JPH0436279A - Production of optically active benzoxepin derivative - Google Patents
Production of optically active benzoxepin derivativeInfo
- Publication number
- JPH0436279A JPH0436279A JP14346190A JP14346190A JPH0436279A JP H0436279 A JPH0436279 A JP H0436279A JP 14346190 A JP14346190 A JP 14346190A JP 14346190 A JP14346190 A JP 14346190A JP H0436279 A JPH0436279 A JP H0436279A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- compound
- optically active
- derivative
- optically
- 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.)
- Pending
Links
- 238000004519 manufacturing process Methods 0.000 title claims description 10
- LWZYUACNWRVDDJ-UHFFFAOYSA-N 1-benzoxepine Chemical class O1C=CC=CC2=CC=CC=C12 LWZYUACNWRVDDJ-UHFFFAOYSA-N 0.000 title abstract 4
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 10
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 6
- 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 4
- 125000003118 aryl group Chemical group 0.000 claims abstract description 4
- 230000003287 optical effect Effects 0.000 claims description 12
- 150000005119 benzoxepines Chemical class 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- JEHUZVBIUCAMRZ-UHFFFAOYSA-N 1,1'-binaphthyl-2,2'-diyl hydrogenphosphate Chemical compound O1P(O)(=O)OC2=CC=C(C=CC=C3)C3=C2C2=C1C=CC1=CC=CC=C21 JEHUZVBIUCAMRZ-UHFFFAOYSA-N 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 abstract description 25
- 230000008485 antagonism Effects 0.000 abstract description 6
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 abstract description 4
- 229960001340 histamine Drugs 0.000 abstract description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 150000003839 salts Chemical class 0.000 description 15
- 239000002904 solvent Substances 0.000 description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- 239000013078 crystal Substances 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 230000003042 antagnostic effect Effects 0.000 description 6
- 229940125782 compound 2 Drugs 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 238000000921 elemental analysis Methods 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- LGWGHIVCHVTBRS-UHFFFAOYSA-N methyl oxepine-2-carboxylate Chemical compound COC(=O)C1=CC=CC=CO1 LGWGHIVCHVTBRS-UHFFFAOYSA-N 0.000 description 3
- 239000012046 mixed solvent Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- DSNBHJFQCNUKMA-SCKDECHMSA-N thromboxane A2 Chemical compound OC(=O)CCC\C=C/C[C@@H]1[C@@H](/C=C/[C@@H](O)CCCCC)O[C@@H]2O[C@H]1C2 DSNBHJFQCNUKMA-SCKDECHMSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- BWLBGMIXKSTLSX-UHFFFAOYSA-N 2-hydroxyisobutyric acid Chemical compound CC(C)(O)C(O)=O BWLBGMIXKSTLSX-UHFFFAOYSA-N 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004208 3-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C([H])C(*)=C1[H] 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-L Phosphate ion(2-) Chemical compound OP([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-L 0.000 description 1
- LLRWRTWNPWVMCY-UHFFFAOYSA-M [Na+].[O-]C(=O)C1=CC=CC=CO1 Chemical compound [Na+].[O-]C(=O)C1=CC=CC=CO1 LLRWRTWNPWVMCY-UHFFFAOYSA-M 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 125000000490 cinnamyl group Chemical group C(C=CC1=CC=CC=C1)* 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- PMDLIAGAGUCEGN-UHFFFAOYSA-N oxepine-2-carboxylic acid Chemical compound OC(=O)C1=CC=CC=CO1 PMDLIAGAGUCEGN-UHFFFAOYSA-N 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- -1 propatool Chemical compound 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 125000005504 styryl group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 230000002747 voluntary effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
【発明の詳細な説明】
産業上の利用分野
本発明は、トロンボキサンＡ２ （以下、Ｔ、＾２とい
う）拮抗作用および／またはヒスタミン１ （以下、Ｈ
，という）拮抗作用を持つベンゾオキセピン誘導体の光
学活性体の製造法に関する。DETAILED DESCRIPTION OF THE INVENTION Industrial Field of Application The present invention is directed to thromboxane A2 (hereinafter referred to as T) antagonism and/or histamine 1 (hereinafter referred to as H
The present invention relates to a method for producing optically active benzoxepine derivatives having antagonistic effects.
従来の技術
Ｔｌ１Ａ２拮抗作用および／またはＨ３拮抗作用を有す
るベンゾオキセピン誘導体が特開平１−３０８２７４号
公報に開示されている。BACKGROUND OF THE INVENTION Benzoxepine derivatives having Tl1A2 antagonism and/or H3 antagonism are disclosed in JP-A-1-308274.
また一方、１．１′−ビナフチル−２，２′−ジイルハ
イドロゲンホスフェート （以下、ＢＮＰＰΔという）
を光学分割剤として用いる光学活性な３（３−ヒドロキ
シフェニル）−Ｎ−（ｎ−プロビル〉ピペリジンの製造
法が知られている〔テトラヘドロンレターズ（Ｔｅｔｒ
ａｈｅｄｒｏｎ Ｌｅｔｔｅｒｓ） 、 ２４巻。On the other hand, 1,1'-binaphthyl-2,2'-diyl hydrogen phosphate (hereinafter referred to as BNPPΔ)
A method for producing optically active 3(3-hydroxyphenyl)-N-(n-propyl)piperidine using Tetrahedron Letters as an optical resolving agent is known.
ahedron Letters), 24 volumes.
３４３頁（１９８３年）〕。343 pages (1983)].
発明が解決しようとする課題
一般にある薬理作用が知られているうセミ化合物におい
てはその光学活性体が研究、開発上、常に期待され求め
られている。Problems to be Solved by the Invention Generally speaking, optically active forms of semi-compounds known to have certain pharmacological effects are always expected and sought after in research and development.
本発明の目的は、ＢＮＰＰＡを光学分割剤として用いた
ＴＸＡ２拮抗作用および／または旧拮抗作用を有するベ
ンゾオキセピン誘導体の光学活性体の製造法を提供する
ことである。An object of the present invention is to provide a method for producing an optically active benzoxepine derivative having TXA2 antagonistic activity and/or former antagonistic activity using BNPPA as an optical resolving agent.
課題を解決するための手段
本発明は式（１）
（式中、ｎは１，２．３または４であり、ＲＡおよびＲ
６は一方が水素を、他方が一１ｃｏＯＲ３［式中、Ｒ３
は低級アルキルを表わし、Ｙは−（ＣＨ２）ｍ （式
中、ｍは０．１．２．３または４である）または−ＣＲ
’ＣＲ’−（ＣＬ）ｍ−（式中、Ｒ１およびＲ２は同一
または異なって、水素または低級アルキルを意味し、ｍ
は前記と同義である）なお、式の左側が母核に結合して
いるものとするを表わす〕を表わし、Ｅは単結合または
ＣＤ−を表わし、Ｑは置換もしくは非置換のアリ−／ぺ
置換もしくは非置換のアラルキル、置換もしくは非置換
のアラルケニルを表わす）で表わされるベンゾオキセピ
ン誘導体〔以下、化合物（Ｉ）という〕を、（＋）−ま
たは（−） −１，１’−ビナフチル−２，２′−ジイ
ルハイドロゲンホスフェートを光学分割剤として用い、
光学分割することを特徴とする光学活性なベンゾオキセ
ピン誘導体の製造法に関する。Means for Solving the Problems The present invention provides formula (1) (where n is 1, 2.3 or 4, RA and R
6 has hydrogen on one side and 11coOR3 on the other [where R3
represents lower alkyl, Y is -(CH2)m (wherein m is 0.1.2.3 or 4) or -CR
'CR'-(CL)m- (wherein R1 and R2 are the same or different and mean hydrogen or lower alkyl, m
(has the same meaning as above) where the left side of the formula is bonded to the mother nucleus], E represents a single bond or CD-, and Q represents a substituted or unsubstituted ali-/petroleum. (representing substituted or unsubstituted aralkyl, substituted or unsubstituted aralkenyl) [hereinafter referred to as compound (I)], (+)- or (-)-1,1'-binaphthyl-2, Using 2'-diyl hydrogen phosphate as an optical resolving agent,
The present invention relates to a method for producing an optically active benzoxepine derivative, which is characterized by optical resolution.
式（１）の定義において、Ｑで表わされるアリールとは
炭素数６〜１０のフェニルおよびナフチル等が、アラル
キルとは、炭素数７〜２０のベンジル、フェネチルおよ
びトリチル等が、アラルケニルとは炭素数８〜１３のス
チリルおよびシンナミル等がそれぞれ包含され、各基に
おける置換基とは、同一または異なって置換数ｌ〜３の
芳香環への置換基を意味し、低級アルキル、ハロゲン、
トリフルオロメチノペヒドロキシル、低級アルコキシル
ちよびオルト位と一緒になって形成されるメチレンジオ
キンから選ばれる基を表わす。In the definition of formula (1), aryl represented by Q refers to phenyl and naphthyl having 6 to 10 carbon atoms, aralkyl refers to benzyl, phenethyl, trityl, etc. having 7 to 20 carbon atoms, and aralkenyl refers to those having 7 to 20 carbon atoms. 8 to 13 styryl and cinnamyl, etc. are included, respectively, and the substituent in each group means the same or different substituent on the aromatic ring with the number of substitutions 1 to 3, lower alkyl, halogen,
Represents a group selected from trifluoromethinopehydroxyl, lower alkoxyl, and methylenedioquine formed together with the ortho position.
また、各基の定義の低級アルキルとは、炭素数１〜６の
直鎖もしくは分岐状のアルキル、例えばメチル、エチル
、プロピル、イソプロピル、ブチル、イソブチル、５ｅ
ｃ−ブチル、ｔｅｒｔ−ブチル、ペンチル、ネオペンチ
ルおよびヘキシル等が包含される。In addition, lower alkyl in the definition of each group refers to straight chain or branched alkyl having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 5e
Included are c-butyl, tert-butyl, pentyl, neopentyl, hexyl, and the like.
以下に、化合物（Ｉ）の光学活性体の製造法について説
明する。なお化合物（１）は特開平ｌ−３０８２７４号
公報に記載されている。Below, a method for producing an optically active form of compound (I) will be explained. Compound (1) is described in JP-A-1-308274.
化合物（１）の光学活性体は、化合物（Ｉ）を溶媒の存
在下、（＋）−または（−）−ＢＮＰＰＡにより、化合
物（１）のジアステレオマー塩を生成させ、該ジアステ
レオマー塩を溶媒に対する溶解度差を利用して分離した
のち、各々のジアステレオマー塩よりＢＮＰＰＡを除去
して得ることができる。The optically active form of compound (1) can be obtained by producing a diastereomeric salt of compound (1) by treating compound (I) with (+)- or (-)-BNPPA in the presence of a solvent. It can be obtained by separating the diastereomeric salts using the difference in solubility in the solvent, and then removing BNPPA from each diastereomeric salt.
ＢＮＰＰＡは（±）−または（−）一体が用いられ、使
用量は、化合物（１）１モルに対し０１〜２０モル、好
ましくは０．４〜ｌ、０モルである。BNPPA is used in the form of (±)- or (-), and the amount used is 01 to 20 mol, preferably 0.4 to 0 mol, per 1 mol of compound (1).
使用する溶媒としては、化合物（１）とＢＮＰＰＡを室
温から使用する溶媒の沸点の範囲で溶解するとともに溶
液中てこれらの化合物を変質させることな（、かつジア
ステレオマー塩を析出させるものであればよ（、例えば
メタノール、エタノール、７’ｏハノール、インプロパ
ツール等の低級アルコール、アセトン、酢酸エチノペテ
トラヒドロフラン、ジオキサン、トルエン、クロロホル
ム、ジクロロメタン、Ｎ、Ｎ−ジメチルホルムアミド、
アセトニ） ＩＪル等の有機溶媒またはこれらの混合溶
媒を用いることができる。The solvent to be used should be one that dissolves compound (1) and BNPPA in the range from room temperature to the boiling point of the solvent used, and that does not alter the properties of these compounds in the solution (and does not precipitate diastereomeric salts). lower alcohols such as methanol, ethanol, 7'o hanol, impropatol, acetone, acetic acid ethynopetrahydrofuran, dioxane, toluene, chloroform, dichloromethane, N,N-dimethylformamide,
An organic solvent such as acetonate, IJ, or a mixed solvent thereof can be used.
ジアステレオマー塩の分離は、ＢＮＰＰＡと反応させた
溶液を冷却および／あるいは濃縮することにより難溶性
のジアステレオマー塩を晶析させる。晶析の際の温度は
使用する溶媒の凝固点から沸点の範囲であれば良く、通
常０〜６０℃である。For separation of the diastereomeric salts, the poorly soluble diastereomeric salts are crystallized by cooling and/or concentrating the solution reacted with BNPPA. The temperature during crystallization may be in the range from the freezing point to the boiling point of the solvent used, and is usually 0 to 60°C.
また晶析した結晶を分離した後、残りの母液をそのまま
、または濃縮および／あるいは冷却することにより、易
溶性のジステレオマー塩を晶析させ、これを分離するこ
ともできる。Furthermore, after separating the crystallized crystals, the remaining mother liquor may be used as is or by concentrating and/or cooling to crystallize easily soluble distereomer salts and then separate them.
該結晶の分離方法は濾過、遠心分離などの通常の固液分
離法によって容易に分離することができる。The crystals can be easily separated by conventional solid-liquid separation methods such as filtration and centrifugation.
次にジアステレオマー塩からＢＮＰＰＡを除去するには
、例えば該ジアステレオマー塩を酢酸エチルと飽和炭酸
水素ナトリウム水溶液等のアルカリ水溶液に懸濁、溶解
させ分取する。有機層は、洗浄、乾燥、濃縮、再結晶、
各種クロマトグラフィー等の単ｎ精製法により、化合物
（１）の光学活性体を得ることができる。Next, in order to remove BNPPA from the diastereomeric salt, for example, the diastereomeric salt is suspended and dissolved in ethyl acetate and an alkaline aqueous solution such as a saturated aqueous sodium bicarbonate solution, and separated. The organic layer was washed, dried, concentrated, recrystallized,
The optically active form of compound (1) can be obtained by various single n purification methods such as chromatography.
前記式（Ｉ）において、Ｒ３が水素である化合物〔以下
、化合物（旧という〕は特に優れたＴイス２拮抗活性お
よび／またはＨ１拮抗活性を有するが、該化合物の光学
活性体を所望の場合、上記製造法で得られる光学活性体
を加水分解することにより得ることができる。In the above formula (I), the compound in which R3 is hydrogen [hereinafter referred to as compound (old)] has particularly excellent T is2 antagonistic activity and/or H1 antagonistic activity, but if an optically active form of the compound is desired. , can be obtained by hydrolyzing the optically active substance obtained by the above production method.
すなわち、化合物（１）の光学活性体を溶媒中塩基の存
在下に処理することにより、化合物（Ｉｔ）の光学活性
体が得られる。That is, by treating the optically active form of compound (1) in the presence of a base in a solvent, the optically active form of compound (It) can be obtained.
溶媒としては、メタノール、エタノール、プロパツール
、イソプロパツール等の低級アルコールと水の混合溶媒
が用いられる。塩基は、水酸化ナトリウムまたは水酸化
カリウムが用いられ、使用量は化合物（１）の光学活性
体に対し、１〜２０当量、好ましく１〜４当量である。As the solvent, a mixed solvent of water and a lower alcohol such as methanol, ethanol, propatool, isopropanol, etc. is used. As the base, sodium hydroxide or potassium hydroxide is used, and the amount used is 1 to 20 equivalents, preferably 1 to 4 equivalents, based on the optically active form of compound (1).
反応は室温から使用する溶媒の沸点、０．５〜２４時間
で終了する。The reaction is completed in 0.5 to 24 hours at room temperature to the boiling point of the solvent used.
上記製造法における目的化合物は濾過、抽出、洗浄、乾
燥、濃縮、再結晶、各種クロマトグラフィー等に付して
単離精製することができる。The target compound in the above production method can be isolated and purified by filtration, extraction, washing, drying, concentration, recrystallization, various chromatography, and the like.
以下に本発明の実施例および参考例を示す。Examples and reference examples of the present invention are shown below.
実施例１゜
（十） −１１−（２−（４−ベンジル−１−ピペリジ
ニル）エチルコチオ−６、１１−ジヒドロジベンゾ（ｂ
、 ｅ）オキセピン−２−カルボン酸メチルエステル
（化合物１）
（±）−１１−Ｃ２−（４−ベンジル−１−ピペリジニ
ル）エチルコチオ−６，１１−ジヒドロジベンゾ（ｂ、
ｅ）オキセピン−２−カルボン酸メチルエステル２
８．０ ｇと（＋）−ＢＮＰＰＡ １００ｇをクロロホ
ルム２００献とメタノール２００ｒｎｌの混合溶媒中、
６５℃で加熱溶解させ、減圧下に溶媒を半量になるまで
濃縮した後、冷却してジアステレオマー塩を晶析させた
。結晶を戸数し、クロロホルム４００ｍｅに加熱還流下
、溶解させ、減圧下に溶媒を半量になるまで濃縮した。Example 1゜(10)-11-(2-(4-benzyl-1-piperidinyl)ethylcothio-6,11-dihydrodibenzo(b)
, e) Oxepin-2-carboxylic acid methyl ester (compound 1) (±)-11-C2-(4-benzyl-1-piperidinyl)ethylcothio-6,11-dihydrodibenzo (b,
e) Oxepin-2-carboxylic acid methyl ester 2
8.0 g and 100 g of (+)-BNPPA in a mixed solvent of 200 g of chloroform and 200 rnl of methanol,
The mixture was dissolved by heating at 65° C., the solvent was concentrated to half its volume under reduced pressure, and then cooled to crystallize the diastereomeric salt. The crystals were separated and dissolved in 400 ml of chloroform under heating under reflux, and the solvent was concentrated under reduced pressure to half the volume.
次いで、メタノール２００−を加え、冷却することによ
りジアステレオマー塩１９．１ｇ（収ｎ３９．７％）を
得た。Next, 200 g of methanol was added and cooled to obtain 19.1 g of diastereomeric salt (yield: 39.7%).
融点 ； ２１７℃
元素分析（％） ：Ｃ１ｏＨｓＪＯ３Ｓ−ＣｔｏＨＩ
ｓＯａＰＣＨＮ
実測値 ＋ ７１．８１ ５．９２ １．４２計
算値 ： ７１．８４ ５．５５ １．６８該ジ
アステレオマー塩 １９．１ ｇを酢酸エチル３９０−
と飽和炭酸水素ナトリウム水溶液３８０艷に懸濁した。Melting point: 217°C Elemental analysis (%): C1oHsJO3S-CtoHI
sOaPCHN Actual value + 71.81 5.92 1.42 Calculated value: 71.84 5.55 1.68 19.1 g of the diastereomeric salt was dissolved in ethyl acetate 390-
and suspended in 380 g of saturated aqueous sodium hydrogen carbonate solution.
懸濁液を１．５時開攪拌後、有機層を飽和炭酸水素ナト
リウム水溶液１００ｒｎｌ、続いて水１００ｄで洗浄し
た。さらに無水硫酸マグネシウムで乾燥後、減圧下に溶
媒を留去することにより化合物１を１０．１ｇ（油伏物
）得た。After stirring the suspension for 1.5 hours, the organic layer was washed with 100 rnl of a saturated aqueous sodium bicarbonate solution and then with 100 ml of water. Further, after drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 10.1 g of Compound 1 (oil paste).
光学純度 ９３１％ｅｅ
［α］’： −＋１０２．６° （Ｃ＝１． りｏｏ
ポルム）実施例２゜
（−）−１１−Ｃ２−（４−ベンジル−１−ピペリジニ
ル）エチルコチオ−６，１１−ジヒドロジベンゾ［ｂ、
ｅ］オキセピン−２−カルボン酸メチルエステル（
化合物２）
（＋）−ＢＮＰＰＡを（−）−ＢＮＰＰＡに代える以外
は、実施例１と同様の方法で、ジアステレオマー塩１９
．０ｇ（収率３９．６％）を得た。Optical purity 931%ee [α]': -+102.6° (C=1.
Example 2゜(-)-11-C2-(4-benzyl-1-piperidinyl)ethylcothio-6,11-dihydrodibenzo[b,
e] Oxepin-2-carboxylic acid methyl ester (
Compound 2) Diastereomeric salt 19 was prepared in the same manner as in Example 1, except that (+)-BNPPA was replaced with (-)-BNPPA.
．． 0 g (yield 39.6%) was obtained.
融点 ； ２１７℃
元素分析（％） ；Ｃ１ｏＨｓＪＯ３Ｓ−Ｃ２ｏＨ＋
３０４ＰＣＨＮ
： ７１．３５ ５．６８ １．４２７１．８４
５，５５ １．６８
実測値
計算値
得られたジアステレオマー塩を実施例１と同様の方法に
より、化合物２を１０．３ｇ（油状物）得た。Melting point: 217℃ Elemental analysis (%): C1oHsJO3S-C2oH+
304PCHN: 71.35 5.68 1.4271.84
5,55 1.68 Actual value Calculated value The resulting diastereomeric salt was treated in the same manner as in Example 1 to obtain 10.3 g (oil) of Compound 2.
光学純度 ９７．９％ｅｅ
〔α］’： ＝−１ｏｓ、１° （Ｃ＝１． クロロ
ホルム）なお、実施例１および２の光学純度は高速液体
クロマトグラフィーを用い、次の条件で測定した。Optical purity 97.9% ee [α]': = -1 os, 1° (C = 1. Chloroform) The optical purity of Examples 1 and 2 was measured using high performance liquid chromatography under the following conditions.
カラム：ＣＨＩＲＡＬＣＢＬ ｏｏ （ダイセル化学工
業）（φ４．６ Ｘ ２５０ｍｍ）
展開溶媒；ｎ−へキサン／エタノール（７／３）流速：
０．５ ｉｆ！／ｍｉｎ
検出二紫外吸収部（２５４０ｍ）
保持時間；化合物１１７分
化合物２ ４０分
参考例１゜
（＋） −１１−（２−（４−ベンジル−１−ピペリジ
ニル）エチルコチオ−６，１１−ジヒドロジベンゾ（ｂ
、ｅ）オキセピン−２−カルボン酸す） ＩＪウム塩（
化合物ａ）
化合物１１０．０ｇ（油状物）にイソプロパツール１１
０ＩｎＩ！、水２．４ｍｌ＃よび４Ｎ−水酸化ナトリウ
ム水溶液８．６−を加え、７０℃で１．５時間反応させ
た。該反応液を徐々に冷却させた後、析出した結晶を戸
数したところ、７．７ｇ（収率７７％）を得た。Column: CHIRALCBL oo (Daicel Chemical Industries) (φ4.6 x 250 mm) Developing solvent: n-hexane/ethanol (7/3) Flow rate:
0.5 if! /min Detection two ultraviolet absorption parts (2540m) Retention time: Compound 117 minutes Compound 2 40 minutes Reference example 1゜(+) -11-(2-(4-benzyl-1-piperidinyl)ethylcothio-6,11-dihydrodibenzo (b
, e) Oxepine-2-carboxylic acid) IJium salt (
Compound a) 110.0 g of compound (oil) and 11 isopropanol
0InI! , 2.4 ml of water and 8.6 mL of 4N aqueous sodium hydroxide solution were added, and the mixture was reacted at 70°C for 1.5 hours. After the reaction solution was gradually cooled, the precipitated crystals were counted, and 7.7 g (yield: 77%) was obtained.
得られた結晶のうち３．７ｇを、ベンゾ ロバノール３
７ｍｆと水３．７ｍＩ！に懸濁させた後６５℃まで加熱
して溶解させた。熱時沖過した後、徐々に冷却して晶析
した結晶を戸数し、化合物ａを２．８ｇ（収率７５％）
得た。3.7 g of the obtained crystals were converted into benzolobanol 3
7mf and water 3.7mI! The mixture was suspended in water and then heated to 65°C to dissolve it. After heating, the crystals were gradually cooled and crystallized, and 2.8 g of compound a (yield 75%) was obtained.
Obtained.
光学純度 ９４．０％ｅｅ
〔α］’： ＝＋８５．２° （Ｃ＝１．メタノール
）融点 ； １３８℃
元素分析（％） ： Ｃ２Ｊｓｏ０３ＮＳＮａＨＮ
？０．５２ ６．０３ ２．６９
７０．２７ ６．１１ ２．８３
実測値 ：
計算値 ：
参考例２゜
（−）−１１−（２−（４−ベンジル−１−ピペリジニ
ル）エチルコチオ−６，１１−ジヒドロベンゾ〔ｂ。Optical purity 94.0%ee [α]': =+85.2° (C=1.methanol) Melting point: 138°C Elemental analysis (%): C2Jso03NSNaHN? 0.52 6.03 2.69 70.27 6.11 2.83 Actual value: Calculated value: Reference example 2゜(-)-11-(2-(4-benzyl-1-piperidinyl)ethylcothio-6, 11-dihydrobenzo [b.
ｅ〕オキセピン−２−カルボン酸ナトリウム塩（化合物
ｂ）
化合物ｌの代わりに化合物２をｌＯ，Ｏｇ（油状物）用
い参考例１の方法に従って化合物すの粗結晶８３ｇ（収
率８３％）を得た。このもの４．３ ｇを参考例１と同
様の方法により再結晶して化合物すを３．４ｇ（収率７
９％）得た。e] Oxepine-2-carboxylic acid sodium salt (compound b) 83 g (yield: 83%) of crude crystals of compound 2 were obtained according to the method of Reference Example 1 using 1O,Og (oil) of compound 2 instead of compound 1. Ta. 4.3 g of this product was recrystallized in the same manner as in Reference Example 1 to obtain 3.4 g of the compound (yield 7.
9%) obtained.
光学純度 ９６．７％ｅｅ
〔α］’： −−９２，１° （Ｃ＝１． メタノ
ール）融点 ； １３９℃
元素分析（％） ； Ｃ２５Ｈ３ｏ０２ＮＳＮａＣＨ
Ｎ
実測値 ： ７０，４１ ５．８９ ２．７１計
算値 ： ７０，２７ ６．１１ ２．８３なお
、参考例１および２の光学純度は高速液体クロマトグラ
フィーを用い、次の条件で測定した。Optical purity 96.7%ee [α]': --92,1° (C=1. Methanol) Melting point: 139°C Elemental analysis (%): C25H3o02NSNaCH
N Actual value: 70,41 5.89 2.71 Calculated value: 70,27 6.11 2.83 The optical purity of Reference Examples 1 and 2 was measured using high performance liquid chromatography under the following conditions.
カラム：ＣＨＩＲＡＬＣＥＬ ｏｏ （ダイセル化学工
業）（φ４．６Ｘ２５０＋ｎｍ）
展開溶媒：ｎ−ヘキサン／エタノール／酢酸（７００／
３００／１）
流速： ０．５ ｍｅ／ｍｉｎ
検出：紫外部吸収（２５４ｒ＋ｍ）
保持時間：化合物２ ２４分
化合物ｂ ３０分
発明の効果
本発明によれば、ＴＸ＾２拮抗作用および／またはＨ６
拮抗作用を有するジベンゾオキセビン誘導体の光学活性
体の製造法が提供される。Column: CHIRALCEL oo (Daicel Chemical Industries) (φ4.6X250+nm) Developing solvent: n-hexane/ethanol/acetic acid (700/
300/1) Flow rate: 0.5 me/min Detection: Ultraviolet absorption (254r+m) Retention time: Compound 2 24 minutes Compound b 30 minutes Effect of the invention According to the present invention, TX^2 antagonism and/or H6
A method for producing an optically active dibenzoxebine derivative having antagonistic effects is provided.
特許出願人（１０２）協和醗酵工業株式会社手続補正書
（自発）Patent applicant (102) Kyowa Hakko Kogyo Co., Ltd. Procedural amendment (voluntary)
Claims (1)
びＲ＾Ｂは一方が水素を、他方が−Ｙ−ＣＯＯＲ＾３〔
式中、Ｒ＾３は低級アルキルを表わし、Ｙは−（ＣＨ＿
２）＿ｍ−（式中、ｍは０，１，２，３または４である
）または−ＣＲ＾１＝ＣＲ＾２−（ＣＨ＿２）＿ｍ−（
式中、Ｒ＾１およびＲ＾２は同一または異なって、水素
または低級アルキルを意味し、ｍは前記と同義である）
なお、式の左側が母核に結合しているものとするを表わ
す〕を表わし、Ｅは単結合または−ＣＯ−を表わし、Ｑ
は置換もしくは非置換のアリール、置換もしくは非置換
のアラルキル、置換もしくは非置換のアラルケニルを表
わす）で表わされるベンゾオキセピン誘導体を、（＋）
−または（−）−１，１′−ビナフチル−２，２′−ジ
イルハイドロゲンホスフェートを光学分割剤として用い
、光学分割することを特徴とする光学活性なベンゾオキ
セピン誘導体の製造法。[Claims] Formula ▲ Numerical formula, chemical formula, table, etc.▼ Y-COOR＾3 [
In the formula, R^3 represents lower alkyl, and Y is -(CH_
2)_m- (where m is 0, 1, 2, 3 or 4) or -CR^1=CR^2-(CH_2)_m-(
In the formula, R^1 and R^2 are the same or different and mean hydrogen or lower alkyl, and m has the same meaning as above)
In addition, the left side of the formula is assumed to be bonded to the mother nucleus], E represents a single bond or -CO-, and Q
represents a substituted or unsubstituted aryl, a substituted or unsubstituted aralkyl, a substituted or unsubstituted aralkenyl).
- or (-)-1,1'-binaphthyl-2,2'-diyl hydrogen phosphate is used as an optical resolving agent to perform optical resolution. A method for producing an optically active benzoxepine derivative.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP14346190A JPH0436279A (en) | 1990-06-01 | 1990-06-01 | Production of optically active benzoxepin derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP14346190A JPH0436279A (en) | 1990-06-01 | 1990-06-01 | Production of optically active benzoxepin derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH0436279A true JPH0436279A (en) | 1992-02-06 |
Family
ID=15339245
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP14346190A Pending JPH0436279A (en) | 1990-06-01 | 1990-06-01 | Production of optically active benzoxepin derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0436279A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6124317A (en) * | 1995-12-22 | 2000-09-26 | Warner-Lambert Company | 2-substituted piperidine analogs and their use as subtype-selective NMDA receptor antagonists |
| JP4836778B2 (en) * | 2003-04-10 | 2011-12-14 | ポクセル ソシエテ パール アクシオン サンプリフィエ | Method for cleaving amines useful in the treatment of diseases associated with insulin resistance syndrome |
-
1990
- 1990-06-01 JP JP14346190A patent/JPH0436279A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6124317A (en) * | 1995-12-22 | 2000-09-26 | Warner-Lambert Company | 2-substituted piperidine analogs and their use as subtype-selective NMDA receptor antagonists |
| US6534525B1 (en) | 1995-12-22 | 2003-03-18 | Warner-Lambert & Company | 2-substituted piperidine analogs and their use as subtype-selective NMDA receptor antagonists |
| JP4836778B2 (en) * | 2003-04-10 | 2011-12-14 | ポクセル ソシエテ パール アクシオン サンプリフィエ | Method for cleaving amines useful in the treatment of diseases associated with insulin resistance syndrome |
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