JPH0522709B2 - - Google Patents
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- Publication number
- JPH0522709B2 JPH0522709B2 JP27992984A JP27992984A JPH0522709B2 JP H0522709 B2 JPH0522709 B2 JP H0522709B2 JP 27992984 A JP27992984 A JP 27992984A JP 27992984 A JP27992984 A JP 27992984A JP H0522709 B2 JPH0522709 B2 JP H0522709B2
- Authority
- JP
- Japan
- Prior art keywords
- formula
- compound
- acid
- hours
- added
- 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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- 150000001875 compounds Chemical class 0.000 claims description 30
- WNZQDUSMALZDQF-UHFFFAOYSA-N 2-benzofuran-1(3H)-one Chemical compound C1=CC=C2C(=O)OCC2=C1 WNZQDUSMALZDQF-UHFFFAOYSA-N 0.000 claims description 10
- 239000003795 chemical substances by application Substances 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- 229910052783 alkali metal Inorganic materials 0.000 claims description 3
- 150000001340 alkali metals Chemical class 0.000 claims description 3
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 3
- 150000001342 alkaline earth metals Chemical class 0.000 claims description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- 239000000243 solution Substances 0.000 description 13
- 239000013078 crystal Substances 0.000 description 12
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 10
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 238000001953 recrystallisation Methods 0.000 description 6
- JHBANOQYSNAWKV-UHFFFAOYSA-N 2-[(4-ethoxycarbonylphenoxy)methyl]benzoic acid Chemical compound C1=CC(C(=O)OCC)=CC=C1OCC1=CC=CC=C1C(O)=O JHBANOQYSNAWKV-UHFFFAOYSA-N 0.000 description 5
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 239000005457 ice water Substances 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 229920000137 polyphosphoric acid Polymers 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 4
- MEFKFJOEVLUFAY-UHFFFAOYSA-N (2,2,2-trichloroacetyl) 2,2,2-trichloroacetate Chemical compound ClC(Cl)(Cl)C(=O)OC(=O)C(Cl)(Cl)Cl MEFKFJOEVLUFAY-UHFFFAOYSA-N 0.000 description 3
- -1 2-(3-methoxycarbonylphenoxy)methylbenzoic acid Chemical compound 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- UOHRIQREJJCNFJ-UHFFFAOYSA-N ethyl oxepine-2-carboxylate Chemical compound CCOC(=O)C1=CC=CC=CO1 UOHRIQREJJCNFJ-UHFFFAOYSA-N 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 239000012264 purified product Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- QPFMBZIOSGYJDE-UHFFFAOYSA-N 1,1,2,2-tetrachloroethane Chemical compound ClC(Cl)C(Cl)Cl QPFMBZIOSGYJDE-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 239000002841 Lewis acid Substances 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- 239000005018 casein Substances 0.000 description 2
- BECPQYXYKAMYBN-UHFFFAOYSA-N casein, tech. Chemical compound NCCCCC(C(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(CC(C)C)N=C(O)C(CCC(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(C(C)O)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(COP(O)(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(N)CC1=CC=CC=C1 BECPQYXYKAMYBN-UHFFFAOYSA-N 0.000 description 2
- 235000021240 caseins Nutrition 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- MNLMJRBQDBRSJQ-UHFFFAOYSA-N ethyl 11-oxo-6h-benzo[c][1]benzoxepine-2-carboxylate Chemical compound O1CC2=CC=CC=C2C(=O)C2=CC(C(=O)OCC)=CC=C21 MNLMJRBQDBRSJQ-UHFFFAOYSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 150000007517 lewis acids Chemical class 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- YKUCHDXIBAQWSF-UHFFFAOYSA-N methyl 3-hydroxybenzoate Chemical compound COC(=O)C1=CC=CC(O)=C1 YKUCHDXIBAQWSF-UHFFFAOYSA-N 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- GRGCWBWNLSTIEN-UHFFFAOYSA-N trifluoromethanesulfonyl chloride Chemical compound FC(F)(F)S(Cl)(=O)=O GRGCWBWNLSTIEN-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- GGYVTHJIUNGKFZ-UHFFFAOYSA-N 1-methylpiperidin-2-one Chemical compound CN1CCCCC1=O GGYVTHJIUNGKFZ-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 150000004703 alkoxides Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 description 1
- 229910052921 ammonium sulfate Inorganic materials 0.000 description 1
- 235000011130 ammonium sulphate Nutrition 0.000 description 1
- 230000003266 anti-allergic effect Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- ZDYIDPMJNKZACE-UHFFFAOYSA-N ethyl 2-[(4-ethoxycarbonylphenoxy)methyl]benzoate Chemical compound C1=CC(C(=O)OCC)=CC=C1OCC1=CC=CC=C1C(=O)OCC ZDYIDPMJNKZACE-UHFFFAOYSA-N 0.000 description 1
- 239000004403 ethyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010228 ethyl p-hydroxybenzoate Nutrition 0.000 description 1
- 229940043351 ethyl-p-hydroxybenzoate Drugs 0.000 description 1
- NUVBSKCKDOMJSU-UHFFFAOYSA-N ethylparaben Chemical compound CCOC(=O)C1=CC=C(O)C=C1 NUVBSKCKDOMJSU-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229940127554 medical product Drugs 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- WWHKMISTXGWOEC-UHFFFAOYSA-N methyl oxepine-3-carboxylate Chemical compound COC(=O)C1=COC=CC=C1 WWHKMISTXGWOEC-UHFFFAOYSA-N 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 235000007715 potassium iodide Nutrition 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
Landscapes
- Pyrane Compounds (AREA)
Description
【発明の詳細な説明】
産業上の利用分野
本発明は抗アレルギー作用を有する化合物の合
成中間体またはそ自体医療品の有効成分として有
用な式（）
〔式中、R1は低級アルキル基を表す。〕
で表されるジベンズ〔ｂ、ｅ〕オキセビン誘導体
〔以下、化合物（）という。他の式番号の化合
物についても同様〕の製造法に関する。DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to a synthetic intermediate for a compound having an antiallergic effect or a compound having the formula () useful as an active ingredient of a medical product per se. [In the formula, R 1 represents a lower alkyl group. ] Dibenz[b,e]oxebine derivative represented by [hereinafter referred to as compound ()]. The same applies to compounds with other formula numbers].
従来の技術
従来、化合物（）の製造法は米国特許第
4282365号等に開示されている。しかしながら、
これらの製造法は多数の工程を要し、収率も低い
ものであつた。Conventional technology Previously, the method for producing compound () was disclosed in U.S. Patent No.
It is disclosed in No. 4282365 etc. however,
These production methods required a large number of steps and had low yields.
発明が解決しようとする問題点
従来法に比べ短工程で収率よく化合物（）を
製造する方法が見出された。Problems to be Solved by the Invention A method for producing compound () in a shorter process and with higher yield than conventional methods has been discovered.
問題点を解決するための手段
本発明はフタリドと式（）
〔式中、R1は低級アルキル基を表し、Ｍはアル
カリ金属あるいはアルカリ土類金属を表す。〕
で表される化合物とを反応させた後、酸を加えて
式（）
〔式中、R1は前記と同意義を表す。〕
で表される化合物を得、ついで式（）で表され
る化合物と縮合剤とを反応させることを特徴とす
る化合物（）の製造法に関する。Means for solving the problems The present invention combines phthalide and the formula () [In the formula, R 1 represents a lower alkyl group, and M represents an alkali metal or an alkaline earth metal. ] After reacting with the compound represented by the formula (), an acid is added to form the formula (). [In the formula, R 1 represents the same meaning as above. ] The present invention relates to a method for producing a compound (), which comprises obtaining a compound represented by the formula (2), and then reacting the compound represented by the formula (2) with a condensing agent.
次に本発明についてさらに詳しく説明する。 Next, the present invention will be explained in more detail.
式（）〜（）の定義中、低級アルキル基と
しては炭素数１〜６のアルキル基、例えばメチル
基、エチル基、プロピル基等があげられる。アル
カリ金属としては、例えばリチウム、ナトリウ
ム、カリウム等があげられる。アルカリ土類金属
としては、例えばマグネシウム、カルシウム等が
あげられる。本発明で使用する縮合剤としては無
水トリフルオロ酢酸、無水トリクロロ酢酸、無水
トリフルオロメタンスルホン酸、トリフルオロメ
タンスルホニルクロリド等あるいはポリリン酸等
が用いられる。 In the definitions of formulas () to (), examples of lower alkyl groups include alkyl groups having 1 to 6 carbon atoms, such as methyl, ethyl, and propyl groups. Examples of alkali metals include lithium, sodium, and potassium. Examples of alkaline earth metals include magnesium and calcium. The condensing agent used in the present invention includes trifluoroacetic anhydride, trichloroacetic anhydride, trifluoromethanesulfonic anhydride, trifluoromethanesulfonyl chloride, polyphosphoric acid, and the like.
本発明の製造法においては、まず、化合物
（）と１〜２当量のフタリドとを無溶媒で、も
しくはＮ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−
ジメチルアセトアミド、ジメチルスルホキシド、
ヘキサメチルホスホリツクトリアミド等の不活性
溶媒中、必要に応じ水溶性の塩、例えば塩化ナト
リウム、塩化カリウム、臭化ナトリウム、臭化カ
リウム、ヨウ化ナトリウム、ヨウ化カリウム、塩
化アンモニウム、硫酸アンモニウム等を適量存在
させて、室温から200℃までの適宜な温度で、好
ましくは100〜180℃の温度で２〜12時間反応させ
た後、酸、例えば塩酸、硫酸、硝酸、リン酸等の
鉱酸、あるいはギ酸、酢酸等の有機酸を加えて中
和して化合物（）を得る。 In the production method of the present invention, first, compound () and 1 to 2 equivalents of phthalide are mixed in a solvent-free solution or in N,N-dimethylformamide, N,N-
dimethylacetamide, dimethyl sulfoxide,
In an inert solvent such as hexamethylphosphoric triamide, water-soluble salts such as sodium chloride, potassium chloride, sodium bromide, potassium bromide, sodium iodide, potassium iodide, ammonium chloride, ammonium sulfate, etc. are added as necessary. After reacting for 2 to 12 hours at a suitable temperature from room temperature to 200°C, preferably at a temperature of 100 to 180°C, an acid such as a mineral acid such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, Alternatively, the compound () is obtained by neutralizing by adding an organic acid such as formic acid or acetic acid.
ついで、縮合剤として無水トリフルオロ酢酸、
無水トリクロロ酢酸、無水トリフルオロメタンス
ルホン酸、トリフルオロメタンスルホニルクロリ
ド等を用いる場合には化合物（）と１〜1.5当
量の縮合剤とを塩化メチレン、クロロホルム、四
塩化炭素、ジクロロエタン、テトラクロロエタン
等の不活性溶媒中、０〜100℃もしくは０℃から
用いた溶媒の沸点の間の適宜な温度で30分〜３時
間反応させた後、さらに必要に応じ触媒量のルイ
ス酸、例えば三フツ化ホウ素エチルエーテル複合
体、四塩化チタン、四塩化スズ、塩化アルミニウ
ム等を加え、同温度で30分〜72時間反応させるこ
とにより化合物（）を得る。また、上記でルイ
ス酸をあらかじめ縮合剤と同時に加えて同温度で
30分〜３時間反応させることによつても化合物
（）を得ることができる。 Then, trifluoroacetic anhydride as a condensing agent,
When using trichloroacetic anhydride, trifluoromethanesulfonic anhydride, trifluoromethanesulfonyl chloride, etc., compound () and 1 to 1.5 equivalents of a condensing agent are mixed in an inert solution such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, tetrachloroethane, etc. After reacting in a solvent at an appropriate temperature between 0 and 100°C or 0°C and the boiling point of the solvent used for 30 minutes to 3 hours, if necessary, a catalytic amount of Lewis acid, such as boron trifluoride ethyl ether, is added. Compound () is obtained by adding the complex, titanium tetrachloride, tin tetrachloride, aluminum chloride, etc., and reacting at the same temperature for 30 minutes to 72 hours. In addition, in the above procedure, the Lewis acid was added in advance at the same time as the condensing agent, and the mixture was heated at the same temperature.
Compound () can also be obtained by reacting for 30 minutes to 3 hours.
また、縮合剤としてポリリン酸等を用いる場合
には化合物（）と化合物（）の重量に対して
１〜20倍の間の適宜な縮合剤とを必要に応じスル
ホラン、Ｎ−メチルピペリドン、Ｎ，Ｎ−ジメチ
ルホルムアミド等の非プロトン性極性溶倍を加え
て、室温から200℃までの適宜な温度、好ましく
は60〜150℃で２〜６時間反応させることにより
化合物（）を得るこができる。 In addition, when polyphosphoric acid or the like is used as a condensing agent, compound () and an appropriate condensing agent in an amount of 1 to 20 times the weight of compound () may be added as necessary, such as sulfolane, N-methylpiperidone, N,N Compound () can be obtained by adding an aprotic polar solvent such as dimethylformamide and reacting at an appropriate temperature from room temperature to 200°C, preferably 60 to 150°C for 2 to 6 hours.
上記各反応の目的物（中間体も含む）の反応液
から単離精製は過、有機溶媒、例えば酢酸エチ
ルによる抽出、濃縮、蒸溜、再結晶、カラムクロ
マトグラフイー、乾燥等の公知の手法により行う
ことができる。また、出発原料として用いられる
化合物（）は式（）
〔式中、R1は前記と同意義を表す〕
で表される化合物とナトリウムメトキシドあるい
はナトリウムエトキシド等の金属アルコキシドと
をメタノール、エタノール等の溶媒中で反応させ
た後、溶媒を留去する等の方法により容易に得る
ことができる。 The target products (including intermediates) of each of the above reactions are isolated and purified from the reaction solution by known methods such as filtration, extraction with organic solvents such as ethyl acetate, concentration, distillation, recrystallization, column chromatography, and drying. It can be carried out. In addition, the compound () used as a starting material has the formula () [In the formula, R 1 represents the same meaning as above] After reacting the compound represented by and a metal alkoxide such as sodium methoxide or sodium ethoxide in a solvent such as methanol or ethanol, the solvent is distilled off. It can be easily obtained by methods such as.
次に本発明の実施例を示す。 Next, examples of the present invention will be shown.
実施例 １
ｐ−ヒドロキシ安息香酸エチルのナトリウム塩
376.3ｇ、フタリド402.4ｇおよび塩化ナトリウム
200ｇを150℃で６時間撹拌する。反応終了後、室
温まで冷却した後、10％酢酸水溶液４を加え、
室温で一晩放置する。室温で３時間撹拌した後、
結晶を別する。結晶に水６を加え、室温で30
分間撹拌した後、結晶を別する。結晶にトルエ
ン３を加え室温で１時間撹拌を行い、結晶を
別後、減圧加熱乾燥することにより、２−（４−
エトキシカルボニルフエノキシ）メチル安息香酸
413.2ｇを得る。Example 1 Sodium salt of ethyl p-hydroxybenzoate
376.3g, phthalide 402.4g and sodium chloride
Stir 200g at 150°C for 6 hours. After the reaction is complete, cool to room temperature, add 10% acetic acid aqueous solution 4,
Leave at room temperature overnight. After stirring at room temperature for 3 hours,
Separate the crystals. Add 6 parts of water to the crystals and let it cool for 30 minutes at room temperature.
After stirring for a minute, separate the crystals. Add 3 toluene to the crystals, stir at room temperature for 1 hour, separate the crystals, and heat dry under reduced pressure to obtain 2-(4-
Ethoxycarbonylphenoxy)methylbenzoic acid
Obtain 413.2g.
IR（KBr錠剤）：3400、1700、1610、1260、1235
cm-1
NMR（CDCl3＋DMSO−d6、δppm）：1.42（ｔ、
3H）、4.36（ｑ、2H）、5.55（ｓ、2H）、6.91−
8.20（ｍ、8H）
このようにして得られた２−（４−エトキシカ
ルボニルフエノキシ）メチル安息香酸412.0ｇを
塩化メチレン5.0に懸濁させ、無水トリフルオ
ロ酢酸266.0ｇを加え、室温で１時間撹拌した後、
三フツ化ホウ素エチルエーテル複合体19.4ｇを加
え室温で２時間撹拌する。反応液を氷水中に注
ぎ、分液後、有機層を希カセインソーダ水溶液、
水で洗つた後、無水硫酸マグネシウムで乾燥し、
減圧下に濃縮し11−オキソジベンズ〔ｂ、ｅ〕オ
キセピン−２−カルボン酸エチル352.9ｇを白色
結晶として得る。IR (KBr tablets): 3400, 1700, 1610, 1260, 1235
cm -1 NMR (CDCl 3 + DMSO-d 6 , δppm): 1.42 (t,
3H), 4.36 (q, 2H), 5.55 (s, 2H), 6.91−
8.20 (m, 8H) 412.0 g of 2-(4-ethoxycarbonylphenoxy)methylbenzoic acid thus obtained was suspended in 5.0 g of methylene chloride, 266.0 g of trifluoroacetic anhydride was added, and 1 After stirring for an hour,
Add 19.4 g of boron trifluoride ethyl ether complex and stir at room temperature for 2 hours. The reaction solution was poured into ice water, and after separation, the organic layer was diluted with a dilute casein soda aqueous solution,
After washing with water, drying with anhydrous magnesium sulfate,
Concentration under reduced pressure yielded 352.9 g of ethyl 11-oxodibenz[b,e]oxepin-2-carboxylate as white crystals.
融点：106.5〜107℃（イソプロピルエーテルより
再結晶）
IR（KBr錠剤）：1710、1650、1610、1250、1010
cm-1
NMR（CDCl3、δppm）：1.38（ｔ、3H）、4.34（ｑ、
2H）、5.13（ｓ、2H）、6.95（ｄ、1H）、7.12−
8.10（ｍ、5H）、8.76（d.1H）
実施例 ２
実施例１と同様な方法によりｍ−ヒドロキシ安
息香酸メチルのナトリウム塩5.7ｇとフタリド6.6
ｇから、２−（３−メトキシカルボニルフエノキ
シ）メチル安息香酸3.1ｇを得る。Melting point: 106.5-107℃ (recrystallized from isopropyl ether) IR (KBr tablet): 1710, 1650, 1610, 1250, 1010
cm -1 NMR (CDCl 3 , δppm): 1.38 (t, 3H), 4.34 (q,
2H), 5.13 (s, 2H), 6.95 (d, 1H), 7.12−
8.10 (m, 5H), 8.76 (d.1H) Example 2 5.7 g of sodium salt of methyl m-hydroxybenzoate and 6.6 g of phthalide were prepared in the same manner as in Example 1.
3.1 g of 2-(3-methoxycarbonylphenoxy)methylbenzoic acid are obtained from g.
IR（KBr錠剤）：3150、1690、1590、1230、1045
cm-1
このようにして得られた２−（３−メトキシカ
ルボニルフエノキシ）メチル安息香酸2.0ｇを塩
化メチレン50mlに懸濁させ、無水トリフルオロ酢
酸1.7ｇを加え室温で４時間撹拌させた後、三フ
ツ化ホウ素エチルエーテル複合体0.1ｇを加え、
10時間還流させる。冷却後反応液を氷水にあけ、
分液した後、有機層を希カセインソーダ水溶液、
水で洗つた後、無水硫酸マグネシウムで乾燥し減
圧下に濃縮を行い、11−オキソジベンズ〔ｂ、
ｅ〕オキセピン−３−カルボン酸メチル0.45ｇを
得る。IR (KBr tablets): 3150, 1690, 1590, 1230, 1045
cm -1 2.0 g of 2-(3-methoxycarbonylphenoxy)methylbenzoic acid thus obtained was suspended in 50 ml of methylene chloride, 1.7 g of trifluoroacetic anhydride was added, and the mixture was stirred at room temperature for 4 hours. After that, add 0.1g of boron trifluoride ethyl ether complex,
Reflux for 10 hours. After cooling, pour the reaction solution into ice water.
After separation, the organic layer was added to a dilute casein soda aqueous solution.
After washing with water, drying with anhydrous magnesium sulfate and concentrating under reduced pressure, 11-oxodibenz [b,
e] Obtain 0.45 g of methyl oxepin-3-carboxylate.
IR（KBr錠剤）：1680、1625、1435、1290cm-1
NMR（CDCl3、δppm）：3.87（ｓ、3H）、5.13（ｓ、
2H）、7.01−8.33（ｍ、7H）
実施例 ３
実施例１で得られる２−（４−エトキシカルボ
ニルフエノキシ）メチル安息香酸エチル1.5ｇを
塩化メチレン25mlに懸濁させ、無水トリフルオロ
メタンスルホン酸1.7ｇを加え、室温で１時間撹
拌する。三フツ化ホウ素エチルエーテル複合体
0.1ｇを加え10時間還流する。反応液を1N−水酸
化ナトリウム水溶液ついで水で洗い、無水硫酸ナ
トリウムで乾燥後、減圧下に濃縮を行う。得られ
た粗結晶をイソプロピルエーテルより再結晶精製
を行い、11−オキソ−6.11−ジヒドロジベンズ
〔ｂ、ｅ〕オキセピン−２−カルボン酸エチル0.5
ｇを得る。このものの物理化学的性質は実施例１
でられた化合物と一致する。IR (KBr tablet): 1680, 1625, 1435, 1290 cm -1 NMR (CDCl 3 , δppm): 3.87 (s, 3H), 5.13 (s,
2H), 7.01-8.33 (m, 7H) Example 3 1.5 g of ethyl 2-(4-ethoxycarbonylphenoxy)methylbenzoate obtained in Example 1 was suspended in 25 ml of methylene chloride, and anhydrous trifluoromethanesulfone was added. Add 1.7 g of acid and stir at room temperature for 1 hour. Boron trifluoride ethyl ether complex
Add 0.1 g and reflux for 10 hours. The reaction solution was washed with a 1N aqueous sodium hydroxide solution and then with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude crystals were purified by recrystallization from isopropyl ether to obtain 0.5 ethyl 11-oxo-6.11-dihydrodibenz[b,e]oxepin-2-carboxylate.
get g. The physicochemical properties of this product are shown in Example 1.
It matches the compound found.
実施例 ４
実施例１で得られる２−（４−エトキシカルボ
ニルフエノキシ）メチル安息香酸3.0ｇを塩化メ
チレン70mlに懸濁させ、無水トリクロロ酢酸4.6
ｇを加え室温で１時間半撹拌する。さらに三フツ
化ホウ素エチルエーテル複合体0.1ｇを加え室温
で一晩撹拌する。反応液を氷水中に注ぎ、振とう
後、分液した水層を棄却する。有機層を1N−水
酸化ナトリウム水溶液、ついで水で洗い、無水硫
酸ナトリウムで乾燥後、減圧下に濃縮を行い、11
−オキソ−６，11−ジヒドロジベンズ〔ｂ、ｅ〕
オキセピン−２−カルボン酸エチルの粗結晶2.8
ｇを得る。粗結晶をイソプロピルエーテルより再
結晶精製を行い精製品2.1ｇを得る。このものの
物理化学的性質は実施例１で得られた化合物のも
のと一致した。Example 4 3.0 g of 2-(4-ethoxycarbonylphenoxy)methylbenzoic acid obtained in Example 1 was suspended in 70 ml of methylene chloride, and 4.6 g of trichloroacetic anhydride was suspended in 70 ml of methylene chloride.
g and stirred at room temperature for 1.5 hours. Furthermore, 0.1 g of boron trifluoride ethyl ether complex was added and stirred overnight at room temperature. Pour the reaction solution into ice water, shake it, and then discard the separated aqueous layer. The organic layer was washed with a 1N aqueous sodium hydroxide solution and then with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
-oxo-6,11-dihydrodibenz [b, e]
Crude crystals of ethyl oxepin-2-carboxylate 2.8
get g. The crude crystals are purified by recrystallization from isopropyl ether to obtain 2.1 g of purified product. The physicochemical properties of this product were consistent with those of the compound obtained in Example 1.
実施例 ５
実施例１で得られる２−（４−エトキシカルニ
ルフエノキシ）メチル安息香酸3.0ｇを１，１，
２，２−テトラクロルエタン70mlに懸濁させ、無
水トリフルオロ酢酸2.5ｇを加え20時間加熱還流
を行う。放冷後、反応液を1N−水酸化ナトリウ
ム水溶液、ついで水で洗い、無水硫酸ナトリウム
で乾燥後、減圧下に濃縮を行う。得られた粗結晶
をイソプロピルエーテルから再結晶精製を行い、
11−オキソ−６，11−ジヒドロジベンズ〔ｂ、
ｅ〕オキセピン−２−カルボン酸エチル0.7ｇを
得る。このものの物理化学的性質は実施例１で得
られた化合物のものと一致した。Example 5 3.0 g of 2-(4-ethoxycarylphenoxy)methylbenzoic acid obtained in Example 1 was mixed with 1,1,
Suspend in 70 ml of 2,2-tetrachloroethane, add 2.5 g of trifluoroacetic anhydride, and heat under reflux for 20 hours. After cooling, the reaction solution was washed with a 1N aqueous sodium hydroxide solution and then with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude crystals were purified by recrystallization from isopropyl ether,
11-oxo-6,11-dihydrodibenz [b,
e] Obtain 0.7 g of ethyl oxepine-2-carboxylate. The physicochemical properties of this product were consistent with those of the compound obtained in Example 1.
実施例 ６
実施例１で得られる２−（４−エトキシカルボ
ニルフエノキシ）メチル安息香酸2.0ｇにポリリ
ン酸20.0ｇとスルホラン20.0ｇを加え、80〜90℃
で３時間加熱撹拌を行う。反応混合物を氷水に加
え酢酸エチルで抽出を行う。有機層を水、飽和重
ソウ水、水、飽和食塩水で洗い、無水硫酸ナトリ
ウムで乾燥後、減圧下に濃縮を行い、11−オキソ
−６，11−ジヒドロジベンズ〔ｂ、ｅ〕オキセピ
ン−２−カルボン酸エチルの粗結晶1.2ｇを得る。
イソプロピルエーテルより再結晶精製を行い、
0.4ｇの精製品を得る。このものの物理化学的性
質は実施例１で得られた化合物のものと一致し
た。Example 6 20.0 g of polyphosphoric acid and 20.0 g of sulfolane were added to 2.0 g of 2-(4-ethoxycarbonylphenoxy)methylbenzoic acid obtained in Example 1, and the mixture was heated at 80 to 90°C.
Heat and stir for 3 hours. The reaction mixture was added to ice water and extracted with ethyl acetate. The organic layer was washed with water, saturated sodium chloride solution, water, and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 11-oxo-6,11-dihydrodibenz[b,e]oxepin- 1.2 g of crude crystals of ethyl 2-carboxylate were obtained.
Perform recrystallization purification from isopropyl ether,
Obtain 0.4g of purified product. The physicochemical properties of this product were consistent with those of the compound obtained in Example 1.
実施例 ７
実施例１で得られる２−（４−エトキシカルボ
ニルフエノキシ）メチる安息香酸2.0ｇとポリリ
ン酸を80〜90℃で３時間加熱撹拌を行う。反応混
合物を氷水に和え、酢酸エチルで抽出を行う。有
機層を飽和重ソウ水、水、飽和食塩水で洗い、無
水硫酸ナトリウムで乾燥後減圧下に濃縮を行い、
11−オキソ−６，11−ジヒドロジベンズ〔ｂ、
ｅ〕オキセピン−２−カルボン酸エチルの粗結晶
1.0ｇを得る。イソプロピルエーテルより再結晶
精製を行い、精製品0.3ｇを得る。このものの物
理化学的性質は実施例１で得られた化合物のもの
と一致した。Example 7 2.0 g of 2-(4-ethoxycarbonylphenoxy)methylbenzoic acid obtained in Example 1 and polyphosphoric acid are heated and stirred at 80 to 90°C for 3 hours. The reaction mixture was mixed with ice water and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution, water, and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
11-oxo-6,11-dihydrodibenz [b,
e] Crude crystals of ethyl oxepine-2-carboxylate
Obtain 1.0g. Perform recrystallization purification from isopropyl ether to obtain 0.3 g of purified product. The physicochemical properties of this product were consistent with those of the compound obtained in Example 1.
発明の効果
本発明によつて従来法に比べて短工程で収率よ
く化合物（）が製造される。Effects of the Invention According to the present invention, the compound () can be produced in a shorter process and with higher yield than in conventional methods.
Claims (1)
カリ金属あるいはアルカリ土類金属を表す。〕 で表される化合物とを反応させた後、酸を加えて
中和して式（） 〔式中、R1は前記と同意義を表す。〕 で表される化合物を得、ついで式（）で表され
る化合物と縮合剤とを反応させることを特徴とす
る式（） 〔式中、R1は前記と同意義を表す。〕 で表される化合物の製造法。[Claims] 1. Phthalide and formula () [In the formula, R 1 represents a lower alkyl group, and M represents an alkali metal or an alkaline earth metal. ] After reacting with the compound represented by the formula (), an acid is added to neutralize it to form the formula (). [In the formula, R 1 represents the same meaning as above. ] Formula () characterized by obtaining a compound represented by formula () and then reacting the compound represented by formula () with a condensing agent. [In the formula, R 1 represents the same meaning as above. ] A method for producing a compound represented by
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP27992984A JPS61152673A (en) | 1984-12-26 | 1984-12-26 | Production of dibenzo(b,e)oxepine derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP27992984A JPS61152673A (en) | 1984-12-26 | 1984-12-26 | Production of dibenzo(b,e)oxepine derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS61152673A JPS61152673A (en) | 1986-07-11 |
| JPH0522709B2 true JPH0522709B2 (en) | 1993-03-30 |
Family
ID=17617877
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP27992984A Granted JPS61152673A (en) | 1984-12-26 | 1984-12-26 | Production of dibenzo(b,e)oxepine derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS61152673A (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4882351A (en) * | 1987-10-14 | 1989-11-21 | Roussel Uclaf | Tricyclic compounds |
| US4994463A (en) * | 1987-12-14 | 1991-02-19 | Kyowa Hakko Kogyo Co., Ltd. | Tricyclic thromboxane A2 antagonists |
| US4999363A (en) * | 1988-06-09 | 1991-03-12 | Kyowa Hakko Kogyo Co., Ltd. | Tricyclic compounds |
| US5242931A (en) * | 1988-06-09 | 1993-09-07 | Kyowa Hakko Kogyo Co., Ltd. | Tricyclic compounds as TXA2 antagonists |
| NZ596484A (en) | 2001-11-21 | 2013-05-31 | Millennium Pharm Inc | Chemokine receptor antagonists and methods of use thereof |
-
1984
- 1984-12-26 JP JP27992984A patent/JPS61152673A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS61152673A (en) | 1986-07-11 |
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