US2748128A - Nu-(alpha-cycloalkenylbenzyl) piperazines and method of making - Google Patents
Nu-(alpha-cycloalkenylbenzyl) piperazines and method of making Download PDFInfo
- Publication number
- US2748128A US2748128A US446169A US44616954A US2748128A US 2748128 A US2748128 A US 2748128A US 446169 A US446169 A US 446169A US 44616954 A US44616954 A US 44616954A US 2748128 A US2748128 A US 2748128A
- Authority
- US
- United States
- Prior art keywords
- piperazine
- methyl
- cycloalkenylbenzyl
- piperazines
- alpha
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
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
- C07D295/02—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 containing only hydrogen and carbon atoms in addition to the ring hetero elements
- C07D295/027—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 containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
- C07D295/03—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 containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring with the ring nitrogen atoms directly attached to acyclic carbon atoms
Definitions
- This invention relates to a family of compounds represented by Formula Iiin which R is a lower alkyl group and R is selected from the class consisting of the A -cyclo hexenyl and the A -cycloheptenyl radicals.
- the bases and acid addition salts of this formula have marked antihistaminic properties while the mono quaternary salts of Formula II are powerful spasmolytics especially in those cases wherein the phenyl radical has no para substitution.
- This invention also embraces a method of preparing these compounds.
- X- may be any convenient anion, preferably derived from the alkyl halide employed.
- X- is most frequently iodide but for therapeutic purposes chloride, bromide, ethane sulfonate, toluene sulfonate would probably be preferable.
- chloride, bromide, ethane sulfonate, toluene sulfonate would probably be preferable.
- these compounds are extremely potent and would seldom be given in doses exceeding 1 to 2 mg., the identity of the anion is actually of no significance.
- the unsaturated bases of this invention can be reduced catalytically to the corresponding dihydro derivatives which arethe subject of a co-pending application. This reduction may be accomplished by any of the commoncatalysts, preferably however, those not especially addicted to de-benzylation. Adams platinum catalyst, platinized charcoal or Raney nickel are all satisfactory;
- N-methyl-N'-lu-cyclohex-2-enylbenzyll piperazine 2. N-ethyl-N-[a-cyclohex-Z-enylbenzyl] piperazine. 4. N-methyl-N'-[a-M-cycloheptenylbenzyll piperazine. 5. The method of preparing a compound represented by the formula Ar-CH-N N-Alk -CHCH which comprises reacting a compound of the formula Ar-CH-N N-Alk No references cited.
Description
N-(a-CYCLOALKENYLBENZYL) PIPERAZINES AND METHOD OF MAKING Richard Baltzly, Tuckahoe, and Peter B. Russell, Crestwood, N. Y., assignors to Burroughs Wellcome & Co. (U. S. A.) Iuc., Tuckahoe, N. Y., a corporation of New York No Drawing. Application July 27, 1954, Serial No. 446,169
9 Claims. (Cl. 260-268) This invention relates to a family of compounds represented by Formula Iiin which R is a lower alkyl group and R is selected from the class consisting of the A -cyclo hexenyl and the A -cycloheptenyl radicals. The bases and acid addition salts of this formula have marked antihistaminic properties while the mono quaternary salts of Formula II are powerful spasmolytics especially in those cases wherein the phenyl radical has no para substitution. This is a continuation-in-part of application Serial No. 409,764 filed February 11, 1954.
II /R1 This invention also embraces a method of preparing these compounds. For this purpose we employ the sulfonate, especially the p-toluene sulfonate esters of Formula III (wherein n is 4 or 5) and which are described in a co-pending application.
III
When these tosylates (III) are made to react with bases, the elements of toluenesulfonic acid are eliminated, giving rise to unsaturated Compounds Ia. When the base employed for this elimination is fairly bulky (as sodium or potassium t-butoxide, collidine or 2,6-lutidine) the elimination is unilateral and unaccompanied by detectable side reactions so that Ia is isolated with ease in good yield and in high purity.
nited States Patent 0 ice substantially pure but may be recrystallized from alcohol or alcohol-ether mixtures. In the Formula II, X- may be any convenient anion, preferably derived from the alkyl halide employed. In the earlier stage of operations X- is most frequently iodide but for therapeutic purposes chloride, bromide, ethane sulfonate, toluene sulfonate would probably be preferable. However, since these compounds are extremely potent and would seldom be given in doses exceeding 1 to 2 mg., the identity of the anion is actually of no significance.
Aside from their intrinsic value, the unsaturated bases of this invention can be reduced catalytically to the corresponding dihydro derivatives which arethe subject of a co-pending application. This reduction may be accomplished by any of the commoncatalysts, preferably however, those not especially addicted to de-benzylation. Adams platinum catalyst, platinized charcoal or Raney nickel are all satisfactory;
EXAMPLE 1 N -methyl-N a-cyclohex-Z-enylbenzyl piperazine: By
1 potassium tert. butoxide To a solution of potassium tert. butoxide (from 12 gms. potassium) in tert. butanol (900 cc.) was added the p-toluenesulfonate ester of trans-N-methyl-N-[a-(2-hydroxycyclohexyl)benzyl] piperazine (30 g.). The solution was refluxed for 20 hours and then the tert. butanol removed in vacuo. The residue was dissolved in water and the solution extracted with ether. The basic frac tion was removed from the ether with 2 N hydrochloric acid. The acid solution was basified and the separated base taken up in ether. The ether was removed after washing and drying the solution. The residue wasdistilled to give 15 g. clear oil, B. P; 80 (bath temp.)/ .2 mm. The 'material solidified; recrystallized from pentane it formed needles M. P. 84-.
On catalytic reduction this compound gave N-methyl- N'-[a-cyclohexylbenzyl] piperazine identical with a previously described sample.
On treatment with methyl iodide in acetone the above ".base gave a quaternary salt. After recrystallization from ethanol/ethyl acetate this salt formed prisms M. P. 205-206".
With ethyl iodide the corresponding ethiodide M. P. -181 after recrystallization from ethanol/ethyl acetate resulted.
With isopropyl iodide the corresponding quaternary salt melted at 217220.
With ethyl p-toluenesulfonate a quaternary was formed which melted after recrystallization from ether/ethanol at l07108 with foaming.
EXAMPLE 2 N-methyl-N' [a-cyclohex-Z-enylbenzfl] piperazine: By
heating with 2,6 lutidine EXAMPLE 3 N '-methyl-N I a-cyclohex-Z-enyl-o-chlorobenzyl l piperazine Trans N methyl N [a (hydroxycyclohexyl) o chlorobenzyl] piperazine p-toluene sulfonate (1.3 g.) was added to tert. butoxide (from 0.3 g. potassium) in butanol (20 ml.). The mixture was refluxed for 16 hours in the usual manner and then worked up as previously described. The resin boiled at 95l00 bath temp/0.1 mm. (0.8 g.).
EXAMPLE 4 N-ethyl-N-[a-cyclohex-Z-enylbenzyl] piperazine This compound was prepared by treating the corresponding alcohol trans p-toluenesulfonate (3 g.) with potassium tert. butoxide (from 0.2 g. K) in the usual manner. The product (1.6 g.) boiled at 100 (bath temp.)/0.15 mm. Catalytic reduction of this material gave N-ethyl-N'-[a-cyclohexylbenzyl] piperazine identical with previously described samples.
In acetone solution the unsaturated base reacted with ethyl ethanesulfonate to give N,N-diethyl-N'-la-A -cyclohexenylbenzyl] piperazinium ethane sulfonate.
EXAMPLE 5 N -methyl-N a-d -cycloheptenylbenzyl pi perazi ne The tosylate of 2-a-[N'-methyl-N-piperazino] benzylcycloheptanol (3 g.) was dissolved in 2,6-lutidine (25 ml.) and the solution heated on the steam bath for 36 hours. The mixture was dissolved in pentane and washed 5 or 6 times with water. The pentane solution was dried and the solvent removed. The residue (2 g.) was distilled, the distillate (B. P. 95100 [bath temp.] 0.1 mm.) was a pale yellow oil.
On hydrogenation with a platinum catalyst it gave N- methyl-N-[a-cycloheptylbenzyl] piperazine the ethyl iodide of which was identical with an authentic sample.
The unsaturated base gave with ethyl iodide an ethiodide M. P. 177 (dec.) after recrystallization from acetone-ethyl acetate.
What is claimed is:
1. A compound selected from the class consisting of the free base, acid addition salts and mono-quaternary salts, derived from therapeutically acceptable acids, of compounds having the free base formula:
Ar-G H-N N-Alk (C Ha) wherein Ar is a phenyl radical, alk is a lower alkyl radical and n is an integer from 34.
2. N-methyl-N'-lu-cyclohex-2-enylbenzyll piperazine. 3. N-ethyl-N-[a-cyclohex-Z-enylbenzyl] piperazine. 4. N-methyl-N'-[a-M-cycloheptenylbenzyll piperazine. 5. The method of preparing a compound represented by the formula Ar-CH-N N-Alk -CHCH which comprises reacting a compound of the formula Ar-CH-N N-Alk No references cited.
Claims (1)
1. A COMPOUND SLECTED FROM THE CLASS CONSISTING OF THE FREE BASE, ACID ADDITION SALTS AND MONO-QUATERNARY SALTS, DERIVED FROM THERAPEUTICALLY ACCEPTABLE ACIDS, OF COMPOUNDS HAVING THE FREE BASE FORMULA:
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US446169A US2748128A (en) | 1954-07-27 | 1954-07-27 | Nu-(alpha-cycloalkenylbenzyl) piperazines and method of making |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US446169A US2748128A (en) | 1954-07-27 | 1954-07-27 | Nu-(alpha-cycloalkenylbenzyl) piperazines and method of making |
Publications (1)
Publication Number | Publication Date |
---|---|
US2748128A true US2748128A (en) | 1956-05-29 |
Family
ID=23771568
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US446169A Expired - Lifetime US2748128A (en) | 1954-07-27 | 1954-07-27 | Nu-(alpha-cycloalkenylbenzyl) piperazines and method of making |
Country Status (1)
Country | Link |
---|---|
US (1) | US2748128A (en) |
-
1954
- 1954-07-27 US US446169A patent/US2748128A/en not_active Expired - Lifetime
Non-Patent Citations (1)
Title |
---|
None * |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US2441069A (en) | 2-amino-methyl-indenes and their production | |
US2590125A (en) | Quaternary-ammonium alkyl | |
US2649444A (en) | Process for the preparation of amino ketones | |
US2629719A (en) | Aminoalkyl thioxanthene oxides and the production thereof | |
US2625547A (en) | Process of preparing benzhydryl and 9-fluorenyl tertiary aminoalkanoates | |
US2748128A (en) | Nu-(alpha-cycloalkenylbenzyl) piperazines and method of making | |
US3479346A (en) | N-acyl-n- (and n,n-bis-) ((1-piperidyl)-lower-alkyl)amines | |
US2960507A (en) | Piperidine compounds | |
US3077470A (en) | 3-[4-hydroxy-3-(aminomethyl)-phenyl]-4-(4-oxyphenyl)-alkanes and alkenes | |
US2415786A (en) | Unsymmetrically substituted piperazines | |
US3015657A (en) | 1-carbalkoxy-4-(aminoalkanol) piperazines | |
US2691017A (en) | Bis-aminoalkyl carbonate derivatives | |
US2415785A (en) | Unsymmetrically substituted piperazines | |
US2997473A (en) | New 2-substituted piperazine derivatives with central stimulating activity | |
US2683735A (en) | Aromatic esters of basically substituted isocyclyl carbamates | |
US2543764A (en) | Diaralkyl carbinyl esters of dialkylamino alkanoates and the production thereof | |
US2767186A (en) | Quaternary ammonium salts of substi- | |
US2965641A (en) | Derivatives of 1-(2-aminoethyl)-5-alkoxy-4-pyridones | |
US2830049A (en) | Acetylenic tetrahydroisoquinoline derivatives | |
US3324128A (en) | Bis-(phenoxyacetyl)-piperazines | |
US2742472A (en) | Spasmolytic pipergzjnes | |
US2694706A (en) | Alkenylamevoalkanoylphenotfflazine | |
US2551316A (en) | 9-aminoalkyl 9-alkanoyl 9, 10 dihydroanthracenes | |
US2748127A (en) | Nu-[alpha-cyclohexenyl benzyl] piperazines and method of making | |
US1790096A (en) | Tertiary amines containing the 1-amino-2-hydroxypropyl residue |