CH332334A - Manufacturing process of N-benzhydryl-N'-benzylpiperazines - Google Patents
Manufacturing process of N-benzhydryl-N'-benzylpiperazinesInfo
- Publication number
- CH332334A CH332334A CH332334DA CH332334A CH 332334 A CH332334 A CH 332334A CH 332334D A CH332334D A CH 332334DA CH 332334 A CH332334 A CH 332334A
- Authority
- CH
- Switzerland
- Prior art keywords
- nitrile
- benzylpiperazines
- benzhydryl
- toluene solution
- manufacturing process
- Prior art date
Links
- 238000004519 manufacturing process Methods 0.000 title claims description 3
- KUAJKNGLESWEFE-UHFFFAOYSA-N 1-benzhydryl-4-benzylpiperazine Chemical class C=1C=CC=CC=1CN(CC1)CCN1C(C=1C=CC=CC=1)C1=CC=CC=C1 KUAJKNGLESWEFE-UHFFFAOYSA-N 0.000 title description 2
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 27
- 238000000034 method Methods 0.000 claims description 8
- 238000009835 boiling Methods 0.000 claims description 7
- 150000002825 nitriles Chemical class 0.000 claims description 5
- 125000005219 aminonitrile group Chemical group 0.000 claims description 3
- ANRQGKOBLBYXFM-UHFFFAOYSA-M phenylmagnesium bromide Chemical compound Br[Mg]C1=CC=CC=C1 ANRQGKOBLBYXFM-UHFFFAOYSA-M 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- -1 phenyl-magnesium halide Chemical class 0.000 claims description 2
- 239000000243 solution Substances 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 239000000203 mixture Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 238000006467 substitution reaction Methods 0.000 description 3
- AVPYQKSLYISFPO-UHFFFAOYSA-N 4-chlorobenzaldehyde Chemical compound ClC1=CC=C(C=O)C=C1 AVPYQKSLYISFPO-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- 239000007818 Grignard reagent Substances 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 2
- 244000309464 bull Species 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 150000004795 grignard reagents Chemical class 0.000 description 2
- 239000000155 melt Substances 0.000 description 2
- 125000002560 nitrile group Chemical group 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- VTEOTZPEMDQENX-UHFFFAOYSA-N 1-[(3-methylphenyl)methyl]piperazine Chemical compound CC1=CC=CC(CN2CCNCC2)=C1 VTEOTZPEMDQENX-UHFFFAOYSA-N 0.000 description 1
- LCEJWHMPTBPPHG-UHFFFAOYSA-N 1-benzyl-2-tert-butylpiperazine Chemical compound CC(C)(C)C1CNCCN1CC1=CC=CC=C1 LCEJWHMPTBPPHG-UHFFFAOYSA-N 0.000 description 1
- IQXXEPZFOOTTBA-UHFFFAOYSA-N 1-benzylpiperazine Chemical class C=1C=CC=CC=1CN1CCNCC1 IQXXEPZFOOTTBA-UHFFFAOYSA-N 0.000 description 1
- KBIWOOUNWWYICM-UHFFFAOYSA-N CC1=CCC(CN2CCNCC2)(C(C2=CC=CC=C2)C(C=C2)=CC=C2Cl)C=C1 Chemical compound CC1=CCC(CN2CCNCC2)(C(C2=CC=CC=C2)C(C=C2)=CC=C2Cl)C=C1 KBIWOOUNWWYICM-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- ADSXDBCZNVXTRD-UHFFFAOYSA-N [Mg]C1=CC=CC=C1 Chemical class [Mg]C1=CC=CC=C1 ADSXDBCZNVXTRD-UHFFFAOYSA-N 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
Description
<Desc/Clms Page number 1>
Procédé de fabrication de N-benzhydryl-N'-benzylpipérazines La présente invention se rapporte à un procédé de fabrication de N-benzhydryl-N'-benzylpi- pérazines par réaction d'un halogénure de phénylmagnésium avec un nitrile aminé de formule
EMI1.8
dans laquelle Y représente un radical alcoyle contenant de 1 à 4 atomes de carbone. Les produits ainsi obtenus possèdent des propriétés pharmaceutiques.
Ces nitriles peuvent s'obtenir par exemple, selon la technique Goodson et Christopher / J. Am. chem. Soc. 72, (1950), 358-62 / par réaction de p-chlorbenzaldéhyde et de cyanure de potassium sur une mono-benzylpipé- razine substituée.
Le procédé de préparation est basé sur la substitution, dans un composé organique, d'un groupe nitrile par le groupe phényle d'un dérivé du phénylmagnésium. Une telle substitution a déjà été utilisée par P. Bruylants / Bull. Soc. chim. Belg. 33, (1924), 467-78 / pour l'obtention d'amines tertiaires à partir de nitriles aminés.
Il a .été constaté que si on effectue la réaction en milieu éthéré, selon la méthode habituelle de Grignard, les rendements obtenus sont très faibles : apparemment la substitution du groupement nitrile par le groupe phényle du réactif de Grignard se fait difficilement à la température d'ébullition de l'éther.
Toutefois, si on remplace l'éther du réactif de Grignard par un solvant inerte de point d'ébullition plus élevé (par exemple le toluène) et qu'on ajoute une solution toluénique du nitrile à une solution toluénique de bromure de phé- nylmagnésium à ébullition, on obtient les produits escomptés avec des rendements de l'ordre de 70 à 75,0/û. Exemple 1 Préparation de 1-p-chlorbenzhydryl-4-p(t-butyl)-benzylpipérazine
EMI1.37
<Desc/Clms Page number 2>
On ajoute à 0,5 mole de mono-p-(t-butyl)
- benzylpipérazine la quantité d'acide chlorhydri- que nécessaire pour neutraliser une fonction aminée. On ajoute ensuite 0,5 mole de p-chlor- benzaldéhyde. En agitant le mélange, on introduit goutte à goutte une solution aqueuse de 0,55 mole de cyanure de potassium. Après cette addition, on chauffe pendant deux heures au bain-marie.
Après refroidissement, on ajoute du toluène et on décante. La solution toluénique, contenant le nitrile, est séchée sur du carbonate de potassium (le nitrile recristallisé dans l'hexane fond à 90 - 910 C). Cette solution est introduite lentement et avec agitation dans une solution toluénique bouillante de bromure de phénylmagnésium préparée à partir de 1,1 atome de magnésium et de 1 mole de bromure de phényle. Après addition complète, on chauffe encore le milieu réactionnel pendant une heure à l'ébullition.
On refroidit et on verse la suspension obtenue sur un mélange de glace, d'eau et de chlorure d'ammonium. On décante la solution toluénique que l'on sèche et que l'on distille. La p-chlorbenzhydryl-4-p-(t-buthyl)-ben- zylpipérazine de point d'ébullition 230-240C/ 0,001 mm Hg est obtenue avec un rendement de 75 9/0.
Le dichlorhydrate correspondant (point de fusion 265-2660 C après recristallisation dans l'alcool) est préparé par passage d'HCL dans une solution éthanolique de la base.
La mono-p-(t-butyl)-benzylpipérazine (Pt Ebull. 128 - 130o C/0,1 mm Hg), nécessaire pour l'obtention du produit, a été préparée avec un rendement de 65'% selon la méthode de préparation de H. Morren / Bull. Soc. chim. Belg. 60, (1951), 282-95/. Exemple 11 On opère comme dans l'exemple I mais on remplace la 1-p-(t-butyl)-benzylpipérazine par la 1-m-méthylbenzylpipérazine (Pt Ebull. 118- 1210 C/2 mm Hg) préparée selon la technique de Morren (loc. cit.).
La 1-p-chlorbenzhydryl-4-méthylbenzyl-pi- pérazine (Pt Ebull. 2300 C/2 mm Hg) est ob- tenue avec un rendement de 73,%.
Le dichlorhydrate correspondant fond à 215,, C.
<Desc / Clms Page number 1>
The present invention relates to a process for the manufacture of N-benzhydryl-N'-benzylpiperazines by reaction of a phenylmagnesium halide with an amino nitrile of formula
EMI1.8
in which Y represents an alkyl radical containing from 1 to 4 carbon atoms. The products thus obtained have pharmaceutical properties.
These nitriles can be obtained, for example, according to the Goodson technique and Christopher / J. Am. Chem. Soc. 72, (1950), 358-62 / by reacting p-chlorbenzaldehyde and potassium cyanide with a substituted mono-benzylpiperazine.
The preparation process is based on the substitution, in an organic compound, of a nitrile group by the phenyl group of a derivative of phenylmagnesium. Such a substitution has already been used by P. Bruylants / Bull. Soc. chem. Belg. 33, (1924), 467-78 / for obtaining tertiary amines from amino nitriles.
It has been observed that if the reaction is carried out in an ethereal medium, according to the usual Grignard method, the yields obtained are very low: apparently the substitution of the nitrile group by the phenyl group of the Grignard reagent takes place with difficulty at the temperature of 'ether boiling.
However, if the ether of the Grignard reagent is replaced by an inert solvent of a higher boiling point (eg toluene) and a toluene solution of the nitrile is added to a toluene solution of phenylmagnesium bromide at boiling, the expected products are obtained with yields of the order of 70 to 75.0%. Example 1 Preparation of 1-p-chlorbenzhydryl-4-p (t-butyl) -benzylpiperazine
EMI1.37
<Desc / Clms Page number 2>
To 0.5 mole of mono-p- (t-butyl) is added
- benzylpiperazine the quantity of hydrochloric acid necessary to neutralize an amino function. 0.5 mole of p-chlorbenzaldehyde is then added. While stirring the mixture, an aqueous solution of 0.55 mol of potassium cyanide is introduced dropwise. After this addition, the mixture is heated for two hours in a water bath.
After cooling, toluene is added and decanted. The toluene solution, containing the nitrile, is dried over potassium carbonate (the nitrile recrystallized from hexane melts at 90 - 910 C). This solution is introduced slowly and with stirring into a boiling toluene solution of phenylmagnesium bromide prepared from 1.1 atoms of magnesium and 1 mole of phenyl bromide. After complete addition, the reaction medium is still heated for one hour at the boiling point.
The resulting suspension is cooled and poured onto a mixture of ice, water and ammonium chloride. The toluene solution is decanted, dried and distilled. The p-chlorbenzhydryl-4-p- (t-buthyl) -benzylpiperazine of boiling point 230-240C / 0.001 mm Hg is obtained with a yield of 75%.
The corresponding dihydrochloride (melting point 265-2660 C after recrystallization from alcohol) is prepared by passing HCL through an ethanolic solution of the base.
Mono-p- (t-butyl) -benzylpiperazine (Pt Ebull. 128 - 130o C / 0.1 mm Hg), necessary to obtain the product, was prepared with a yield of 65% according to the method of preparation by H. Morren / Bull. Soc. chem. Belg. 60, (1951), 282-95 /. Example 11 The procedure is as in Example I but the 1-p- (t-butyl) -benzylpiperazine is replaced by 1-m-methylbenzylpiperazine (Pt Ebull. 118-1210 C / 2 mm Hg) prepared according to the technique of Morren (loc. Cit.).
1-p-chlorbenzhydryl-4-methylbenzyl-piperazine (Pt Ebull. 2300 C / 2 mm Hg) is obtained with a yield of 73.%.
The corresponding dihydrochloride melts at 215 ° C.
Claims (1)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH332334T | 1955-09-09 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH332334A true CH332334A (en) | 1958-08-31 |
Family
ID=4502393
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH332334D CH332334A (en) | 1955-09-09 | 1955-09-09 | Manufacturing process of N-benzhydryl-N'-benzylpiperazines |
Country Status (1)
| Country | Link |
|---|---|
| CH (1) | CH332334A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3211734A (en) * | 1962-04-16 | 1965-10-12 | Ucb Sa | Substituted 1-(4-phenyl-butyl)-4-phenylpiperazine compounds |
| US4068070A (en) * | 1974-07-16 | 1978-01-10 | Fuji Chemical Industry Co., Ltd. | α-Cyanoamine compounds and a process for producing the same |
-
1955
- 1955-09-09 CH CH332334D patent/CH332334A/en unknown
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3211734A (en) * | 1962-04-16 | 1965-10-12 | Ucb Sa | Substituted 1-(4-phenyl-butyl)-4-phenylpiperazine compounds |
| US4068070A (en) * | 1974-07-16 | 1978-01-10 | Fuji Chemical Industry Co., Ltd. | α-Cyanoamine compounds and a process for producing the same |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CH375017A (en) | Process for the preparation of novel imidazole derivatives | |
| JPH02207083A (en) | Production of 2-nitroiminoimidazolidines | |
| CH332334A (en) | Manufacturing process of N-benzhydryl-N'-benzylpiperazines | |
| FUSON et al. | Replacement of nuclear alkoxyl groups by the action of Grignard reagents | |
| JP3146596B2 (en) | Method for producing 3-hydroxymethyl-1-propargylimidazolidine-2,4-dione | |
| CH369442A (en) | Process for the preparation of 2,2-dichloro-1-aryl-1,3-prpanediol mono- and dicarbamates | |
| JP3596041B2 (en) | O-alkyl-N- (β-nitroethyl) hydroxylamine derivative and method for producing the same | |
| JP3952670B2 (en) | Process for producing 2- (5-halogeno-2-nitrophenyl) -2-substituted acetate derivatives | |
| US4180520A (en) | Preparation of nitriles | |
| EP0003866B1 (en) | 3-azabicyclo(3.1.0)hexane derivatives and a process for their preparation | |
| JPH07316106A (en) | Production of cis-1-aminoindane-2-ol | |
| JP3456269B2 (en) | Method for producing β-nitroenamine | |
| CH332664A (en) | Process for preparing N-benzhydryl-N'-benzylpiperazines | |
| CH301246A (en) | Process for the preparation of a new chemical compound having antispasmodic activity. | |
| BE661226A (en) | ARYLACETHYDROXAMIC ACIDS, CORRESPONDING AMIDS AND METHODS OF PREPARATION. | |
| CH350296A (en) | Process for the preparation of N- (o-halo-phenyl) -piperazines N'-alkylated | |
| BE722813A (en) | ||
| CH271931A (en) | Process for preparing 2-bromo-2-formyl-ethyl-pyridinium bromide. | |
| JPH07252183A (en) | Method for producing phenol derivative | |
| BE564597A (en) | ||
| CH396007A (en) | Manufacturing process for new piperazine derivatives | |
| BE451559A (en) | ||
| CH272504A (en) | Process for preparing 1-piperazine-N, N-diethylcarboxamide. | |
| BE541651A (en) | ||
| CH322817A (en) | Process for the preparation of piperazine derivatives |