JP7424115B2 - Method for producing ester compounds - Google Patents
Method for producing ester compounds Download PDFInfo
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- JP7424115B2 JP7424115B2 JP2020040577A JP2020040577A JP7424115B2 JP 7424115 B2 JP7424115 B2 JP 7424115B2 JP 2020040577 A JP2020040577 A JP 2020040577A JP 2020040577 A JP2020040577 A JP 2020040577A JP 7424115 B2 JP7424115 B2 JP 7424115B2
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- oxepin
- dihydrodibenz
- acetic acid
- oxo
- butyl
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- 238000004519 manufacturing process Methods 0.000 title claims description 11
- -1 ester compounds Chemical class 0.000 title claims description 5
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 42
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 35
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 34
- QFGMXJOBTNZHEL-UHFFFAOYSA-N isoxepac Chemical compound O1CC2=CC=CC=C2C(=O)C2=CC(CC(=O)O)=CC=C21 QFGMXJOBTNZHEL-UHFFFAOYSA-N 0.000 claims description 34
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 claims description 17
- JBIMVDZLSHOPLA-LSCVHKIXSA-N olopatadine Chemical compound C1OC2=CC=C(CC(O)=O)C=C2C(=C/CCN(C)C)\C2=CC=CC=C21 JBIMVDZLSHOPLA-LSCVHKIXSA-N 0.000 claims description 16
- 229960004114 olopatadine Drugs 0.000 claims description 15
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 claims description 12
- MCTWTZJPVLRJOU-UHFFFAOYSA-N 1-methyl-1H-imidazole Chemical compound CN1C=CN=C1 MCTWTZJPVLRJOU-UHFFFAOYSA-N 0.000 claims description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 10
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- UUFGLFHAUFBCQT-UHFFFAOYSA-N 2-[11-[3-(dimethylamino)propyl]-11-hydroxy-6h-benzo[c][1]benzoxepin-2-yl]acetic acid Chemical compound C1OC2=CC=C(CC(O)=O)C=C2C(CCCN(C)C)(O)C2=CC=CC=C21 UUFGLFHAUFBCQT-UHFFFAOYSA-N 0.000 claims description 7
- 238000007257 deesterification reaction Methods 0.000 claims description 6
- NGPAITITALWALP-UHFFFAOYSA-M magnesium;n,n-dimethylpropan-1-amine;chloride Chemical compound [Mg+2].[Cl-].CN(C)CC[CH2-] NGPAITITALWALP-UHFFFAOYSA-M 0.000 claims description 6
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 claims description 5
- 238000006297 dehydration reaction Methods 0.000 claims description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- 230000018044 dehydration Effects 0.000 claims description 3
- BAZTVGDIMQAQBF-UHFFFAOYSA-N 2-(6-oxo-11h-benzo[c][1]benzoxepin-2-yl)acetic acid Chemical compound O1C(=O)C2=CC=CC=C2CC2=CC(CC(=O)O)=CC=C21 BAZTVGDIMQAQBF-UHFFFAOYSA-N 0.000 claims 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 45
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 30
- 239000000243 solution Substances 0.000 description 23
- 239000011259 mixed solution Substances 0.000 description 15
- 239000000203 mixture Substances 0.000 description 15
- 238000006243 chemical reaction Methods 0.000 description 13
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 239000012044 organic layer Substances 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Natural products CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 7
- 238000005886 esterification reaction Methods 0.000 description 7
- 239000013078 crystal Substances 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 238000003756 stirring Methods 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- 238000004445 quantitative analysis Methods 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 4
- LJQNMDZRCXJETK-UHFFFAOYSA-N 3-chloro-n,n-dimethylpropan-1-amine;hydron;chloride Chemical compound Cl.CN(C)CCCCl LJQNMDZRCXJETK-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 230000008034 disappearance Effects 0.000 description 2
- ZDGGJQMSELMHLK-UHFFFAOYSA-N m-Trifluoromethylhippuric acid Chemical compound OC(=O)CNC(=O)C1=CC=CC(C(F)(F)F)=C1 ZDGGJQMSELMHLK-UHFFFAOYSA-N 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- JBIMVDZLSHOPLA-UHFFFAOYSA-N 2-[11-[3-(dimethylamino)propylidene]-6H-benzo[c][1]benzoxepin-2-yl]acetic acid Chemical compound C1OC2=CC=C(CC(O)=O)C=C2C(=CCCN(C)C)C2=CC=CC=C21 JBIMVDZLSHOPLA-UHFFFAOYSA-N 0.000 description 1
- 208000035285 Allergic Seasonal Rhinitis Diseases 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- VQTUBCCKSQIDNK-UHFFFAOYSA-N Isobutene Chemical group CC(C)=C VQTUBCCKSQIDNK-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- ADCKLEHCNOWEEY-UHFFFAOYSA-M NCCC[Mg]Cl Chemical compound NCCC[Mg]Cl ADCKLEHCNOWEEY-UHFFFAOYSA-M 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 206010039085 Rhinitis allergic Diseases 0.000 description 1
- 208000024780 Urticaria Diseases 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 201000010105 allergic rhinitis Diseases 0.000 description 1
- 201000010435 allergic urticaria Diseases 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- MYTMXVHNEWBFAL-UHFFFAOYSA-L dipotassium;carbonate;hydrate Chemical compound O.[K+].[K+].[O-]C([O-])=O MYTMXVHNEWBFAL-UHFFFAOYSA-L 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 239000004210 ether based solvent Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000011282 treatment Methods 0.000 description 1
- 238000004065 wastewater treatment Methods 0.000 description 1
- 239000008096 xylene 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Pulmonology (AREA)
- Immunology (AREA)
- Epidemiology (AREA)
- Pyrane Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Description
本発明はエステル化合物の製造方法に関する。 The present invention relates to a method for producing an ester compound.
（Ｚ）－１１－（３’－ジメチルアミノプロピリデン）－６，１１－ジヒドロジベンズ［ｂ，ｅ］オキセピン－２－酢酸
は花粉症、アレルジー性鼻炎、蕁麻疹等のアレルギー性疾患に適用される有用な医薬化合物であり（特許文献１）、一般名のオロパタジンとして知られている。 is a useful pharmaceutical compound applied to allergic diseases such as hay fever, allergic rhinitis, and urticaria (Patent Document 1), and is known as the generic name olopatadine.
１１－オキソ－６，１１－ジヒドロジベンズ［ｂ，ｅ］オキセピン－２－酢酸のｔ－ブチルエステル
はオロパタジンの製造中間体として有用であることが知られている（特許文献２）。 is known to be useful as an intermediate for the production of olopatadine (Patent Document 2).
また、カルボン酸のｔ－ブチルエステル化反応をジメチルアミノピリジンの存在下でｔ－ブチルアルコールと二炭酸ジ－ｔ－ブチルとを使用して行えることが知られている（非特許文献１）。 It is also known that the t-butyl esterification reaction of carboxylic acid can be carried out using t-butyl alcohol and di-t-butyl dicarbonate in the presence of dimethylaminopyridine (Non-Patent Document 1).
特許文献２には、１１－オキソ－６，１１－ジヒドロジベンズ［ｂ，ｅ］オキセピン－２－酢酸
をｔ－ブチルアルコールと無水トリフルオロ酢酸とで又はイソブチレンとオキシ塩化リン等のリンハロゲン化物とでｔ－ブチルエステル化できることが記載されているが、無水トリフルオロ酢酸のような高価な試薬を用いる方法や排水処理が面倒なリンハロゲン化物を使用する方法は工業的な製法として十分なものではない。 It has been described that t-butyl esterification can be performed with t-butyl alcohol and trifluoroacetic anhydride or with isobutylene and a phosphorous halide such as phosphorus oxychloride, but using an expensive reagent such as trifluoroacetic anhydride. Methods using phosphorus halides, which require troublesome methods and wastewater treatment, are not sufficient as industrial production methods.
本発明は工業的に有利な１１－オキソ－６，１１－ジヒドロジベンズ［ｂ，ｅ］オキセピン－２－酢酸のｔ－ブチルエステルの製造方法を提供し、さらにはオロパタジンの製造方法を提供することを課題とする。 The present invention provides an industrially advantageous method for producing t-butyl ester of 11-oxo-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid, and further provides a method for producing olopatadine. That is the issue.
本発明によれば、１１－オキソ－６，１１－ジヒドロジベンズ［ｂ，ｅ］オキセピン－２－酢酸、ｔ－ブチルアルコール及び二炭酸ジ－ｔ－ブチルをジメチルアミノピリジンとトリエチルアミン、ピリジン、ジイソプロピルエチルアミン及びジメチルアニリンから選ばれる１種以上の塩基との存在下で反応させることにより、ｔ－ブチルエステルを製造することができる。また、ジメチルアミノピリジンの代わりにＮ－メチルイミダゾールを用いてもよい。 According to the invention, 11-oxo-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid, t-butyl alcohol and di-t-butyl dicarbonate are combined with dimethylaminopyridine and triethylamine, pyridine, diisopropyl T-butyl ester can be produced by reacting it in the presence of one or more bases selected from ethylamine and dimethylaniline. Furthermore, N-methylimidazole may be used instead of dimethylaminopyridine.
さらに、得られたｔ－ブチルエステルを３－ジメチルアミノプロピルマグネシウムクロリドと反応させて１１－ヒドロキシ－１１－（３’－ジメチルアミノプロピル）－６，１１－ジヒドロジベンズ［ｂ，ｅ］オキセピン－２－酢酸のｔ－ブチルエステル
を製造し、次いで脱水反応及び脱エステル化反応によりオロパタジンに導くことができる。 can be produced and then led to olopatadine by dehydration and deesterification reactions.
本発明のｔ－ブチルエステル化反応により、１１－オキソ－６，１１－ジヒドロジベンズ［ｂ，ｅ］オキセピン－２－酢酸のｔ－ブチルエステルを工業的に有利に製造することができる。 By the t-butyl esterification reaction of the present invention, t-butyl ester of 11-oxo-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid can be advantageously produced industrially.
以下、１１－オキソ－６，１１－ジヒドロジベンズ［ｂ，ｅ］オキセピン－２－酢酸のｔ－ブチルエステル化反応をより詳細に説明する。 The t-butyl esterification reaction of 11-oxo-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid will be described in more detail below.
ｔ－ブチルエステル化反応は通常、溶媒中で行われる。溶媒は、エステル化反応に不活性な溶媒であれば特に限定されるものではなく、トルエン、キシレン等の炭化水素溶媒、テトラヒドロフラン、ジエチルエーテル等のエーテル溶媒が好ましい。 The t-butyl esterification reaction is usually carried out in a solvent. The solvent is not particularly limited as long as it is inert to the esterification reaction, and preferred are hydrocarbon solvents such as toluene and xylene, and ether solvents such as tetrahydrofuran and diethyl ether.
１１－オキソ－６，１１－ジヒドロジベンズ［ｂ，ｅ］オキセピン－２－酢酸、ｔ－ブチルアルコール、二炭酸ジ－ｔ－ブチル、ジメチルアミノピリジン又はＮ－メチルイミダゾール、及び塩基（トリエチルアミン、ピリジン、ジイソプロピルエチルアミン又はジメチルアニリン）の混合順序は特に限定されないが、１１－オキソ－６，１１－ジヒドロジベンズ［ｂ，ｅ］オキセピン－２－酢酸、ｔ－ブチルアルコール及びジメチルアミノピリジン又はＮ－メチルイミダゾールと塩基との混合物に二炭酸ジ－ｔ－ブチルを滴下するのが好ましい。 11-oxo-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid, t-butyl alcohol, di-t-butyl dicarbonate, dimethylaminopyridine or N-methylimidazole, and bases (triethylamine, pyridine , diisopropylethylamine or dimethylaniline) is not particularly limited; Preferably, di-t-butyl dicarbonate is added dropwise to the mixture of imidazole and base.
ｔ－ブチルエステル化反応は通常２０～８０℃で行われ、４０～７０℃で行うのが好ましい。反応時間は通常１～１２時間である。 The t-butyl esterification reaction is usually carried out at 20 to 80°C, preferably 40 to 70°C. The reaction time is usually 1 to 12 hours.
用いられるｔ－ブチルアルコール及び二炭酸ジ－ｔ－ブチルの量は、１１－オキソ－６，１１－ジヒドロジベンズ［ｂ，ｅ］オキセピン－２－酢酸の１モルに対して通常各々、０．３～３．０モル及び０．9～１．５モルの割合である。また、ジメチルアミノピリジン又はＮ－メチルイミダゾール及び塩基の量は、１１－オキソ－６，１１－ジヒドロジベンズ［ｂ，ｅ］オキセピン－２－酢酸の１モルに対して通常各々、０．０２～１．０モル及び０．３～１．５モルの割合である。 The amounts of t-butyl alcohol and di-t-butyl dicarbonate used are usually 0.0000,000 per mole of 11-oxo-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid. The proportions are 3 to 3.0 moles and 0.9 to 1.5 moles. The amounts of dimethylaminopyridine or N-methylimidazole and the base are usually 0.02 to 0.02 to 1 mole of 11-oxo-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid. The ratio is 1.0 mol and 0.3 to 1.5 mol.
反応終了後は、例えば水を加えてトルエン等の有機溶媒で抽出、有機溶媒の留去などの通常の後処理を行うことで目的のｔ－ブチルエステルを得ることができる。また、必要により再結晶などの方法で精製することができる。 After the reaction is completed, the desired t-butyl ester can be obtained by performing usual post-treatments such as adding water, extraction with an organic solvent such as toluene, and distilling off the organic solvent. Further, if necessary, it can be purified by a method such as recrystallization.
次に、オロパタジンの製造方法を説明する。 Next, a method for producing olopatadine will be explained.
１１－オキソ－６，１１－ジヒドロジベンズ［ｂ，ｅ］オキセピン－２－酢酸ｔ－ブチルは３－ジメチルアミノプロピルマグネシウムクロリドと反応させることにより１１－ヒドロキシ－１１－（３’－ジメチルアミノプロピル）－６，１１－ジヒドロジベンズ［ｂ，ｅ］オキセピン－２－酢酸のｔ－ブチルエステルに導くことができる。 11-Oxo-6,11-dihydrodibenz[b,e]oxepin-2-t-butyl acetate is reacted with 3-dimethylaminopropylmagnesium chloride to form 11-hydroxy-11-(3'-dimethylaminopropyl )-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid t-butyl ester.
３－ジメチルアミノプロピルマグネシウムクロリドは、例えば、３－ジメチルアミノプロピルクロリド塩酸塩とマグネシウムとから通常のグリニア試薬の製造法に従って製造することができる。３－ジメチルアミノプロピルクロリドの使用量は、１１－オキソ－６，１１－ジヒドロジベンズ［ｂ，ｅ］オキセピン－２－酢酸ｔ－ブチルの１モルに対して、１～２モルの割合が好ましい。３－ジメチルアミノプロピルクロリドは、トルエンとテトラヒドロフランとの混合溶媒等の適当な溶媒に１０～４０％程度の濃度で溶解させた溶液として使用するのが好ましく、１１－オキソ－６，１１－ジヒドロジベンズ［ｂ，ｅ］オキセピン－２－酢酸ｔ－ブチルをテトラヒドロフラン等の不活性溶媒に溶解させた溶液中に徐々に滴下して添加することが好ましい。適下時の液温は－１０～３０℃程度が好ましい。 3-dimethylaminopropylmagnesium chloride can be produced, for example, from 3-dimethylaminopropyl chloride hydrochloride and magnesium according to a conventional Grignard reagent production method. The amount of 3-dimethylaminopropyl chloride used is preferably 1 to 2 moles per mole of 11-oxo-6,11-dihydrodibenz[b,e]oxepin-2-t-butyl acetate. . 3-Dimethylaminopropyl chloride is preferably used as a solution in a suitable solvent such as a mixed solvent of toluene and tetrahydrofuran at a concentration of about 10 to 40%. It is preferable to gradually add dropwise to a solution of benz[b,e]oxepin-2-t-butyl acetate dissolved in an inert solvent such as tetrahydrofuran. The temperature of the solution at the time of dropping is preferably about -10 to 30°C.
上記で得た１１－ヒドロキシ－１１－（３’－ジメチルアミノプロピル）－６，１１－ジヒドロジベンズ［ｂ，ｅ］オキセピン－２－酢酸のｔ－ブチルエステルは脱水反応により、（Ｚ）－１１－（３’－ジメチルアミノプロピリデン）－６，１１－ジヒドロジベンズ［ｂ，ｅ］オキセピン－２－酢酸のｔ－ブチルエステルに導くことができ、これを脱エステル化することでオロパタジンを製造することができる。 The t-butyl ester of 11-hydroxy-11-(3'-dimethylaminopropyl)-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid obtained above was dehydrated to (Z)- It can lead to t-butyl ester of 11-(3'-dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid, and deesterification of this leads to olopatadine. can be manufactured.
脱水反応と脱エステル化反応とは、例えば、濃度１～３５％程度の塩酸を１１－ヒドロキシ－１１－（３’－ジメチルアミノプロピル）－６，１１－ジヒドロジベンズ［ｂ，ｅ］オキセピン－２－酢酸のｔ－ブチルエステル１モルに対して１～５モル程度の割合で加え、２０～１００℃程度の温度で０．５～１０時間程度攪拌することにより同時に行うことができる。 The dehydration reaction and the deesterification reaction are, for example, hydrochloric acid with a concentration of about 1 to 35% mixed with 11-hydroxy-11-(3'-dimethylaminopropyl)-6,11-dihydrodibenz[b,e]oxepin- They can be simultaneously carried out by adding at a ratio of about 1 to 5 moles per mole of t-butyl ester of 2-acetic acid and stirring at a temperature of about 20 to 100°C for about 0.5 to 10 hours.
実施例１
１１－オキソ－６，１１－ジヒドロジベンズ［ｂ，ｅ］オキセピン－２－酢酸 １．００ｇ（０．００３７モル）、ｔ－ブチルアルコール ０．３６ｇ（０．００４８モル）、ジメチルアミノピリジン ０．０２３ｇ（０．０００２モル）、トリエチルアミン ０．３８ｇ（０．００３７モル）及び二炭酸ジ－ｔ－ブチル １．０６ｇ（０．００４８モル）をトルエン ８．６６ｇと室温で混合した。この混合液を５０℃に昇温し、５０℃で５時間攪拌した。この反応液をＨＰＬＣで定量分析したところ、１１－オキソ－６，１１－ジヒドロジベンズ［ｂ，ｅ］オキセピン－２－酢酸のｔ－ブチルエステルが７０％の収率で得られたことが確認された。
参考例
１１－オキソ－６，１１－ジヒドロジベンズ［ｂ，ｅ］オキセピン－２－酢酸 １．００ｇ（０．００３７モル）、ｔ－ブチルアルコール ０．４０ｇ（０．００５４モル）、ジメチルアミノピリジン０．０２２ｇ（０．０００２モル）及び二炭酸ジ－ｔ－ブチル １．０６ｇ（０．００４８モル）をトルエン ８．６６ｇと室温で混合した。この混合液を５０℃に昇温し、５０℃で５時間攪拌した。この反応液をＨＰＬＣで定量分析したところ、１１－オキソ－６，１１－ジヒドロジベンズ［ｂ，ｅ］オキセピン－２－酢酸のｔ－ブチルエステルが５１％の収率で得られたことが確認された。
実施例２
１１－オキソ－６，１１－ジヒドロジベンズ［ｂ，ｅ］オキセピン－２－酢酸 ２．００ｇ（０．００７５モル）、ｔ－ブチルアルコール １．１１ｇ（０．０１５モル）、ジメチルアミノピリジン ０．０９３ｇ（０．０００８モル）及びトリエチルアミン ０．７５ｇ（０．００７５モル）をトルエン ８．６６ｇと室温で混合し、４０℃に昇温した。この混合液中に二炭酸ジ－ｔ－ブチル １．７９ｇ（０．００８２モル）とトルエン ３．９０ｇとの混合液を４０℃で６．５時間かけて滴下し、滴下終了後、４０℃で２時間攪拌した。この反応液をＨＰＬＣで定量分析したところ、１１－オキソ－６，１１－ジヒドロジベンズ［ｂ，ｅ］オキセピン－２－酢酸のｔ－ブチルエステルが９５％の収率で得られたことが確認された。
実施例３～５
実施例２のトリエチルアミンの代わりにピリジン（実施例３）、ジイソプロピルエチルアミン（実施例４）、ジメチルアニリン（実施例５）をそれぞれ使用し、それ以外は実施例２と同様の方法で反応を行った。得られた１１－オキソ－６，１１－ジヒドロジベンズ［ｂ，ｅ］オキセピン－２－酢酸のｔ－ブチルエステルの収率は下表の通りであった。
11-oxo-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid 1.00 g (0.0037 mol), t-butyl alcohol 0.36 g (0.0048 mol), dimethylaminopyridine 0. 0.38 g (0.0037 mole) of triethylamine and 1.06 g (0.0048 mole) of di-t-butyl dicarbonate were mixed with 8.66 g of toluene at room temperature. This mixed solution was heated to 50°C and stirred at 50°C for 5 hours. Quantitative analysis of this reaction solution by HPLC confirmed that t-butyl ester of 11-oxo-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid was obtained with a yield of 70%. It was done.
Reference example 11-oxo-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid 1.00 g (0.0037 mol), t-butyl alcohol 0.40 g (0.0054 mol), dimethylaminopyridine 0.022 g (0.0002 mole) and 1.06 g (0.0048 mole) of di-t-butyl dicarbonate were mixed with 8.66 g of toluene at room temperature. This mixed solution was heated to 50°C and stirred at 50°C for 5 hours. Quantitative analysis of this reaction solution by HPLC confirmed that t-butyl ester of 11-oxo-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid was obtained in a yield of 51%. It was done.
Example 2
11-oxo-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid 2.00 g (0.0075 mol), t-butyl alcohol 1.11 g (0.015 mol), dimethylaminopyridine 0. 093 g (0.0008 mol) and triethylamine 0.75 g (0.0075 mol) were mixed with 8.66 g of toluene at room temperature, and the temperature was raised to 40°C. A mixture of 1.79 g (0.0082 mol) of di-t-butyl dicarbonate and 3.90 g of toluene was added dropwise to this mixture at 40°C over 6.5 hours. Stirred for 2 hours. Quantitative analysis of this reaction solution by HPLC confirmed that t-butyl ester of 11-oxo-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid was obtained with a yield of 95%. It was done.
Examples 3-5
Pyridine (Example 3), diisopropylethylamine (Example 4), and dimethylaniline (Example 5) were used in place of triethylamine in Example 2, and the reaction was otherwise carried out in the same manner as in Example 2. . The yield of the obtained t-butyl ester of 11-oxo-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid is shown in the table below.
実施例６
１１－オキソ－６，１１－ジヒドロジベンズ［ｂ，ｅ］オキセピン－２－酢酸 ２．００ｇ（０．００７５モル）、ｔ－ブチルアルコール １．１１ｇ（０．０１５モル）、Ｎ－メチルイミダゾール ０．０６１ｇ（０．０００７モル）及びトリエチルアミン ０．７５ｇ（０．００７５モル）をトルエン８．６６ｇと室温で混合し、５０℃に昇温した。
この混合液中に二炭酸ジ－ｔ－ブチル １．７９ｇ（０．００８２モル）とトルエン ３．９０ｇとの混合液を５０℃で６．５時間かけて滴下し、滴下終了後、５０℃で２時間攪拌した。この反応液をＨＰＬＣで定量分析したところ、１１－オキソ－６，１１－ジヒドロジベンズ［ｂ，ｅ］オキセピン－２－酢酸のｔ－ブチルエステルが９７％の収率で得られたことが確認された。
実施例７
１１－オキソ－６，１１－ジヒドロジベンズ［ｂ，ｅ］オキセピン－２－酢酸 ４０．００ｇ（０．１５モル）、ｔ－ブチルアルコール ２２．１０ｇ（０．３０モル）、Ｎ－メチルイミダゾール ６．１５ｇ（０．０７５モル）、及びトリエチルアミン ７．５４ｇ（０．０７５モル）をトルエン１７３．２０ｇに室温で混合し５５℃に昇温した。この混合液中に二炭酸ジ－ｔ－ブチル ３４．５０ｇ（０．１６モル）とトルエン ７７．９４ｇとの混合液を５５℃で７時間かけて滴下し、滴下終了後、５５℃で１．５時間攪拌した。この反応液を２２℃まで冷却した後、５％塩酸 １０８．６５ｇをこの反応液に滴下して３０分攪拌後、静置して有機層を分取した。有機層を１０％炭酸カリウム水 ７８．３０ｇで洗浄し、有機層 ３１４．５７ｇを分取した。有機層を減圧濃縮により１０９．２４ｇまで濃縮し、濃縮液に２－プロパノール １００．０１ｇを混合した。混合液を減圧濃縮により９５．３４ｇまで濃縮し、濃縮液に２－プロパノール１００．１０ｇを混合した。混合液を減圧濃縮により５６．５９ｇまで濃縮し、濃縮液に２－プロパノール３９．９３ｇを混合した。混合液を減圧濃縮により８９．０６ｇまで濃縮し、濃縮液に２－プロパノール ４８．９９ｇを混合した。混合液を５０℃まで昇温した後、４０℃まで冷却して、水 ２６．３１ｇをこの混合液に４０℃で２時間かけて滴下し、４０℃で２時間攪拌して結晶の析出を確認した。ここに水 ２６．３１ｇを４０℃で２時間かけて滴下し、４０℃で１時間攪拌した後、３．５時間かけて４０℃から７℃まで冷却し、７℃で１３．５時間攪拌した。このスラリー状の反応液を７℃でろ過して結晶を分取した。得られた結晶を７℃の２－プロパノール ４２．１３ｇと水 ２６．４０ｇとの混合液で洗浄後、減圧乾燥して１１－オキソ－６，１１－ジヒドロジベンズ［ｂ，ｅ］オキセピン－２－酢酸のｔ－ブチルエステル ４４．５５ｇ（０．１４モル）を収率９２％で得た。
実施例８
１１－オキソ－６，１１－ジヒドロジベンズ［ｂ，ｅ］オキセピン－２－酢酸 ２０．００ｇ（０．０７５モル）、ｔ－ブチルアルコール １１．０６ｇ（０．１５モル）、Ｎ－メチルイミダゾール ０．６１ｇ（０．００７５モル）、及びトリエチルアミン ７．５４ｇ（０．０７５モル）をトルエン８６．６５ｇに室温で混合し５５℃に昇温した。この混合液中に二炭酸ジ－ｔ－ブチル １７．２５ｇ（０．0７９モル）とトルエン ３８．９７ｇとの混合液を５５℃で７．５時間かけて滴下し、滴下終了後、５５℃で３時間攪拌した。この反応液を２８℃まで冷却した後、５％塩酸 ５９．９２ｇをこの反応液に滴下して３０分攪拌後、静置して有機層を分取した。有機層を５％炭酸水素ナトリウム水 １２７．７９ｇで洗浄し、有機層 １５２．８０ｇを分取した。有機層を減圧濃縮により４８．１１ｇまで濃縮し、濃縮液に２－プロパノール ４９．９９ｇを混合した。混合液を減圧濃縮により５０．９２ｇまで濃縮し、濃縮液に２－プロパノール５０．００ｇを混合した。混合液を減圧濃縮により４０．４６ｇまで濃縮し、濃縮液に２－プロパノール１９．９９ｇを混合した。混合液を減圧濃縮により４３．１７ｇまで濃縮し、濃縮液に２－プロパノール １９．９９ｇを混合した。混合液を５０℃まで昇温した後、４０℃まで冷却して、水 １３．１０ｇをこの混合液に４０℃で２時間かけて滴下し、４０℃で２時間攪拌して結晶の析出を確認した。ここに水 １３．１０ｇを４０℃で２時間かけて滴下し、４０℃で１時間攪拌した後、３．５時間かけて４０℃から７℃まで冷却し、７℃で１３時間攪拌した。このスラリー状の反応液を７℃でろ過して結晶を分取した。得られた結晶を７℃の２－プロパノール ２１．０６ｇと水 １３．２０ｇとの混合液で洗浄後、減圧乾燥して１１－オキソ－６，１１－ジヒドロジベンズ［ｂ，ｅ］オキセピン－２－酢酸のｔ－ブチルエステル ２２．６３ｇ（０．０７０モル）を収率９４％で得た。
実施例９
１１－オキソ－６，１１－ジヒドロジベンズ［ｂ，ｅ］オキセピン－２－酢酸のｔ－ブチルエステル ６．４９ｇ（０．０２モル）及びテトラヒドロフラン５０ｍｌの混合物に１５～２０℃で、３－ジメチルアミノプロピルマグネシウムクロリド０．０３モルを含有するトルエン（１５．４ｍｌ）／テトラヒドロフラン（１１．７ｍｌ）混合溶媒溶液を２．５時間かけて滴下した。滴下終了後、３０分間攪拌し、ＨＰＬＣで原料の消失を確認した。この反応液を、３０ｍｌの水と５．４ｇの酢酸との混合液に加えた後、２８％アンモニア水でｐＨを９．６にした。分液した有機層を１５％食塩水５０ｍｌで洗浄後、濃縮し、１１－ヒドロキシ－１１－（３’－ジメチルアミノプロピル）－６，１１－ジヒドロジベンズ［ｂ，ｅ］オキセピン－２－酢酸のｔ－ブチルエステルを９７．７％の収率で得た。
1Ｈ ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）
δ １．４１（ｓ，９Ｈ），１．４３－１．４５（ｍ，２Ｈ），１．９６（ｑ，Ｊ＝８．４Ｈｚ，１Ｈ），２．１９－２．２６（ｍ，２Ｈ），２．２６（ｓ，６Ｈ），３．２０（ｑ，Ｊ＝８．０Ｈｚ，１Ｈ），３．４８（ｓ，１Ｈ），５．０２（ｄ，Ｊ＝１５．６Ｈｚ，１Ｈ），５．４５（ｄ，Ｊ＝１５．６Ｈｚ，１Ｈ），６．８７（ｄ，Ｊ＝６．８Ｈｚ，１Ｈ），７．０３（ｄ，Ｊ＝７．６Ｈｚ，１Ｈ），７．１３－７．１６（ｍ，２Ｈ），７．２３（ｔ，Ｊ＝８．０Ｈｚ，２Ｈ），７．６７（ｄ，Ｊ＝２．０Ｈｚ，１Ｈ），８．０８（ｄ，Ｊ＝９．６Ｈｚ，１Ｈ）
実施例１０
１１－ヒドロキシ－１１－（３’－ジメチルアミノプロピル）－６，１１－ジヒドロジベンズ［ｂ，ｅ］オキセピン－２－酢酸のｔ－ブチルエステル ８．０４ｇ（０．０２モル）、３５％塩酸４．２ｇ（０．０４モル）及びトルエン１６．０ｍｌの混合物を１００℃で６時間攪拌し、ＨＰＬＣで原料の消失を確認し、オロパタジンが得られたことを確認した。
Example 6
11-oxo-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid 2.00 g (0.0075 mol), t-butyl alcohol 1.11 g (0.015 mol), N-methylimidazole 0 0.061 g (0.0007 mol) and 0.75 g (0.0075 mol) of triethylamine were mixed with 8.66 g of toluene at room temperature, and the temperature was raised to 50°C.
A mixture of 1.79 g (0.0082 mol) of di-t-butyl dicarbonate and 3.90 g of toluene was added dropwise to this mixture at 50°C over 6.5 hours. Stirred for 2 hours. Quantitative analysis of this reaction solution by HPLC confirmed that t-butyl ester of 11-oxo-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid was obtained with a yield of 97%. It was done.
Example 7
11-oxo-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid 40.00 g (0.15 mol), t-butyl alcohol 22.10 g (0.30 mol), N-methylimidazole 6 .15 g (0.075 mol) and 7.54 g (0.075 mol) of triethylamine were mixed with 173.20 g of toluene at room temperature, and the temperature was raised to 55°C. A mixed solution of 34.50 g (0.16 mol) of di-t-butyl dicarbonate and 77.94 g of toluene was added dropwise to this mixed solution at 55°C over 7 hours, and after completion of the dropwise addition, 1. Stirred for 5 hours. After cooling the reaction solution to 22° C., 108.65 g of 5% hydrochloric acid was added dropwise to the reaction solution, and after stirring for 30 minutes, the mixture was allowed to stand and the organic layer was separated. The organic layer was washed with 78.30 g of 10% potassium carbonate water, and 314.57 g of the organic layer was separated. The organic layer was concentrated under reduced pressure to 109.24 g, and 100.01 g of 2-propanol was mixed with the concentrated solution. The mixed solution was concentrated to 95.34 g by vacuum concentration, and 100.10 g of 2-propanol was mixed with the concentrated solution. The mixed solution was concentrated to 56.59 g by vacuum concentration, and 39.93 g of 2-propanol was mixed with the concentrated solution. The mixed solution was concentrated to 89.06 g by vacuum concentration, and 48.99 g of 2-propanol was mixed with the concentrated solution. After heating the mixed solution to 50°C, cool it to 40°C, drop 26.31 g of water to this mixed solution over 2 hours at 40°C, stir at 40°C for 2 hours, and confirm the precipitation of crystals. did. 26.31 g of water was added dropwise at 40°C over 2 hours, stirred at 40°C for 1 hour, cooled from 40°C to 7°C over 3.5 hours, and stirred at 7°C for 13.5 hours. . This slurry-like reaction solution was filtered at 7°C to collect crystals. The obtained crystals were washed with a mixture of 42.13 g of 2-propanol and 26.40 g of water at 7°C and dried under reduced pressure to give 11-oxo-6,11-dihydrodibenz[b,e]oxepin-2. - 44.55 g (0.14 mol) of t-butyl ester of acetic acid was obtained in a yield of 92%.
Example 8
11-oxo-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid 20.00g (0.075 mol), t-butyl alcohol 11.06g (0.15 mol), N-methylimidazole 0 .61 g (0.0075 mol) and 7.54 g (0.075 mol) of triethylamine were mixed with 86.65 g of toluene at room temperature, and the temperature was raised to 55°C. A mixture of 17.25 g (0.079 mol) of di-t-butyl dicarbonate and 38.97 g of toluene was added dropwise to this mixture at 55°C over 7.5 hours. Stirred for 3 hours. After cooling this reaction solution to 28° C., 59.92 g of 5% hydrochloric acid was added dropwise to this reaction solution, and after stirring for 30 minutes, the mixture was allowed to stand and the organic layer was separated. The organic layer was washed with 127.79 g of 5% aqueous sodium hydrogen carbonate, and 152.80 g of the organic layer was separated. The organic layer was concentrated to 48.11 g by vacuum concentration, and 49.99 g of 2-propanol was mixed with the concentrated solution. The mixed solution was concentrated to 50.92 g by vacuum concentration, and 50.00 g of 2-propanol was mixed with the concentrated solution. The mixed solution was concentrated to 40.46 g by vacuum concentration, and 19.99 g of 2-propanol was mixed with the concentrated solution. The mixed solution was concentrated to 43.17 g by vacuum concentration, and 19.99 g of 2-propanol was mixed with the concentrated solution. After raising the temperature of the mixed solution to 50°C, cool it to 40°C, add 13.10 g of water to this mixed solution over 2 hours at 40°C, stir at 40°C for 2 hours, and confirm the precipitation of crystals. did. 13.10 g of water was added dropwise at 40°C over 2 hours, and the mixture was stirred at 40°C for 1 hour, then cooled from 40°C to 7°C over 3.5 hours, and stirred at 7°C for 13 hours. This slurry-like reaction solution was filtered at 7°C to collect crystals. The obtained crystals were washed with a mixture of 21.06 g of 2-propanol and 13.20 g of water at 7°C and dried under reduced pressure to give 11-oxo-6,11-dihydrodibenz[b,e]oxepin-2. -22.63 g (0.070 mol) of t-butyl ester of acetic acid was obtained in a yield of 94%.
Example 9
Add 3-dimethyl to a mixture of 6.49 g (0.02 mol) of t-butyl ester of 11-oxo-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid and 50 ml of tetrahydrofuran at 15-20°C. A mixed solvent solution of toluene (15.4 ml)/tetrahydrofuran (11.7 ml) containing 0.03 mol of aminopropylmagnesium chloride was added dropwise over 2.5 hours. After the dropwise addition was completed, the mixture was stirred for 30 minutes, and disappearance of the raw materials was confirmed by HPLC. This reaction solution was added to a mixed solution of 30 ml of water and 5.4 g of acetic acid, and then the pH was adjusted to 9.6 with 28% aqueous ammonia. The separated organic layer was washed with 50 ml of 15% brine, concentrated and 11-hydroxy-11-(3'-dimethylaminopropyl)-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid. The t-butyl ester of was obtained in a yield of 97.7%.
1H NMR (400MHz, CDCl3 )
δ 1.41 (s, 9H), 1.43-1.45 (m, 2H), 1.96 (q, J=8.4Hz, 1H), 2.19-2.26 (m, 2H) , 2.26 (s, 6H), 3.20 (q, J = 8.0Hz, 1H), 3.48 (s, 1H), 5.02 (d, J = 15.6Hz, 1H), 5 .45 (d, J=15.6Hz, 1H), 6.87 (d, J=6.8Hz, 1H), 7.03 (d, J=7.6Hz, 1H), 7.13-7. 16 (m, 2H), 7.23 (t, J = 8.0Hz, 2H), 7.67 (d, J = 2.0Hz, 1H), 8.08 (d, J = 9.6Hz, 1H )
Example 10
11-hydroxy-11-(3'-dimethylaminopropyl)-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid t-butyl ester 8.04 g (0.02 mol), 35% hydrochloric acid A mixture of 4.2 g (0.04 mol) and 16.0 ml of toluene was stirred at 100° C. for 6 hours, and disappearance of the raw material was confirmed by HPLC, confirming that olopatadine was obtained.
本発明方法によりオロパタジンの製造中間体として有用な１１－オキソ－６，１１－ジヒドロジベンズ［ｂ，ｅ］オキセピン－２－酢酸のｔ－ブチルエステルを製造することができる。さらに、オロパタジンを製造することができる。 By the method of the present invention, t-butyl ester of 11-oxo-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid, which is useful as an intermediate for producing olopatadine, can be produced. Additionally, olopatadine can be produced.
Claims (6)
１１－オキソ－６，１１－ジヒドロジベンズ［ｂ，ｅ］オキセピン－２－酢酸ｔ－ブチルエステルと３－ジメチルアミノプロピルマグネシウムクロリドとを反応させて１１－ヒドロキシ－１１－（３’－ジメチルアミノプロピル）－６，１１－ジヒドロジベンズ［ｂ，ｅ］オキセピン－２－酢酸のｔ－ブチルエステルを製造する工程、
１１－ヒドロキシ－１１－（３’－ジメチルアミノプロピル）－６，１１－ジヒドロジベンズ［ｂ，ｅ］オキセピン－２－酢酸のｔ－ブチルエステルの脱水反応及び脱エステル化反応によりオロパタジンを製造する工程
を含むオロパタジンの製造方法。 11-oxo-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid, t-butyl alcohol and di-t-butyl dicarbonate with dimethylaminopyridine or N-methylimidazole with triethylamine, pyridine, diisopropylethylamine A step of producing t-butyl ester of 11-oxo-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid by reacting it in the presence of one or more bases selected from and dimethylaniline. ,
11-oxo-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid t-butyl ester and 3-dimethylaminopropylmagnesium chloride are reacted to form 11-hydroxy-11-(3'-dimethylamino a step of producing t-butyl ester of propyl)-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid;
Olopatadine is produced by dehydration and deesterification of t-butyl ester of 11-hydroxy-11-(3'-dimethylaminopropyl)-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid. A method for producing olopatadine, including the steps.
１１－オキソ－６，１１－ジヒドロジベンズ［ｂ，ｅ］オキセピン－２－酢酸のｔ－ブチルエステルと３－ジメチルアミノプロピルマグネシウムクロリドとを反応させて１１－ヒドロキシ－１１－（３’－ジメチルアミノプロピル）－６，１１－ジヒドロジベンズ［ｂ，ｅ］オキセピン－２－酢酸のｔ－ブチルエステルを製造する工程、
１１－ヒドロキシ－１１－（３’－ジメチルアミノプロピル）－６，１１－ジヒドロジベンズ［ｂ，ｅ］オキセピン－２－酢酸のｔ－ブチルエステルの脱水反応及び脱エステル化反応によりオロパタジンを製造する工程を含む請求項４に記載のオロパタジンの製造方法。 11 by reacting 11-oxo-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid, t-butyl alcohol and di-t-butyl dicarbonate in the presence of dimethylaminopyridine and triethylamine. -Producing t-butyl ester of oxo-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid,
The t-butyl ester of 11-oxo-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid and 3-dimethylaminopropylmagnesium chloride are reacted to form 11-hydroxy-11-(3'-dimethyl A process for producing t-butyl ester of (aminopropyl)-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid,
Olopatadine is produced by dehydration reaction and deesterification reaction of t-butyl ester of 11-hydroxy-11-(3'-dimethylaminopropyl)-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid. The method for producing olopatadine according to claim 4, comprising the step of:
１１－オキソ－６，１１－ジヒドロジベンズ［ｂ，ｅ］オキセピン－２－酢酸ｔ－ブチルエステルと３－ジメチルアミノプロピルマグネシウムクロリドとを反応させて１１－ヒドロキシ－１１－（３’－ジメチルアミノプロピル）－６，１１－ジヒドロジベンズ［ｂ，ｅ］オキセピン－２－酢酸のｔ－ブチルエステルを製造する工程、
１１－ヒドロキシ－１１－（３’－ジメチルアミノプロピル）－６，１１－ジヒドロジベンズ［ｂ，ｅ］オキセピン－２－酢酸のｔ－ブチルエステルの脱水反応及び脱エステル化反応によりオロパタジンを製造する工程
を含む請求項４に記載のオロパタジンの製造方法。 By reacting 11-oxo-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid, t-butyl alcohol and di-t-butyl dicarbonate in the presence of N-methylimidazole and triethylamine. A step of producing t-butyl ester of 11-oxo-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid,
11-oxo-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid t-butyl ester and 3-dimethylaminopropylmagnesium chloride are reacted to form 11-hydroxy-11-(3'-dimethylamino a step of producing t-butyl ester of propyl)-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid;
Olopatadine is produced by dehydration and deesterification of t-butyl ester of 11-hydroxy-11-(3'-dimethylaminopropyl)-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid. The method for producing olopatadine according to claim 4, comprising the step of:
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| WO2008041734A1 (en) | 2006-10-02 | 2008-04-10 | Sumitomo Chemical Company, Limited | Tertiary alkyl ester of oxodibenzoxepin acetic acid |
| JP2009062296A (en) | 2007-09-05 | 2009-03-26 | Fujifilm Corp | Method for producing carboxylic acid ester compound |
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| WO2008041734A1 (en) | 2006-10-02 | 2008-04-10 | Sumitomo Chemical Company, Limited | Tertiary alkyl ester of oxodibenzoxepin acetic acid |
| JP2009062296A (en) | 2007-09-05 | 2009-03-26 | Fujifilm Corp | Method for producing carboxylic acid ester compound |
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