GB2061947A

GB2061947A - Dibenzocycloheptenimines

Info

Publication number: GB2061947A
Application number: GB8037685A
Authority: GB
Original assignee: Merck and Co Inc
Current assignee: Merck and Co Inc
Priority date: 1977-09-19
Filing date: 1978-09-19
Publication date: 1981-05-20
Also published as: CY1283A; ES483284A1; DK153843B; CH637954A5; PL209632A1; SU895288A3; GB2004872A; GB2004872B; FI65618C; FI782680A; JPS5639315B2; FR2403334B1; ZA785291B; NO783017L; SG9585G; FR2403334A1; SU915800A3; AR231544A1; PL121605B1; DK389978A

Abstract

This invention provides certain 5- substituted-10,11-dihydro-5H- dibenzo[a,d]cyclohepten-5,10-imines. The compounds have the formula: <IMAGE> where R<1> and R<2> are hydrogen or certain hydrocarbon radicals, and R<3> and R<4> and H, halogen, alkoxy, CF3S-, -CN, -COOH or OH.

Description

1

SPECIFICATION

Dibenzoeycloheptenimines GB 2 061 947 A 1 5" This invention is concerned with 5-substituted-10,11-dihydro-5H- dibenzo[a,dlcyclohepten-5,10-imines. The 5 novel compounds of the present invention, which have the formula:

R1 HO N R A -- R3 CH20 are intermediate compounds obtained in the process for producing pharmaceutically useful dibenzocycloheptenimines claimed in the specification of our copending application No. 37284/78 (2004872).

In te above formula R' is (1) hydrogen, (2) C1-5 alkyl, preferably methyl or ethyl, 20 (3) C2-5 alkeny], preferably vinyl or allyl, (4) phenyl-(C13 alkyl), preferably benzyi, (5) C3-6 cycloalkyl, preferably cyclopropyl or cyclohexy], or (6) (C3-6 cycloalkyl)-(C1-3 alkyl), -CH2R % 25 (1) C1-5 alky], preferably methyl or ethyl, (2) C3-5 alkenyl, preferably allyl, (3) phenyl-(C1-3 alkyl), preferably benzy], (4) (C3.6 cycloalkyi)-(C1-3 alkyl), (5) d! (C1-5 alkyl)amino-(C1-5 alkyl), especially dimethylaminopropyl; or (6) C2-3 hydroxyalky], preferably hydroxyethy]; and R 3 and R4 are independently, (1) hydrogen, (2) halogen, such as chloro, bromo, fluoro, or iodo, (3) C1-5 alkoxy, preferably methoxy, (4) trifluoromethylthio, (5)cyano, (6) carboxy, or (7)hydroxy A preferred group of compounds is that in which R' is hydrogen.

Another preferred group of compounds is that in which W, R 3 and R 4 are hydrogen.

Where R 3 and/or R 4 are other than hydrogen, it is preferred that they occupy the 2,3, 7 or 8 positions of the 40 tricyclic ring system.

Preferred definitions for -CH2R 2 are C1-5 alky], especially methyl or ethyl, and hydroxyethyl.

The compounds of the present invention can be prepared by methods analogous to those set forth in the following Examples.

EXAMPLE 1

5-Methy]-1 2-hydroxy-1 0,11 -dihydro-5H-dibenzo[a,dlcyclohepten-5,1 Oimine Step A: Preparation of 10-(1-piperidyl)-5H-dibenzo [a, djcyclohepten-5- one A mixture of 71.3 g of 1 0-bromo-5H-dibenzo[a,dlcyclohepten-5-one, 50 m]. of piperidine, 1 liter of t-butanol 50. and finally 33.6 g of potassium t-butoxide was stirred under reflux 2 hours, then at room temperature 50 overnight. The mixture was filtered, and concentrated to dryness. The residue was slurried with water and decanted. The residue was slurried with methanol and filtered to give 59. 8 9 of 10-(1-piperidyl)-5H Aibenzo[a,d]cyclohepten-5-one, m.p. 103-105'C.

Step 8: Preparation of5-hydroxy-5-methyl-10-(1-piperidyl)-5Hdibenzofadjcycloheptene A solution of 140 ml. of 1.8 molar methyl lithium in ether and 250 mi. of ether at 5-10'C under nitrogen was treated dropwise with a solution of 59 g of 10-(1-piperidyi)-5H-dibenzo[a,dleyclohepten-5-one in 250 mi of tetrahydrofuran. After a total of 2 hours, the mixture was poured onto ice and allowed to stand until the ice melted. The mixture was extracted well with ether and the extract was dried (Na2S04), filtered, and concentrated to dryness, the residue being used directly in the next step.

Step C.. Preparation of 5-methylene- 10-oxo- 10, 1 1-dihydro-5H-dibenzo[a, dlcycloheptene The carbinol from Step B was dissolved in 500 mi of 1 ON ethanolic hydrogen chloride and 30 mi concentrated hydrochloric acid and heated under reflux overnight. The solvent was evaporated and the residue was extracted with 500 mi of benzene. The extract was dried and concentrated to dryness. The 65 2 : 5 2 GB 2 061 947 A residue was extracted with 300 m] of boiling hexane. On cooling the extract deposited 18.5 g solid which after recrystallization from hexane gave 16.5 g of 5-methylene-1 0-oxo-1 0,11 -dihydro-5Hdibenzo[a, dlcycloheptene, m.p. 84-86'C.

Step D: Preparation of 10-hydroximino-5-methe- 10, 1 1-dihydro-5Hdibenzo[adjcycloheptene A mixture of 16.5 9 of the oxo-compound from Step C, 6.6 g of hydroxylamine hydrochloride, 8.2 of sodium acetate and 300 mi of methanol was heated under reflux for 5 hours. The solvent was evaporated and the residue was treated with 250 m] of water. The mixture was extracted with 3 x 150 m] of ether, and the extract was dried, filtered, and evaporated to give 16.8 9 of 1 0-hydroximino-5-methylene-1 0,11 -dihydro5H-dibenzo[a, dleycloheptene, m.p. 156-160'C.

Step E.. Preparation of 10-hydroxamino-5-methe- 10, 1 1-dihydro-5Hdibenzofadlcycloheptene A mixture of 15.3 of oxime from Step D, 500 M1 of methanol, 12 9 of sodium cya noboro hyd ride in 450 mi of methanol was treated dropwise with a solution of 12 mi of 12N hydrochloric acid in 50 mi of methanol over 5 hours, and then stirred overnight at room temperature. The solvent was evaporated, the residue was stirred with 200 m[ of 1 N aqueous hydrochloric acid, made alkaline with concentrated ammonium hydroxide and extracted with 3 X 175 m[ of ether. The combined extracts were dried (Na2SO4), filtered and evaporated. The crystalline residue was washed with methanol to give 9.6 g of 1 0-hydroxamino-5-methylene-1 0,11 - dihydro5H-dibenzo[a,dlcycioheptene,m.p. 145-147'C.

7 z Step A. Preparation of 5-methyl-12-hydroxy-10, 1 1-dihydro-5Hdibenzo[adlcyclohepten-5, 10-imine A solution of 8.8 9 of the hydroxamino compound from Step E in 200 mi of xylene was added dropwise to m] of refluxing xylene. After 1 hour of refluxing the solvent was evaporated. The residue was treated with 250 m] of water and 7 mi of concentrated hydrochloric acid and the mixture was washed with 100 m[ of ether and the wash was discarded. The aqueous phase was made basic with concentrated ammonium hydroxide 25 and extracted with 3 x 100 m] of ether. The extractwas dried (Na2SO4), filtered and evaporated. The residue was recrystallized from cyclohexane to give 8.5 g of 5-methy]-12-hydroxy- 10,1 1-dihydro-5H-dibenzo[adj cyclohepten-5,10-imine, m.p. 141-1440C.

EXAMPLE2

5-Ethyl-12-hydroxy-10,1 1-dihydro-5H-dibenzo[a,dl-cyclohepten-5,10-imine StepA: Preparation of 5-ethylidene-10-oxo-10, 1 1-dihydro-5Hdibenzo[adlcycloheptene To a stirred slurry of ethyltriphenylphosphonium bromide (21 g, 0.057 mole) in ether (400 m]) was added dropwise butyllithium in hexane (48 mi, 1.3 M). To the resulting solution was addded a solution of 1-(5-keto-5H-dibenzo[a,dlcycloheptene-1 0-yl)-4-m ethyl pi perazi n e (13. 5 g, 0.044 mole) in THF (100 mi). The 35 resulting mixture was stirred and heated under reflux for 3.5 hours, cooled and poured into ice H20 (300 m[).

The organic phase was separated and the aqueous phase extracted with ether (2 x 150 mi). The combined organic solutions were concentrated under reduced pressure. The concentrate was stirred with a mixture of 1N aqueous hydrochloric acid (300 mi) and ether (300 m]). The ether phase was separated, the aqueous phase extracted with ether and the combined ether solutions dried over Na2S04, filtered and the filtrate concentrated to 100 m[. Triphenylphosphine oxide was removed byfiltration and the filtrate was chromatographed on silica-gel which was eluted with chloroform to yield 10.1 g (98%) of 5-ethylidene-10 oxo-10,1 1-dihydro-5H-dibenzo[a,dleycloheptene, m.p. 93-95'C.

Following the procedure substantially as described in Example 1, Steps D to F but substituting forthe 5-methylene-10-oxo-10,1 1-dihydro-5H-dibenzo[a,dlcycloheptene used in Step D thereof, an equimolecular 45 amount of 5-ethylidene-10-oxo-10,1 1-dihydro-5H-dibenzo[a,dleycloheptene, there are produced in sequ ence:

5-ethylidene-10-hydroximino-10,1 1-dihydro-5H-dibenzola,dl-cycloheptene, (86% yield), m.p. 128-131'C; 5-ethylidene-10-hydroxamino-10,1 1-dihydro-5H-dibenzo[a,dl-cycloheptene (89% yield), m.p.121-124OC; and 5-ethy]-12-hydroxy-10,1 1-dihydro-5H-dibenzo[a,dlcyclohepten-5,10-imine, (21% yield), m.p. 112-116'C.

By the procedure substantially as described in Example 2 but substituting for the ethyltriphenyl phosphonium bromide used in Step A, an equimolecular amount of a Wittig reagent of formula (C6H5)3P'-CH2R 2( Br), wherein -CH2R 2 is -CH3, -CH2CH2CH3, or -(CHA3CH3, there are produced the compounds of formula:

i - - 50 11 C P, 60 where -CH2 R2 represents -CH3, -CH2CH2CH3 (m.p. 298-299.5'C as the I- ICIA/2 CH3COCH3) and -(CH26CH3.

is 3 GB 2 061 947 A 3 EXAMPLE 3 (3- and 7)-Bromo-5-methy]-1 2-hydroxy-10,1 1 -dihydro-5H-dibenzo[a, dlcyclohepten-5,1 0-imine Step A: Preparation of 3, 10, 1 1-tribromo-5H-dibenzo-[adlcyclohepten-5- one A solution of bromine (53 g., 0.33 mole) in glacial acetic acid (125 m].) was added dropwise to a stirred slurry of 3-bromo-5H-dibenzo[a,dleyclohepten-5-one (71.25 g., 0.25 mole) in glacial acetic acid (775 mQ. 5 After the mixture had been stirred at room temperature for several hours, the solid was collected, washed with glacial acetic acid and dried; yield, 105.8 g (95%), m.p. 173-175'C.

Step 8: Preparation of 3, 10-dibromo-5H-dibenzo[ad]cyclohepten-5-one and 3, 1 1-dibromo-5H-dibenzo [adjcyclohepten-5-one The product from Step A was added to a stirred solution of sodium hydroxide (28 g., 0.7 mole) in methanol (2 liters). The thick mixture was stirred at reflux for 11/4 hours. After cooling, the solid was collected, washed with methanol and then with water, and dried to obtain 819 (90%) of the mixture of 3,10-dibromo-5H dibenzo[a,dlcyclohepten-5-one and 3,1 1-dibromo-5H-dibenzo[a, dlcyclohepten-5-one, m.p. 146-156'C.

Step C: Preparation of 3-bromo- 10-(4-methyl-piperazinyl)-5Hdibenzo[adlcyclohepten-5-one and 3-bromo 11-(4-methylpiperazinyl)-5H-dibenzo[a,dlcyclohepten-5-one Potassium tert-butoxide X6.8 g., 0.06 mole) was added to a stirred slurry of 3,10-dibromo-5H dibenzo[a,dlcyclohepten-5-one and 3,1 1-dibromo-5H-dibenzo[a, dlcyclohepten-5-one (18.2 g., 0.05 mole), 4-methyl-piperazine (10 m].), and dry tert-butyl alcohol (200 mi.) at room temperature and under nitrogen. 20 The dark orange mixture was heated to refluxing for 2 hours and then stirred at room temperature overnight.

The mixture was poured into approximately 800 mi. of ice and water and extracted with ether. The ether extract was washed with water, dried over anhydrous sodium sulfate, filtered, and evaporated. The mixture of 3-bromo-1 0-(4-methylpiperazinyi)-5H-dibenzo[a,d]cyclohepten-5-one and 3-bromo-1 1-(4 methylpiperazinyi)-5H-dibenzo[a,dl-cyclohepten-5-one- was obtained as a residual red-yellow gum; yield, 19.4 g. 100%.

Step D: Preparation of 3-bromo-5-methyl- 10-(4-methyl-piperazinyl)-5Hdibenzo[adlcyclohepten-5-oI and 3-bromo-5-methyl-ll-(4-methylpiperazinyl)-5H-dibenzo[a,dlcyclohepten-5-oI Methyllithium, 35 m[. of a 1.6 M solution in ether, was added dropwise to a stirred solution of the product 30 from Step C (18 g., 0.047 mole) in ether (200 mi) and tetrahydrofuran (60 mi), and cooled in an ice bath and under nitrogen. Stirring was continued at room temperature for 3 hours. The mixture was cooled in ice and hydrolysed by the dropwise addition of water. After dilution with ether and water, the layers were separated and the aqueous phase was re-extracted with ether. The combined ether extracts were washed with water, dried over anhydrous sodium sulfate and evaporated. The mixture of 3- bromo-5-methyl-10-(4-methylpiperazinyi)-5H-dibenzo[a,d]cyclohepten-5-ol and 3-bromo-5-methyi-l 1-(4methylpiperazinyi)-5H dibenzo[a,d]cyclohepten-5-ol was obtained as a residual dark-yellow glass; yield, 18 g. (96%).

Step E.. Preparation of 3-bromo-5-methylene- 10, 1 1-dihydro-5H-dibenzo[a. dlcyclohepten- 10-one and 7- bromo-5-methylene- 10. 1 1-dihydro5H dibenzo[adlcyclohepten- 10-one A mixture of the product from Step D (18 g., 0.045 mole), 95% ethanol (85 mi.), 7N ethanolic hydrogen chloride (40 mi.), and 6N aqueous hydrochloric acid (80 mi.) was stirred at room temperature for 30 minutes and at ref lux temperature for 1 hour. The mixture consisted of a brown oily lower phase and an aqueous alcoholic upper phase. The latter was decanted and the alcohol was stripped in vacuo. The residual aqueous mixture was extracted with chloroform. The previously obtained brown oil was dissolved in chloroform and 45 the combined chloroform phases were washed with water and dried over anhydrous magnesium sulfate.

Evaporation of the filtered extract left the crude product as a residual dark-yellow glass. This material was chromatographed on a silica gel column, eluting with toluene. Evaporation of the appropriately combined fractions leftthe partially purified product as an oil solid (8.5 g.). Trituration with cyclohexane afforded one of the isomers of the product as a white solid; yield, 2.6 g., m.p. 125- 1580C. Two recrystallizations from cyclohexane gave m.p. 158-163'C. Evaporation of the first cyclohexane mother liquor left the remaining isomer of the product as a dark-yellow oil, Trituration with three successive 1 0-mi. portions of hexane afforded a yellow solid; yield 3.3 g., m.p. 75.83'C. Two recrystallizations from hexane gave m.p. 84-89'C.

The higher-melting isomer (m.p 160-164'C) has structural formula:

0 CH,. Br 60 and is named 7-bromo-5-methylene-10,1 1-dihydro-5H-dibenzo[a,dl- cyclohepten-10-one.

The other isomer, 3-bromo-5-methylene-10,1 1-dihydro-5.H-dibenzo[a, dlcyclohepten-10one (m.p. 84-91'C) has structural formula:

4 4 GB 2 061947 A CH2Br Steps F to H. Preparation of (3 and 7)-bromo-5-methyl-10,11-dihydro-5H- dibenzo[adl-cyclohepten-5,10imine By the procedure substantially as described in Example 1, Steps D to G, but substituting for the 5methylene-10-oxo-10,11-dihydro-5H-dibenzo[a, dlcycioheptene an equimoiecular amount of the corresponding 3- and 7bromo- compounds, there are produced in sequence, the following:

(StepF): (3 and 7)-bromo-10-hydroximino-5-methylene-10,11-dihydro-5Hdibenzo[a,dlcyclohepten e, m.p.s.

1 171-175T and 179-181T respectively; (Step G). (3 and 7)-bromo-1 0-hydroxamino-5-methylene-1 0,11 -dihydro-5H- dibenzo[a,dleycloheptene, m.p.s 149-1530C and 136-13TC respectively; and (Step H): (3 and 7)-bromo-5-methyi-1 2-hydroxy-l 0,11 -dihydro-5Hdibenzo[a,dlcyclohepten-5,1 04mine, m.p.s. 175-180T and 187-189T respectively. Similarly prepared are: 8-bromo-5-methyi-l 2-hydroxy-l 0,11 -dihydro-5H-dibenzo [a,dlcyclohepten-5,1 0-imine; 2-bromo-5-ethyi-l 2hydroxy-l 0,11 -dihydro-5H-dibenzo-[a,dlcyclohepten-5,1 0-imine; and 7bromo-5-ethy]-1 2-hydroxy-l 0,11 -dihydro-5h-dibenzo-[a,dlcyclohepten-5,1 04mine.

Claims

1. A compound of formula:

R1 A HO 30 N R R3 6H2R2 35 in which R' is (1) hydrogen, (2) Cl-5 alkyl, (3) C2-r, alkenyl, 40 (4) phenyl-(C1-3 alkyl), (5) C3-6 cycloalkyl, or (6) (C3-6 cycloalkyi)-(C1-3 alkyl), -CH2R 2 is (1) Cl-s alkyl, (2) C3-r, alkenyl, (3) phenyl-(C1-3 alkyl), (4) (C3.6 akyl)-(C1-,, alkyl), (5) di(C1-5 alkyl)amino-(C1-5 aikyl), or (6) C2-3 hydroxyalkyl; and R 3 and R 4 are independently (1) hydrogen, (2) halogen, (3) Cl-E; alkoxy, (4) trifluoromethylthio, (5) cyano, (6) carboxy, or (7) hydroxy.

2. 5-Methyl-12-hydroxy-10,11-dihydro-5H-dibenzo[a,dlcyclohepten-5,10imine.

3. 5-Ethyl-12-hydroxy-10,11-dihydro-5H-dibenzo[a,dlcyclohepten-5,10-imine.

4. A process for producing a compound as claimed in Claim 1 substantially as hereinbefore described in anyone of Examples land 3.

5. A compound as claimed in Claim 1 when prepared by a process as claimed in Claim 4.

Printed for Her Majesty's Stationery Office, by Croydon Printing Company Limited, Croydon, Surrey, 1981. Published by The Patent Office, 25 Southampton Buildings, London, WC2A lAY, from which copies may be obtained.