US3329728A - Process and intermediates for the preparation of dibenzo[a, d] cycloheptenes - Google Patents
Process and intermediates for the preparation of dibenzo[a, d] cycloheptenes Download PDFInfo
- Publication number
- US3329728A US3329728A US356346A US35634664A US3329728A US 3329728 A US3329728 A US 3329728A US 356346 A US356346 A US 356346A US 35634664 A US35634664 A US 35634664A US 3329728 A US3329728 A US 3329728A
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- US
- United States
- Prior art keywords
- dibenzo
- cycloheptene
- dihydrocycloheptene
- ether
- hydroxy
- 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
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- 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
Definitions
- This invention relates to a novel method for making derivatives of dibenzocycloheptenes and, more particularly, the invention relates to a method of making 5H- dibenzo[a,d]cycloheptenes and 5H-d-ibenzo[a,d]10,11-dihydrocycloheptenes which are substituted at the S-carbon atom with an aminopropylidene radical.
- the invention also includes the synthesis of intermediates used for obtaining these products.
- the compounds of the invention are useful in the treatment of mental health conditions as they are antidepressants and serve as mood elevators or psychic energizers.
- the daily dosage is within the range of 5 mg. to 250 mg., preferably taken in divided amounts over the day.
- the compounds are preferably administered in the form of their acid salts and these salts are included in the scope of this invention.
- X and X may be similar or dissimilar and are selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, lower alkenyl, haloloweralkyl, phenyl or substituted phenyl, an acyl group having up tov4 carbon atoms, haloacyl having up to 4 carbon atoms, amino, loweralkylamino, diloweralkylamino, acylamine, having up to 4 carbon atoms, haloacylamino having up to 4 carbon atoms, a loweralkylsulfonylamino, halogen, hydroxyl, haloloweralkoxy, cyano, carboxy, carbamyl, loweralkylcarbamyl, diloweralkoxy, alkylmercapto, haloloweral
- R and R are selected from the group consisting of hydrogen, lower alkyl radicals, lower alkenyl, cyclolowen alkyl, phenyl, benzyl and lower alkyl radicals linked together through an atom selected from the group consisting of carbon, nitrogen and oxygen to form a hetenocyclic ring selected from the group consisting of 1- piperidyl, l-pyrrolidyl, 4-morpholinyl and 1-loweralkyl-4- piperazinyl.
- the method of the present invention may be illustrated schematically by the following flowsheet in which the dotted line indicates that the compound may be saturated (10,11 dihydro) or unsaturated at the 10,11 positions and X, X, R and R are as previously defined:
- the method of the present invention begins with the known ketone which may be prepared by using the process described by A. C. Cope et al., entitled Cyclic Polyolefins, XV, 1-methylene-2,3,6,7-dibenzocycloheptatriene, appearing in J.A.C.S. 73, 1673, 1678 (1951); or the starting compounds, and particularly those having substituents on the benzene rings, may be made by the following teachings of T. W.
- the first step in the method of the present invention involves the condensation of a 5H-dibenzo[a,d] cycloheptene-S-one with a Grignard reagent derived from a cyclopropylhalide to form the corresponding cy-clopropyl carbinol, e.g. 5-cyclopropyl-5-hydroxy-5H-dibenzo[a,d]10,1l-dihydrocycloheptene.
- cyclopropylbromide in tetrahydrofuran is added dropwise with stirring to a quantity of magnesium in dry tetrahydrofuran to form cyclopropylmagnesium bromide.
- the ketone is added to the cyclopropylmagnesium bromide and the reaction mixture is refluxed for a suitable period of time to produce the cyclopropylcarbinol intermediate.
- the next step in the method involves the rearrangement of the cyclopropylcarbinol to produce the corresponding 'y hydroxy-propenylcycloheptene, e.g. S-(y-hybromopropylidene) 5H dibenzo[a,d]10,11 dihydrocycloheptene.
- the 7 hydroxy-propenylcycloheptane is then treated with a halogen agent to give the corresponding 7 halopropenylcycloheptene derivative, e.g. 5 ('ybromopropylidene) 5H dibenzo[a,d]l0,11 dihydrocycloheptene.
- the rearrangement and halogenation steps described above may be carried out simultaneously or separately.
- the corresponding 'y-halopropenylcycloheptene may be formed directly in one step.
- the corresponding iodo derivative when desired, preferably is formed from the chloro or bromo derivative by reacting the latter with sodium iodide in acetone under reflux.
- the 'y-hydroxypropenylcycloheptane derivative itself may be isolated by treatment of the cyclopropylcarbinol with an acid that is not a halogen acid.
- Dilute perchloric acid in dioxane is a suitable reagent, although other acids including sulfuric acid, phosphoric acid and p-toluenesulfonic acid may be used as well.
- the 'y-hydroxy compound may be converted to the corresponding 'y-halo propenylcycloheptane by reaction with an appropriate halogenation agent, suitably thionyl chloride or phosporous trichloride, although others may be used as well.
- v-halopropenylcycloheptane compound is converted to the desired aminopropylidene derivative by a process of amination.
- the amination may proceed by direct reaction of the halogen compound with an amine whereby the desired aminopropylidene compound is subsequently isolated as the hydrochloride.
- the desired amine derivative may be prepared by an amination reaction using potassium phthalirnide followed by hydrazinolysis.
- the reaction mixture (6 hours) is chilled in an ice bath and treated with 45 ml. of saturated ammonium chloride solution. The layers are separated and just enough water is added to dissolve the solid salts in the aqueous layer. The latter is extracted with 2 x 25 ml. of ether. The combined organic layers are Washed with 25 ml. of saturated salt solution, dried over magnesium sulfate and taken to dryness in vacuo to yield 9.88 g. of a yellow-orange oil. Treatment of this oil with charcoal, in ether, and crystallization from petroleum ether yields 5.49 g. (62.5%) of crude crystalline cyclopropyl carbinol, single spot by TLC. Further recrystallization yields material melting at 72.873.8 C;
- Example 5 .5 -chloropropylidene) -5 H -d ibenzo [a,d] -1 0,1 I-dihydrocycloheptene S-cyclopropyl-5-hydroxy-5H-dibenzo[a,d]-10,11 dihydrocycloheptene (100 ml., 0.4 millimole) is dissolved in 5 ml. of glacial acetic acid in a 25 ml. flask with a magnetic stirring bar, and the solution is cooled to 10 C. HCl/ acetic acid (1 ml. of a 15% solution) is added with stirring and the reaction mixture is stirred at l0-l5 C. for 3 hours.
- Example 6.-5- ('y-chloropropylidene-SH-dibenzo [rad] cycloheptene Following the procedure described in detail in Example 5 and using equivalent quantities of S-cyclopropyl-S-hydroxy-SH-dibenzo[a,d]-cycloheptene there is produced the corresponding 5-(' -chloropropylidene-SH-dibenzo[a, d]-cycloheptene.
- Example 1 0.-5- ('y-hydroxypropylidene) -5H-dibenz0 [a,d] -cycl0heptene Following the procedure described in detail in Example 9 and using equivalent quantities of 5-cyclopropyl-5-hydroxy-SH-dibenzo[a,d]-cycloheptene there is produced the corresponding S-(y-hydroxypropylidene)-5H-dibenzo [a,d]-cycloheptene.
- Example 1 1 .5 ('y-Clt loro pro py lidene-5H -dibenz0 [a,d 10,11-dihydr0cycl0heptene Treatment of a solution of 50 mg. of 5-('y-hydroxypropylidene-SH-dibenzo[a,d]-10,1l-dihydrocycloheptene in 3 ml. of dry benzene containing one drop of pyridine with 65 mg. of thionylchloride in 2 ml. of dry benzene and refluxing for 3 hours on a steam bath yields a crystalline product, M.P. 7879 C. which, by TLC and mixed (M.P. 7881 C.) was shown to be identical with the compound obtained from treatment of 5-hydroxy-5-cyclopro pyl-5H-dibenzo[a,d] 10,11 dihydrocycloheptene with HCl/ acetic acid.
- Example 12.5-(y-chloropropylidene -5H-dibenz0 [a,d] cycloheptene Following the procedure described in detail in Example 11 and using equivalent quantities of 5-( -hydroxypropylidene)-5H-dibenzo[a,d]-cycloh-eptene there is produced the corresponding 5-('y-chloropropylidene-SH-dibenzo[a,d]-cycloheptene.
- Example 13.5-(' -dimethylaminopropylidene)-5H-dibenzo[a,d] -10,1l-dihydrocycloheptene H Cl A solution of 100 mg. (0.372 millimole) of 5-( chloropropylidene)-5H-dibenzo[a,d] 10,11 dihydrocycloheptene in 1 ml. of benzene in a thick-walled Pyrex tube is saturated with dimethylarnine at 10 C. The tube is sealed, allowed to stand at 95 C. for 18 hours, then cooled and opened.
- the benzene solution is washed successively with 5% potassium bicarbonate, water and saturated salt solution, dried over magnesium sulfate, and taken to dryness in vacuo.
- the residual oil is dissolved in ether and treated with ether saturated with HCl.
- the re- 6 sulting mixture of oil and ether is blown dry to remove the excess HCl, and the residue upon trituration with ether yields crystalline 5-('y-dimethylaminopropylidene)-5H-dibenzo[a,d]-l0,1l-dihydrocycloheptene material, M.P. 190-192 C.
- 5-('y-chloropropylidene)-5H-dibenzo[a,d]-cycloheptene there is produced the corresponding 5-('y-dimethylaminopropylidene)-5H- dibenzo [a,d] -cycloheptene, NCl.
- Example 15 -5 ('y-methylaminopropylidene)-5H-dibenz0- [a,d] -10,1l-dihydrocycloheptene H Cl
- the benzene solution is washed successively with 5% potassium bicarbonate, water and saturated salt solution, dried over magnesium sulfate, and taken to dryness in vacuo.
- the residual oil is dissolved in 3 ml. of ether and treated with 3 ml, of ether saturated with HCl.
- the resulting mixture of oil and ether is blown dry to remove the excess HCl.
- Trituration of the residue in ether yields a crystalline crude, M.P. 200-2l0 C., which after recrystallization from ether-ethanol, produces crystals, M.P. 2l3215 C.
- Example 1 6 --5 'y-methylam inopropylidene -5H -dibenzo [a,d] -cycl0heptene' H Cl Following the procedure described in detail in Example 15 and using equivalent quantities of 5-('y-chloropropylidene) -5H-dibenzo [a,d]-cycloheptene there is produced the corresponding 5-('y-methylaminopropylidene)-5H-dibenzo [a,d] -cycloheptene HCl.
- Example 1 7. SMbstituted 5 -cyclop ropy l-5 -hydroxy-5H dibenz0[a,d] 10,l1-dihydracycloh-eptenes Following the procedure described in detail in the above Examples 1 through 16 and using equivalent quantities of the corresponding 5H dibenzo[a,d]-10,l1-dihydrocycloheptene-S-ones and SH-dibenzo-cycloheptene-5-ones substituted with the nuclear substituents X and X given above there are produced the corresponding substituted 5- cyclopropyl 5 hydroxy-SH-dibenzo[a,d]-10,1l-dihydrocycloheptenes and substituted 5-cyclopropyl-5-hydroxy- 5H-dibenzo[a,d]-cycloheptenes.
- Example 18 Substituted 5 -cycl0propyl-5 -hydr0xy-5H dibenzo [a,d] -cycl0heptenes Following the procedure described in detail in the above Examples 1 through 17 and using equivalent quantities of the corresponding 5H-dibenzo[a,d]-cycloheptene-5-ones and SH-dibenzo [a,d]-cycloheptene-5-ones substituted with the nuclear substituents X and X given above in the general formula there are produced compounds corresponding to the aminopropylidene compounds formed in the above examples.
- Example 20 -5-('y-aminopropylidene)-5H-dibenz0[w,d]- cycloheptene HCl 8 cyclopropyl-5-hydroxy-5H-dibenzo a,d] cycloheptene and 5 cyclopropyl S-hydroxy-SH-dibenzo[a,d]-10,11-dihydrocycloheptene.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Priority Applications (12)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
NL291744D NL291744A (xx) | 1962-04-19 | ||
GB31825/65A GB1039374A (en) | 1962-04-19 | 1963-04-17 | Dibenzocycloheptene derivatives |
GB31826/65A GB1039375A (en) | 1962-04-19 | 1963-04-17 | Dibenzocycloheptene compounds |
GB15086/63A GB1039373A (en) | 1962-04-19 | 1963-04-17 | Dibenzocycloheptene derivatives |
NO148342A NO118106B (xx) | 1962-04-19 | 1963-04-18 | |
DK182163AA DK112654B (da) | 1962-04-19 | 1963-04-18 | Fremgangsmåde til fremstilling af 5-(γ-aminopropyliden)-5H-dibenzo[a,d]-10,11-dihydrocycloheptener og 5-γ-aminopropyliden)-5H-dibenzo[a,d]-cycloheptener. |
FI0770/63A FI41019B (xx) | 1962-04-19 | 1963-04-18 | |
FR931957A FR1522210A (fr) | 1962-04-19 | 1963-04-18 | Nouveaux dibenzocycloheptènes et leur production |
BR148552/63A BR6348552D0 (pt) | 1962-04-19 | 1963-04-19 | Novo processo para a producao de derivados de dibenzociclo-heptenos |
CH490863A CH446309A (de) | 1962-04-19 | 1963-04-19 | Verfahren zur Herstellung von Dibenzo-cycloheptenen |
US356346A US3329728A (en) | 1962-04-19 | 1964-02-10 | Process and intermediates for the preparation of dibenzo[a, d] cycloheptenes |
DK478664AA DK112167B (da) | 1962-04-19 | 1964-09-29 | Fremgangsmåde til fremstilling af 5-(γ-aminopropyliden)-5H-dibenzo[a,d]-10,11-dihydrocycloheptener og 5-(γ-aminopropyliden)-5H-dibenzo[a,d]-cycloheptener. |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US188873A US3272864A (en) | 1962-04-19 | 1962-04-19 | Process for preparing 5-(3-aminopropylidene)-5h-dibenzo [a, d] cycloheptene and 5h-dibenzo [a, d]-10, 11-dihydro-cycloheptene derivatives |
US356346A US3329728A (en) | 1962-04-19 | 1964-02-10 | Process and intermediates for the preparation of dibenzo[a, d] cycloheptenes |
Publications (1)
Publication Number | Publication Date |
---|---|
US3329728A true US3329728A (en) | 1967-07-04 |
Family
ID=26884535
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US356346A Expired - Lifetime US3329728A (en) | 1962-04-19 | 1964-02-10 | Process and intermediates for the preparation of dibenzo[a, d] cycloheptenes |
Country Status (8)
Country | Link |
---|---|
US (1) | US3329728A (xx) |
BR (1) | BR6348552D0 (xx) |
CH (1) | CH446309A (xx) |
DK (2) | DK112654B (xx) |
FI (1) | FI41019B (xx) |
GB (3) | GB1039373A (xx) |
NL (1) | NL291744A (xx) |
NO (1) | NO118106B (xx) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3832405A (en) * | 1970-05-18 | 1974-08-27 | American Home Prod | 5-cycloalkylidene dibenzocycloheptene derivatives |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3189657A (en) * | 1960-11-03 | 1965-06-15 | Lilly Co Eli | 5-(3-bromopropylidene) dibenzo-[a, d] cyclohepta (1.4)diene |
US3215739A (en) * | 1960-10-12 | 1965-11-02 | Kefalas As | Method of producing dibenzo (a, d) cyclohepta (1, 4) dienes |
-
0
- NL NL291744D patent/NL291744A/xx unknown
-
1963
- 1963-04-17 GB GB15086/63A patent/GB1039373A/en not_active Expired
- 1963-04-17 GB GB31825/65A patent/GB1039374A/en not_active Expired
- 1963-04-17 GB GB31826/65A patent/GB1039375A/en not_active Expired
- 1963-04-18 NO NO148342A patent/NO118106B/no unknown
- 1963-04-18 FI FI0770/63A patent/FI41019B/fi active
- 1963-04-18 DK DK182163AA patent/DK112654B/da unknown
- 1963-04-19 CH CH490863A patent/CH446309A/de unknown
- 1963-04-19 BR BR148552/63A patent/BR6348552D0/pt unknown
-
1964
- 1964-02-10 US US356346A patent/US3329728A/en not_active Expired - Lifetime
- 1964-09-29 DK DK478664AA patent/DK112167B/da unknown
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3215739A (en) * | 1960-10-12 | 1965-11-02 | Kefalas As | Method of producing dibenzo (a, d) cyclohepta (1, 4) dienes |
US3189657A (en) * | 1960-11-03 | 1965-06-15 | Lilly Co Eli | 5-(3-bromopropylidene) dibenzo-[a, d] cyclohepta (1.4)diene |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3832405A (en) * | 1970-05-18 | 1974-08-27 | American Home Prod | 5-cycloalkylidene dibenzocycloheptene derivatives |
Also Published As
Publication number | Publication date |
---|---|
NO118106B (xx) | 1969-11-10 |
DK112167B (da) | 1968-11-18 |
BR6348552D0 (pt) | 1973-07-17 |
DK112654B (da) | 1969-01-06 |
CH446309A (de) | 1967-11-15 |
NL291744A (xx) | |
FI41019B (xx) | 1969-04-30 |
GB1039373A (en) | 1966-08-17 |
GB1039375A (en) | 1966-08-17 |
GB1039374A (en) | 1966-08-17 |
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