Tricyclic aromatic compounds

Abstract: The present invention relates to novel compounds, in particular: ( E )/ Z )-3-(2-bromo-6,11-dihydrodibenz[b,e]oxepin-11-ylidene-N,­ N-dimethylpropylamine; (E)/(Z)-3-(3-bromo-6,11-dihydrodibenz[b,e]oxepin-11-ylidene)-N,­ N-dimethylpropylamine; (E)/(Z)-3-(8-bromo-6,11-dihydrodibenz[b,e]-11-ylidene)-N,­ N-dimethylpropylamine; and (E)/(Z)-3-(9-bromo-6,11-dihydrodibenz[b,e]oxepin-11-ylidene) -N,­ N-dimethylpropylamine.

Description: The present invention relates to new chemical compounds which are useful as intermediates in the preparation of certain doxepin derivatives having antihistaminic and antiasthmatic properties and to processes for preparing said intermediates. In our European Application No. 214779 there are disclosed novel carboxylic acid derivatives of doxepin, which possess surprisingly potent antihistaminic and antiasthmatic properties, namely compounds of formula (I) or a salt, ester or amide thereof; wherein R¹ is -CH₂-CH₂-, -CH₂-O- or -O-CH₂-; R² and R³ are the same or different and are each hydrogen, C₁₋₄ alkyl or taken together with the nitrogen comprise a nitrogen-containing heterocyclic ring having four to six ring members; R⁴ is a single bond or a C₁₋₇ bivalent aliphatic hydrocarbon group and may be joined to the aromatic ring system at the 2,3, 8 or 9 positions. n is 0 to 3. Said application also describes inter alia a process for preparing compounds of formula (I) which comprises carboxylation of a compound of formula (V) wherein R¹, R², R³ and n are as defined in formula (i) and X is bromo attached to the ring system in the 2,3,8 or 9 positions. The present invention provides the following novel compounds of formula (V): ( E )/( Z )-3-(2-bromo-6,11-dihydrodibenz[b,e]oxepin-11-ylidene)-N,N-dimethylpropylamine; (E)/( Z )-3-(3-bromo-6,11-dihydrodibenz[b,e]oxepin-11-ylidene)-N,N-dimethylpropylamine; (E)/( Z )-3-(8-bromo-6,11-dihydrodibenz[b,e]oxepin-11-ylidene)-N,N-dimethylpropylamine; (E)/( Z )-3-(9-bromo-6,11-dihydrodibenz[b,e]oxepin-11-ylidene)-N,N-dimethylpropylamine; A compound of formula (I) wherein R⁴ is a single bond can be prepared by carboxylation of a compound of formula (V) wherein R¹,R²,R³ and n are as defined, vide supra and X is bromine attached directly to the ring system in the 2,3,8 or 9 positions. For example, a compound of formula (V) can be treated with a metalating agent such as butyl lithium followed by a reaction with carbon dioxide. A compound of formula (V) can be reacted with magnesium in an appropriate solvent followed by reaction with carbon dioxide via the Grignard procedure ( The Merck Index , ninth ed., page ONR-38, Merck and Co., Rahway, N.J. (1976). Example: 1. a) 2-Bromo-6,11-dihydrodibenz[ b,e ]oxepin-11-one 2-Bromo-6,11-dihydrodibenz[ b,e ]oxepin-11-one was prepared as described in US Patent 4,282,365, m.p. 132-134°C (Lit. .p. 136-139°C). pmr (DMSO/d₆) δ: 8.13 (d,J=2.6 Hz, 1H, H₁), 7.48-7.83 (m, 5H, aromatic), 7.07 (d, J=8.8 Hz, 1H, H₄), 5.31 (s, 2H, CH₂O). Analysis: Calcd. for C₁₄H₉BrO₂: C, 58.16; H, 3.14; Br, 27.64. Found: C, 58.20; H, 3.18; Br, 27.73. b) ( E )/( Z )-3-(2-Bromo-6,11-dihydrodibenz[b,e]oxepin-11-ylidene)-N,N-dimethylpropylamine Anhydrous 3-(dimethylamino)propyltriphenylphosphonium bromide hydrobromide (39.4 g., 0.08 mole) was suspended in 450 mL of dry tetrahydrofuran and 100 mL of a solution of n-butyl lithium in hexane (1.6 M) was added dropwise at 0°C under a nitrogen atmosphere during a 30 minute period. After an additional 10 minutes, 2-bromo-6,11-dihydrodibenz[ b,e ]oxepin-11-one (16.8 g., 0.06 mole) in 150 mL dry tetrahydrofuran was added slowly to the deep red solution and the reaction mixture was then refluxed for 18 hours. The reaction mixture was poured onto ice-water, and the mixture was extracted with diethyl ether. The ether layer was concentrated under reduced pressure and the residue was suspended in water and then acidified with 6N hydrochloric acid. The acidic aqueous layer was washed with hexanes and then was concentrated to give a gummy residue. The residue was crystallized from ethyl acetate/methanol to provide 5.3 g. of pure Z -isomer as its hydrochloride salt, m.p. 201-204°C. The mother liquor was chromatographed on a silica gel column (Waters Associates -Prep. 500) with ethyl acetate/methanol (8:2) to give an additional 2.55 g. of pure Z -isomer as the hydrochloride salt and 2.79 g. of E -isomer as its hydrochloride salt, m.p. 230-233°C. pmr ( Z -isomer) (DMSO/d₆) δ: 7.25-7.44 (m, 6H, aromatic), 6.81 (degenerate d, J=9.1 Hz, 1H, H₄), 5.72 (t, J=7.1 Hz, 1H, CH=), 5.22 (s, 2H, CH₂O), 3.18 (m, 2H, NCH₂), 2.70 (m, 2H, CH₂), 2.66 (s, 6H, NMe₂). pmr ( E -isomer) (DMSO/d6) δ: 7.23-7.50 (m, 6H, aromatic), 6.70 (d, J=8.6 Hz, 1H, H₄), 6.10 (t, J=7.2 Hz, 1H, CH=) 5.15 (br s, 2H, CH₂O), 3.07 (m, 2H, NCH₂), 2.65 (s, 6H, NMe₂), 2.50 (m overlap with DMSO, 2H, CH₂). Example 2: a) Methyl 2-(3-bromophenoxymethyl)benzoate To a mixture of 3-bromophenol (60 g, 0.35 mole) and potassium carbonate (25 g, 0.18 mole) in 250 mL of N,N-dimethylformamide was added methyl α-bromo-2-toluate (65 g, 0.28 mole). The reaction mixture was stirred at room temperature for 18 hours, then heated on a steam bath for 3 hours. The mixture was poured into ice-water, and the solids were collected by filtration and washed with water to give the crude product. Analytical sample was obtained by recrystallization from methylene chloride/hexanes, m.p. 84-85°C. pmr (CDCl₃) δ: 8.0 (m, 1H, H₆), 6.93-7.69 (m, 7H, aromatic H), 5.47 (s, 2H, ArCH₂O), 3.89 (s, 3H, CO₂CH₃). Analysis: Calcd. for C₁₅H₁₃ BrO₃: C, 56.09; H, 4.08; Br, 24.88. Found: C, 56.20; H, 4.12; Br, 24.77. b) 2-(3-bromophenoxy)methylbenzoic acid Methyl 2-(3-bromophenoxy)methylbenzoate (34 g) was refluxed in a mixture of 100 mL of 10% sodium hydroxide and 200 mL of methanol for 3 hours. The reaction mixture was concentrated under reduced pressure and water was added to the residue. The mixture was then acidified with concentrated hydrochloric acid. Extracting the acidic solution with ethyl acetate and then concentration of the organic layer gave the 2-(3-bromophenoxy)methyl benzoic acid (35 g) m.p. 158-159°C. pmr (CDCL₃) δ: 8.10 (m, 1H, H₆), 6.84-7.74 (m, 7H, aromatic H), 6.16 (br s, 1H, CO₂H), 5.49 (s, 2H, ArCH₂O). Analysis: Calcd. for C₁₄H₁₁BrO₃: C, 54.74; H, 3.61; Br, 26.02. Found: C, 54.65; H, 3.61; Br, 26.08. c) 3-Bromo-6,11-dihydrodibenz[ b,e ]oxepin-11-one A suspension of 2-(3-bromophenoxymethyl)benzoate (35 g, 0.11 mole) in 100 mL of trifluoroacetic anhydride containing 20 drops of boron trifluoride-ether complex was refluxed for 4 hours. The mixture was poured into ice-water and then extracted with diethyl ether. Concentration of ether solution under reduced pressure and chromatography of the residue on a silica gel column (Waters Associates, Prep 500) with hexane/methylene chloride (70:30) gave the pure product (14 g). m.p. 110-112°C. pmr (CDCL₃) δ: 8.10 (d, J=9.1 Hz, 1H, H₁), 7.90 (dd, J=1.4, 7.6 Hz, 1H, H₁₀) 7.57 (dt, J=1.4, 7.4, 7.4 Hz, 1H H8), 7.48 (dt, J=1.4, 7.6, 7.6 Hz, 1H, H9), 7.36 (dd, J=1.3, 7.3 Hz, 1H, H₇), 7.27 (d,J=1.8 Hz, 1H, H₄), 7.24 (dd, J=1.8, 9.1 Hz, 1H, H₂), 5.18 (s, 2H, ArCH₂O). Analysis: Calcd. for C₁₄H₉BrO₂: C, 58.16; H, 3.14; Br, 27.64. Found: C, 58.13; H, 3.19; Br, 27.72. d) ( E )/( Z )-3-(3-Bromo-6,11-dihydrodibenz[ b,e ]oxepin-11-ylidene)-N,N-dimethylpropylamine Anhydrous 3-(dimethylamino)propyltriphenylphosphonium bromide hydrobromide (24.5 g, 48.0 mmole), 96 mmole of n-butyl lithium in hexane, and 3-bromo-6,11-dihydrodibenz[ b,e ]oxepin-11-one (10 g, 34.6 mmole) were reacted in 580 mL dry tetrahydrofuran by the procedure of Example I, step b. This provided an ( E )/( Z )-(1:3) isomeric mixture of bromoamines (6.0 g). Recrystallization of half of the mixtures (3.0 g) from ethyl acetate gave 1.45 g of Z-isomer of ≧93% stereoisomeric purity (assayed by 'H-NMR) as a white solid. pmr (CDCl₃) δ: 7.23-7.31 (m, 4H, aromatic H), 6.92-7.05 (m, 3H, aromatic H), 5.91 (t, 1H, CH=, 7% E -isomer), 5.60 (t, 1H, CH=, 93% Z -isomer) 5.15 (very br s, 2H, ArCH₂O), 3.12 (m, 2H, CH₂), 2.99 (m, 2H, NCH₂), 2.78 (s, 6H, NMe₂, 93% Z -isomer), 2.71 (s, 6H, NMe₂, 3% E -isomer). Analysis: Calcd. for C₁₉H₂₀BrNO·1.0 HCl: C, 57.81; H, 5.36; N, 3.55. Found: C, 57.62; H, 5.33; N, 3.54. Example 3: a) 8-Bromo-6,11-dihydrodibenz[ b,e ]oxepin-11-one Phenol (8 g, 85 mmole) and potassium carbonate (11.7 g, 85 mmole) in 150 mL of N,N-dimethylformamide was reacted with methyl 4-bromo-α-bromo-2-toluate (20 g, 65 mmole) by the procedure of Example 2, step a and followed with alkaline hydrolysis by the procedure of Example 2, step b to give the crude 4-bromo-2-phenoxybenzoic acid (13 g) which was used without further purification. The crude 4-bromo-(2-phenoxymethyl)benzoic acid (13 g, 42 mmole) was cyclized in 50 mL of trifluroacetic anhydride containing 1 mL of boron trifluorideether complex by the procedure of Example 2, step c. The solid was collected by filtration and washed with water to give 11.9 g of the tricyclic ketone, m.p. 125-126°C. pmr (CDCL₃) δ: 8.17-8.30 (m, 1H, H1), 6.99-7.86 (m, 6H, aromatic H), 5.14 (s, 2H, ArCH₂O). Analysis: Calcd. for C₁₄H₉BrO₂: C, 58.16; H, 3.14; Br, 27.64. Found: C, 58.15; H, 3.17; Br, 27.73. b) ( E )/( Z )-3-(8-Bromo-6,11-dihydrodibenz[ b,e ]oxepin-11-ylidene)-N,N-dimethylpropylamine Anhydrous 3-(dimethylamino)propyltriphenylphosphonium bromide hydrobromide (24.5 g, 48 mmole), 96 mmole of n-butyl lithium in hexane, and 8-bromo-6,11-dihydrodibenz[ b,e ]oxepin-11-one (10 g, 34.6 mmole) were reacted in 580 mL dry tetrahydrofuran by the procedure of Example I, step b. This provided an E/Z (1:3.5) isomeric mixture of bromoamines. Recrystallization of the mixture from diethyl ether gave 0.17 g of Z -isomer and 1.8 g of an E/Z (1:4) (assayed by HPLC on C18) isomeric mixture which was used in the next step without further purification. pmr ( Z -isomer) (CDCl₃) δ: 7.38-7.44 (m, 2H, H₇ and H₉); 7.13-7.18 (m, 3H, aromatic H); 6.84-6.93 (m, 2H, H₂ and H₄); 5.70 (t, 1H, CH=); 5.15 (br s, 2H, ArCH₂O); 2.55 (q, 2H, CH₂); 2.43 (t, 2H, NCH₂); 2.22 (s, 6H, NMe₂). Analysis: Calcd. for C₁₉H₂₀BrNO: C, 63.70; H, 5.63; N, 3.91. Found ( Z -isomer): C, 63.85; H, 5.65; N, 3.92. Example 4: a) 9-Bromo-6,11-dihydrodibenz[ b,e ]oxepin-11-one 9-Bromo-6,11-dihydrodibenz[ b,e ]oxepin-11-one was prepared as described in US Patent 4,282,365, m.p. 104-106°C (Lit. m.p. 107.5-108.5°C). pmr (CDCl₃) δ: 8.02-8.27 (m, 2H, H₁ and H₁₀), 6.98-7.73 (m, 5H, aromatic), 5.14 (s, 2H, CH₂O). Analysis: Calcd. for C₁₄H₉BrO₂: C, 58.16; H, 3.14; Br, 27.64. Found: C, 58.24; H, 3.18; Br, 27.51. b) ( E )/( Z )-3-(9-Bromo-6,11-dihydrodibenz[ b,e ]oxepin-11-ylidene)- N , N -dimethylpropylamine. Anhydrous 3-(dimethylamino)propyltriphenylphosphonium bromide hydrobromide (31 g., 60.9 mmole), 122 mmole of n-butyl lithium in hexane, and 9-bromo-6,11-dihydrodibenz[ b,e ]oxepin-11-one (12.7 g., 43.8 mmole) were reacted in 750 mL dry tetrahydrofuran by the procedure of Example I, Step b. This provided an E/Z (1:6) isomeric mixture of bromoamines. Recrystallization of the mixture from ethyl acetate/methanol gave 1.2 g. of pure Z -isomer as its hydrochloride salt, melting range 91-100°C and 2.16 g. of an E/Z (1:4) isomeric mixture which was used in the next step without further purification. pmr ( Z -isomer) (CDCl₃) δ: 6.94-7.46 (m, 7H, aromatic), 5.64 (t, J=8.0 Hz, 1H, CH=), 5.15 (br s, 2H, CH₂O), 3.07 (m, 4H, NCH₂ CH₂), 2.75 (s, 6H, NMe₂). Analysis: Calcd. for C₁₉H₂₀BrNO·HCl: C, 57.80; H, 5.36; N, 3.54. Found ( Z -isomer): C, 57.56; H, 5.41; N, 3.45.

Claims: A compound selected from ( E )/( Z )-3-(2-bromo-6,11-dihydrodibenz[b,e]oxepin-11-ylidene-N, N-dimethylpropylamine; (E)/(Z)-3-(3-bromo-6,11-dihydrodibenz[b,e]oxepin-11-ylidene)-N, N-dimethylpropylamine; (E)/(Z)-3-(8-bromo-6,11-dihydrodibenz[b,e]oxepin-11-ylidene)-N, N-dimethylpropylamine; and (E)/(Z)-3-(9-bromo-6,11-dihydrodibenz[b,e]oxepin-11-ylidene)-N, N-dimethylpropylamine.

Inventors: LEIGHTON HARRY JEFFERSON, LEVER O WILLIAM JR, LEIGHTON, HARRY JEFFERSON, LEVER, O. WILLIAM, JR.
Applicants: WELLCOME FOUND, THE WELLCOME FOUNDATION LIMITED
Application year: 1986
Main classification: C07D313
IPC codes: C07C229, C07D313