CA1176265A - Process for the manufacture of dibenzoxepinones - Google Patents
Process for the manufacture of dibenzoxepinonesInfo
- Publication number
- CA1176265A CA1176265A CA000420425A CA420425A CA1176265A CA 1176265 A CA1176265 A CA 1176265A CA 000420425 A CA000420425 A CA 000420425A CA 420425 A CA420425 A CA 420425A CA 1176265 A CA1176265 A CA 1176265A
- Authority
- CA
- Canada
- Prior art keywords
- formula
- compound
- acid
- defined above
- isolation
- 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
Links
- 238000000034 method Methods 0.000 title claims abstract description 33
- 238000004519 manufacturing process Methods 0.000 title abstract 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 32
- 238000002955 isolation Methods 0.000 claims abstract description 12
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 8
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 8
- 150000002367 halogens Chemical class 0.000 claims abstract description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 7
- 239000001257 hydrogen Substances 0.000 claims abstract description 7
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 5
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims abstract description 4
- 125000004738 (C1-C6) alkyl sulfinyl group Chemical group 0.000 claims abstract description 4
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims abstract description 4
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims abstract description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 4
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims abstract description 3
- 239000003054 catalyst Substances 0.000 claims description 7
- 150000002989 phenols Chemical class 0.000 claims description 7
- 239000012442 inert solvent Substances 0.000 claims description 4
- 150000001879 copper Chemical class 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims 1
- 230000000202 analgesic effect Effects 0.000 abstract description 2
- 230000001773 anti-convulsant effect Effects 0.000 abstract description 2
- 230000001430 anti-depressive effect Effects 0.000 abstract description 2
- 239000000935 antidepressant agent Substances 0.000 abstract description 2
- 229940005513 antidepressants Drugs 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
- 235000013350 formula milk Nutrition 0.000 description 30
- 238000002844 melting Methods 0.000 description 12
- 230000008018 melting Effects 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- IUJAAIZKRJJZGQ-UHFFFAOYSA-N 2-(2-chlorophenyl)acetic acid Chemical compound OC(=O)CC1=CC=CC=C1Cl IUJAAIZKRJJZGQ-UHFFFAOYSA-N 0.000 description 7
- QPLDLSVMHZLSFG-UHFFFAOYSA-N Copper oxide Chemical compound [Cu]=O QPLDLSVMHZLSFG-UHFFFAOYSA-N 0.000 description 7
- 239000010949 copper Substances 0.000 description 7
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 6
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 229910052802 copper Inorganic materials 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 5
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 239000008096 xylene Substances 0.000 description 5
- AERWYILGTIIYAD-UHFFFAOYSA-N 2-[2-(4-fluorophenoxy)phenyl]acetic acid Chemical compound OC(=O)CC1=CC=CC=C1OC1=CC=C(F)C=C1 AERWYILGTIIYAD-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- 229960000443 hydrochloric acid Drugs 0.000 description 4
- 235000011167 hydrochloric acid Nutrition 0.000 description 4
- 239000005457 ice water Substances 0.000 description 4
- 229920000137 polyphosphoric acid Polymers 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- ZGNHLWKYNFSKCD-UHFFFAOYSA-N Dibenzoxepine Chemical class O1C=CC2=CC=CC=C2C2=CC=CC=C12 ZGNHLWKYNFSKCD-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- -1 alkyl metal hydroxides Chemical class 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 3
- AUHZEENZYGFFBQ-UHFFFAOYSA-N mesitylene Substances CC1=CC(C)=CC(C)=C1 AUHZEENZYGFFBQ-UHFFFAOYSA-N 0.000 description 3
- 125000001827 mesitylenyl group Chemical group [H]C1=C(C(*)=C(C([H])=C1C([H])([H])[H])C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 230000000269 nucleophilic effect Effects 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 2
- MLGQCJSEUUWVLJ-UHFFFAOYSA-N 2h-benzo[d][1]benzoxepin-1-one Chemical class C12=CC=CC=C2C=COC2=C1C(=O)CC=C2 MLGQCJSEUUWVLJ-UHFFFAOYSA-N 0.000 description 2
- RHMPLDJJXGPMEX-UHFFFAOYSA-N 4-fluorophenol Chemical compound OC1=CC=C(F)C=C1 RHMPLDJJXGPMEX-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- 229910017489 Cu I Inorganic materials 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 230000003213 activating effect Effects 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 150000005524 benzylchlorides Chemical class 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical class OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 2
- 229940072033 potash Drugs 0.000 description 2
- 235000015320 potassium carbonate Nutrition 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- ZDOYHCIRUPHUHN-UHFFFAOYSA-N 1-(2-chlorophenyl)ethanone Chemical class CC(=O)C1=CC=CC=C1Cl ZDOYHCIRUPHUHN-UHFFFAOYSA-N 0.000 description 1
- XDXCBCXNCQGZPG-UHFFFAOYSA-N 1-(2-iodophenyl)ethanone Chemical compound CC(=O)C1=CC=CC=C1I XDXCBCXNCQGZPG-UHFFFAOYSA-N 0.000 description 1
- WVYIZGMCLSGZGG-UHFFFAOYSA-N 10-hydroxy-cis-12-octadecenoic acid Natural products CCCCCC=CCC(O)CCCCCCCCC(O)=O WVYIZGMCLSGZGG-UHFFFAOYSA-N 0.000 description 1
- DWXSYDKEWORWBT-UHFFFAOYSA-N 2-(2-bromophenyl)acetic acid Chemical compound OC(=O)CC1=CC=CC=C1Br DWXSYDKEWORWBT-UHFFFAOYSA-N 0.000 description 1
- IUHXGZHKSYYDIL-UHFFFAOYSA-N 2-(2-iodophenyl)acetic acid Chemical compound OC(=O)CC1=CC=CC=C1I IUHXGZHKSYYDIL-UHFFFAOYSA-N 0.000 description 1
- XRXMNWGCKISMOH-UHFFFAOYSA-N 2-bromobenzoic acid Chemical compound OC(=O)C1=CC=CC=C1Br XRXMNWGCKISMOH-UHFFFAOYSA-N 0.000 description 1
- CJNZAXGUTKBIHP-UHFFFAOYSA-N 2-iodobenzoic acid Chemical compound OC(=O)C1=CC=CC=C1I CJNZAXGUTKBIHP-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 238000006898 Intramolecular Friedel-Crafts reaction Methods 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- 229910006124 SOCl2 Inorganic materials 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 238000006887 Ullmann reaction Methods 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
- 150000008041 alkali metal carbonates Chemical class 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 150000004996 alkyl benzenes Chemical class 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 150000001491 aromatic compounds Chemical class 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 238000010533 azeotropic distillation Methods 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 150000003997 cyclic ketones Chemical class 0.000 description 1
- VGHOWOWLIXPTOA-UHFFFAOYSA-N cyclohexane;toluene Chemical compound C1CCCCC1.CC1=CC=CC=C1 VGHOWOWLIXPTOA-UHFFFAOYSA-N 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 235000020061 kirsch Nutrition 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 229910000000 metal hydroxide Inorganic materials 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000003541 multi-stage reaction Methods 0.000 description 1
- 238000007040 multi-step synthesis reaction Methods 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 125000006678 phenoxycarbonyl group Chemical group 0.000 description 1
- SUSQOBVLVYHIEX-UHFFFAOYSA-N phenylacetonitrile Chemical class N#CCC1=CC=CC=C1 SUSQOBVLVYHIEX-UHFFFAOYSA-N 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D313/00—Heterocyclic compounds containing rings of more than six members having one oxygen atom as the only ring hetero atom
- C07D313/02—Seven-membered rings
- C07D313/06—Seven-membered rings condensed with carbocyclic rings or ring systems
- C07D313/10—Seven-membered rings condensed with carbocyclic rings or ring systems condensed with two six-membered rings
- C07D313/14—[b,f]-condensed
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Abstract of the disclosure A process for the manufacture of a compound of the formula (II) wherein X and Y are identical or different from each other and each denote hydrogen, halogen, trifluoro-methyl, C1-C6-alkoxy, C1-C6-alkyl, C1-C6-alkylthio, C1-C6-alkylsulfonyl, C1-C6-alkylsulfinyl, amino or nitro, which comprises a) reacting a compound of the formula XI
(XI) wherein X is as defined above, with a phenol of the formula IV
(IV) wherein Y is as defined above, to give a compound of the formula IX
(XI) wherein X is as defined above, with a phenol of the formula IV
(IV) wherein Y is as defined above, to give a compound of the formula IX
Description
~76265
- 2 - HOE 82/F 012 European laid open specification No. 0,002,508 describes dibenzoxepine derivatives of the formula I
S- ~CH2)n~Z
X
wherein X and Y are identical or different from each other and each denote hydrogen, halogen, trifluoromethyl, C1-C6-alkoxy, C1-C6-alkyl, alkylthio, C1-C6-alkylsulfonyl, C1-C6-alkylsulfinyl, amino or nitro, Z is halogen or -NR R with R1 denoting hydrogen, straight-chain or branched C1-C6-alkyl, cyano, cycloalkyl-C1-C6-alkyl, the cycloalkyl ring of which having 3 to 6 carbon atoms, phenoxycarbonyl and R is straight~chain or branched C1-C6-alkyl or cycloalkyl-C1-C6-alkyl, the cycloalkyl moiety having from 3 to 6 carbon atomsl or R and R together with the nitrogen atom form a heterocycle and n is an integer of from 2 to 4, and salts thereof with physiologically acce~table acids.
These compounds possess analgetic, soothing, anti-depressant and anticonvulsant properties.
The key compound for the synthesis of said derivatives is a dibenzoxepinone derivative of the formula II
~ Y (II) wherein X and Y are as defined above. These cyclic ketones can be synthesized inter alia in the following manner:
Method I:
(V. SEIDLOVA et al., Collect. Czechoslov. ChemO Commun. 34 (8), 2258-77 (1969); U.S.-Pat. 4 094 900; ~I. MARONA, Pol. J. Chem. 53 (7/8) 1645~48 (1979); U.S.-Pat. 4 198 421;
J. A~KRELL et al., J. Med. Chem. 21 (1978) 10, 1035-1044;
*
, . .. , . .. ~ ..
il76Z65
S- ~CH2)n~Z
X
wherein X and Y are identical or different from each other and each denote hydrogen, halogen, trifluoromethyl, C1-C6-alkoxy, C1-C6-alkyl, alkylthio, C1-C6-alkylsulfonyl, C1-C6-alkylsulfinyl, amino or nitro, Z is halogen or -NR R with R1 denoting hydrogen, straight-chain or branched C1-C6-alkyl, cyano, cycloalkyl-C1-C6-alkyl, the cycloalkyl ring of which having 3 to 6 carbon atoms, phenoxycarbonyl and R is straight~chain or branched C1-C6-alkyl or cycloalkyl-C1-C6-alkyl, the cycloalkyl moiety having from 3 to 6 carbon atomsl or R and R together with the nitrogen atom form a heterocycle and n is an integer of from 2 to 4, and salts thereof with physiologically acce~table acids.
These compounds possess analgetic, soothing, anti-depressant and anticonvulsant properties.
The key compound for the synthesis of said derivatives is a dibenzoxepinone derivative of the formula II
~ Y (II) wherein X and Y are as defined above. These cyclic ketones can be synthesized inter alia in the following manner:
Method I:
(V. SEIDLOVA et al., Collect. Czechoslov. ChemO Commun. 34 (8), 2258-77 (1969); U.S.-Pat. 4 094 900; ~I. MARONA, Pol. J. Chem. 53 (7/8) 1645~48 (1979); U.S.-Pat. 4 198 421;
J. A~KRELL et al., J. Med. Chem. 21 (1978) 10, 1035-1044;
*
, . .. , . .. ~ ..
il76Z65
- 3 - HOE 82/F 012 P. CAGNIANT, G. KIRSCH, C.X. Acad. Sci. Ser. C 283 (1976) 15, 683-86).
O~I _~ K2C3 X Cu-Cat.
(III) (IV~
X ~ Y "Vit~ides"
(V) (VI) .
~ ~ _____~ ~ B2504 (VII) (VIII) O
CH2-COOH Socl2/Alcl3 ~ Y ~
X - ~ or X ~ y ,., PPA, (IX~ Y (II) Following these steps, a corresponding substituted o-halogeno-benzoic acid of the formula III wherein the halogen is chlorine, bromine or iodine, is treated with a phenol of the formula IV, the acid is reduced to give a ~76Z65
O~I _~ K2C3 X Cu-Cat.
(III) (IV~
X ~ Y "Vit~ides"
(V) (VI) .
~ ~ _____~ ~ B2504 (VII) (VIII) O
CH2-COOH Socl2/Alcl3 ~ Y ~
X - ~ or X ~ y ,., PPA, (IX~ Y (II) Following these steps, a corresponding substituted o-halogeno-benzoic acid of the formula III wherein the halogen is chlorine, bromine or iodine, is treated with a phenol of the formula IV, the acid is reduced to give a ~76Z65
4 - HOE 82/F 012 benzyl alcohol V and the latter is converted to the benzyl chloride derivative VII~ The subsequent nitrile synthesis gives a benzyl cyanide derivative of the formula VIII which may be saponified to give a phenylacetic acid derivative IX.
An intramolecular Friedel-Crafts reaction of the latter with SOCl2 in the presence of AlC13 or an other Lewis acid or an intramolecular condensation of compounds of the formula IX in polyphosphoric acid gives derivatives of the formula II.
Method II:
(A.~I. CHOUD'~URY, K. SCHOFIELD, R.S. W~RD, J. Che~.Soc. (c) 1g70 (1~), 2543-47) ~CH2-COOH ~3_ (X) (IV) 20 ~ ~ - analo~ously to~ (II) X ~ method I- --~-(IX) y Thereafter o-bromophenylacetic acid or o-iodophenyl-acetic acid of the formula X prepared in a manner known in literature is treated with a phenol of the formula IV by an Ullmann reaction to give a phenylacetic acid derivative of the formula IX, which latter can be cyclized in the manner specified above to give dibenzoxepinones II.
Both of said methods have some disadvantages, however.
For example, method I is a multi-step synthesis process, which is very complicated and gives the wanted ketones II
only in a small total yield. The 2-iodobenzoic acid and the 2-bromobenzoic acid of the formula III are difficult to obtain and reduction of the carboxylic acid of the formula V to give the corresponding alcohol of the formula VI can be carried out only with difficulty for safety reasons.
.
~176265
An intramolecular Friedel-Crafts reaction of the latter with SOCl2 in the presence of AlC13 or an other Lewis acid or an intramolecular condensation of compounds of the formula IX in polyphosphoric acid gives derivatives of the formula II.
Method II:
(A.~I. CHOUD'~URY, K. SCHOFIELD, R.S. W~RD, J. Che~.Soc. (c) 1g70 (1~), 2543-47) ~CH2-COOH ~3_ (X) (IV) 20 ~ ~ - analo~ously to~ (II) X ~ method I- --~-(IX) y Thereafter o-bromophenylacetic acid or o-iodophenyl-acetic acid of the formula X prepared in a manner known in literature is treated with a phenol of the formula IV by an Ullmann reaction to give a phenylacetic acid derivative of the formula IX, which latter can be cyclized in the manner specified above to give dibenzoxepinones II.
Both of said methods have some disadvantages, however.
For example, method I is a multi-step synthesis process, which is very complicated and gives the wanted ketones II
only in a small total yield. The 2-iodobenzoic acid and the 2-bromobenzoic acid of the formula III are difficult to obtain and reduction of the carboxylic acid of the formula V to give the corresponding alcohol of the formula VI can be carried out only with difficulty for safety reasons.
.
~176265
- 5 - HOE 82/F 012 Method II has so far been considered as being feasible only to compounds of formula X wherein Hal is bromine or iodine, as it has been believed that an exchange of the chlorine atom at a non-activated aromatic compound, for example 2-chlorophenylacetic acid, for oxy~en nucleophilic compounds, for example phenols, could be carried out not at all or only with extremely low yields.
An exchange of halogen denoting chlorine for sulfur nucleophilic compounds, for example thiophenollhas been su~cessful hitherto only in the presence of activating groups, for example a nitro group (K. SINDELAR et al., Collect. Czechoslov. Chem. Common. 42, (7), 2231-39 (1977)).
~ CH2-COO~ ¦ ~ CH2-COO~
~Z~f CE~2--COOH
The exchange of chlorine in o-chlorophenylacetic acid derivatives, even in the presence of activating groups, for oxygen nucleophilic groups, as for example phenols, has not been described up to now.
~ethod III:
A third method for the synthesis of dibenzoxepine derivatives of the formula II (Dainippon Pharm KK European patent application A 2,893: I. KEDA, Y. SATO, S. MAENO, S. UMIO Chem. Pharm. Bull. 26, (1978) 10, 3058-3070) uses o-halogenoacetophenone derivatives of the formula XII as starting compounds, which are reacted in a multi-step reaction sequence according to the scheme shown below to give compounds of the formula XVI, from which the wanted ~1762~i5
An exchange of halogen denoting chlorine for sulfur nucleophilic compounds, for example thiophenollhas been su~cessful hitherto only in the presence of activating groups, for example a nitro group (K. SINDELAR et al., Collect. Czechoslov. Chem. Common. 42, (7), 2231-39 (1977)).
~ CH2-COO~ ¦ ~ CH2-COO~
~Z~f CE~2--COOH
The exchange of chlorine in o-chlorophenylacetic acid derivatives, even in the presence of activating groups, for oxygen nucleophilic groups, as for example phenols, has not been described up to now.
~ethod III:
A third method for the synthesis of dibenzoxepine derivatives of the formula II (Dainippon Pharm KK European patent application A 2,893: I. KEDA, Y. SATO, S. MAENO, S. UMIO Chem. Pharm. Bull. 26, (1978) 10, 3058-3070) uses o-halogenoacetophenone derivatives of the formula XII as starting compounds, which are reacted in a multi-step reaction sequence according to the scheme shown below to give compounds of the formula XVI, from which the wanted ~1762~i5
- 6 - HOE 82/F 012 compounds of the formula II may be prepared in a manner known in literature. A in the formulae below denotes S or O:
~ Hal ~A ~ Ullmann-~ -CH3 ~ -reaction X O
(XII) (XIII) -CH reaction X CH -C-N(R) ~XIV) (XV~ .
.
O
-COOH
~V~ - . (II) This method involves a multi-step procedure and requires on principle long reaction times and high tempera-tures and a further disadvantage resides in the fact that the o-iodo- or o-chloroacetophenone derivative used as starting compound is rather difficult to obtain.
Surprisingly it has now been found that an o-chloro-phenylacetic acid derivative of the formula XI
~f CH2cooH
~ Cl (XI) ~176~6S
~ Hal ~A ~ Ullmann-~ -CH3 ~ -reaction X O
(XII) (XIII) -CH reaction X CH -C-N(R) ~XIV) (XV~ .
.
O
-COOH
~V~ - . (II) This method involves a multi-step procedure and requires on principle long reaction times and high tempera-tures and a further disadvantage resides in the fact that the o-iodo- or o-chloroacetophenone derivative used as starting compound is rather difficult to obtain.
Surprisingly it has now been found that an o-chloro-phenylacetic acid derivative of the formula XI
~f CH2cooH
~ Cl (XI) ~176~6S
- 7 - HOE 82/F 012 wherein X is hydrogen, halogen, trifluoromethyl, C1-C6-alkoxy, C1-C6-alkyl, C1-C6-alkylthio, C1-C6-alkylsulfonyl, C1-C6-alkylsulfinyl, amino or a nitro group, can be reacted with a phenol derivative of the formula IV
HO - ~ (IV) wherein Y has the same meaning as X or wherein Y and X are identical or different from each other, to give an ortho-phenoxyphenylacetic acid derivative of the formula IX
~ CH2-COOH ~IX~
wherein X and ~ are as defined above, in good yields. The compound of formula IX can be cyclized in a manner known in literature to give a dibenzoxepine derivative of the formula II
.
~0 Y
~ O ~ (II) wherein X and Y are as defined above.
Arlother variant of the process of the invention consists in reacting an ortho-chlorophenylacetic acid derivative of the formula XI with a phenol derivative of the formula IV wherein X and Y are as defined above, to ~ive directly compounds of formula II.
.
In this process X is preferably hydrogen and Y is preferably hydrogen and halogen.
The ortho-chlorophenylacetic acid derivatives XI and phenols IV are known in literature or can be prepared by methods known in literature (Organikum, Organisch chemisches Grundpraktikum, Reprint of the 15th revised edition of VEB
Deutscher Verlag der Wlssenschaften Berlin 1977, pages i~762~5
HO - ~ (IV) wherein Y has the same meaning as X or wherein Y and X are identical or different from each other, to give an ortho-phenoxyphenylacetic acid derivative of the formula IX
~ CH2-COOH ~IX~
wherein X and ~ are as defined above, in good yields. The compound of formula IX can be cyclized in a manner known in literature to give a dibenzoxepine derivative of the formula II
.
~0 Y
~ O ~ (II) wherein X and Y are as defined above.
Arlother variant of the process of the invention consists in reacting an ortho-chlorophenylacetic acid derivative of the formula XI with a phenol derivative of the formula IV wherein X and Y are as defined above, to ~ive directly compounds of formula II.
.
In this process X is preferably hydrogen and Y is preferably hydrogen and halogen.
The ortho-chlorophenylacetic acid derivatives XI and phenols IV are known in literature or can be prepared by methods known in literature (Organikum, Organisch chemisches Grundpraktikum, Reprint of the 15th revised edition of VEB
Deutscher Verlag der Wlssenschaften Berlin 1977, pages i~762~5
- 8 - HOE 82/F 012 269-271 and pages 532-534).
Variant A
_ In variant A the ortho-chlorophenylacetic acid of formula XI is reacted with the phenol derivative of for~
mula IV under basic conditions in an inert solvent at elevated temperature in the presence of copper or copper salts as catalysts. Examples of inert solvents include alkylbenzenes, preferably xylene or mesitylene, or other high-boiling solvents such as diethylene glycol dimethyl ether. Examples of basic catalysts include alkyl metal hydroxides, alkali metal alcoholates and alkali metal carbonates, preferably potassium carbonate.
The reaction takes place in a temperature range of from 120 to 180C, preferably of from 130 to 160C.
Examples of suitahle copper catalysts are metallic copper, copper-I salts such as Cu-I chloride, Cu-I oxide or copper-II salts such as Cu-II chloride, Cu-II oxide and Cu-II acetate.
Tne 2-phenoxy-phenyiacetic acid derivative of for-mula IX obtained may be isolated from the reaction mixture by extraction with water and acidification of the aqueous solution with a mineral acid, for example hydrochloric acid or sulfuric acid and be converted to the dibenzoxepinone derivative of formula II in a manner known in literature.
Variant B
The derivatives of the formulae XI and IV are reacted in the manner specified sub A. The desired product is extracted from the reaction mixture by an inert solvent, preferably methylene chloride and the extract is dropped into polyphosphoric acid at elevated temperature. Thedibenzoxepinone derivatives of formula II may be isolated easily from the reaction mixture in a high purity by dilution with water.
The process according to the invention has ~reat advan-tages, as compared to the known methods: The process steps - are reduced from 6 to 2 and 3, respectively, and the . .
process pexmi~s the use of o-chlorophenylacetic acid derivatives which can be readily prepared from o-chloro-~176Z1~5
Variant A
_ In variant A the ortho-chlorophenylacetic acid of formula XI is reacted with the phenol derivative of for~
mula IV under basic conditions in an inert solvent at elevated temperature in the presence of copper or copper salts as catalysts. Examples of inert solvents include alkylbenzenes, preferably xylene or mesitylene, or other high-boiling solvents such as diethylene glycol dimethyl ether. Examples of basic catalysts include alkyl metal hydroxides, alkali metal alcoholates and alkali metal carbonates, preferably potassium carbonate.
The reaction takes place in a temperature range of from 120 to 180C, preferably of from 130 to 160C.
Examples of suitahle copper catalysts are metallic copper, copper-I salts such as Cu-I chloride, Cu-I oxide or copper-II salts such as Cu-II chloride, Cu-II oxide and Cu-II acetate.
Tne 2-phenoxy-phenyiacetic acid derivative of for-mula IX obtained may be isolated from the reaction mixture by extraction with water and acidification of the aqueous solution with a mineral acid, for example hydrochloric acid or sulfuric acid and be converted to the dibenzoxepinone derivative of formula II in a manner known in literature.
Variant B
The derivatives of the formulae XI and IV are reacted in the manner specified sub A. The desired product is extracted from the reaction mixture by an inert solvent, preferably methylene chloride and the extract is dropped into polyphosphoric acid at elevated temperature. Thedibenzoxepinone derivatives of formula II may be isolated easily from the reaction mixture in a high purity by dilution with water.
The process according to the invention has ~reat advan-tages, as compared to the known methods: The process steps - are reduced from 6 to 2 and 3, respectively, and the . .
process pexmi~s the use of o-chlorophenylacetic acid derivatives which can be readily prepared from o-chloro-~176Z1~5
- 9 ~ HOE 82/F 012 benzyl chlorides.
The following examples illustrate the invention:
E X A M P L E
2-(4-Fluorophenoxy)-phenylacetic acid 34.1 g (0.2 mol) of 2-chlorophenylacetic acid, 22.4 g (0.2 mol) of 4-fluorophenol, 0.2 g of copper-II oxide and 52.2 g (0.375 mol) of anhydrous ground potash are refluxed in 580 ml of xylene for 2.5 hours under energetic stirring, while the water fo~med by the reaction is separated by azeotropic distillation. The reaction mixture is allowed to cool, decomposed with 400 ml of water and the aqueous phase is separated and acidified with concentrated hydro-chloric acid. The precipitate formed is filtered off and washed with water. Drying in vacuo at room temperature gives 46.55 g of the title compound having a melting point of from 96-97C.
.
The procedure is analogous to that of Example 1, except that 5.0 g of metallic copper is used instead of CuO. Isolation gives 46.1 g of the title compound having a melting point of from 92-94C.
.
The procedure is analogous to that of Example 1, except that 0.2 g of copper-II acetate is used instead of CuO. Isolation gives 45.9 g of the title compound having a melting point of from 95-96C.
_ A M P I, E 4 The procedure is analogous to that of Example 1, except that 0.2 g of copper-I chloride is used instead of -30 CuO. Recrystallization from cyclohexane-toluene (2:1) gives 40.1 g of the title compound having a melting point of from 97-99C.
The procedure is analogous to that of Example 1, except that 0.2 g of copper-II chloride is used instead of CuO. There are obtained 49 g of the crude title compound having a melting point of 86~C.
The following examples illustrate the invention:
E X A M P L E
2-(4-Fluorophenoxy)-phenylacetic acid 34.1 g (0.2 mol) of 2-chlorophenylacetic acid, 22.4 g (0.2 mol) of 4-fluorophenol, 0.2 g of copper-II oxide and 52.2 g (0.375 mol) of anhydrous ground potash are refluxed in 580 ml of xylene for 2.5 hours under energetic stirring, while the water fo~med by the reaction is separated by azeotropic distillation. The reaction mixture is allowed to cool, decomposed with 400 ml of water and the aqueous phase is separated and acidified with concentrated hydro-chloric acid. The precipitate formed is filtered off and washed with water. Drying in vacuo at room temperature gives 46.55 g of the title compound having a melting point of from 96-97C.
.
The procedure is analogous to that of Example 1, except that 5.0 g of metallic copper is used instead of CuO. Isolation gives 46.1 g of the title compound having a melting point of from 92-94C.
.
The procedure is analogous to that of Example 1, except that 0.2 g of copper-II acetate is used instead of CuO. Isolation gives 45.9 g of the title compound having a melting point of from 95-96C.
_ A M P I, E 4 The procedure is analogous to that of Example 1, except that 0.2 g of copper-I chloride is used instead of -30 CuO. Recrystallization from cyclohexane-toluene (2:1) gives 40.1 g of the title compound having a melting point of from 97-99C.
The procedure is analogous to that of Example 1, except that 0.2 g of copper-II chloride is used instead of CuO. There are obtained 49 g of the crude title compound having a melting point of 86~C.
- 10 - HOE 82/F 012 The procedure is analogous to that of Example 1, except that mesitylene is used instead of xylene as the solvent and that metallic copper is used instead of CuO as a catalyst. Isolation following a reaction time of 1 and a quarter of an hour gives 51.3 -g of the title compound having a melting point of from 88-94C.
The procedure is analogous to that of Example 1, except that mesitylene is used instead of xylene as the solvent and that a Cu catalyst is omitted. Isolation follo-wing a reaction time of 5 hours ~ives 43.0 g of a compound having a melting point of from 48-55C and 61 % of which consisting of the title compound wanted and 38 % consisting of unreacted o-chlorophenylacetic acid.
- The procedure is analogous to that of Example 1, except that diethylene glycol dimethyl ether is used as the solvent and 5 g of metallic copper as the catalyst. Isola-tion gives the title compound in a yield of 10.1 ~.
E X A M P L E g 2-Fluro-10,11-dihydro-11 oxodibenz/ b,f 7 -oxepine 24.6 g (0.1 mol) of the 2-(4-fluorophenoxy)-phenyl-acetic acid prepared according to Example 1 are dissolved in 50 ml of 1.2-dichloroethane and heated until refluxing.
7.65 ml (0.105 mol) of thionyl chloride are dropped to the resultant solution within 15 minutes and the batch is refluxed for 1 hour, diluted with a further 50 ml of 1,2-dichloroethane and dropped at room temperature within 30 minutes to a suspension of 14.7 g ~0.11 mol) of aluminum chloride in 50 ml of dichloroethane. The batch is refluxed for 2 hours, allowed to cool and decomposed with 229 ml of ice water and 82 ml of concentrated hydrochloric acid.
The mixture is extracted twice with 150 ml of methylene chloride and the combined organic phases are washed twice with 90 ml of a 5 ~ NaOH solution~ The methylene chloride phases are dried, filtered and the solvent is evaporated in vacuo. Isolation gives 21.8 g of the crude title compound ~176Z65 ~ OE 82/F 012 having a melting point of from 78~84C, which, after re-crystallization from methanol, melts at 82-84C.
The procedure is analogous to that of Example 9, except that 15.0 g (0.11 mol) of zinc-II chloride are used instead of AlCl3. Isolation gives 23.2 g of the title compound having a melting point of from 80-90C.
E ~ A M P L E _ 11 The procedure is analogous to that of Example 9~
except that 100 ml of methylene chloride are used to obtain the acid chloride wanted and that the acid chloride solution is dropped to a suspension of 14~7 g (0.11 mol) of AlCl3 in 50 ml of methylene chloride.
-2-Fluoro-10,11-dihydro-11-oxodibenz/ b,f 7-oxepine 345 g of polyphosphoric acid are heated to 75-80C and 67.4 g (0.273 mol) of the 2-(4-fluorophenoxy)-phenylacetic acid prepared according to Example 1 are added in solid form. Upon complete addition, the product is stirred for 1 hour at 75-80C and 621 ml of ice water are added carefully to decompose the product. The precipitate obtained is filtered off, washed with water and dried. There are obtained 63.1 g of the title compound having a melting point of from 83-86C.
According to the procedure of Example 12 508 g of phosphoric acid are heated to 75-80C and a solution of 97.7 g ~0.4 mol) of 2-(4-fluoro phenoxy)-phenylacetic acid in 275 ml of methylene chloride is added dropwise within 15 minutes, while distilling off the methylene chloride.
Following this addition, the reaction mixture is stirred for one hour at 75-80C and the hot solution is added to 914 ml of ice water. Isolation gives 92.1 g of 2-fluoro-10,11-dihydro-11-oxodibenz/ b,f 7-oxepine having a melting point of from 82-85C.
2-Fluoro-10,11-dihydro-11-oxodibenz/ b,f 7-oxepine 34.1 g ~0.2 mol) of 2-chlorophenylacetic acid, 22.4 g i~176265 (0.2 mol) of 4-fluorophenol, 52.2 g (0.374 mol) of anhydrous ground potash and 0.2 g of copper-II oxide are refluxed for 2.5 hours in 580 ml of xylene, while the reaction water formed is separated by a~eotropic distilla-tion. The product is left to cool to room temperature anddecomposed with 100 ml of water. The alkaline aqueous phase is separated and 450 ml of methylene chloride are added and 450 ml of methylene chloride are added and form a bottom layer. About 70 ml of concentrated hydrochloric acid is added, the batch is stirred for a quarter of an nour, the methylene chloride phase is separated and added subsequently within 30 minutes at 75-80C to 250 g of polyphosphoric acid, while C~2Cl2 separates by distillation. Stirring is continued for 1 hour at 75-80C and the hot reaction solution is dropped into 500 ml of ice water. The precipi-tate is filtered off, washed with water and dried in vacuo.
There are obtained 44.1 g of the title compound having a melting point of from 77-83C.
The procedure is analogous to that of Example 1, except that mesitylene is used instead of xylene as the solvent and that a Cu catalyst is omitted. Isolation follo-wing a reaction time of 5 hours ~ives 43.0 g of a compound having a melting point of from 48-55C and 61 % of which consisting of the title compound wanted and 38 % consisting of unreacted o-chlorophenylacetic acid.
- The procedure is analogous to that of Example 1, except that diethylene glycol dimethyl ether is used as the solvent and 5 g of metallic copper as the catalyst. Isola-tion gives the title compound in a yield of 10.1 ~.
E X A M P L E g 2-Fluro-10,11-dihydro-11 oxodibenz/ b,f 7 -oxepine 24.6 g (0.1 mol) of the 2-(4-fluorophenoxy)-phenyl-acetic acid prepared according to Example 1 are dissolved in 50 ml of 1.2-dichloroethane and heated until refluxing.
7.65 ml (0.105 mol) of thionyl chloride are dropped to the resultant solution within 15 minutes and the batch is refluxed for 1 hour, diluted with a further 50 ml of 1,2-dichloroethane and dropped at room temperature within 30 minutes to a suspension of 14.7 g ~0.11 mol) of aluminum chloride in 50 ml of dichloroethane. The batch is refluxed for 2 hours, allowed to cool and decomposed with 229 ml of ice water and 82 ml of concentrated hydrochloric acid.
The mixture is extracted twice with 150 ml of methylene chloride and the combined organic phases are washed twice with 90 ml of a 5 ~ NaOH solution~ The methylene chloride phases are dried, filtered and the solvent is evaporated in vacuo. Isolation gives 21.8 g of the crude title compound ~176Z65 ~ OE 82/F 012 having a melting point of from 78~84C, which, after re-crystallization from methanol, melts at 82-84C.
The procedure is analogous to that of Example 9, except that 15.0 g (0.11 mol) of zinc-II chloride are used instead of AlCl3. Isolation gives 23.2 g of the title compound having a melting point of from 80-90C.
E ~ A M P L E _ 11 The procedure is analogous to that of Example 9~
except that 100 ml of methylene chloride are used to obtain the acid chloride wanted and that the acid chloride solution is dropped to a suspension of 14~7 g (0.11 mol) of AlCl3 in 50 ml of methylene chloride.
-2-Fluoro-10,11-dihydro-11-oxodibenz/ b,f 7-oxepine 345 g of polyphosphoric acid are heated to 75-80C and 67.4 g (0.273 mol) of the 2-(4-fluorophenoxy)-phenylacetic acid prepared according to Example 1 are added in solid form. Upon complete addition, the product is stirred for 1 hour at 75-80C and 621 ml of ice water are added carefully to decompose the product. The precipitate obtained is filtered off, washed with water and dried. There are obtained 63.1 g of the title compound having a melting point of from 83-86C.
According to the procedure of Example 12 508 g of phosphoric acid are heated to 75-80C and a solution of 97.7 g ~0.4 mol) of 2-(4-fluoro phenoxy)-phenylacetic acid in 275 ml of methylene chloride is added dropwise within 15 minutes, while distilling off the methylene chloride.
Following this addition, the reaction mixture is stirred for one hour at 75-80C and the hot solution is added to 914 ml of ice water. Isolation gives 92.1 g of 2-fluoro-10,11-dihydro-11-oxodibenz/ b,f 7-oxepine having a melting point of from 82-85C.
2-Fluoro-10,11-dihydro-11-oxodibenz/ b,f 7-oxepine 34.1 g ~0.2 mol) of 2-chlorophenylacetic acid, 22.4 g i~176265 (0.2 mol) of 4-fluorophenol, 52.2 g (0.374 mol) of anhydrous ground potash and 0.2 g of copper-II oxide are refluxed for 2.5 hours in 580 ml of xylene, while the reaction water formed is separated by a~eotropic distilla-tion. The product is left to cool to room temperature anddecomposed with 100 ml of water. The alkaline aqueous phase is separated and 450 ml of methylene chloride are added and 450 ml of methylene chloride are added and form a bottom layer. About 70 ml of concentrated hydrochloric acid is added, the batch is stirred for a quarter of an nour, the methylene chloride phase is separated and added subsequently within 30 minutes at 75-80C to 250 g of polyphosphoric acid, while C~2Cl2 separates by distillation. Stirring is continued for 1 hour at 75-80C and the hot reaction solution is dropped into 500 ml of ice water. The precipi-tate is filtered off, washed with water and dried in vacuo.
There are obtained 44.1 g of the title compound having a melting point of from 77-83C.
Claims (3)
OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of a compound of the formula II
II
wherein X and Y are identical or different from each other and each denote hydrogen, halogen, trifluoromethyl, C1-C6-alkoxy, C1-C6-alkyl, C1-C6-alkylthio, C1-C6-alkylsulfonyl, C1-C6-alkyl-sulfinyl, amino or nitro, in which (a) a compound of the formula XI
XI
wherein X is as defined above is reacted with a phenol of the formula IV IV
wherein Y is as defined above, to give a compound of the formula IX
IX
wherein X and Y are as defined above and (b) the compound obtained is cyclized without isolation or after isolation.
II
wherein X and Y are identical or different from each other and each denote hydrogen, halogen, trifluoromethyl, C1-C6-alkoxy, C1-C6-alkyl, C1-C6-alkylthio, C1-C6-alkylsulfonyl, C1-C6-alkyl-sulfinyl, amino or nitro, in which (a) a compound of the formula XI
XI
wherein X is as defined above is reacted with a phenol of the formula IV IV
wherein Y is as defined above, to give a compound of the formula IX
IX
wherein X and Y are as defined above and (b) the compound obtained is cyclized without isolation or after isolation.
2. A process as claimed in claim 1 in which the compound of the formula XI is reacted with a phenol derivative of the formula IV under basic conditions in an inert solvent at an elevated temperature in the presence of a copper salt as a catalyst.
3. A process as claimed in claim 2 in which the temperature range is from 120 to 180°C.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19823203065 DE3203065A1 (en) | 1982-01-30 | 1982-01-30 | Process for the preparation of dibenzoxepinones |
| DEP3203065.7 | 1982-01-30 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1176265A true CA1176265A (en) | 1984-10-16 |
Family
ID=6154336
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000420425A Expired CA1176265A (en) | 1982-01-30 | 1983-01-28 | Process for the manufacture of dibenzoxepinones |
Country Status (3)
| Country | Link |
|---|---|
| CA (1) | CA1176265A (en) |
| DE (1) | DE3203065A1 (en) |
| ES (1) | ES8400741A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6602898B1 (en) | 1999-06-03 | 2003-08-05 | Nippon Suisan Kaisha, Ltd. | Tricyclic fused heterocycle compounds, process for preparing the same and use thereof |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997025985A1 (en) | 1996-01-19 | 1997-07-24 | Nippon Suisan Kaisha, Ltd. | Tracheal smooth muscle relaxant |
-
1982
- 1982-01-30 DE DE19823203065 patent/DE3203065A1/en not_active Withdrawn
-
1983
- 1983-01-28 CA CA000420425A patent/CA1176265A/en not_active Expired
- 1983-01-28 ES ES519344A patent/ES8400741A1/en not_active Expired
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6602898B1 (en) | 1999-06-03 | 2003-08-05 | Nippon Suisan Kaisha, Ltd. | Tricyclic fused heterocycle compounds, process for preparing the same and use thereof |
| US6700013B2 (en) | 1999-06-03 | 2004-03-02 | Nippon Suisan Kaisha, Ltd. | Tricyclic fused heterocycle compounds, process for preparing the same and use thereof |
| US7410997B2 (en) | 1999-06-03 | 2008-08-12 | Nippon Sulsan Kaisha, Ltd. | Tricyclic fused heterocycle compounds, process for preparing the same and use thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| ES519344A0 (en) | 1983-11-01 |
| DE3203065A1 (en) | 1983-08-04 |
| ES8400741A1 (en) | 1983-11-01 |
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