alkylačniho činidla ve formě hydrochloridu, náhrada amidu sodného hydroxidem sodným a reakce probíhá bez rozpouštědla při poměrně nízké teplotě.The implementation of the method according to the invention is very simple and safe even on a larger scale, and the technical and economic benefit is evident. It is mainly the use of an alkylating agent in the form of the hydrochloride, the replacement of the sodium amide by sodium hydroxide and the reaction taking place without solvent at a relatively low temperature.
Bližší podrobnosti způsobu podle vynálezu vyplývají z následujícího přikladu provedení, který tento způsob pouze ilustruje ale nijak neomezuje.Further details of the method according to the invention follow from the following exemplary embodiment, which merely illustrates but does not limit this method.
K 60 g práškového hydroxidu sodného se přidá 77 g difenylacetonitrilu a 92,2 g hydrochloridu 2-piperidinoethylchloridu, směs se zahřeje na 100 °C a udržuje se 6 h při 96 až 100 °C. Po skončené reakci se k horké reakčni směsi ihned přidá 300 ml toluenu, v mícháni se pokračuje za samovolného chlazeni ještě 1 h, směs se promyje vodou a vrstvy se rozdělí. Vodná se extrahuje toluenem a spojené toluenové roztoky se promyji 4 x 250 ml 2N kyseliny chlorovodíkové. Vodná vrstva /roztok hydrochloridu/ seTo 60 g of powdered sodium hydroxide were added 77 g of diphenylacetonitrile and 92.2 g of 2-piperidinoethyl chloride hydrochloride, and the mixture was heated to 100 ° C and maintained at 96-100 ° C for 6 hours. After completion of the reaction, 300 ml of toluene was immediately added to the hot reaction mixture, stirring was continued under self-cooling for 1 hour, the mixture was washed with water, and the layers were separated. The aqueous was extracted with toluene and the combined toluene solutions were washed with 4 x 250 mL of 2N hydrochloric acid. The aqueous layer (hydrochloride solution) was removed
CS 268273 Bl převrstvi toluenem, směs se ochladí na O až 5 °C a alkalizuje přebytkem pevného hydroxidu sodného. Vrstvy se rozdělí, vodná se extrahuje toluenem, spojené toluenové roztoky se vysuší bezvodným uhličitanem draselným a po filtraci sušidla se toluenový roztok zahustí za sníženého tlaku k suchu. K rezultujíčímu olejovitému odparku se přidá 60 ml benzinu a směs se ponechá při teplotě + 5 °C. Produkt se odsaje, promyje benzinem, vychlazeným na - 5 °C a překrystaluje z benzinu. Získá se Θ4 g čisté látky.CS 268273 B1 overlaid with toluene, the mixture was cooled to 0-5 ° C and basified with excess solid sodium hydroxide. The layers were separated, the aqueous was extracted with toluene, the combined toluene solutions were dried over anhydrous potassium carbonate, and after filtering off the desiccant, the toluene solution was concentrated to dryness under reduced pressure. 60 ml of petrol are added to the resulting oily residue and the mixture is left at + 5 ° C. The product is filtered off with suction, washed with petrol cooled to -5 [deg.] C. and recrystallized from petrol. G4 g of pure substance are obtained.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS875318A CS268273B1 (en) | 1987-07-13 | 1987-07-13 | Method of 2,2-diphenyl-4-piperidinobutanoic acid's nitrile production |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS875318A CS268273B1 (en) | 1987-07-13 | 1987-07-13 | Method of 2,2-diphenyl-4-piperidinobutanoic acid's nitrile production |
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| Publication Number | Publication Date |
|---|---|
| CS531887A1 CS531887A1 (en) | 1989-08-14 |
| CS268273B1 true CS268273B1 (en) | 1990-03-14 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CS875318A CS268273B1 (en) | 1987-07-13 | 1987-07-13 | Method of 2,2-diphenyl-4-piperidinobutanoic acid's nitrile production |
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1987
- 1987-07-13 CS CS875318A patent/CS268273B1/en unknown
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| CS531887A1 (en) | 1989-08-14 |
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