JP2005120070A - Elastase release-inhibitor and cerebral infarction-treating agent - Google Patents
Elastase release-inhibitor and cerebral infarction-treating agent Download PDFInfo
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- JP2005120070A JP2005120070A JP2004066192A JP2004066192A JP2005120070A JP 2005120070 A JP2005120070 A JP 2005120070A JP 2004066192 A JP2004066192 A JP 2004066192A JP 2004066192 A JP2004066192 A JP 2004066192A JP 2005120070 A JP2005120070 A JP 2005120070A
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Images
Abstract
Description
本発明は新規なヒドロキシ脂肪族スルホン酸類縁体および水和物を有効成分とするエラスターゼ遊離抑制剤及び脳梗塞治療薬に関する。 The present invention relates to an elastase release inhibitor and a therapeutic agent for cerebral infarction, which comprise a novel hydroxyaliphatic sulfonic acid analog and hydrate as active ingredients.
リンパ球の一種である好中球から出されるプロテアーゼは主に細菌等の外来微生物や損傷細胞の分解等の役割を有し生体防御反応において重要な役目を担っている。セリンプロテアーゼの一種である好中球エラスターゼ（以下、単にエラスターゼと称する）は、感染や炎症性疾患時に出現する好中球の顆粒から大量に放出される。エラスターゼは、主として肺、軟骨、血管壁、皮膚、靱帯などの生体内結合組織の間質を構成するタンパク質エラスチン、コラーゲン、プロテオグリカン、フィブロネクチンなどを分解する酵素である。また、その他のタンパク質や細胞にも作用する事が明らかにされてきている。 Proteases released from neutrophils, which are a type of lymphocyte, mainly play a role in the host defense reaction, having a role of degrading foreign microorganisms such as bacteria and damaged cells. Neutrophil elastase (hereinafter simply referred to as elastase), which is a type of serine protease, is released in large quantities from neutrophil granules that appear during infection and inflammatory diseases. Elastase is an enzyme that mainly degrades the proteins elastin, collagen, proteoglycan, fibronectin, and the like that constitute the stroma of in vivo connective tissues such as lung, cartilage, blood vessel wall, skin, and ligament. It has also been shown to act on other proteins and cells.
生体内でエラスターゼは、内因性インヒビタータンパク質であるα１−プロテアーゼインヒビター、α２−マクログロブリン、分泌性白血球プロテアーゼインヒビターなどによってその作用が制御されつつ生体の恒常性を維持している。しかしながら,炎症部位でのエラスターゼの過剰放出やインヒビターレベルの低下によりエラスターゼと内因性インヒビターのバランスが損なわれると、エラスターゼ作用の制御が崩れ組織が傷害される。 In vivo, elastase maintains its homeostasis while its action is controlled by α1-protease inhibitor, α2-macroglobulin, secretory leukocyte protease inhibitor and the like which are endogenous inhibitor proteins. However, if the balance between elastase and endogenous inhibitor is impaired by excessive release of elastase at the site of inflammation or a decrease in inhibitor level, the control of elastase action is lost and the tissue is damaged.
エラスターゼの病態への関与が示唆されている疾患としては、肺気腫、成人呼吸窮迫症候群、特発性肺線維症、嚢胞性肺線維症、慢性間質性肺炎、慢性気管支炎、慢性気道感染症、びまん性汎細気管支炎、気管支拡張症、喘息、膵炎、腎炎、肝不全、慢性関節リュウマチ、関節硬化症、変形性関節炎、乾せん、歯周炎、アテローム性動脈硬化症、臓器移植における拒絶反応、早期破水、水疱症、ショック、敗血症、全身性エリテマトーデス、クローン病、播種性血管内凝固症、脳梗塞、心疾患、腎疾患時に認められる虚血再灌流障害、角膜瘢痕組織の形成、脊椎炎などが知られている。 Diseases that have been implicated in the pathogenesis of elastase include emphysema, adult respiratory distress syndrome, idiopathic pulmonary fibrosis, cystic pulmonary fibrosis, chronic interstitial pneumonia, chronic bronchitis, chronic respiratory tract infections, diffuse Panbronchiolitis, bronchiectasis, asthma, pancreatitis, nephritis, liver failure, rheumatoid arthritis, arthrosclerosis, osteoarthritis, psoriasis, periodontitis, atherosclerosis, rejection in organ transplantation, early Such as rupture, blistering, shock, sepsis, systemic lupus erythematosus, Crohn's disease, disseminated intravascular coagulation, cerebral infarction, heart disease, renal disease, ischemia-reperfusion injury, formation of corneal scar tissue, spondylitis, etc. Are known.
従って、エラスターゼ遊離抑制剤はこれらの疾患の治療剤、あるいは予防剤として有用である。かかる期待のもとに近年盛んに研究が行われており、種々のエラスターゼ遊離抑制剤が報告されているが、その作用は必ずしも十分とは言えない。また、ヒドロキシ脂肪族スルホン酸類縁体からなるエラスターゼ遊離抑制物質としては未だ臨床上有用な薬剤は見い出されていない。 Therefore, the elastase release inhibitor is useful as a therapeutic agent or preventive agent for these diseases. In recent years, active research has been carried out under such expectation, and various elastase release inhibitors have been reported, but their actions are not necessarily sufficient. In addition, no clinically useful drug has been found as an elastase release inhibitor comprising a hydroxyaliphatic sulfonic acid analog.
本発明の目的は、優れたエラスターゼ遊離抑制作用を有する新規なヒドロキシエイコセン酸類縁体、その製薬学的に許容される塩またはその水和物を有効成分とするエラスターゼ遊離抑制剤及び脳梗塞治療薬を提供することにある。 An object of the present invention is to provide a novel hydroxyeicosenoic acid analog having an excellent elastase release inhibitory activity, a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient, and a cerebral infarction treatment To provide medicine.
本発明者らは鋭意研究を進めた結果、下記に示す新規なヒドロキシエイコセン酸類縁体が、優れたエラスターゼ遊離抑制作用を有し、エラスターゼ遊離抑制剤及び脳梗塞治療薬として有用であることを見出し、本発明を完成した。 As a result of diligent research, the present inventors have found that the following novel hydroxyeicosenoic acid analogs have excellent elastase release inhibitory activity and are useful as elastase release inhibitors and cerebral infarction therapeutic agents. The headline and the present invention were completed.
本発明により、優れたエラスターゼ遊離抑制作用を有するエラスターゼ遊離抑制剤及び脳梗塞治療薬を提供することができる。 The present invention can provide an elastase release inhibitor and a cerebral infarction therapeutic agent having an excellent elastase release inhibitory action.
本発明は、下記式（Ｉ）で表される新規なヒドロキシエイコセン酸類縁体、その製薬学的に許容される塩またはその水和物を有効成分とするエラスターゼ遊離抑制剤及び脳梗塞治療薬である。
すなわち、本発明は、式（Ｉ）
The present invention relates to a novel hydroxyeicosenoic acid analog represented by the following formula (I), a pharmaceutically acceptable salt or hydrate thereof, and an elastase release inhibitor and a therapeutic agent for cerebral infarction. It is.
That is, the present invention provides a compound of formula (I)
（式中、Ｘはエチレン基、ビニレン基またはエチニレン基を示し、Ｙはエチレン基、ビニレン基、エチニレン基、ＯＣＨ2またはＳ（Ｏ）pＣＨ2を示し、ｐは０、１または２を示し、ｍは１から５の整数で、ｎは０から４の整数を示し、Ｒ1はＣ1-8のアルキル基、Ｃ3-8のシクロアルキル基、Ｃ3-8のシクロアルキル基で置換されたＣ1-4のアルキル基、アリール基で置換されたＣ1-4のアルキル基またはアリールオキシ基で置換されたＣ1-4のアルキル基を示し、Ｒ2は水素原子またはメチル基を示し、Ｒ1およびＲ2は互いに結合してＣ3-8のシクロアルキル基を形成する基を示し、Ｒ3は水素原子またはＣ2-8のアシル基を示し、Ｒ4はＯＲ5またはＮＨＲ6を示し、Ｒ5は水素原子、Ｃ1-4のアルキル基、アルカリ金属、アルカリ土類金属またはアンモニウム基を示し、Ｒ6は水素原子またはＣ1-4のアルキル基を示す。）で表されるヒドロキシ脂肪族スルホン酸類縁体またはその水和物を有効成分とするエラスターゼ遊離抑制剤である。 (Wherein X represents an ethylene group, vinylene group or ethynylene group, Y represents an ethylene group, vinylene group, ethynylene group, OCH 2 or S (O) p CH 2 , p represents 0, 1 or 2) , M is an integer from 1 to 5, n is an integer from 0 to 4, and R 1 is substituted with a C 1-8 alkyl group, a C 3-8 cycloalkyl group, or a C 3-8 cycloalkyl group alkyl group C 1-4, an alkyl group or an alkyl group of C 1-4 substituted by an aryl group having C 1-4 which is substituted with an aryl group, an R 2 represents a hydrogen atom or a methyl group R 1 and R 2 are bonded to each other to form a C 3-8 cycloalkyl group, R 3 is a hydrogen atom or a C 2-8 acyl group, and R 4 is OR 5 or NHR 6 wherein R 5 is a hydrogen atom, a C 1-4 alkyl group, an alkali metal, an alkaline earth metal or an amine R 6 represents a hydrogen atom or a C 1-4 alkyl group.) An elastase release inhibitor containing a hydroxy aliphatic sulfonic acid analog represented by the following formula or an hydrate thereof as an active ingredient.
また、本発明は、上記エラスターゼ遊離抑制剤からなる脳梗塞治療薬である。 The present invention is also a therapeutic agent for cerebral infarction comprising the elastase release inhibitor.
本発明において、ビニレン基とは、シスビニレン基、トランスビニレン基を示す。 In the present invention, the vinylene group refers to a cis vinylene group or a trans vinylene group.
Ｃ1-4のアルキル基とは、直鎖状又は分枝鎖状のアルキル基を示し、例えばメチル基、エチル基、プロピル基、イソプロピル基、ブチル基、イソブチル基などを挙げることができる。 The C 1-4 alkyl group represents a linear or branched alkyl group, and examples thereof include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, and an isobutyl group.
Ｃ1-8のアルキル基とは、直鎖状又は分枝鎖状のアルキル基を示し、例えばメチル基、エチル基、プロピル基、ブチル基、イソブチル基、ペンチル基、ヘキシル基、へプチル基、オクチル基、２−メチルヘキサ−１−イル基、2，4−ジメチルペンタ−１−イル基などを挙げることができる。 The C 1-8 alkyl group represents a linear or branched alkyl group, for example, methyl group, ethyl group, propyl group, butyl group, isobutyl group, pentyl group, hexyl group, heptyl group, An octyl group, a 2-methylhex-1-yl group, a 2,4-dimethylpent-1-yl group, and the like can be given.
Ｃ3-8のシクロアルキル基とは、例えばシクロプロピル基、シクロブチル基、シクロペンチル基、シクロヘキシル基、シクロヘプチル基、シクロオクチル基などを挙げることができる。 Examples of the C 3-8 cycloalkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group.
アリール基で置換されたＣ1-4のアルキル基とは、例えばベンジル基、メトキシベンジル基、フェネチル基、フェニルプロピル基、２−フェニルプロパ−２−イル基、３−フェニルブタ−１−イル基などを挙げることができる。 Examples of the C 1-4 alkyl group substituted with an aryl group include a benzyl group, a methoxybenzyl group, a phenethyl group, a phenylpropyl group, a 2-phenylprop-2-yl group, and a 3-phenylbut-1-yl group. And so on.
Ｃ3-8のシクロアルキル基で置換されたＣ1-4のアルキル基とは、例えばシクロペンチルメチル基、シクロヘキシルメチル基、シクロヘキシルエチル基、シクロプロピルエチル基、シクロヘプチルプロピル基などを挙げることができる。 Examples of the C 1-4 alkyl group substituted with a C 3-8 cycloalkyl group include a cyclopentylmethyl group, a cyclohexylmethyl group, a cyclohexylethyl group, a cyclopropylethyl group, and a cycloheptylpropyl group. .
アリールオキシ基で置換されたＣ1-4のアルキル基とは、例えばフェノキシメチル基、フェノキシエチル基、フェノキシプロピル基、2−フェノキシプロパ−２−イル基、トリルオキシメチル基などを挙げることができる。 Examples of the C 1-4 alkyl group substituted with an aryloxy group include a phenoxymethyl group, a phenoxyethyl group, a phenoxypropyl group, a 2-phenoxyprop-2-yl group, and a tolyloxymethyl group. .
Ｃ2-8のアシル基とは、例えばアセチル基、プロピオニル基、ブチリル基、イソブチリル基、バレリル基、ピバロイル基、ベンゾイル基、トルオイル基などを挙げることができる。 Examples of the C 2-8 acyl group include an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, a valeryl group, a pivaloyl group, a benzoyl group, and a toluoyl group.
アルカリ金属とは、例えばリチウム、ナトリウム、カリウムなどを挙げることができる。 Examples of the alkali metal include lithium, sodium, and potassium.
アルカリ土類金属とは、例えばカルシウム、マグネシウムなどを挙げることができる。 Examples of the alkaline earth metal include calcium and magnesium.
アンモニウム基とは、例えばアンモニア、メチルアミン、ジメチルアミン、ジエチルアミン、シクロペンチルアミン、ベンジルアミン、ピペリジン、モノエタノールアミン、ジエタノールアミン、モノメチルモノエタノールアミン、トリエタノールアミン、トロメタミン、リジン、オルニチン、ピペラジン、ベンザチン、アミノピリジン、プロカイン、コリン、トリス（ヒドロキシメチル）アミノメタン、エチレンジアミンなどとの塩およびテトラアルキルアンモニウム塩が挙げられる。 Examples of ammonium groups include ammonia, methylamine, dimethylamine, diethylamine, cyclopentylamine, benzylamine, piperidine, monoethanolamine, diethanolamine, monomethylmonoethanolamine, triethanolamine, tromethamine, lysine, ornithine, piperazine, benzathine, amino Examples thereof include salts with pyridine, procaine, choline, tris (hydroxymethyl) aminomethane, ethylenediamine, and tetraalkylammonium salts.
式（Ｉ）の化合物は、例えば以下の反応式に要約する方法により製造できる。
（反応式中、Ｚ、Ｚ2は同一または異なってはハロゲン原子もしくはメタンスルホニルオキシ基、 ｐ−トルエンスルホニルオキシ基などの脱離基を示し、Ｙ2はＯＣＨ2、ＳＣＨ2を示し、Ｙ3はエチレン基、ビニレン基、エチニレン基、ＯＣＨ2、ＳＣＨ2を示し、Ｙ4はエチレン基、シスビニレン基、ＯＣＨ2、ＳＣＨ2を示し、Ｘ2はビニレン基、エチニレン基を示し、Ｘ3はエチレン基、シスビニレン基、を示し、Ｒ7およびＲ8は同一または異なって例えばトリメチルシリル基、 トリエチルシリル基、 ｔｅｒｔ−ブチルジメチルシリル基、 ｔｅｒｔ−ブチルジフェニルシリル基、 メトキシメチル基、 エトキシエチル基, テトラヒドロピラニル基, ベンジル基, ｐ−メトキシベンジル基などの塩基に対して安定な水酸基の保護基を示し、Ｒ31は水素原子以外のＲ3を示し、Ｒ51はＣ1-4のアルキル基を示し、ｐ１は１または２の整数を示し、Ｒ1、Ｒ2、Ｒ3、Ｒ4、Ｒ5、Ｒ6、Ｘ、Ｙ、ｍ、ｎおよびｐは前記と同義である。）
Compounds of formula (I) can be prepared, for example, by the methods summarized in the following reaction scheme.
(In the reaction formula, Z and Z 2 are the same or different and represent a leaving group such as a halogen atom, a methanesulfonyloxy group or a p-toluenesulfonyloxy group, Y 2 represents OCH 2 or SCH 2 , Y 3 Represents ethylene group, vinylene group, ethynylene group, OCH 2 , SCH 2 , Y 4 represents ethylene group, cisvinylene group, OCH 2 , SCH 2 , X 2 represents vinylene group, ethynylene group, X 3 represents ethylene R 7 and R 8 are the same or different, for example, trimethylsilyl group, triethylsilyl group, tert-butyldimethylsilyl group, tert-butyldiphenylsilyl group, methoxymethyl group, ethoxyethyl group, tetrahydropyrani A hydroxyl-protecting group which is stable against a base such as a ru group, a benzyl group or a p-methoxybenzyl group; 31 represents R 3 other than a hydrogen atom, R 51 represents a C 1-4 alkyl group, p1 represents an integer of 1 or 2, and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X, Y, m, n, and p are as defined above.
（１）式（ＩＩ）で表される化合物と式（ＩＩＩ）で表される化合物とを適当な有機溶媒（例えば、テトラヒドロフラン、ヘキサメチルホスホリック トリアミド、Ｎ，Ｎ'−ジメチルプロピレンウレア、アンモニア、ジメチルスルホキシド、ジメチルホルムアミドなど）、またはこれらの混合溶媒中、塩基（例えば、ｎ−ブチルリチウム、リチウムアミド、ナトリウムアミドなど）の存在下 −78℃〜室温で反応させ式（ＩＶ）で表される化合物を得る。 (1) A compound represented by formula (II) and a compound represented by formula (III) are mixed with a suitable organic solvent (for example, tetrahydrofuran, hexamethylphosphoric triamide, N, N′-dimethylpropylene urea, ammonia, Dimethyl sulfoxide, dimethylformamide, etc.) or a mixed solvent thereof in the presence of a base (for example, n-butyllithium, lithium amide, sodium amide, etc.) at −78 ° C. to room temperature, represented by the formula (IV) A compound is obtained.
（２）式（ＩＶ）の化合物に適当な有機溶媒（例えば、メタノール、エタノールなどのアルコール系溶媒もしくはテトラヒドロフラン、ジエチルエーテルなどのエーテル系溶媒あるいはこれらの混合溶媒）中、有機酸（例えば、ｐ−トルエンスルホン酸、酢酸など）もしくはそのアミン塩（例えば、ｐ−トルエンスルホン酸 ピリジン塩など）、または無機酸（例えば、塩酸、硫酸など）を用い、０℃〜60℃、好ましくは室温〜40℃で反応させ水酸基の保護基をはずして式（ＩＶ2）で表される化合物を得る。 (2) In an organic solvent suitable for the compound of formula (IV) (for example, an alcohol solvent such as methanol or ethanol, an ether solvent such as tetrahydrofuran or diethyl ether or a mixed solvent thereof), an organic acid (for example, p- Toluenesulfonic acid, acetic acid, etc.) or amine salts thereof (for example, p-toluenesulfonic acid, pyridine salt, etc.) or inorganic acids (for example, hydrochloric acid, sulfuric acid, etc.) are used. To remove the hydroxyl protecting group to obtain a compound represented by the formula (IV 2 ).
（３）式（ＩＶ2）の化合物と式（Ｖ）で表される化合物とを上記（１）と同様に反応を行い、式（ＶＩ）で表される化合物を得る。 (3) The reaction was conducted in the same manner as Formula (IV 2) compounds with compounds represented by formula (V) and the (1) to obtain a compound of formula (VI).
（４）式（ＶＩ）の化合物を、四塩化炭素−トリフェニルホスフィン、三臭化リン、四臭化炭素−トリフェニルホスフィン、ヨウ素−トリフェニルホスフィンなどを用いた直接的ハロゲン化、もしくはメタンスルホニルクロリド、ｐ−トルエンスルホニルクロリドなどを用いて脱離基への変換などを行って式（ＶＩ2）で表される化合物を得る。 (4) Direct halogenation using carbon tetrachloride-triphenylphosphine, phosphorus tribromide, carbon tetrabromide-triphenylphosphine, iodine-triphenylphosphine, or the like, or methanesulfonyl Conversion to a leaving group is performed using chloride, p-toluenesulfonyl chloride and the like to obtain a compound represented by the formula (VI 2 ).
（５）式（ＶＩ）または（ＶＩ2）の化合物を上記（２）と同様に反応を行い、それぞれ式（ＶＩ5）または（ＶＩ3）で表される化合物を得る。 (5) A compound of the formula (VI) or (VI 2 ) is reacted in the same manner as in the above (2) to obtain a compound represented by the formula (VI 5 ) or (VI 3 ), respectively.
（６）式（ＶＩ3）の化合物を還元（ 例えば、水素雰囲気下、パラジウム系触媒[Pd-CaCO3, Pd(OAc)2]、ニッケル系触媒[Ni(OAc)2+ NaBH4]を用いる方法（さらに必要に応じてエチレンジアミン、キノリンなどを添加）、メタノールや酢酸中亜鉛を還元剤として用いる方法など）することにより式（ＶＩ4）で表される化合物を得る。 (6) Reduction of the compound of formula (VI 3 ) (for example, using a palladium-based catalyst [Pd-CaCO 3 , Pd (OAc) 2 ] and a nickel-based catalyst [Ni (OAc) 2 + NaBH 4 ] in a hydrogen atmosphere) The compound represented by the formula (VI 4 ) is obtained by a method (addition of ethylenediamine, quinoline or the like, if necessary), a method using methanol or zinc in acetic acid as a reducing agent).
（７）ジエチルエーテル、テトラヒドロフラン、ＤＭＥ（エチレングリコール ジメチルエーテル）、トルエンなどの溶媒中、ＬＡＨ（水素化リチウムアルミニウム）、Ｒｅｄ−Ａｌ（ナトリウム水素化ビス（２−メトキシエトキシ）アルミニウム）などのを用いたヒドリド還元系を用い、またはリチウム−液体アンモニア、ナトリウム−液体アンモニアなどを用いたディスソルビング−メタル還元系を用いて、式（ＶＩ5）の化合物を還元し式（ＶＩ6）で表される化合物を得る。 (7) LAH (lithium aluminum hydride), Red-Al (sodium bis (2-methoxyethoxy) aluminum hydride), etc. were used in solvents such as diethyl ether, tetrahydrofuran, DME (ethylene glycol dimethyl ether) and toluene. A compound represented by the formula (VI 6 ) by reducing the compound of the formula (VI 5 ) using a hydride reduction system or a dissolving-metal reduction system using lithium-liquid ammonia, sodium-liquid ammonia or the like. Get.
（８）式（ＶＩ6）の化合物を上記（４）と同様に反応を行い、式（ＶＩ7）で表される化合物を得る。 (8) The compound of the formula (VI 6 ) is reacted in the same manner as in the above (4) to obtain the compound represented by the formula (VI 7 ).
（９）式（ＩＩ2）で表される化合物と式（Ｖ）の化合物とを、上記（１）と同様に反応を行い、式（ＶＩＩ）で表される化合物を得る。 (9) The compound represented by the formula (II 2 ) is reacted with the compound of the formula (V) in the same manner as in the above (1) to obtain the compound represented by the formula (VII).
（１０）式（ＶＩＩ）の化合物を、上記（２）と同様の反応を行い、式（ＶＩＩ2）で表される化合物を得る。 (10) The compound of formula (VII) is reacted in the same manner as in the above (2) to obtain a compound represented by formula (VII 2 ).
（１１）式（ＶＩＩ2）の化合物を、上記（６）と同様の反応を行い、式（ＶＩＩ3）で表される化合物を得る。 (11) The compound of the formula (VII 2 ) is subjected to the same reaction as in the above (6) to obtain a compound represented by the formula (VII 3 ).
（１２）式（ＩＩ3）で表される化合物と式（Ｖ）の化合物とを、上記（１）と同様に反応を行い、式（ＶＩＩＩ）で表される化合物を得る。 (12) The compound represented by the formula (II 3 ) and the compound of the formula (V) are reacted in the same manner as in the above (1) to obtain the compound represented by the formula (VIII).
（１３）式（ＶＩＩＩ）の化合物を、上記（６）と同様の反応を行い、式（ＶＩＩＩ4）で表される化合物を得る。 (13) The compound of formula (VIII) is reacted in the same manner as in the above (6) to obtain a compound represented by formula (VIII 4 ).
（１４）式（ＶＩＩＩ）の化合物を、上記（２）と同様の反応を行い、式（ＶＩＩＩ7）で表される化合物を得る。 (14) The compound of the formula (VIII) is reacted in the same manner as in the above (2) to obtain a compound represented by the formula (VIII 7 ).
（１５）式（ＶＩＩＩ7）の化合物を、上記（７）と同様の還元を行い、式（ＶＩＩＩ8）で表される化合物を得る。 (15) The compound of the formula (VIII 7 ) is reduced in the same manner as in the above (7) to obtain a compound represented by the formula (VIII 8 ).
（１６）式（ＶＩＩＩ）、（ＶＩＩＩ4）または（ＶＩＩＩ8）の化合物を、上記（４）と同様の反応を行い、それぞれ式（ＶＩＩＩ2）、（ＶＩＩＩ5）または（ＶＩＩＩ9）で表される化合物を得る。 (16) A compound of the formula (VIII), (VIII 4 ) or (VIII 8 ) is reacted in the same manner as in the above (4), and is represented by the formula (VIII 2 ), (VIII 5 ) or (VIII 9 ), respectively. To obtain the compound.
（１７）式（ＶＩＩＩ2）または（ＶＩＩＩ5）の化合物を、上記（２）と同様の反応を行い、式（ＶＩＩＩ3）または（ＶＩＩＩ6）で表される化合物を得る。 (17) A compound of the formula (VIII 2 ) or (VIII 5 ) is subjected to the same reaction as in the above (2) to obtain a compound represented by the formula (VIII 3 ) or (VIII 6 ).
（１８）式（ＩＩ）の化合物と式（Ｖ）の化合物とを、上記（１）と同様の反応を行い、式（ＩＸ）で表される化合物を得る。 (18) The compound of formula (II) and the compound of formula (V) are reacted in the same manner as in the above (1) to obtain a compound represented by formula (IX).
（１９）式（ＩＸ）の化合物を、上記（２）と同様の反応を行い、式（ＸＩ4）
で表される化合物を得る。
(19) The compound of formula (IX) is reacted in the same manner as in the above (2) to give a compound of formula (XI 4 )
To obtain a compound represented by:
（２０）式（ＸＩ4）の化合物を、上記（６）と同様の還元を行い、式（ＸＩ5）で表される化合物を得る。 (20) The compound of formula (XI 4 ) is reduced in the same manner as in the above (6) to obtain a compound represented by formula (XI 5 ).
（２１）式（ＸＩ4）の化合物を、上記（７）と同様の反応を行い、式（ＸＩ8）で表される化合物を得る。 (21) The compound of the formula (XI 4 ) is reacted in the same manner as in the above (7) to obtain a compound represented by the formula (XI 8 ).
（２２）式（ＩＸ）、（ＸＩ5）または（ＸＩ8）と式（Ｘ）とを、適当な有機溶媒（例えば、メタノール、エタノール、ｔｅｒｔ−ブタノール、アセトン、ジメチルホルムアミド、テトラヒドロフランまはたアセトニトリルなど）中、適当な塩基（例えば、トリエチルアミン、水素化ナトリウム、水素化カリウム、炭酸水素ナトリウム、炭酸カリウム、水酸化ナトリウム、炭酸カルシウムなど）または四級アンモニウム塩（例えば、Ｅｔ4ＮＢｒなど）の存在下、必要に応じてヨウ化ナトリウムなどを加えて反応を行い、それぞれ式（ＸＩ）、（ＸＩ6）または（ＸＩ9）で表される化合物を得る。 (22) Formula (IX), (XI 5 ) or (XI 8 ) and Formula (X) are converted into a suitable organic solvent (for example, methanol, ethanol, tert-butanol, acetone, dimethylformamide, tetrahydrofuran or acetonitrile) In the presence of a suitable base (eg, triethylamine, sodium hydride, potassium hydride, sodium bicarbonate, potassium carbonate, sodium hydroxide, calcium carbonate, etc.) or a quaternary ammonium salt (eg, Et 4 NBr) Then, if necessary, the reaction is carried out by adding sodium iodide or the like to obtain a compound represented by the formula (XI), (XI 6 ) or (XI 9 ).
（２３）式（ＸＩ）、（ＸＩ6）または（ＸＩ9）の化合物を、上記（４）と同様にハロゲン化を行い、それぞれ式（ＸＩ2）、（ＸＩ7）または（ＸＩ10）で表される化合物を得る。 (23) A compound of the formula (XI), (XI 6 ) or (XI 9 ) is halogenated in the same manner as in the above (4), and the compound of the formula (XI 2 ), (XI 7 ) or (XI 10 ) is used. The compound represented is obtained.
（２４）式（ＸＩ2）の化合物を、上記（２）と同様に反応を行い、式（ＸＩ3）で表される化合物を得る。 (24) The compound of the formula (XI 2 ) is reacted in the same manner as in the above (2) to obtain a compound represented by the formula (XI 3 ).
（２５）ピリジン、ジクロロメタンなどの適当な有機溶媒中、式（ＸＩＩ）の化合物と酸無水物（例えば、無水酢酸、無水酪酸、無水ピバリン酸、無水吉草酸など）または酸クロリド（例えば、アセチルクロリド、ピバロイルクロリド、バレリルクロリド、ベンゾイルクロリド、トルオイルクロリドなど）とを、必要に応じて４−（ジメチルアミノ）ピリジンなどを加えて反応させて式（ＸＩＩ2）で表される化合物を得る。 (25) A compound of formula (XII) and an acid anhydride (eg, acetic anhydride, butyric anhydride, pivalic anhydride, valeric anhydride, etc.) or an acid chloride (eg, acetyl chloride) in a suitable organic solvent such as pyridine or dichloromethane. , Pivaloyl chloride, valeryl chloride, benzoyl chloride, toluoyl chloride, etc.) and 4- (dimethylamino) pyridine, etc., as necessary, and reacted to give a compound represented by the formula (XII 2 ) obtain.
（２６）式（ＸＩＩ）または（ＸＩＩ2）の化合物を、適当な有機溶媒（例えば、ジメチルスルホキシド、ジメチルホルムアミド、テトラヒドロフラン、ジオキサン、メタノール、エタノールまたはアセトンなど）と水との混合溶媒中、必要に応じてヨウ化ナトリウムを加えて亜硫酸ナトリウムとを反応させて、式（Ｉａ）または（Ｉｃ）で表される化合物を得る。 (26) The compound of the formula (XII) or (XII 2 ) is necessary in a mixed solvent of a suitable organic solvent (for example, dimethyl sulfoxide, dimethylformamide, tetrahydrofuran, dioxane, methanol, ethanol or acetone) and water. Accordingly, sodium iodide is added and reacted with sodium sulfite to obtain a compound represented by the formula (Ia) or (Ic).
（２７）式（Ｉａ）または（Ｉｃ）の化合物を、水素雰囲気下、パラジウム系触媒[例えば、Pd-炭素、Pd-CaCO3、 Pb(OAc)2など]を用い、還元してそれぞれ式（Ｉｂ）または式（Ｉｄ）で表される化合物を得る。 (27) A compound of formula (Ia) or (Ic) is reduced using a palladium-based catalyst [for example, Pd-carbon, Pd-CaCO 3 , Pb (OAc) 2, etc.] under a hydrogen atmosphere, A compound represented by Ib) or formula (Id) is obtained.
（２８）式（Ｉｄ）の化合物を、通常加水分解に用いられる塩基（例えば、ナトリウムメトキシド、ナトリウムエトキシド、水酸化ナトリウムなど）を用いて、適当な有機溶媒（例えば、メタノール、エタノール、ジオキサン）または水、もしくはそれらと水との混合溶媒中反応させて式（Ｉｂ）で表される化合物を得る。 (28) A compound of formula (Id) is converted into a suitable organic solvent (eg, methanol, ethanol, dioxane) using a base usually used for hydrolysis (eg, sodium methoxide, sodium ethoxide, sodium hydroxide, etc.). ) Or water or a mixed solvent thereof with water to obtain a compound represented by the formula (Ib).
（２９）式（Ｉｅ）で表される化合物を水、メタノール、エタノールなどの適当な溶媒中、−２０℃から溶媒還流下でメタ過ヨウ素酸ナトリウムと反応させ、式（Ｉｆ）で表される化合物を得る。 (29) A compound represented by the formula (Ie) is reacted with sodium metaperiodate in a suitable solvent such as water, methanol, ethanol and the like at −20 ° C. under solvent reflux, and represented by the formula (If) A compound is obtained.
（３０）式（Ｉｇ）で表される化合物を、ジメチルスルホキシド、ジメチルホルムアミドなどの適当な有機溶媒中、塩化チオニル、三塩化リンまたは五塩化リンと反応させ、次いでＮＨ2Ｒ6と反応させることにより、式（Ｉｈ）で表される化合物を得る。 (30) reacting a compound represented by the formula (Ig) with thionyl chloride, phosphorus trichloride or phosphorus pentachloride in a suitable organic solvent such as dimethyl sulfoxide, dimethylformamide and then reacting with NH 2 R 6 To obtain a compound represented by the formula (Ih).
（３１）式（Ｉｈ）の化合物を、上記（２８）と同様に反応を行い、式（Ｉｉ）で表される化合物を得る。 (31) The compound of formula (Ih) is reacted in the same manner as in the above (28) to obtain a compound represented by formula (Ii).
（３２）式（Ｉｉ）の化合物を、メタノール、エタノールまたはジオキサンなどの適当な有機溶媒中、塩酸または硫酸と反応させた後、ジアゾメタン、ジアゾエタン、ジアゾプロパンまたは（トリメチルシリル）ジアゾメタンなどのジアゾアルカンと反応させ、式（Ｉｋ）で表される化合物を得る。 (32) A compound of formula (Ii) is reacted with hydrochloric acid or sulfuric acid in a suitable organic solvent such as methanol, ethanol or dioxane and then reacted with a diazoalkane such as diazomethane, diazoethane, diazopropane or (trimethylsilyl) diazomethane. To obtain a compound represented by the formula (Ik).
本発明のエラスターゼ遊離抑制剤または脳梗塞治療薬は、全身的または局所的に経口または直腸内、皮下、筋肉内、静脈内経皮等の非経口的に投与される。例えば、通常の方法により製造することができる錠剤、粉剤、顆粒剤、散剤、カプセル剤、液剤、乳剤、懸濁剤等の形で経口投与することができる。静脈内投与の製剤としては、水性または非水性溶液剤、乳剤、懸濁剤、使用直前に注射溶媒に溶解して使用する固形製剤等を用いることができる。また、本発明のエラスターゼ遊離抑制剤または脳梗塞治療薬は、式（Ｉ）で表される化合物をα、βもしくはγ−シクロデキストリンまたは各修飾シクロデキストリン等と包接化合物を形成させて製剤化することもできる。更に、その水性または非水性溶液剤、乳剤、懸濁剤等を注射等により投与することができる。投与量は年齢、体重等により異なるが、成人に対し、１ng／kg／日〜1000／kg／日であり、これを１日１回または数回に分けて投与する。 The elastase release inhibitor or therapeutic agent for cerebral infarction of the present invention is administered systemically or locally orally or parenterally such as intrarectally, subcutaneously, intramuscularly, intravenously or transdermally. For example, it can be orally administered in the form of tablets, powders, granules, powders, capsules, solutions, emulsions, suspensions and the like that can be produced by conventional methods. As a preparation for intravenous administration, an aqueous or non-aqueous solution, an emulsion, a suspension, a solid preparation dissolved in an injection solvent immediately before use, or the like can be used. Also, the elastase release inhibitor or cerebral infarction drug of the present invention is formulated by forming a compound represented by the formula (I) with α, β or γ-cyclodextrin or each modified cyclodextrin and the like to form an inclusion compound. You can also Furthermore, the aqueous or non-aqueous solution, emulsion, suspension and the like can be administered by injection or the like. Although the dosage varies depending on age, weight, etc., it is 1 ng / kg / day to 1000 / kg / day for adults, and this is administered once or divided into several times a day.
本発明のエラスターゼ遊離抑制剤または脳梗塞治療薬に係る代表的な式（Ｉ）の化合物としては下記を挙げることができる。 Typical examples of the compound of the formula (I) relating to the elastase release inhibitor or the cerebral infarction therapeutic agent of the present invention include the following.
以下、実施例および試験例を挙げて本発明をより具体的に説明する。 Hereinafter, the present invention will be described more specifically with reference to examples and test examples.
(R)-(4Z, 13Z)-15-ヒドロキシノナデカ-4,13-ジエン-1-スルホン酸 ナトリウム塩（化合物２３）
(1) アルゴン気流下、5-テトラヒドロピラニルオキシ-1-ペンチン(5.0 g, 29.7 mmol)のTHF (テトラヒドロフラン) (30 mL)溶液に、n-ブチルリチウム (13.4 mL, 2.66M ヘキサン溶液, 35.6 mmol) を 10oCで滴下し、さらに同温度で30分間攪拌した。この反応液を、1,7-ジブロモヘプタン(15.32 g, 59.41 mmol)のTHF (100 mL) および DMPU (N, N'-ジメチルプロピレンウレア) (10 mL)の混合溶液に1 oCで滴下し、０℃で1時間さらに室温で1時間攪拌した。反応液に塩酸 (20 mL, 3.0M)を加えAcOEt (150 mL x 2)抽出した。有機層を飽和食塩水 (500 mL)洗浄, 無水硫酸マグネシウム乾燥、濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィーで精製して、2-(12-ブロモドデカ-4-イニルオキシ)テトラヒドロピラン (9.51 g)を得た。
(R)-(4Z, 13Z) -15-Hydroxynonadeca-4,13-diene-1-sulfonic acid sodium salt (Compound 23)
(1) Under a stream of argon, a solution of 5-tetrahydropyranyloxy-1-pentyne (5.0 g, 29.7 mmol) in THF (tetrahydrofuran) (30 mL) was added to n-butyllithium (13.4 mL, 2.66 M hexane solution, 35.6 mmol) was added dropwise at 10 ° C., and the mixture was further stirred at the same temperature for 30 minutes. The reaction solution was added dropwise to a mixed solution of 1,7-dibromoheptane (15.32 g, 59.41 mmol) in THF (100 mL) and DMPU (N, N'-dimethylpropylene urea) (10 mL) at 1 ° C. The mixture was stirred at 0 ° C. for 1 hour and further at room temperature for 1 hour. Hydrochloric acid (20 mL, 3.0M) was added to the reaction mixture, and AcOEt (150 mL x 2) was extracted. The organic layer was washed with saturated brine (500 mL), dried over anhydrous magnesium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography to obtain 2- (12-bromododec-4-ynyloxy) tetrahydropyran (9.51 g).
1H-NMR (CDCl3, 300MHz) δppm: 1.20-1.63 (m, 12H), 1.64-1.92 (m, 6H), 2.09-2.17 (m, 2H), 2.20-2.30 (m, 2H), 3.41 (t, J=6.8Hz, 2H), 3.44-3.55 (m, 2H), 3.77-3.92 (m, 2H), 4.57-4.63 (m, 1H)
IR (neat): 3400, 2934, 2857, 1440, 1384, 1354, 1200, 1260, 1138, 1120, 1034, 1063, 990, 902, 869, 815, 646, 563 cm-1 1 H-NMR (CDCl 3 , 300MHz) δppm: 1.20-1.63 (m, 12H), 1.64-1.92 (m, 6H), 2.09-2.17 (m, 2H), 2.20-2.30 (m, 2H), 3.41 ( t, J = 6.8Hz, 2H), 3.44-3.55 (m, 2H), 3.77-3.92 (m, 2H), 4.57-4.63 (m, 1H)
IR (neat): 3400, 2934, 2857, 1440, 1384, 1354, 1200, 1260, 1138, 1120, 1034, 1063, 990, 902, 869, 815, 646, 563 cm -1
(2)上記(1)で得た化合物 (7.0 g, 20.3 mmol)のメタノール(29 mL)溶液に塩酸 (0.58 mL, 3.0M)を室温で加え、室温で一夜攪拌した。反応液に飽和重曹水を加え、AcOEt (100 mL)抽出した。有機層を飽和食塩水で洗浄、無水硫酸マグネシウム乾燥、濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィーで精製して、 12-ブロモドデカ-4-イン-1-オール (4.75 g)を得た。アルゴン気流下、この化合物(3.96 g, 15 mmol)と(R)-3-tert-ブチルジメチルシラニルオキシ-1-ヘプチン (3.82 g, 16.9 mmol)のTHF (169 mL) および HMPA (ヘキサメチルホスホリックトリアミド) (67.6 mL)の混合溶液に、n-ブチルリチウム (16.8 mL, 2.66M ヘキサン溶液, 44.6 mmol)を60oC で滴下した。次いで、反応液の温度を3.5時間かけて0℃へ昇温した。反応液に水を加え、 AcOEt (200 mL x 2)抽出した。有機層を塩酸 (20 mL, 3.0M)、水および飽和食塩水洗浄、無水硫酸マグネシウム乾燥、濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィーで精製して、(R)-15-(tert-ブチルジメチルシラニルオキシ)ノナデカ-4,13-ジイン-1-オール (6.38 g)を得た。 (2) Hydrochloric acid (0.58 mL, 3.0M) was added to a solution of the compound obtained in (1) (7.0 g, 20.3 mmol) in methanol (29 mL) at room temperature and stirred overnight at room temperature. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with AcOEt (100 mL). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography to obtain 12-bromododec-4-yn-1-ol (4.75 g). Under an argon stream, this compound (3.96 g, 15 mmol) and (R) -3-tert-butyldimethylsilanyloxy-1-heptin (3.82 g, 16.9 mmol) in THF (169 mL) and HMPA (hexamethylphosphine) N-butyllithium (16.8 mL, 2.66M hexane solution, 44.6 mmol) was added dropwise at 60 ° C. to a mixed solution of (holic triamide) (67.6 mL). Next, the temperature of the reaction solution was raised to 0 ° C. over 3.5 hours. Water was added to the reaction mixture, and AcOEt (200 mL x 2) was extracted. The organic layer was washed with hydrochloric acid (20 mL, 3.0M), water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography to obtain (R) -15- (tert-butyldimethylsilanyloxy) nonadeca-4,13-diin-1-ol (6.38 g).
1H-NMR (CDCl3, 300MHz) δppm: 0.10 (s, 3H), 0.12 (s, 3H), 0.84-0.97 (m, 12H), 1.23-1.58 (m, 14H), 1.59-1.68 (m, 2H), 1.69-1.80 (m, 2H), 2.10-2.22 (m, 4H), 2.25-2.32 (m, 2H), 3.76 (t, J=6.0Hz, 2H), 4.28-4.35 (m, 1H)
IR (neat): 3368, 2931, 2858, 2360, 1712, 1463, 1385, 1361, 1337, 1251, 1152, 1078, 937, 838, 778, 669, 424 cm-1 1 H-NMR (CDCl 3 , 300MHz) δppm: 0.10 (s, 3H), 0.12 (s, 3H), 0.84-0.97 (m, 12H), 1.23-1.58 (m, 14H), 1.59-1.68 (m, 2H), 1.69-1.80 (m, 2H), 2.10-2.22 (m, 4H), 2.25-2.32 (m, 2H), 3.76 (t, J = 6.0Hz, 2H), 4.28-4.35 (m, 1H)
IR (neat): 3368, 2931, 2858, 2360, 1712, 1463, 1385, 1361, 1337, 1251, 1152, 1078, 937, 838, 778, 669, 424 cm -1
(3)上記(2)で得た化合物 (2.73 g, 6.95 mmol)と四臭化炭素(3.0g, 9.0mmol)のジクロロメタン溶液(100 mL)に、トリフェニルホスフィン(2.20 g, 9.73 mmol)のジクロロメタン (10 mL)溶液を0oCで加えた。混合液を室温で1時間攪拌した後濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィーで精製して、 (R)-(15-ブロモ-1-ブチルペンタデカ-2,11-ジイニルオキシ)-tert-ブチルジメチルシラン (2.69 g, 5.73 mmol)を得た。 (3) Triphenylphosphine (2.20 g, 9.73 mmol) was added to a dichloromethane solution (100 mL) of the compound (2.73 g, 6.95 mmol) obtained in (2) above and carbon tetrabromide (3.0 g, 9.0 mmol). A solution of dichloromethane (10 mL) was added at 0 ° C. The mixture was stirred at room temperature for 1 hour and then concentrated. The resulting crude product was purified by silica gel column chromatography to obtain (R)-(15-bromo-1-butylpentadeca-2,11-diynyloxy) -tert-butyldimethylsilane (2.69 g, 5.73 mmol) Got.
1H-NMR (CDCl3, 300MHz) δppm: 0.10 (s, 3H), 0.12 (s, 3H), 0.84-0.96 (m, 12H), 1.23-1.68 (m, 16H), 1.95-2.05 (m, 2H), 2.10-2.22 (m, 4H), 2.30-2.38 (m, 2H), 3.52 (t, J=6.5Hz, 2H), 4.28-4.35 (m, 1H)
IR (neat): 2931, 2857, 2214, 1709, 1676, 1595, 1463, 1433, 1350, 1249, 1082, 1005, 938, 837, 778, 668, 566 cm-1 1 H-NMR (CDCl 3 , 300 MHz) δppm: 0.10 (s, 3H), 0.12 (s, 3H), 0.84-0.96 (m, 12H), 1.23-1.68 (m, 16H), 1.95-2.05 (m, 2H), 2.10-2.22 (m, 4H), 2.30-2.38 (m, 2H), 3.52 (t, J = 6.5Hz, 2H), 4.28-4.35 (m, 1H)
IR (neat): 2931, 2857, 2214, 1709, 1676, 1595, 1463, 1433, 1350, 1249, 1082, 1005, 938, 837, 778, 668, 566 cm -1
(4)上記(3)で得た化合物(2.69 g, 5.73 mmol)のMeOH (50 mL)溶液に、塩酸(0.3 mL, 3.0M) を室温で加え、室温で2.5時間攪拌した。反応液に飽和重曹水(50 mL)を加え、AcOEt (100 mL x 2)抽出した。有機層を水 (50 mL)および飽和食塩水 (50 mL)洗浄、無水硫酸マグネシウム乾燥、濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィーで精製して、(R)-19-ブロモノナデカ-6,15-ジイン-5-オール (1.51 g)を得た。 (4) To a solution of the compound (2.69 g, 5.73 mmol) obtained in (3) above in MeOH (50 mL) was added hydrochloric acid (0.3 mL, 3.0M) at room temperature, and the mixture was stirred at room temperature for 2.5 hours. Saturated aqueous sodium hydrogen carbonate (50 mL) was added to the reaction solution, and AcOEt (100 mL x 2) was extracted. The organic layer was washed with water (50 mL) and saturated brine (50 mL), dried over anhydrous magnesium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography to obtain (R) -19-bromononadeca-6,15-diin-5-ol (1.51 g).
1H-NMR (CDCl3, 300MHz) δppm: 0.92 (t, J=7.1Hz, 3H), 1.25-1.72 (m, 16H), 1.96-2.05 (m, 2H), 2.09-2.24 (m, 4H), 2.30-2.38 (m, 2H), 3.52 (t, J=6.5Hz, 2H), 4.28-4.40 (m, 1H)
IR (neat): 3400, 2931, 2858, 2360, 1672, 1433, 1384, 1331, 1272, 1248, 1148, 1104, 1037 cm-1 1 H-NMR (CDCl 3 , 300MHz) δppm: 0.92 (t, J = 7.1Hz, 3H), 1.25-1.72 (m, 16H), 1.96-2.05 (m, 2H), 2.09-2.24 (m, 4H) , 2.30-2.38 (m, 2H), 3.52 (t, J = 6.5Hz, 2H), 4.28-4.40 (m, 1H)
IR (neat): 3400, 2931, 2858, 2360, 1672, 1433, 1384, 1331, 1272, 1248, 1148, 1104, 1037 cm -1
(5)水素雰囲気下、室温でNaBH4 (33 mg, 0.86 mmol) の EtOH (10 mL)懸濁液をNi(OAc)2・4H2O (122 mg, 0.43 mmol) の EtOH (10 mL) 溶液に滴下し、30分間攪拌した。反応液にエチレンジアミン (0.28 mL, 4.25 mmol) を室温で加え、さらに上記(4)で得た化合物 (1.51 g, 4.25 mmol)のEtOH（10 mL）溶液を滴下し、水素ガスの吸収がなくなるまで室温で3時間攪拌した。反応液に Et2O (50 mL)を加え、10分間攪拌しシリカゲルパッドで濾過、濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィーで精製して、(R)-(6Z, 15Z)-19-ブロモノナデカ-6,15-ジエン-5-オール (0.68 g)を得た。 (5) under a hydrogen atmosphere, NaBH 4 (33 mg, 0.86 mmol) at room temperature EtOH (10 mL) suspension Ni (OAc) 2 · 4H 2 O (122 mg, 0.43 mmol) in EtOH the (10 mL) The solution was added dropwise and stirred for 30 minutes. Ethylenediamine (0.28 mL, 4.25 mmol) was added to the reaction solution at room temperature, and then a solution of the compound obtained in (4) (1.51 g, 4.25 mmol) in EtOH (10 mL) was added dropwise until no hydrogen gas was absorbed. Stir at room temperature for 3 hours. Et 2 O (50 mL) was added to the reaction solution, stirred for 10 minutes, filtered through a silica gel pad, and concentrated. The obtained crude product was purified by silica gel column chromatography to obtain (R)-(6Z, 15Z) -19-bromononadeca-6,15-dien-5-ol (0.68 g).
1H-NMR (CDCl3, 300MHz) δppm: 0.91 (t, J=6.8Hz, 3H), 1.22-1.68 (m, 16H), 1.86-1.97 (m, 2H), 1.98-2.14 (m, 4H), 2.19 (q, J=7.4Hz, 2H), 3.41 (t, J=6.7Hz, 2H), 4.38-4.49 (m, 1H), 5.25-5.54 (m, 4H)
IR (neat): 3368, 3006, 2927, 2855, 2361, 1656, 1460, 1384, 1246, 1007, 727, 650, 565 cm-1 1 H-NMR (CDCl 3 , 300MHz) δppm: 0.91 (t, J = 6.8Hz, 3H), 1.22-1.68 (m, 16H), 1.86-1.97 (m, 2H), 1.98-2.14 (m, 4H) , 2.19 (q, J = 7.4Hz, 2H), 3.41 (t, J = 6.7Hz, 2H), 4.38-4.49 (m, 1H), 5.25-5.54 (m, 4H)
IR (neat): 3368, 3006, 2927, 2855, 2361, 1656, 1460, 1384, 1246, 1007, 727, 650, 565 cm -1
(6)上記(5)で得た化合物 (0.49 g, 1.364 mmol)のEtOH (20 mL) および水 (20 mL)混合溶液に亜硫酸ナトリウム(517 mg, 4.1 mmol) およびヨウ化ナトリウム (205 mg, 1.364 mmol)を室温で加え、還流下4時間攪拌した。反応液を濃縮後、シリカゲルカラムクロマトグラフィーおよび樹脂(HP-20, 日本連水)精製して、標記化合物(400 mg)を得た。 (6) To a mixed solution of the compound obtained in (5) above (0.49 g, 1.364 mmol) in EtOH (20 mL) and water (20 mL), sodium sulfite (517 mg, 4.1 mmol) and sodium iodide (205 mg, 1.364 mmol) was added at room temperature, and the mixture was stirred for 4 hours under reflux. The reaction mixture was concentrated and purified by silica gel column chromatography and resin (HP-20, Nipponrensui) to obtain the title compound (400 mg).
1H-NMR (DMSO-d6, 300MHz) δppm: 0.85 (t, J=6.5Hz, 3H), 1.13-1.67 (m, 18H), 1.89-2.10 (m, 6H), 2.33-2.41 (m, 2H), 4.12-4.28 (m, 1H), 4.44-4.51 (m, 1H), 5.20-5.42 (m, 4H)
IR (KBr): 3423, 3009, 2927, 2855, 2385, 2281, 1672, 1562, 1468, 1226, 1183, 1072, 797, 613, 427, 418 cm-1 1 H-NMR (DMSO-d 6 , 300MHz) δppm: 0.85 (t, J = 6.5Hz, 3H), 1.13-1.67 (m, 18H), 1.89-2.10 (m, 6H), 2.33-2.41 (m, 2H), 4.12-4.28 (m, 1H), 4.44-4.51 (m, 1H), 5.20-5.42 (m, 4H)
IR (KBr): 3423, 3009, 2927, 2855, 2385, 2281, 1672, 1562, 1468, 1226, 1183, 1072, 797, 613, 427, 418 cm -1
(R)-16-ヒドロキシエイコサ-5,14-ジイン-1-スルホン酸 ナトリウム塩（化合物３）
(1)実施例１(1)において、5-テトラヒドロピラニルオキシ-1-ペンチンの代わりに 6-テトラヒドロピラニルオキシ-1-ヘキシンを用い、実施例１(2)と実質的に同様にして、(R)-16-(tert-ブチルジメチルシラニルオキシ)エイコサ-5,14-ジイン-1-オールを得た。
(R) -16-Hydroxyeicosa-5,14-diyne-1-sulfonic acid sodium salt (Compound 3)
(1) In Example 1 (1), 6-tetrahydropyranyloxy-1-hexyne was used instead of 5-tetrahydropyranyloxy-1-pentyne, and substantially the same as in Example 1 (2). (R) -16- (tert-butyldimethylsilanyloxy) eicosa-5,14-diin-1-ol was obtained.
1H-NMR (CDCl3, 300MHz) δppm: 0.10 (s, 3H), 0.12 (s, 3H), 0.84-0.94 (m, 3H), 0.90 (s, 3H), 1.22-1.73 (m, 20H), 2.09-2.24 (m, 6H), 3.68 (t, J=6.3Hz, 2H), 4.27-4.35 (m, 1H)
IR (neat): 3340, 2930, 2233, 1463, 1435, 1361, 1338, 1251, 1214, 1152, 1110, 1078, 1006, 983, 938, 899, 837, 777, 724, 668, 551 cm-1 1 H-NMR (CDCl 3 , 300MHz) δppm: 0.10 (s, 3H), 0.12 (s, 3H), 0.84-0.94 (m, 3H), 0.90 (s, 3H), 1.22-1.73 (m, 20H) , 2.09-2.24 (m, 6H), 3.68 (t, J = 6.3Hz, 2H), 4.27-4.35 (m, 1H)
IR (neat): 3340, 2930, 2233, 1463, 1435, 1361, 1338, 1251, 1214, 1152, 1110, 1078, 1006, 983, 938, 899, 837, 777, 724, 668, 551 cm -1
(2)上記(1)で得た化合物を用い、実施例１(3)と実質的に同様にして、(R)-(16-ブロモ-1-ブチルヘキサデカ-2,11-ジイニルオキシ)-tert-ブチルジメチルシランを得た。 (2) (R)-(16-Bromo-1-butylhexadeca-2,11-diynyloxy)-is used in substantially the same manner as in Example 1 (3) using the compound obtained in (1) above. tert-Butyldimethylsilane was obtained.
1H-NMR (CDCl3, 300MHz) δppm: 0.10 (s, 3H), 0.12 (s, 3H), 0.87-0.96 (m, 3H), 0.90 (s, 9H), 1.24-1.69 (m, 18H), 1.91-2.03 (m, 2H), 2.09-2.25 (m, 6H), 3.44 (t, J=6.8Hz, 2H), 4.32 (tt, J=6.5, 2.0Hz, 1H)
IR (neat): 3119, 2931, 2858, 2234, 1463, 1433, 1402, 1361, 1336, 1251, 1152, 1110, 1083, 1005, 938, 837, 778, 667, 564 cm-1 1 H-NMR (CDCl 3 , 300MHz) δppm: 0.10 (s, 3H), 0.12 (s, 3H), 0.87-0.96 (m, 3H), 0.90 (s, 9H), 1.24-1.69 (m, 18H) , 1.91-2.03 (m, 2H), 2.09-2.25 (m, 6H), 3.44 (t, J = 6.8Hz, 2H), 4.32 (tt, J = 6.5, 2.0Hz, 1H)
IR (neat): 3119, 2931, 2858, 2234, 1463, 1433, 1402, 1361, 1336, 1251, 1152, 1110, 1083, 1005, 938, 837, 778, 667, 564 cm -1
(3)上記(2)で得た化合物を用い、実施例１(4)と実質的に同様にして、(R)-20-ブロモエイコサ-6,15-ジイン-5-オールを得た。 (3) Using the compound obtained in (2) above, (R) -20-bromoeicosa-6,15-diin-5-ol was obtained in substantially the same manner as in Example 1 (4).
1H-NMR (CDCl3, 300MHz) δppm: 0.92 (t, J=7.1Hz, 3H), 1.25-1.72 (m, 18H), 1.92-2.03 (m, 2H), 2.10-2.24 (m, 6H), 3.44 (t, J=6.8Hz, 2H), 4.30-4.39 (m, 1H)
IR (neat): 3231, 2933, 2858, 2214, 1672, 1630, 1460, 1433, 1383, 1333, 1293, 1251, 1148, 1104, 1036, 730, 630, 596, 563 cm-1 1 H-NMR (CDCl 3 , 300MHz) δppm: 0.92 (t, J = 7.1Hz, 3H), 1.25-1.72 (m, 18H), 1.92-2.03 (m, 2H), 2.10-2.24 (m, 6H) , 3.44 (t, J = 6.8Hz, 2H), 4.30-4.39 (m, 1H)
IR (neat): 3231, 2933, 2858, 2214, 1672, 1630, 1460, 1433, 1383, 1333, 1293, 1251, 1148, 1104, 1036, 730, 630, 596, 563 cm -1
(4)上記(3)で得た化合物を用い、実施例 1 (6) と実質的に同様にして、標記化合物を得た。
1H-NMR (DMSO-d6, 300MHz) δppm: 0.86 (t, J=7.1Hz,3H), 1.18-1.68 (m,20H), 2.04-2.21 (m,6H), 2.33-2.43 (m,2H), 4.09-4.19 (m,1H), 5.08 (d,J=5.6Hz,1H)
IR (KBr): 3534, 2935, 2857, 2232, 1630, 1466, 1282, 1246, 1201, 1180, 1080, 1060, 892, 796, 728, 608, 536, 482, 421 cm-1
(4) The title compound was obtained in substantially the same manner as in Example 1 (6) using the compound obtained in (3) above.
1 H-NMR (DMSO-d 6 , 300MHz) δppm: 0.86 (t, J = 7.1Hz, 3H), 1.18-1.68 (m, 20H), 2.04-2.21 (m, 6H), 2.33-2.43 (m, 2H), 4.09-4.19 (m, 1H), 5.08 (d, J = 5.6Hz, 1H)
IR (KBr): 3534, 2935, 2857, 2232, 1630, 1466, 1282, 1246, 1201, 1180, 1080, 1060, 892, 796, 728, 608, 536, 482, 421 cm -1
(R)-(Z)-15-ヒドロキシノナデカ-13-エン-1-スルホン酸 ナトリウム塩（化合物３３）
(1) 実施例１(1)において、1,7-ジブロモヘプタンおよび5-テトラヒドロピラニルオキシ-1-ペンチンの代わりに、それぞれ1,12-ジブロモドデカンおよび (R)-3-tert-ブチルジメチルシラニルオキシ-1-ヘプチンを用い、実施例 1 (1)と実質的に同様にして、(R)-(15-ブロモ-1-ブチルペンタデカ-2-イニルオキシ)-tert-ブチルジメチルシランを得た。
(R)-(Z) -15-Hydroxynonadeca-13-ene-1-sulfonic acid sodium salt (Compound 33)
(1) In Example 1 (1), instead of 1,7-dibromoheptane and 5-tetrahydropyranyloxy-1-pentine, 1,12-dibromododecane and (R) -3-tert-butyldimethyl, respectively Using silanyloxy-1-heptin, substantially as in Example 1 (1), (R)-(15-bromo-1-butylpentadec-2-ynyloxy) -tert-butyldimethylsilane was Obtained.
1H-NMR (CDCl3, 300MHz) δppm: 0.10 (s, 3H), 0.12 (s, 3H), 0.88-0.92 (m, 12H), 1.24-1.52 (m, 22H), 1.58-1.67 (m, 2H), 1.80-1.93 (m, 2H), 2.18 (dt, J=2.0, 6.9Hz, 2H), 3.41 (t, J=6.8Hz, 2H), 4.31 (ddt, J=1.9, 1.9, 6.5Hz, 1H)
IR (neat): 2930, 2856, 1464, 1361, 1341, 1251, 1152, 1110, 1083, 1005, 938, 838, 778, 667, 566 cm-1 1 H-NMR (CDCl 3 , 300MHz) δppm: 0.10 (s, 3H), 0.12 (s, 3H), 0.88-0.92 (m, 12H), 1.24-1.52 (m, 22H), 1.58-1.67 (m, 2H), 1.80-1.93 (m, 2H), 2.18 (dt, J = 2.0, 6.9Hz, 2H), 3.41 (t, J = 6.8Hz, 2H), 4.31 (ddt, J = 1.9, 1.9, 6.5Hz , 1H)
IR (neat): 2930, 2856, 1464, 1361, 1341, 1251, 1152, 1110, 1083, 1005, 938, 838, 778, 667, 566 cm -1
(2)上記(1)で得た化合物を用い、実施例 1 (4) と実質的に同様にして、(R)-19-ブロモノナデカ-6-イン-5-オールを得た。 (2) Using the compound obtained in (1) above, (R) -19-bromononadeca-6-in-5-ol was obtained in substantially the same manner as in Example 1 (4).
1H-NMR (CDCl3, 300MHz) δppm: 0.91 (t, J=7.1Hz, 3H), 1.23-1.58 (m, 24H), 1.60-1.74 (m, 2H), 1.79-1.92 (m, 2H), 2.20 (dt, J=2.0, 7.0Hz, 2H), 3.41 (t, J=6.8Hz, 2H), 4.30-4.39 (m, 1H)
IR (neat): 3368, 2927, 2855, 2230, 1466, 1148, 1037, 722, 646, 563 cm-1 1 H-NMR (CDCl 3 , 300MHz) δppm: 0.91 (t, J = 7.1Hz, 3H), 1.23-1.58 (m, 24H), 1.60-1.74 (m, 2H), 1.79-1.92 (m, 2H) , 2.20 (dt, J = 2.0, 7.0Hz, 2H), 3.41 (t, J = 6.8Hz, 2H), 4.30-4.39 (m, 1H)
IR (neat): 3368, 2927, 2855, 2230, 1466, 1148, 1037, 722, 646, 563 cm -1
(3)上記(2)で得た化合物を用い、実施例 1 (5)と実質的に同様にして、(R)-(Z)-19-ブロモノナデカ-6-エン-5-オールを得た。 (3) Using the compound obtained in (2) above, (R)-(Z) -19-bromononadeca-6-en-5-ol was obtained in substantially the same manner as in Example 1 (5). .
1H-NMR (CDCl3, 300MHz) δppm: 0.91 (t, J=6.9Hz, 3H), 1.20-1.65 (m, 24H), 1.79-1.92 (m, 2H), 2.01-2.15 (m, 2H), 3.41 (t, J=6.8Hz, 2H), 4.37-4.47 (m, 1H), 5.31 (m, 2H)
IR (neat): 3368, 3005, 2925, 2854, 1656, 1466, 1378, 1251, 1008, 722, 647, 564 cm-1 1 H-NMR (CDCl 3 , 300MHz) δppm: 0.91 (t, J = 6.9Hz, 3H), 1.20-1.65 (m, 24H), 1.79-1.92 (m, 2H), 2.01-2.15 (m, 2H) , 3.41 (t, J = 6.8Hz, 2H), 4.37-4.47 (m, 1H), 5.31 (m, 2H)
IR (neat): 3368, 3005, 2925, 2854, 1656, 1466, 1378, 1251, 1008, 722, 647, 564 cm -1
(4)上記(3)で得た化合物を用い、実施例 1 (6)と実質的に同様にして、標記化合物を得た。 (4) The title compound was obtained in substantially the same manner as in Example 1 (6) using the compound obtained in (3) above.
1H-NMR (DMSO-d6, 300MHz) δppm: 0.90 (t, J=6.8Hz, 3H), 1.20-1.61 (m, 26H), 1.90-2.07 (m, 2H), 2.31-2.41 (m, 2H), 4.13-4.25 (m, 1H), 4.46-4.53 (m, 1H), 5.21-5.53 (m, 2H)
IR (KBr): 3447, 3007, 2922, 2852, 1653, 1471, 1380, 1190, 1080, 1054, 968, 898, 798, 720, 611, 560, 535, 497, 471, 446, 418 cm-1 1 H-NMR (DMSO-d 6 , 300MHz) δppm: 0.90 (t, J = 6.8Hz, 3H), 1.20-1.61 (m, 26H), 1.90-2.07 (m, 2H), 2.31-2.41 (m, 2H), 4.13-4.25 (m, 1H), 4.46-4.53 (m, 1H), 5.21-5.53 (m, 2H)
IR (KBr): 3447, 3007, 2922, 2852, 1653, 1471, 1380, 1190, 1080, 1054, 968, 898, 798, 720, 611, 560, 535, 497, 471, 446, 418 cm -1
(R)-15-ヒドロキシノナデカ-13-イン-1-スルホン酸 ナトリウム塩（化合物１０）
実施例 3 (2)で得た化合物を用い、実施例 1 (6)と実質的に同様にして、標記化合物を得た。
(R) -15-Hydroxynonadeca-13-in-1-sulfonic acid sodium salt (Compound 10)
The title compound was obtained in substantially the same manner as in Example 1 (6), using the compound obtained in Example 3 (2).
1H-NMR (DMSO-d6, 300MHz) δppm: 0.86 (t, J=7.0Hz, 3H), 1.18-1.62 (m, 26H), 2.16 (dt, J=1.9, 6.6Hz, 2H), 2.32-2.39 (m, 2H), 4.09-4.18 (m, 1H), 5.07 (d, J=5.4Hz, 1H)
IR (KBr): 3366, 2920, 2851, 2229, 1656, 1472, 1380, 1195, 1181, 1064, 1011, 890, 799, 719, 613, 550, 530, 497, 432 cm-1 1 H-NMR (DMSO-d 6 , 300MHz) δppm: 0.86 (t, J = 7.0Hz, 3H), 1.18-1.62 (m, 26H), 2.16 (dt, J = 1.9, 6.6Hz, 2H), 2.32 -2.39 (m, 2H), 4.09-4.18 (m, 1H), 5.07 (d, J = 5.4Hz, 1H)
IR (KBr): 3366, 2920, 2851, 2229, 1656, 1472, 1380, 1195, 1181, 1064, 1011, 890, 799, 719, 613, 550, 530, 497, 432 cm -1
(R)-(Z)-14-ヒドロキシオクタデカ-12-エン-1-スルホン酸 ナトリウム塩（化合物４２）
(1) 実施例１(1)において、1,7-ジブロモヘプタンおよび5-テトラヒドロピラニルオキシ-1-ペンチンの代わりに、それぞれ1,11-ジブロモウンデカンおよび(R)-3-tert-ブチルジメチルシラニルオキシ-1-ヘプチンを用い、実施例 1 (1)と実質的に同様にして、(R)-(14-ブロモ-1-ブチルテトラデカ-2-イニルオキシ)-tert-ブチルジメチルシランを得た。
(R)-(Z) -14-Hydroxyoctadeca-12-ene-1-sulfonic acid sodium salt (Compound 42)
(1) Instead of 1,7-dibromoheptane and 5-tetrahydropyranyloxy-1-pentine in Example 1 (1), 1,11-dibromoundecane and (R) -3-tert-butyldimethyl, respectively Using silanyloxy-1-heptin, substantially as in Example 1 (1), (R)-(14-bromo-1-butyltetradec-2-ynyloxy) -tert-butyldimethylsilane was Obtained.
1H-NMR (CDCl3, 300MHz) δppm: 0.10 (s, 3H), 0.12 (s, 3H), 0.84-0.96 (m, 12H), 1.20-1.68 (m, 26H), 1.80-1.91 (m, 2H), 2.18 (dt, J=1.9, 6.9Hz, 2H), 3.41 (t, J=6.8Hz, 2H), 4.27-4.35 (m, 1H)
IR (neat): 2929, 2856, 1464, 1361, 1341, 1251, 1110, 1083, 1006, 938, 837, 778, 667, 565 cm-1 1 H-NMR (CDCl 3 , 300MHz) δppm: 0.10 (s, 3H), 0.12 (s, 3H), 0.84-0.96 (m, 12H), 1.20-1.68 (m, 26H), 1.80-1.91 (m, 2H), 2.18 (dt, J = 1.9, 6.9Hz, 2H), 3.41 (t, J = 6.8Hz, 2H), 4.27-4.35 (m, 1H)
IR (neat): 2929, 2856, 1464, 1361, 1341, 1251, 1110, 1083, 1006, 938, 837, 778, 667, 565 cm -1
(2)上記(1)で得た化合物を用い、実施例 1 (4)と実質的に同様にして、(R)-18-ブロモオクタデカ-6-イン-5-オールを得た。 (2) Using the compound obtained in (1) above, (R) -18-bromooctadeca-6-in-5-ol was obtained in substantially the same manner as in Example 1 (4).
1H-NMR (CDCl3, 300MHz) δppm: 0.92 (t, J=7.1Hz, 3H), 1.21-1.57 (m, 20H), 1.60-1.74 (m, 2H), 1.80-1.92 (m, 2H), 2.20 (dt, J=2.0, 7.0Hz, 1H), 3.41 (t, J=6.9Hz, 2H), 4.30-4.40 (m, 1H)
IR (neat): 3368, 2929, 2855, 2215, 1672, 1466, 1384, 1148, 1039, 723, 646, 564 cm-1 1 H-NMR (CDCl 3 , 300MHz) δppm: 0.92 (t, J = 7.1Hz, 3H), 1.21-1.57 (m, 20H), 1.60-1.74 (m, 2H), 1.80-1.92 (m, 2H) , 2.20 (dt, J = 2.0, 7.0Hz, 1H), 3.41 (t, J = 6.9Hz, 2H), 4.30-4.40 (m, 1H)
IR (neat): 3368, 2929, 2855, 2215, 1672, 1466, 1384, 1148, 1039, 723, 646, 564 cm -1
(3)上記(2)で得た化合物を用い、実施例 1 (5) と実質的に同様にして、 (R)-(Z)-18-ブロモオクタデカ-6-エン-5-オールを得た。 (3) Using the compound obtained in (2) above, substantially (R)-(Z) -18-bromooctadeca-6-en-5-ol was obtained in substantially the same manner as in Example 1 (5). Obtained.
1H-NMR (CDCl3, 300MHz) δppm: 0.91 (t, J=6.9Hz, 3H), 1.18-1.67 (m, 22H), 1.70-1.82 (m, 2H), 1.97-2.18 (m, 2H), 3.53 (t, J=6.8Hz, 2H), 4.37-4.48 (m, 1H), 5.30-5.41 (m, 1H), 5.43-5.54 (m, 1H)
IR (neat): 3368, 2927, 2855, 1466, 1379, 1311, 1007, 729, 654 cm-1 1 H-NMR (CDCl 3 , 300MHz) δppm: 0.91 (t, J = 6.9Hz, 3H), 1.18-1.67 (m, 22H), 1.70-1.82 (m, 2H), 1.97-2.18 (m, 2H) , 3.53 (t, J = 6.8Hz, 2H), 4.37-4.48 (m, 1H), 5.30-5.41 (m, 1H), 5.43-5.54 (m, 1H)
IR (neat): 3368, 2927, 2855, 1466, 1379, 1311, 1007, 729, 654 cm -1
(4)上記(3)で得た化合物を用い、実施例 1 (6) と実質的に同様にして、標記化合物を得た。 (4) The title compound was obtained in substantially the same manner as in Example 1 (6) using the compound obtained in (3) above.
1H-NMR (DMSO-d6, 300MHz) δppm: 0.85 (t, J=6.7Hz, 3H), 1.12-1.59 (m, 24H), 1.92-2.05 (m, 2H), 2.31-2.39 (m, 2H), 4.16-4.26 (m, 1H), 4.46 (d, J=4.7Hz, 1H), 5.21-5.53 (m, 2H)
IR (KBr): 3359, 2923, 2852, 1656, 1468, 1379, 1185, 1055, 1024, 970, 898, 797, 722, 610, 557, 531, 420 cm-1 1 H-NMR (DMSO-d 6 , 300MHz) δppm: 0.85 (t, J = 6.7Hz, 3H), 1.12-1.59 (m, 24H), 1.92-2.05 (m, 2H), 2.31-2.39 (m, 2H), 4.16-4.26 (m, 1H), 4.46 (d, J = 4.7Hz, 1H), 5.21-5.53 (m, 2H)
IR (KBr): 3359, 2923, 2852, 1656, 1468, 1379, 1185, 1055, 1024, 970, 898, 797, 722, 610, 557, 531, 420 cm -1
(R)-14-ヒドロキシノナデカ-12-イン-1-スルホン酸 ナトリウム塩（化合物７）
(1)実施例１(1)において、1,7-ジブロモヘプタンおよび5-テトラヒドロピラニルオキシ-1-ペンチンの代わりに、それぞれ1,11-ジブロモウンデカンおよび(R)-3-tert-ブチルジメチルシラニルオキシ-1-オクチンを用い、実施例 1 (1) と実質的に同様に反応を行い、引き続き実施例１(4)と実質的に同様に反応を行い、(R)-19-ブロモノナデカ-7-イン-6-オールを得た。
(R) -14-Hydroxynonadeca-12-in-1-sulfonic acid sodium salt (Compound 7)
(1) In Example 1 (1), instead of 1,7-dibromoheptane and 5-tetrahydropyranyloxy-1-pentyne, respectively, 1,11-dibromoundecane and (R) -3-tert-butyldimethyl Using silanyloxy-1-octyne, the reaction was carried out in substantially the same manner as in Example 1 (1), followed by the reaction in substantially the same manner as in Example 1 (4), and (R) -19-bromononadeca. -7-In-6-ol was obtained.
1H-NMR (CDCl3, 300MHz) δppm: 0.90 (t, J=7.0Hz, 3H), 1.24-1.56 (m, 22H), 1.60-1.74 (m, 2H), 1.80-1.91 (m, 2H), 2.20 (dt, J=2.0, 7.0Hz, 2H), 3.41 (t, J=6.9Hz, 2H), 4.30-4.39 (m, 1H)
IR (neat): 3400, 2928, 2855, 2212, 1672, 1466, 1384, 1148, 1024, 723, 646, 564 cm-1 1 H-NMR (CDCl 3 , 300MHz) δppm: 0.90 (t, J = 7.0Hz, 3H), 1.24-1.56 (m, 22H), 1.60-1.74 (m, 2H), 1.80-1.91 (m, 2H) , 2.20 (dt, J = 2.0, 7.0Hz, 2H), 3.41 (t, J = 6.9Hz, 2H), 4.30-4.39 (m, 1H)
IR (neat): 3400, 2928, 2855, 2212, 1672, 1466, 1384, 1148, 1024, 723, 646, 564 cm -1
(2)上記(1)で得た化合物を用い、実施例 1 (6)と実質的に同様にして、標記化合物を得た。 (2) Using the compound obtained in (1) above, the title compound was obtained in substantially the same manner as in Example 1 (6).
1H-NMR (DMSO-d6, 300MHz) δppm: 0.86 (t, J=6.8Hz, 3H), 1.16-1.70 (m, 26H), 2.11-2.20 (m, 2H), 2.32-2.40 (m, 2H), 4.09-4.19 (m, 1H), 5.07 (d, J=5.4Hz, 1H)
IR (KBr): 3509, 2919, 2850, 2229, 1659, 1466, 1412, 1304, 1277, 1228, 1212, 1161, 1085, 1062, 914, 799, 723, 622, 548, 535, 420 cm-1 1 H-NMR (DMSO-d 6 , 300MHz) δppm: 0.86 (t, J = 6.8Hz, 3H), 1.16-1.70 (m, 26H), 2.11-2.20 (m, 2H), 2.32-2.40 (m, 2H), 4.09-4.19 (m, 1H), 5.07 (d, J = 5.4Hz, 1H)
IR (KBr): 3509, 2919, 2850, 2229, 1659, 1466, 1412, 1304, 1277, 1228, 1212, 1161, 1085, 1062, 914, 799, 723, 622, 548, 535, 420 cm -1
(R)-(Z)-14-ヒドロキシノナデカ-12-エン-1-スルホン酸 ナトリウム塩（化合物２９）
(1)実施例 6 (1)で得た化合物を用い,実施例 1 (5)と実質的に同様にして、(R)-(Z)-19-ブロモノナデカ-7-エン-6-オールを得た。
(R)-(Z) -14-Hydroxynonadeca-12-en-1-sulfonic acid sodium salt (Compound 29)
(1) Example 6 Using the compound obtained in (1), (R)-(Z) -19-bromononadeca-7-en-6-ol was prepared in substantially the same manner as in Example 1 (5). Obtained.
1H-NMR (CDCl3, 300MHz) δppm: 0.89 (t, J=6.7Hz, 3H), 1.20-1.67 (m, 24H), 1.79-1.91 (m, 2H), 1.98-2.16 (m, 2H), 3.41 (t, J=6.9Hz, 2H), 4.37-4.47 (m, 1H), 5.32-5.40 (m, 1H), 5.43-5.53 (m, 1H)
IR (neat): 3368, 3005, 2926, 2854, 1658, 1466, 1384, 1255, 1123, 1084, 1022, 724, 647, 564 cm-1 1 H-NMR (CDCl 3 , 300MHz) δppm: 0.89 (t, J = 6.7Hz, 3H), 1.20-1.67 (m, 24H), 1.79-1.91 (m, 2H), 1.98-2.16 (m, 2H) , 3.41 (t, J = 6.9Hz, 2H), 4.37-4.47 (m, 1H), 5.32-5.40 (m, 1H), 5.43-5.53 (m, 1H)
IR (neat): 3368, 3005, 2926, 2854, 1658, 1466, 1384, 1255, 1123, 1084, 1022, 724, 647, 564 cm -1
(2)上記(1)で得た化合物を用い、実施例 1 (6) と実質的に同様にして、標記化合物を得た。 (2) The title compound was obtained in substantially the same manner as in Example 1 (6) using the compound obtained in (1) above.
1H-NMR (DMSO-d6, 300MHz) δppm: 0.85 (t, J=6.7Hz, 3H), 1.16-1.59 (m, 26H), 1.92-2.06 (m, 2H), 2.30-2.39 (m, 2H), 4.15-4.25 (m, 1H), 4.46-4.50 (m, 1H), 5.20-5.39 (m, 2H)
IR (KBr): 3358, 2921, 2852, 1656, 1469, 1411, 1379, 1207, 1191, 1084, 1051, 910, 796, 722, 608, 542, 530, 446, 420 cm-1 1 H-NMR (DMSO-d 6 , 300MHz) δppm: 0.85 (t, J = 6.7Hz, 3H), 1.16-1.59 (m, 26H), 1.92-2.06 (m, 2H), 2.30-2.39 (m, 2H), 4.15-4.25 (m, 1H), 4.46-4.50 (m, 1H), 5.20-5.39 (m, 2H)
IR (KBr): 3358, 2921, 2852, 1656, 1469, 1411, 1379, 1207, 1191, 1084, 1051, 910, 796, 722, 608, 542, 530, 446, 420 cm -1
(R)-(Z)-16-ヒドロキシエイコサ-14-エン-1-スルホン酸 ナトリウム塩（化合物３０）
(1)実施例１(1)において、1,7-ジブロモヘプタンおよび5-テトラヒドロピラニルオキシ-1-ペンチンの代わりに、それぞれ1,13-ジブロモトリデカンおよび(R)-3-tert-ブチルジメチルシラニルオキシ-1-ヘプチンを用い、実施例 1 (1)と実質的に同様に反応を行い、引き続き実施例 1 (4) さらに 実施例 1 (5)と実質的に同様にして、(R)-(Z)-20-ブロモエイコサ-6-エン-5-オールを得た。
(R)-(Z) -16-Hydroxyeicosa-14-en-1-sulfonic acid sodium salt (Compound 30)
(1) In Example 1 (1), instead of 1,7-dibromoheptane and 5-tetrahydropyranyloxy-1-pentyne, 1,13-dibromotridecane and (R) -3-tert-butyl, respectively Using dimethylsilanyloxy-1-heptin, the reaction was carried out in substantially the same manner as in Example 1 (1), followed by Example 1 (4) and in substantially the same manner as in Example 1 (5). R)-(Z) -20-bromoeicosa-6-en-5-ol was obtained.
1H-NMR (CDCl3, 300MHz) δppm: 0.90 (t, J=6.8Hz, 3H), 1.19-1.64 (m, 26H), 1.79-1.92 (m, 2H), 1.97-2.17 (m, 2H), 3.41 (t, J=6.8Hz, 2H), 4.38-4.47 (m, 1H), 5.31-5.41 (m, 1H), 5.42-5.54 (m, 1H)
IR (neat): 3152, 3006, 2925, 2854, 1466, 1401, 1008, 723, 647, 564 cm-1 1 H-NMR (CDCl 3 , 300MHz) δppm: 0.90 (t, J = 6.8Hz, 3H), 1.19-1.64 (m, 26H), 1.79-1.92 (m, 2H), 1.97-2.17 (m, 2H) , 3.41 (t, J = 6.8Hz, 2H), 4.38-4.47 (m, 1H), 5.31-5.41 (m, 1H), 5.42-5.54 (m, 1H)
IR (neat): 3152, 3006, 2925, 2854, 1466, 1401, 1008, 723, 647, 564 cm -1
(2)上記(1)で得た化合物を用い、実施例 1 (6)と実質的に同様にして、標記化合物を得た。 (2) Using the compound obtained in (1) above, the title compound was obtained in substantially the same manner as in Example 1 (6).
1H-NMR (DMSO-d6, 300MHz) δppm: 0.85 (t, J=6.6Hz, 3H), 1.15-1.59 (m, 28H), 1.91-2.06 (m, 2H), 2.30-2.40 (m, 2H), 4.13-4.25 (m, 1H), 4.48 (d, J=4.5Hz, 1H), 5.20-5.40 (m, 2H)
IR (KBr): 3508, 3360, 3008, 2919, 2850, 1660, 1468, 1410, 1221, 1161, 1060, 964, 898, 799, 722, 623, 547, 534, 450, 418 cm-1 1 H-NMR (DMSO-d 6 , 300MHz) δppm: 0.85 (t, J = 6.6Hz, 3H), 1.15-1.59 (m, 28H), 1.91-2.06 (m, 2H), 2.30-2.40 (m, 2H), 4.13-4.25 (m, 1H), 4.48 (d, J = 4.5Hz, 1H), 5.20-5.40 (m, 2H)
IR (KBr): 3508, 3360, 3008, 2919, 2850, 1660, 1468, 1410, 1221, 1161, 1060, 964, 898, 799, 722, 623, 547, 534, 450, 418 cm -1
(S)-(Z)-15-ヒドロキシノナデカ-13-エン-1-スルホン酸 ナトリウム塩（化合物３４）
(1) 実施例１(1)において、1,7-ジブロモヘプタンおよび5-テトラヒドロピラニルオキシ-1-ペンチンの代わりに、それぞれ1,12-ジブロモドデカンおよび(S)-3-tert-ブチルジメチルシラニルオキシ-1-ヘプチンを用い、実施例 1 (1)と実質的に同様に反応を行い、引き続き実施例 1 (4)と実質的に同様に反応を行い、(S)-19-ブロモノナデカ-6-イン-5-オールを得た。
(S)-(Z) -15-Hydroxynonadeca-13-ene-1-sulfonic acid sodium salt (Compound 34)
(1) In Example 1 (1), instead of 1,7-dibromoheptane and 5-tetrahydropyranyloxy-1-pentyne, 1,12-dibromododecane and (S) -3-tert-butyldimethyl, respectively Using silanyloxy-1-heptin, the reaction was carried out in substantially the same manner as in Example 1 (1), followed by the reaction in substantially the same manner as in Example 1 (4), and (S) -19-bromononadeca. -6-In-5-ol was obtained.
1H-NMR (CDCl3, 300MHz) δppm: 0.92 (t, J=7.1Hz, 3H), 1.20-1.75 (m, 24H), 1.80-1.92 (m, 2H), 2.20 (dt, J=1.9, 7.0Hz, 2H), 3.41 (t, J=6.9Hz, 2H), 4.29-4.40 (m, 1H)
IR (neat): 3229, 2927, 2854, 1630, 1461, 1404, 1384, 1294, 1148, 1036, 722, 629, 596 cm-1 1 H-NMR (CDCl 3 , 300MHz) δppm: 0.92 (t, J = 7.1Hz, 3H), 1.20-1.75 (m, 24H), 1.80-1.92 (m, 2H), 2.20 (dt, J = 1.9, 7.0Hz, 2H), 3.41 (t, J = 6.9Hz, 2H), 4.29-4.40 (m, 1H)
IR (neat): 3229, 2927, 2854, 1630, 1461, 1404, 1384, 1294, 1148, 1036, 722, 629, 596 cm -1
(2)上記(1)で得た化合物を用い、実施例 1 (5)と実質的に同様にして、(S)-(Z)-19-ブロモノナデカ-6-エン-5-オールを得た。 (2) Using the compound obtained in (1) above, (S)-(Z) -19-bromononadeca-6-en-5-ol was obtained in substantially the same manner as in Example 1 (5). .
1H-NMR (CDCl3, 300MHz) δppm: 0.91 (t, J=6.8Hz, 3H), 1.20-1.66 (m, 24H), 1.79-1.91 (m, 2H), 1.98-2.15 (m, 2H), 3.41 (t, J=6.8Hz, 2H), 4.37-4.47 (m, 1H), 5.31-5.40 (m, 1H), 5.43-5.54 (m, 1H)
IR (neat): 3118, 3010, 2926, 2854, 1466, 1401, 1084, 1021, 723, 648, 564, 500 cm-1 1 H-NMR (CDCl 3 , 300MHz) δppm: 0.91 (t, J = 6.8Hz, 3H), 1.20-1.66 (m, 24H), 1.79-1.91 (m, 2H), 1.98-2.15 (m, 2H) , 3.41 (t, J = 6.8Hz, 2H), 4.37-4.47 (m, 1H), 5.31-5.40 (m, 1H), 5.43-5.54 (m, 1H)
IR (neat): 3118, 3010, 2926, 2854, 1466, 1401, 1084, 1021, 723, 648, 564, 500 cm -1
(3)上記(2)で得た化合物を用い、実施例 1 (6)と実質的に同様にして、標記化合物を得た。 (3) The title compound was obtained in substantially the same manner as in Example 1 (6) using the compound obtained in (2) above.
1H-NMR (DMSO-d6, 300MHz) δppm: 0.85 (t, J=6.6Hz, 3H), 1.12-1.58 (m, 26H), 1.92-2.05 (m, 2H), 2.30-2.38 (m, 2H), 4.13-4.25 (m, 1H), 4.47 (d, J=4.5Hz, 1H), 5.21-5.35 (m, 2H)
IR (KBr): 3445, 2921, 2852, 1656, 1470, 1379, 1190, 1054, 798, 720, 613, 560, 535, 424, 418 cm-1 1 H-NMR (DMSO-d 6 , 300MHz) δppm: 0.85 (t, J = 6.6Hz, 3H), 1.12-1.58 (m, 26H), 1.92-2.05 (m, 2H), 2.30-2.38 (m, 2H), 4.13-4.25 (m, 1H), 4.47 (d, J = 4.5Hz, 1H), 5.21-5.35 (m, 2H)
IR (KBr): 3445, 2921, 2852, 1656, 1470, 1379, 1190, 1054, 798, 720, 613, 560, 535, 424, 418 cm -1
(RS)-17-ヒドロキシヘニコサ-15-イン-1-スルホン酸 ナトリウム塩（化合物９）
(1) 実施例１(1)において、1,7-ジブロモヘプタンおよび5-テトラヒドロピラニルオキシ-1-ペンチンの代わりに、それぞれ1,14-ジブロモテトラデカンおよび(RS)-3-tert-ブチルジメチルシラニルオキシ-1-ヘプチンを用い、実施例 1 (1)と実質的に同様に反応を行い、引き続き実施例 1 (4)と実質的に同様に反応を行い、(RS)-21-ブロモヘニコサ-6-イン-5-オールを得た。
(RS) -17-Hydroxyhexicos-15-in-1-sulfonic acid sodium salt (Compound 9)
(1) In Example 1 (1), instead of 1,7-dibromoheptane and 5-tetrahydropyranyloxy-1-pentine, 1,14-dibromotetradecane and (RS) -3-tert-butyldimethyl, respectively Using silanyloxy-1-heptin, the reaction was carried out in substantially the same manner as in Example 1 (1), followed by the reaction in substantially the same manner as in Example 1 (4) to obtain (RS) -21-bromohenicososa. -6-In-5-ol was obtained.
1H-NMR (CDCl3, 300MHz) δppm: 0.92 (t, J=7.1Hz, 3H), 1.19-1.74 (m, 28H), 1.79-1.92 (m, 2H), 2.20 (dt, J=2.0, 7.0Hz, 2H), 3.41 (t, J=6.8Hz, 2H), 4.30-4.40 (m, 1H)
IR (neat): 3232, 2926, 2854, 2215, 1630, 1466, 1384, 1294, 1148, 1036, 723, 645, 596 cm-1 1 H-NMR (CDCl 3 , 300MHz) δppm: 0.92 (t, J = 7.1Hz, 3H), 1.19-1.74 (m, 28H), 1.79-1.92 (m, 2H), 2.20 (dt, J = 2.0, 7.0Hz, 2H), 3.41 (t, J = 6.8Hz, 2H), 4.30-4.40 (m, 1H)
IR (neat): 3232, 2926, 2854, 2215, 1630, 1466, 1384, 1294, 1148, 1036, 723, 645, 596 cm -1
(2)上記(1)で得た化合物を用い、実施例 1 (6)と実質的に同様にして、標記化合物を得た。
1H-NMR (DMSO-d6, 300MHz) δppm: 0.86 (t, J=7.1Hz, 3H), 1.10-1.60 (m, 30H), 2.12-2.20 (m, 2H), 2.32-2.40 (m, 2H), 4.09-4.19 (m, 1H), 5.07 (d, J=5.6Hz, 1H)
IR (KBr): 3508, 2920, 2850, 2226, 1661, 1470, 1410, 1380, 1300, 1254, 1234, 1220, 1160, 1060, 960, 890, 799, 721, 623, 548, 534, 434 cm-1
(2) Using the compound obtained in (1) above, the title compound was obtained in substantially the same manner as in Example 1 (6).
1 H-NMR (DMSO-d 6 , 300MHz) δppm: 0.86 (t, J = 7.1Hz, 3H), 1.10-1.60 (m, 30H), 2.12-2.20 (m, 2H), 2.32-2.40 (m, 2H), 4.09-4.19 (m, 1H), 5.07 (d, J = 5.6Hz, 1H)
IR (KBr): 3508, 2920 , 2850, 2226, 1661, 1470, 1410, 1380, 1300, 1254, 1234, 1220, 1160, 1060, 960, 890, 799, 721, 623, 548, 534, 434 cm - 1
(R)-10-ヒドロキシテトラデカ-8-イン-1-スルホン酸 ナトリウム塩（化合物１１）
(1) 実施例１(1)において、5-テトラヒドロピラニルオキシ-1-ペンチンの代わりに、(R)-3-tert-ブチルジメチルシラニルオキシ-1-ヘプチンを用い、実施例 1 (1)と実質的に同様にして、(R)-(10-ブロモ-1-ブチルデカ-2-イニルオキシ)-tert-ブチルジメチルシランを得た。
(R) -10-hydroxytetradec-8-in-1-sulfonic acid sodium salt (compound 11)
(1) In Example 1 (1), instead of 5-tetrahydropyranyloxy-1-pentyne, (R) -3-tert-butyldimethylsilanyloxy-1-heptin was used. ) To give (R)-(10-bromo-1-butyldec-2-ynyloxy) -tert-butyldimethylsilane.
1H-NMR (CDCl3, 300MHz) δppm: 0.10 (s, 3H), 0.12 (s, 3H), 0.84-0.96 (m, 3H), 0.91 (s, 9H), 1.24-1.68 (m, 14H), 1.80-1.92 (m, 2H), 2.19 (dt, J=1.9, 6.9Hz, 2H), 3.41 (t, J=6.4Hz, 2H), 4.32 (tt, J=6.5, 1.9Hz, 1H)
IR (neat): 2930, 2858, 2233, 1463, 1407, 1389, 1361, 1341, 1251, 1217, 1152, 1110, 1083, 1006, 938, 837, 778, 725, 667, 565 cm-1 1 H-NMR (CDCl 3 , 300MHz) δppm: 0.10 (s, 3H), 0.12 (s, 3H), 0.84-0.96 (m, 3H), 0.91 (s, 9H), 1.24-1.68 (m, 14H) , 1.80-1.92 (m, 2H), 2.19 (dt, J = 1.9, 6.9Hz, 2H), 3.41 (t, J = 6.4Hz, 2H), 4.32 (tt, J = 6.5, 1.9Hz, 1H)
IR (neat): 2930, 2858, 2233, 1463, 1407, 1389, 1361, 1341, 1251, 1217, 1152, 1110, 1083, 1006, 938, 837, 778, 725, 667, 565 cm -1
(2)上記(1)で得た化合物を用い、実施例 1 (4)と実質的に同様にして、(R)-14-ブロモテトラデカ-6-イン-5-オールを得た。 (2) Using the compound obtained in (1) above, (R) -14-bromotetradec-6-in-5-ol was obtained in substantially the same manner as in Example 1 (4).
1H-NMR (CDCl3, 300MHz) δppm: 0.92 (t, J=7.1Hz, 3H), 1.24-1.75 (m, 14H), 1.80-1.92 (m, 2H), 2.21 (dt, J=2.0, 6.9Hz, 2H), 3.41 (t, J=6.8Hz, 2H), 4.31-4.39 (m, 1H)
IR (neat): 3231, 2932, 2858, 1630, 1461, 1384, 1294, 1148, 1104, 1036, 726, 630, 596, 563, 418 cm-1 1 H-NMR (CDCl 3 , 300MHz) δppm: 0.92 (t, J = 7.1Hz, 3H), 1.24-1.75 (m, 14H), 1.80-1.92 (m, 2H), 2.21 (dt, J = 2.0, 6.9Hz, 2H), 3.41 (t, J = 6.8Hz, 2H), 4.31-4.39 (m, 1H)
IR (neat): 3231, 2932, 2858, 1630, 1461, 1384, 1294, 1148, 1104, 1036, 726, 630, 596, 563, 418 cm -1
(3)上記(2)で得た化合物を用い、実施例 1 (6) と実質的に同様にして、標記化合物を得た。 (3) The title compound was obtained in substantially the same manner as in Example 1 (6) using the compound obtained in (2) above.
1H-NMR (DMSO-d6, 300MHz) δppm: 0.86 (t, J=7.1Hz, 3H), 1.18-1.60 (m, 16H), 2.16 (dt, J=1.9, 6.8Hz, 2H), 2.32-2.40 (m, 2H), 4.09-4.19 (m, 1H), 5.08 (d, J=5.6Hz, 1H)
IR (KBr): 3324, 2934, 2858, 2230, 1648, 1467, 1332, 1234, 1186, 1059, 1011, 890, 798, 727, 612, 547, 529, 418 cm-1 1 H-NMR (DMSO-d 6 , 300MHz) δppm: 0.86 (t, J = 7.1Hz, 3H), 1.18-1.60 (m, 16H), 2.16 (dt, J = 1.9, 6.8Hz, 2H), 2.32 -2.40 (m, 2H), 4.09-4.19 (m, 1H), 5.08 (d, J = 5.6Hz, 1H)
IR (KBr): 3324, 2934, 2858, 2230, 1648, 1467, 1332, 1234, 1186, 1059, 1011, 890, 798, 727, 612, 547, 529, 418 cm -1
(RS)-15-ヒドロキシ-15-メチルエイコサ-13-イン-1-スルホン酸 ナトリウム塩（化合物８）
(1)実施例１(1)において、1,7-ジブロモヘプタンおよび5-テトラヒドロピラニルオキシ-1-ペンチンの代わりに、それぞれ1,12-ジブロモドデカンおよび(RS)-3-トリエチルシラニルオキシ-3-メチル-1-オクチンを用い、実施例 1 (1)と実質的に同様に反応を行い、引き続き実施例 1 (4)と実質的に同様に反応を行い、(RS)-20-ブロモ-6-メチルエイコサ-7-イン-6-オールを得た。
(RS) -15-hydroxy-15-methyleicosa-13-in-1-sulfonic acid sodium salt (compound 8)
(1) In Example 1 (1), instead of 1,7-dibromoheptane and 5-tetrahydropyranyloxy-1-pentyne, 1,12-dibromododecane and (RS) -3-triethylsilanyloxy, respectively Using 3-methyl-1-octyne, the reaction was carried out in substantially the same manner as in Example 1 (1), followed by the reaction in substantially the same manner as in Example 1 (4), and (RS) -20- Bromo-6-methyleicosa-7-in-6-ol was obtained.
1H-NMR (CDCl3, 300MHz) δppm: 0.90 (d, J=6.9Hz, 3H), 1.20-1.68 (m, 29H), 1.74-1.91 (m, 2H), 2.18 (t, J=7.0Hz, 2H), 3.41 (t, J=6.8Hz, 2H)
IR (neat): 3119, 2929, 2855, 2238, 1465, 1399, 1128, 1056, 934, 772, 724, 647, 563 cm-1 1 H-NMR (CDCl 3 , 300MHz) δppm: 0.90 (d, J = 6.9Hz, 3H), 1.20-1.68 (m, 29H), 1.74-1.91 (m, 2H), 2.18 (t, J = 7.0Hz , 2H), 3.41 (t, J = 6.8Hz, 2H)
IR (neat): 3119, 2929, 2855, 2238, 1465, 1399, 1128, 1056, 934, 772, 724, 647, 563 cm -1
(2)上記(1)で得た化合物を用い、実施例 1 (6)と実質的に同様にして、標記化合物を得た。 (2) Using the compound obtained in (1) above, the title compound was obtained in substantially the same manner as in Example 1 (6).
1H-NMR (DMSO-d6, 300MHz) δppm: 0.86 (t, J=6.9Hz, 3H), 1.15-1.59 (m, 31H), 2.14 (t, J=6.5Hz, 2H), 2.30-2.40 (m, 2H), 4.96 (s, 1H)
IR (KBr): 3529, 2920, 2850, 2236, 1660, 1470, 1409, 1376, 1268, 1244, 1225, 1161, 1058, 943, 895, 799, 721, 623, 547, 533, 490, 418 cm-1 1 H-NMR (DMSO-d 6 , 300MHz) δppm: 0.86 (t, J = 6.9Hz, 3H), 1.15-1.59 (m, 31H), 2.14 (t, J = 6.5Hz, 2H), 2.30-2.40 (m, 2H), 4.96 (s, 1H)
IR (KBr): 3529, 2920 , 2850, 2236, 1660, 1470, 1409, 1376, 1268, 1244, 1225, 1161, 1058, 943, 895, 799, 721, 623, 547, 533, 490, 418 cm - 1
(RS)-15-ヒドロキシ-17-メチルオクタデカ-13-イン-1-スルホン酸 ナトリウム塩（化合物１２）
(1)実施例１(1)において、1,7-ジブロモヘプタンおよび5-テトラヒドロピラニルオキシ-1-ペンチンの代わりに、それぞれ1,12-ジブロモドデカンおよび (RS)-3-tert-ブチルジメチルシラニルオキシ-5-メチル-1-ヘキシンを用い、実施例 1 (1)と実質的に同様に反応を行い、引き続き実施例 1 (4)と実質的に同様に反応を行い、(RS)-18-ブロモ-2-メチルオクタデカ-5-イン-4-オールを得た。
(RS) -15-hydroxy-17-methyloctadeca-13-in-1-sulfonic acid sodium salt (compound 12)
(1) In Example 1 (1), instead of 1,7-dibromoheptane and 5-tetrahydropyranyloxy-1-pentyne, 1,12-dibromododecane and (RS) -3-tert-butyldimethyl, respectively Using silanyloxy-5-methyl-1-hexyne, the reaction was carried out in substantially the same manner as in Example 1 (1), followed by the reaction in substantially the same manner as in Example 1 (4) (RS) 18-Bromo-2-methyloctadeca-5-in-4-ol was obtained.
1H-NMR (CDCl3, 300MHz) δppm: 0.89-0.97 (m, 6H), 1.20-1.67 (m, 20H), 1.76-1.92 (m, 3H), 2.20 (dt, J=2.0, 7.0Hz, 2H), 3.41 (t, J=6.8Hz, 2H), 4.35-4.45 (m, 1H)
IR (neat): 3228, 2927, 2854, 1630, 1466, 1404, 1385, 1367, 1294, 1153, 1036, 722, 629, 596 cm-1 1 H-NMR (CDCl 3 , 300MHz) δppm: 0.89-0.97 (m, 6H), 1.20-1.67 (m, 20H), 1.76-1.92 (m, 3H), 2.20 (dt, J = 2.0, 7.0Hz, 2H), 3.41 (t, J = 6.8Hz, 2H), 4.35-4.45 (m, 1H)
IR (neat): 3228, 2927, 2854, 1630, 1466, 1404, 1385, 1367, 1294, 1153, 1036, 722, 629, 596 cm -1
(2)上記(1)で得た化合物を用い、実施例 1 (6)と実質的に同様にして、標記化合物を得た。 (2) Using the compound obtained in (1) above, the title compound was obtained in substantially the same manner as in Example 1 (6).
1H-NMR (DMSO-d6, 300MHz) δppm: 0.85 (d, J=6.5Hz, 3H), 0.87 (d, J=6.7Hz, 3H), 1.16-1.60 (m, 22H), 1.66-1.82 (m, 1H), 2.16 (dt, J=1.9, 6.7Hz, 2H), 2.32-2.39 (m, 2H), 4.13-4.23 (m, 1H), 5.05 (d, J=5.8Hz, 1H)
IR (KBr): 3540, 2918, 2852, 2235, 1638, 1472, 1369, 1297, 1268, 1204, 1186, 1119, 1056, 966, 837, 801, 719, 611, 536, 481 cm-1 1 H-NMR (DMSO-d 6 , 300MHz) δppm: 0.85 (d, J = 6.5Hz, 3H), 0.87 (d, J = 6.7Hz, 3H), 1.16-1.60 (m, 22H), 1.66-1.82 (m, 1H), 2.16 (dt, J = 1.9, 6.7Hz, 2H), 2.32-2.39 (m, 2H), 4.13-4.23 (m, 1H), 5.05 (d, J = 5.8Hz, 1H)
IR (KBr): 3540, 2918, 2852, 2235, 1638, 1472, 1369, 1297, 1268, 1204, 1186, 1119, 1056, 966, 837, 801, 719, 611, 536, 481 cm -1
(S)-15-シクロヘキシル-15-ヒドロキシペンタデカ-13-イン-1-スルホン酸 ナトリウム塩（化合物１３）
(1) 実施例１(1)において、1,7-ジブロモヘプタンおよび5-テトラヒドロピラニルオキシ-1-ペンチンの代わりに、それぞれ1,12-ジブロモドデカンおよび (S)-3-tert-ブチルジメチルシラニルオキシ-3-シクロヘキシル-1-プロピンを用い、実施例 1 (1)と実質的に同様に反応を行い、引き続き実施例 1 (4)と実質的に同様に反応を行い、(S)-15-ブロモ-1-シクロヘキシルペンタデカ-2-イン-1-オールを得た。
(S) -15-cyclohexyl-15-hydroxypentadeca-13-in-1-sulfonic acid sodium salt (compound 13)
(1) In Example 1 (1), instead of 1,7-dibromoheptane and 5-tetrahydropyranyloxy-1-pentine, 1,12-dibromododecane and (S) -3-tert-butyldimethyl, respectively Using silanyloxy-3-cyclohexyl-1-propyne, the reaction was carried out in substantially the same manner as in Example 1 (1), followed by the reaction in substantially the same manner as in Example 1 (4). -15-Bromo-1-cyclohexylpentadec-2-yn-1-ol was obtained.
1H-NMR (CDCl3, 300MHz) δppm: 0.98-1.91 (m, 31H), 2.21 (dt, J=2.0, 7.0Hz, 2H), 3.41 (t, J=6.8Hz, 2H), 4.10-4.17 (m, 1H)
IR (neat): 3119, 2925, 2853, 1450, 1399, 1084, 1010, 893, 722, 647, 563 cm-1 1 H-NMR (CDCl 3 , 300MHz) δppm: 0.98-1.91 (m, 31H), 2.21 (dt, J = 2.0, 7.0Hz, 2H), 3.41 (t, J = 6.8Hz, 2H), 4.10-4.17 (m, 1H)
IR (neat): 3119, 2925, 2853, 1450, 1399, 1084, 1010, 893, 722, 647, 563 cm -1
(2)上記(1)で得た化合物を用い、実施例 1 (6)と実質的に同様にして、標記化合物を得た。 (2) Using the compound obtained in (1) above, the title compound was obtained in substantially the same manner as in Example 1 (6).
1H-NMR (DMSO-d6, 300MHz) δppm: 0.87-1.82 (m, 31H), 2.12-2.21 (m, 2H), 2.31-2.40 (m, 2H), 3.90-3.97 (m, 1H), 5.01 (d, J=5.6Hz, 1H)
IR (KBr): 3396, 2920, 2851, 2235, 1627, 1472, 1454, 1272, 1179, 1055, 1005, 890, 799, 782, 752, 718, 676, 609, 552, 528, 497, 426 cm-1 1 H-NMR (DMSO-d 6 , 300 MHz) δppm: 0.87-1.82 (m, 31H), 2.12-2.21 (m, 2H), 2.31-2.40 (m, 2H), 3.90-3.97 (m, 1H), 5.01 (d, J = 5.6Hz, 1H)
IR (KBr): 3396, 2920 , 2851, 2235, 1627, 1472, 1454, 1272, 1179, 1055, 1005, 890, 799, 782, 752, 718, 676, 609, 552, 528, 497, 426 cm - 1
(S)-15-ヒドロキシ-16-フェニルへヘキサデカ-13-イン-1-スルホン酸 ナトリウム塩（化合物１５）
(1) 実施例１(1)において、1,7-ジブロモヘプタンおよび5-テトラヒドロピラニルオキシ-1-ペンチンの代わりに、それぞれ1,12-ジブロモドデカンおよび (S)-3-tert-ブチルジメチルシラニルオキシ-4-フェニル-1-ブチンを用い、実施例 1 (1)と実質的に同様に反応を行い、引き続き実施例 1 (4)と実質的に同様に反応を行い、(S)-16-ブロモ-1-フェニルヘキサデカ-3-イン-2-オールを得た。
(S) -15-Hydroxy-16-phenylhexadeca-13-in-1-sulfonic acid sodium salt (compound 15)
(1) In Example 1 (1), instead of 1,7-dibromoheptane and 5-tetrahydropyranyloxy-1-pentine, 1,12-dibromododecane and (S) -3-tert-butyldimethyl, respectively Using silanyloxy-4-phenyl-1-butyne, the reaction was carried out in substantially the same manner as in Example 1 (1), followed by the reaction in substantially the same manner as in Example 1 (4). -16-Bromo-1-phenylhexadec-3-yn-2-ol was obtained.
1H-NMR (CDCl3, 300MHz) δppm: 1.21-1.58 (m, 18H), 1.80-1.91 (m, 2H), 2.19 (dt, J=2.0, 7.0Hz, 2H), 2.95 (dd, J=13.4, 6.8Hz, 1H), 3.01 (dd, J=13.4, 6.3Hz, 1H), 3.41 (t, J=6.8Hz, 2H), 4.52-4.62 (m, 1H), 7.21-7.35 (m, 5H)
IR (neat): 3229, 3001, 2924, 2853, 1630, 1495, 1455, 1404, 1385, 1294, 1036, 739, 699, 629, 596 cm-1 1 H-NMR (CDCl 3 , 300MHz) δppm: 1.21-1.58 (m, 18H), 1.80-1.91 (m, 2H), 2.19 (dt, J = 2.0, 7.0Hz, 2H), 2.95 (dd, J = 13.4, 6.8Hz, 1H), 3.01 (dd, J = 13.4, 6.3Hz, 1H), 3.41 (t, J = 6.8Hz, 2H), 4.52-4.62 (m, 1H), 7.21-7.35 (m, 5H )
IR (neat): 3229, 3001, 2924, 2853, 1630, 1495, 1455, 1404, 1385, 1294, 1036, 739, 699, 629, 596 cm -1
(2)上記(1)で得た化合物を用い、実施例 1 (6)と実質的に同様にして、標記化合物を得た。 (2) Using the compound obtained in (1) above, the title compound was obtained in substantially the same manner as in Example 1 (6).
1H-NMR (DMSO-d6, 300MHz) δppm: 0.98-1.62 (m, 20H), 2.12 (dt, J=1.8, 6.7Hz, 2H), 2.32-2.40 (m, 2H), 2.76 (dd, J=13.1, 6.9Hz, 1H), 2.85 (dd, J=13.1, 6.8Hz, 1H), 4.29-4.39 (m, 1H), 5.31 (d, J=5.8Hz, 1H), 7.41-7.29 (m, 5H)
IR (KBr): 3384, 3030, 2919, 2850, 2227, 1659, 1497, 1471, 1455, 1426, 1224, 1160, 1057, 846, 798, 742, 720, 698, 621, 545, 473 cm-1 1 H-NMR (DMSO-d 6 , 300MHz) δppm: 0.98-1.62 (m, 20H), 2.12 (dt, J = 1.8, 6.7Hz, 2H), 2.32-2.40 (m, 2H), 2.76 (dd, J = 13.1, 6.9Hz, 1H), 2.85 (dd, J = 13.1, 6.8Hz, 1H), 4.29-4.39 (m, 1H), 5.31 (d, J = 5.8Hz, 1H), 7.41-7.29 (m , 5H)
IR (KBr): 3384, 3030, 2919, 2850, 2227, 1659, 1497, 1471, 1455, 1426, 1224, 1160, 1057, 846, 798, 742, 720, 698, 621, 545, 473 cm -1
(R)-15-ヒドロキシ-16-フェノキシヘキサデカ-13-イン-1-スルホン酸 ナトリウム塩（化合物１７）
(1)実施例１(1)において、1,7-ジブロモヘプタンおよび5-テトラヒドロピラニルオキシ-1-ペンチンの代わりに、それぞれ1,12-ジブロモドデカンおよび(R)-3-tert-ブチルジメチルシラニルオキシ-4-フェノキシ-1-ブチンを用い、実施例 1 (1)と実質的に同様に反応を行い、引き続き実施例 1 (4)と実質的に同様に反応を行い、(R)-16-ブロモ-1-フェノキシヘキサデカ-3-イン-2-オールを得た。
(R) -15-Hydroxy-16-phenoxyhexadeca-13-in-1-sulfonic acid sodium salt (Compound 17)
(1) In Example 1 (1), instead of 1,7-dibromoheptane and 5-tetrahydropyranyloxy-1-pentine, 1,12-dibromododecane and (R) -3-tert-butyldimethyl, respectively Using silanyloxy-4-phenoxy-1-butyne, the reaction was carried out in substantially the same manner as in Example 1 (1), followed by the reaction in substantially the same manner as in Example 1 (4). -16-Bromo-1-phenoxyhexadec-3-yn-2-ol was obtained.
1H-NMR (CDCl3, 300MHz) δppm: 1.23-1.58 (m, 18H), 1.78-1.91 (m, 2H), 2.23 (dt, J=2.0, 7.1Hz, 2H), 2.33-2.42 (m, 1H), 3.40 (t, J=6.8Hz, 2H), 4.02 (dd, J=9.6, 7.7Hz, 1H), 4.11 (dd, J=9.6, 3.6Hz, 1H), 4.71-4.80 (m, 1H), 6.90-7.02 (m, 3H), 7.25-7.34 (m, 2H)
IR (neat): 3400, 2927, 2854, 2238, 1600, 1588, 1497, 1456, 1401, 1301, 1246, 1173, 1143, 1081, 1045, 903, 754, 691, 645, 562, 509 cm-1 1 H-NMR (CDCl 3 , 300MHz) δppm: 1.23-1.58 (m, 18H), 1.78-1.91 (m, 2H), 2.23 (dt, J = 2.0, 7.1Hz, 2H), 2.33-2.42 (m, 1H), 3.40 (t, J = 6.8Hz, 2H), 4.02 (dd, J = 9.6, 7.7Hz, 1H), 4.11 (dd, J = 9.6, 3.6Hz, 1H), 4.71-4.80 (m, 1H ), 6.90-7.02 (m, 3H), 7.25-7.34 (m, 2H)
IR (neat): 3400, 2927, 2854, 2238, 1600, 1588, 1497, 1456, 1401, 1301, 1246, 1173, 1143, 1081, 1045, 903, 754, 691, 645, 562, 509 cm -1
(2)上記(1)で得られた化合物を用い、実施例 1 (6)と実質的に同様にして、標記化合物を得た。 (2) The title compound was obtained in substantially the same manner as in Example 1 (6) using the compound obtained in (1) above.
1H-NMR (DMSO-d6, 300MHz) δppm: 1.14-1.60 (m, 20H), 2.19 (dt, J=1.8, 6.8Hz, 2H), 2.31-2.39 (m, 2H), 3.88-3.99 (m, 2H), 4.48-4.57 (m, 1H), 5.59 (d, J=5.9Hz, 1H), 6.89-6.97 (m, 3H), 7.23-7.32 (m, 2H)
IR (KBr): 3412, 2920, 2850, 1602, 1588, 1501, 1471, 1451, 1306, 1256, 1212, 1183, 1070, 1044, 896, 853, 788, 753, 721, 694, 620, 546 cm-1 1 H-NMR (DMSO-d 6 , 300MHz) δppm: 1.14-1.60 (m, 20H), 2.19 (dt, J = 1.8, 6.8Hz, 2H), 2.31-2.39 (m, 2H), 3.88-3.99 ( m, 2H), 4.48-4.57 (m, 1H), 5.59 (d, J = 5.9Hz, 1H), 6.89-6.97 (m, 3H), 7.23-7.32 (m, 2H)
IR (KBr): 3412, 2920 , 2850, 1602, 1588, 1501, 1471, 1451, 1306, 1256, 1212, 1183, 1070, 1044, 896, 853, 788, 753, 721, 694, 620, 546 cm - 1
14-(1-ヒドロキシシクロペンチル)テトラデカ-13-イン-1-スルホン酸 ナトリウム塩（化合物１８）
(1)実施例１(1)において、1,7-ブロモヘプタンおよび5-テトラヒドロピラニルオキシ-1-ペンチンの代わりに、それぞれ1,12-ジブロモドデカンおよび 1-エチニル-1-トリエチルシラニルオキシシクロペンタンを用い、実施例 1 (1)と実質的に同様に反応を行い、引き続き実施例 1 (4)と実質的に同様に反応を行い、1-(14-ブロモテトラデカ-1-イニル)シクロペンタノールを得た。
14- (1-Hydroxycyclopentyl) tetradec-13-in-1-sulfonic acid sodium salt (Compound 18)
(1) In Example 1 (1), instead of 1,7-bromoheptane and 5-tetrahydropyranyloxy-1-pentyne, 1,12-dibromododecane and 1-ethynyl-1-triethylsilanyloxy, respectively Using cyclopentane, the reaction was carried out in substantially the same manner as in Example 1 (1), followed by the reaction in substantially the same manner as in Example 1 (4), and 1- (14-bromotetradec-1-ynyl ) Cyclopentanol was obtained.
1H-NMR (CDCl3, 300MHz) δppm: 1.19-2.00 (m, 28H), 2.19 (t, J=7.1Hz, 2H), 3.41 (t, J=6.8Hz, 2H)
IR (neat): 3228, 2927, 2854, 2360, 1630, 1461, 1404, 1385, 1294, 1219, 1063, 1036, 994, 723, 629, 596, 564 cm-1 1 H-NMR (CDCl 3 , 300MHz) δppm: 1.19-2.00 (m, 28H), 2.19 (t, J = 7.1Hz, 2H), 3.41 (t, J = 6.8Hz, 2H)
IR (neat): 3228, 2927, 2854, 2360, 1630, 1461, 1404, 1385, 1294, 1219, 1063, 1036, 994, 723, 629, 596, 564 cm -1
(2)上記(1)で得た化合物を用い、実施例 1 (6)と実質的に同様にして、標記化合物を得た。 (2) Using the compound obtained in (1) above, the title compound was obtained in substantially the same manner as in Example 1 (6).
1H-NMR (DMSO-d6, 300MHz) δppm: 1.15-1.82 (m, 28H), 2.15 (t, J=6.8Hz, 2H), 2.31-2.39 (m, 2H), 4.96 (s, 1H)
IR (KBr): 3530, 2920, 2850, 1656, 1627, 1471, 1356, 1224, 1165, 1082, 1057, 993, 879, 800, 722, 613, 554, 528, 485, 426 cm-1 1 H-NMR (DMSO-d 6 , 300MHz) δppm: 1.15-1.82 (m, 28H), 2.15 (t, J = 6.8Hz, 2H), 2.31-2.39 (m, 2H), 4.96 (s, 1H)
IR (KBr): 3530, 2920, 2850, 1656, 1627, 1471, 1356, 1224, 1165, 1082, 1057, 993, 879, 800, 722, 613, 554, 528, 485, 426 cm -1
(R)-15-ヒドロキシノナデカン-1-スルホン酸 ナトリウム塩（化合物５３）
水素ガス雰囲気下、実施例３で得た化合物 (100 mg, 0.26 mmol)およびＰｄ−炭素 (5 mg, 5 wt %)のMeOH (5 mL) 懸濁液を水素ガスの吸収がなくなるまで約4時間室温で攪拌した。反応液をセライトパッドで濾過後、濃縮して標記化合物(87 mg)を得た。
(R) -15-Hydroxynonadecane-1-sulfonic acid sodium salt (Compound 53)
Under a hydrogen gas atmosphere, a suspension of the compound obtained in Example 3 (100 mg, 0.26 mmol) and Pd-carbon (5 mg, 5 wt%) in MeOH (5 mL) was dissolved in about 4 until there was no absorption of hydrogen gas. Stir for hours at room temperature. The reaction mixture was filtered through a celite pad and concentrated to give the title compound (87 mg).
1H-NMR (DMSO-d6, 300MHz) δppm: 0.86 (t, J=6.8Hz, 3H), 1.15-1.61 (m, 32H), 2.31-2.39 (m, 2H), 3.27-3.39 (m, 1H), 4.19 (d, J=5.3Hz, 1H)
IR (KBr): 3330, 2919, 2851, 1708, 1469, 1418, 1379, 1346, 1183, 1133, 1069, 1058, 937, 878, 857, 798, 722, 622, 536, 420 cm-1 1 H-NMR (DMSO-d 6 , 300MHz) δppm: 0.86 (t, J = 6.8Hz, 3H), 1.15-1.61 (m, 32H), 2.31-2.39 (m, 2H), 3.27-3.39 (m, 1H), 4.19 (d, J = 5.3Hz, 1H)
IR (KBr): 3330, 2919, 2851, 1708, 1469, 1418, 1379, 1346, 1183, 1133, 1069, 1058, 937, 878, 857, 798, 722, 622, 536, 420 cm -1
(R)-(Z)-15-アセトキシノナデカ-13-エン-1-スルホン酸 ナトリウム塩（化合物３１）
実施例 3 (3)で得た化合物 (1.55 g, 4.29 mmol)、 DMAP ((4-ジメチルアミノ)ピリジン) (10 mg, 0.082 mmol) およびピリジン (678 mg, 8.58 mmol) のTHF (45 mL)溶液に、無水酢酸 (657 mg, 6.44 mmol) を 0oC で加え、室温で一夜攪拌した。反応液を水に注ぎ AcOEt (100 mL x 2)抽出した。有機層を塩酸(5mL, 3.0M)および飽和食塩水洗浄、無水硫酸マグネシウム乾燥後、濃縮した。得られた
粗生成物をシリカゲルカラムクロマトグラフィーで精製して、(R)-(Z)-5-アセトキシ-19-ブロモノナデカ-6-エン (1.60 g)を得た。
(R)-(Z) -15-Acetoxynonadeca-13-en-1-sulfonic acid sodium salt (Compound 31)
Example 3 Compound obtained in (3) (1.55 g, 4.29 mmol), DMAP ((4-dimethylamino) pyridine) (10 mg, 0.082 mmol) and pyridine (678 mg, 8.58 mmol) in THF (45 mL) Acetic anhydride (657 mg, 6.44 mmol) was added to the solution at 0 ° C., and the mixture was stirred overnight at room temperature. The reaction mixture was poured into water and extracted with AcOEt (100 mL x 2). The organic layer was washed with hydrochloric acid (5 mL, 3.0 M) and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography to obtain (R)-(Z) -5-acetoxy-19-bromononadeca-6-ene (1.60 g).
1H-NMR (CDCl3, 300MHz) δppm: 0.89 (t, J=6.9Hz, 3H), 1.18-1.73 (m, 24H), 1.80-1.91 (m, 2H), 2.02 (s, 3H), 2.05-2.21 (m, 2H), 3.41 (t, J=6.9Hz, 2H), 5.24-5.33 (m, 1H), 5.47-5.58 (m, 2H)
IR (neat): 3468, 2927, 2855, 2360, 1737, 1466, 1370, 1241, 1018, 955, 723, 648, 608, 564 cm-1 1 H-NMR (CDCl 3 , 300MHz) δppm: 0.89 (t, J = 6.9Hz, 3H), 1.18-1.73 (m, 24H), 1.80-1.91 (m, 2H), 2.02 (s, 3H), 2.05 -2.21 (m, 2H), 3.41 (t, J = 6.9Hz, 2H), 5.24-5.33 (m, 1H), 5.47-5.58 (m, 2H)
IR (neat): 3468, 2927, 2855, 2360, 1737, 1466, 1370, 1241, 1018, 955, 723, 648, 608, 564 cm -1
(2)上記(1)で得た化合物を用い、実施例 1 (6)と実質的に同様にして、標記化合物を得た。 (2) Using the compound obtained in (1) above, the title compound was obtained in substantially the same manner as in Example 1 (6).
1H-NMR (DMSO-d6, 300MHz) δppm: 0.85 (t, J=7.0Hz, 3H), 1.14-1.68 (m, 26H), 1.97 (s, 3H), 2.01-2.12 (m, 2H), 2.31-2.40 (m, 2H), 5.24-5.34 (m, 1H), 5.39-5.56 (m, 2H)
IR (KBr): 3630, 3549, 2920, 2853, 1740, 1624, 1469, 1372, 1245, 1200, 1180, 1055, 1019, 958, 865, 796, 722, 609, 535, 482, 417 cm-1 1 H-NMR (DMSO-d 6 , 300MHz) δppm: 0.85 (t, J = 7.0Hz, 3H), 1.14-1.68 (m, 26H), 1.97 (s, 3H), 2.01-2.12 (m, 2H) , 2.31-2.40 (m, 2H), 5.24-5.34 (m, 1H), 5.39-5.56 (m, 2H)
IR (KBr): 3630, 3549, 2920, 2853, 1740, 1624, 1469, 1372, 1245, 1200, 1180, 1055, 1019, 958, 865, 796, 722, 609, 535, 482, 417 cm -1
(S)-(E)-15-ヒドロキシノナデカ-13-エン-1-スルホン酸 ナトリウム塩（化合物４４）
(1)アルゴン気流下、12-ブロモ-1-ドデカノール (15.0 g, 56.6 mmol) および (R)-3-tert-ブチルジメチルシラニルオキシ-1-ヘプチン (10.67 g, 47.1 mmol) の THF (200 mL) および DMPU (100 mL)の混合溶液中、n-ブチルリチウム (46.8 mL, 2.66M ヘキサン溶液, 124.4 mmol) を 60oCで15分間かけて滴下し、45分間かけて0oCまで昇温した。反応液に塩酸(100 mL, 3.0M) を加え、AcOEt (150 mL x 2)抽出した。有機層を飽和食塩水 (200 mL)洗浄, 無水硫酸マグネシウム乾燥後、濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィーで精製して、(R)-15-(tert-ブチルジメチルシラニルオキシ)ノナデカ-13-イン-1-オール(18.0 g)を得た。
(S)-(E) -15-Hydroxynonadeca-13-ene-1-sulfonic acid sodium salt (Compound 44)
(1) 12-bromo-1-dodecanol (15.0 g, 56.6 mmol) and (R) -3-tert-butyldimethylsilanyloxy-1-heptine (10.67 g, 47.1 mmol) in THF (200 n-Butyllithium (46.8 mL, 2.66M hexane solution, 124.4 mmol) was added dropwise at 60 ° C over 15 minutes and the temperature was raised to 0 ° C over 45 minutes. Warm up. Hydrochloric acid (100 mL, 3.0M) was added to the reaction solution, and AcOEt (150 mL x 2) was extracted. The organic layer was washed with saturated brine (200 mL), dried over anhydrous magnesium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography to obtain (R) -15- (tert-butyldimethylsilanyloxy) nonadeca-13-in-1-ol (18.0 g).
1H-NMR (CDCl3, 300MHz) δppm: 0.10 (s, 3H), 0.12 (s, 3H), 0.85-0.96 (m, 12H), 1.15-1.70 (m, 26H), 2.18 (dt, J=1.9, 6.9Hz, 2H), 3.64 (m, J=6.6Hz, 2H), 4.31 (tt, J=6.5, 1.9Hz, 1H)
IR (neat): 3368, 2929, 2855, 2361, 1463, 1385, 1250, 1079, 938, 837, 777 cm-1 1 H-NMR (CDCl 3 , 300MHz) δppm: 0.10 (s, 3H), 0.12 (s, 3H), 0.85-0.96 (m, 12H), 1.15-1.70 (m, 26H), 2.18 (dt, J = 1.9, 6.9Hz, 2H), 3.64 (m, J = 6.6Hz, 2H), 4.31 (tt, J = 6.5, 1.9Hz, 1H)
IR (neat): 3368, 2929, 2855, 2361, 1463, 1385, 1250, 1079, 938, 837, 777 cm -1
(2)上記(1)で得た化合物を用い、実施例 1 (4)と実質的に同様にして、(R)-ノナデカ-13-イン-1,15-ジオールを得た。
1H-NMR (CDCl3, 300MHz) δppm: 0.92 (t, J=7.1Hz, 3H), 1.21-1.74 (m, 26H), 2.20 (dt, J=1.9, 7.0Hz, 2H), 3.64 (m, J=6.6Hz, 2H), 4.35 (tt, J=6.5, 1.9Hz, 1H)
IR (KBr): 3197, 2919, 2853, 1741, 1466, 1324, 1277, 1144, 1112, 1053, 1015, 992, 968, 895, 812, 724, 643, 545, 494, 452 cm-1
(2) Using the compound obtained in (1) above, (R) -nonadec-13-in-1,15-diol was obtained in substantially the same manner as in Example 1 (4).
1 H-NMR (CDCl 3 , 300MHz) δppm: 0.92 (t, J = 7.1Hz, 3H), 1.21-1.74 (m, 26H), 2.20 (dt, J = 1.9, 7.0Hz, 2H), 3.64 (m , J = 6.6Hz, 2H), 4.35 (tt, J = 6.5, 1.9Hz, 1H)
IR (KBr): 3197, 2919, 2853, 1741, 1466, 1324, 1277, 1144, 1112, 1053, 1015, 992, 968, 895, 812, 724, 643, 545, 494, 452 cm -1
(3)上記(2)で得た化合物 (190 mg, 0.64 mmol)、安息香酸 (235 mg, 1.92 mmol) およびトリフェニルホスフィン(504 mg, 1.92 mmol)のTHF (20 mL) 溶液に、アゾジカルボン酸ジエチルエステル(335 mg, 40% トルエン溶液, 1.92 mmol) を 0oCで加え、同温度で30分間攪拌した。 反応液を濃縮後、シリカゲルカラムクロマトグラフィーで精製し、安息香酸 (S)-15-ベンゾイルオキシノナデカ-13-イニル エステルを得た。得られたこの化合物のMeOH (10 mL)溶液にナトリウムメトキシド(139 mg, 2.56 mmol)を室温で加え、さらに1.5時間攪拌した。反応液に塩酸(10 mL, 3.0M) を加え、AcOEt (20 mL x 2)抽出した。有機層を 飽和食塩水 (30 mL)洗浄、無水硫酸マグネシウム乾燥後、濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィーで精製して、(S)-ノナデカ-13-イン-1,15-ジオール (170 mg)を得た。 (3) A solution of the compound obtained in (2) above (190 mg, 0.64 mmol), benzoic acid (235 mg, 1.92 mmol) and triphenylphosphine (504 mg, 1.92 mmol) in THF (20 mL) was mixed with azodicarboxylic acid. Acid diethyl ester (335 mg, 40% toluene solution, 1.92 mmol) was added at 0 ° C., and the mixture was stirred at the same temperature for 30 min. The reaction solution was concentrated and purified by silica gel column chromatography to obtain benzoic acid (S) -15-benzoyloxynonadeca-13-ynyl ester. Sodium methoxide (139 mg, 2.56 mmol) was added to a solution of the obtained compound in MeOH (10 mL) at room temperature, and the mixture was further stirred for 1.5 hours. Hydrochloric acid (10 mL, 3.0M) was added to the reaction solution, and extracted with AcOEt (20 mL x 2). The organic layer was washed with saturated brine (30 mL), dried over anhydrous magnesium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography to obtain (S) -nonadeca-13-in-1,15-diol (170 mg).
1H-NMR (CDCl3, 300MHz) δppm: 0.92 (t, J=7.1Hz, 3H), 1.19-1.77 (m, 26H), 2.20 (dt, J=1.9, 7.0Hz, 2H), 3.64 (t, J=6.6Hz, 2H), 4.35 (tt, J=6.6, 1.9Hz, 1H)
IR (KBr): 3314, 2919, 2852, 1741, 1465, 1324, 1276, 1193, 1144, 1112, 1069, 1015, 992, 968, 895, 803, 724, 622, 545, 494 cm-1 1 H-NMR (CDCl 3 , 300MHz) δppm: 0.92 (t, J = 7.1Hz, 3H), 1.19-1.77 (m, 26H), 2.20 (dt, J = 1.9, 7.0Hz, 2H), 3.64 (t , J = 6.6Hz, 2H), 4.35 (tt, J = 6.6, 1.9Hz, 1H)
IR (KBr): 3314, 2919, 2852, 1741, 1465, 1324, 1276, 1193, 1144, 1112, 1069, 1015, 992, 968, 895, 803, 724, 622, 545, 494 cm -1
(4)アルゴン気流下、ナトリウムメトキシド (117 mg, 2.16 mmol)のTHF (20 mL)溶液に、水素化リチウムアルミニウム (41 mg, 1.08 mmol)を室温で加えた。この混合液に上記(3)で得た化合物 (160 mg, 0.54 mmol) を加え、70oCで1.5 時間攪拌した。反応液に水および塩酸(5.0 mL, 3.0M)を加え、AcOEt (50 mL)抽出した。有機層を飽和食塩水 (50 mL)洗浄、無水硫酸マグネシウム乾燥後、濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィーで精製して、(S)-(E)-ノナデカ-13-エン-1,15-ジオール(119 mg)を得た。 (4) Lithium aluminum hydride (41 mg, 1.08 mmol) was added at room temperature to a solution of sodium methoxide (117 mg, 2.16 mmol) in THF (20 mL) under an argon stream. The compound obtained in (3) above (160 mg, 0.54 mmol) was added to the mixture, and the mixture was stirred at 70 ° C. for 1.5 hours. Water and hydrochloric acid (5.0 mL, 3.0M) were added to the reaction solution, and extracted with AcOEt (50 mL). The organic layer was washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography to obtain (S)-(E) -nonadeca-13-ene-1,15-diol (119 mg).
1H-NMR (CDCl3, 300MHz) δppm: 0.90 (t, J=6.8Hz, 3H), 1.20-1.63 (m, 26H), 1.97-2.07 (m, 2H), 3.64 (t, J=6.6Hz, 2H), 4.03 (q, J=6.6Hz, 1H), 5.40-5.50 (m, 1H), 5.57-5.69 (m, 1H)
IR (KBr): 3267, 2956, 2917, 2851, 1672, 1471, 1380, 1341, 1146, 1126, 1058, 1012, 981, 958, 884, 788, 720, 527, 499, 460 cm-1 1 H-NMR (CDCl 3 , 300MHz) δppm: 0.90 (t, J = 6.8Hz, 3H), 1.20-1.63 (m, 26H), 1.97-2.07 (m, 2H), 3.64 (t, J = 6.6Hz , 2H), 4.03 (q, J = 6.6Hz, 1H), 5.40-5.50 (m, 1H), 5.57-5.69 (m, 1H)
IR (KBr): 3267, 2956, 2917, 2851, 1672, 1471, 1380, 1341, 1146, 1126, 1058, 1012, 981, 958, 884, 788, 720, 527, 499, 460 cm -1
(5)アルゴン気流下、上記(4)で得た化合物(160 mg, 0.54 mmol) のジクロロメタン (20 mL)溶液にトリエチルアミン (50 mL, 0.38 mmol)を 0oCで加えた。この混合液にメタンスルホニルクロリド (30 mL, 0.38 mmol)を室温で滴下し、1.5時間攪拌した。反応液に水および塩酸 (5 mL, 3.0M)を加え、Et2O (50 mL)抽出した。有機層を水(50 mL) および 飽和食塩水 (50 mL)で洗浄、無水硫酸マグネシウム乾燥後、濃縮した。得られた粗生成物のアセトン(20mL)溶液に、臭化リチウム(120 mg, 1.34 mmol)を加え、還流下5時間攪拌した。反応液に水を加え、AcOEt (50 mL x 2)抽出した。 有機層を飽和食塩水 (100 mL)洗浄、無水硫酸マグネシウム乾燥後、濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィーで精製して、(S)-(E)-19-ブロモノナデカ-6-エン-5-オール (70 mg)を得た。 (5) Triethylamine (50 mL, 0.38 mmol) was added at 0 ° C. to a dichloromethane (20 mL) solution of the compound (160 mg, 0.54 mmol) obtained in (4) above under an argon stream. Methanesulfonyl chloride (30 mL, 0.38 mmol) was added dropwise to the mixture at room temperature, and the mixture was stirred for 1.5 hours. Water and hydrochloric acid (5 mL, 3.0M) were added to the reaction mixture, and the mixture was extracted with Et 2 O (50 mL). The organic layer was washed with water (50 mL) and saturated brine (50 mL), dried over anhydrous magnesium sulfate, and concentrated. Lithium bromide (120 mg, 1.34 mmol) was added to a solution of the obtained crude product in acetone (20 mL), and the mixture was stirred for 5 hours under reflux. Water was added to the reaction mixture, and AcOEt (50 mL x 2) was extracted. The organic layer was washed with saturated brine (100 mL), dried over anhydrous magnesium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography to obtain (S)-(E) -19-bromononadeca-6-en-5-ol (70 mg).
1H-NMR (CDCl3, 300MHz) δppm: 0.90 (t, J=6.8Hz, 3H), 1.18-1.62 (m, 24H), 1.80-1.91 (m, 2H), 1.97-2.07 (m, 2H), 3.41 (t, J=6.8Hz, 2H), 3.99-4.09 (m, 1H), 5.40-5.50 (m, 1H), 5.58-5.69 (m, 1H)
IR (neat): 3368, 2924, 2854, 1670, 1466, 1378, 1262, 1126, 1006, 969, 898, 723, 647, 564 cm-1 1 H-NMR (CDCl 3 , 300MHz) δppm: 0.90 (t, J = 6.8Hz, 3H), 1.18-1.62 (m, 24H), 1.80-1.91 (m, 2H), 1.97-2.07 (m, 2H) , 3.41 (t, J = 6.8Hz, 2H), 3.99-4.09 (m, 1H), 5.40-5.50 (m, 1H), 5.58-5.69 (m, 1H)
IR (neat): 3368, 2924, 2854, 1670, 1466, 1378, 1262, 1126, 1006, 969, 898, 723, 647, 564 cm -1
(6)上記(5)で得た化合物を用い、実施例 1 (6)と実質的に同様にして、標記化合物を得た。 (6) The title compound was obtained in substantially the same manner as in Example 1 (6) using the compound obtained in (5) above.
1H-NMR (DMSO-d6, 300MHz) δppm: 0.86 (t, J=6.6Hz, 3H), 1.24-1.59 (m, 26H), 1.91-2.01 (m, 2H), 2.31-2.39 (m, 2H), 3.78-3.88 (m, 1H), 4.49 (d, J=4.7Hz, 1H), 5.30-5.40 (m, 1H), 5.43-5.54 (m, 1H)
IR (KBr): 3540, 3486, 2919, 2852, 1636, 1472, 1202, 1179, 1056, 967, 899, 801, 720, 611, 536, 483, 429 cm-1 1 H-NMR (DMSO-d 6 , 300MHz) δppm: 0.86 (t, J = 6.6Hz, 3H), 1.24-1.59 (m, 26H), 1.91-2.01 (m, 2H), 2.31-2.39 (m, 2H), 3.78-3.88 (m, 1H), 4.49 (d, J = 4.7Hz, 1H), 5.30-5.40 (m, 1H), 5.43-5.54 (m, 1H)
IR (KBr): 3540, 3486, 2919, 2852, 1636, 1472, 1202, 1179, 1056, 967, 899, 801, 720, 611, 536, 483, 429 cm -1
(R)-(E)-15-ヒドロキシノナデカ-13-エン-1-スルホン酸 ナトリウム塩（化合物４３）
(1)実施例20(4)において、(S)-ノナデカ-13-イン-1,15-ジオールの代わりに、実施例 20 (2)で得た化合物を用い、実施例 20 (4)と実質的に同様にして、(R)-(E)-ノナデカ-13-エン-1,15-ジオールを得た。
(R)-(E) -15-Hydroxynonadeca-13-ene-1-sulfonic acid sodium salt (Compound 43)
(1) In Example 20 (4), instead of (S) -nonadeca-13-in-1,15-diol, the compound obtained in Example 20 (2) was used, and Example 20 (4) and In substantially the same manner, (R)-(E) -nonadeca-13-ene-1,15-diol was obtained.
1H-NMR (CDCl3, 300MHz) δppm: 0.90 (t, J=6.9Hz, 3H), 1.22-1.74 (m, 26H), 1.97-2.07 (m, 2H), 3.64 (t, J=6.6Hz, 2H), 3.99-4.07 (m, 1H), 5.40-5.50 (m, 1H), 5.57-5.69 (m, 1H)
IR (neat): 3340, 2925, 2854, 1711, 1466, 1056, 969, 722 cm-1 1 H-NMR (CDCl 3 , 300MHz) δppm: 0.90 (t, J = 6.9Hz, 3H), 1.22-1.74 (m, 26H), 1.97-2.07 (m, 2H), 3.64 (t, J = 6.6Hz , 2H), 3.99-4.07 (m, 1H), 5.40-5.50 (m, 1H), 5.57-5.69 (m, 1H)
IR (neat): 3340, 2925, 2854, 1711, 1466, 1056, 969, 722 cm -1
(2)上記(1)で得た化合物を用い、実施例 20 (5)と実質的に同様にして、(R)-(E)-19-ブロモノナデカ-6-エン-5-オールを得た。 (2) Using the compound obtained in (1) above, (R)-(E) -19-bromononadeca-6-en-5-ol was obtained in substantially the same manner as in Example 20 (5). .
1H-NMR (CDCl3, 300MHz) δppm: 0.90 (t, J=6.8Hz, 3H), 1.20-1.61 (m, 24H), 1.79-1.91 (m, 2H), 1.97-2.07 (m, 2H), 3.41 (t, J=6.8Hz, 2H), 3.99-4.08 (m, 1H), 5.40-5.49 (m, 1H), 5.57-5.69 (m, 1H)
IR (neat): 3368, 2925, 2854, 2361, 1466, 1385 cm-1 1 H-NMR (CDCl 3 , 300MHz) δppm: 0.90 (t, J = 6.8Hz, 3H), 1.20-1.61 (m, 24H), 1.79-1.91 (m, 2H), 1.97-2.07 (m, 2H) , 3.41 (t, J = 6.8Hz, 2H), 3.99-4.08 (m, 1H), 5.40-5.49 (m, 1H), 5.57-5.69 (m, 1H)
IR (neat): 3368, 2925, 2854, 2361, 1466, 1385 cm -1
(3)上記(2)で得た化合物を用い、実施例 1 (6)と実質的に同様にして、標記化合物を得た。 (3) The title compound was obtained in substantially the same manner as in Example 1 (6) using the compound obtained in (2) above.
1H-NMR (DMSO-d6, 300MHz) δppm: 0.78-0.96 (m, 3H), 1.10-1.61 (m, 26H), 1.88-2.03 (m, 2H), 2.31-2.42 (m, 2H), 3.78-3.90 (m, 1H), 4.49 (d, J=4.5Hz, 1H), 5.30-5.54 (m, 2H)
IR (KBr): 3386, 2958, 2920, 2851, 1669, 1472, 1186, 1082, 1056, 965, 897, 803, 720, 614, 570, 524, 432 cm-1 1 H-NMR (DMSO-d 6 , 300 MHz) δppm: 0.78-0.96 (m, 3H), 1.10-1.61 (m, 26H), 1.88-2.03 (m, 2H), 2.31-2.42 (m, 2H), 3.78-3.90 (m, 1H), 4.49 (d, J = 4.5Hz, 1H), 5.30-5.54 (m, 2H)
IR (KBr): 3386, 2958, 2920, 2851, 1669, 1472, 1186, 1082, 1056, 965, 897, 803, 720, 614, 570, 524, 432 cm -1
(R)-3-(10-ヒドロキシテトラデカ-8-イニルスルファニル)プロパン-1-スルホン酸 ナトリウム塩（化合物１９）
(1) 実施例 11 (1)で得た化合物 (700 mg, 1.74 mmol)、 3-メルカプト-1-プロパノール (224 mL, 2.60 mmol) およびヨウ化ナトリウム (30 mg, 0.20 mmol) のTHF (9.0 mL)溶液に、水素化ナトリウム (153 mg, 鉱油40％添加, 3.82 mmol)を加え、45oCで 7時間攪拌した。反応液に飽和塩化アンモニウム水溶液(50 mL) を加え、AcOEt (50 mL x 2)抽出した。有機層を水 (50 mL) および 飽和食塩水 (50 mL)で洗浄、無水硫酸マグネシウム乾燥後、濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィーで精製して、(R)-3-[10-(tert-ブチルジメチルシラニルオキシ)テトラデカ-8-イニルスルファニル]プロパン-1-オール (650 mg)を得た。
(R) -3- (10-Hydroxytetradec-8-ynylsulfanyl) propane-1-sulfonic acid sodium salt (Compound 19)
(1) THF (9.0 mg) of the compound obtained in Example 11 (1) (700 mg, 1.74 mmol), 3-mercapto-1-propanol (224 mL, 2.60 mmol) and sodium iodide (30 mg, 0.20 mmol) To the solution, sodium hydride (153 mg,
1H-NMR (CDCl3, 300MHz) δppm: 0.10 (s, 3H), 0.12 (s, 3H), 0.84-0.97 (m, 3H), 0.90 (s, 9H), 1.25-1.70 (m, 16H), 1.80-1.91 (m, 2H), 2.18 (dt, J=1.9, 6.9Hz, 2H), 2.53 (t, J=7.3Hz, 2H), 2.64 (t, J=7.1Hz, 2H), 3.77 (t, J=6.1Hz, 2H), 4.31 (tt, J=6.5, 1.9Hz, 1H)
IR (neat): 3231, 2930, 2857, 1630, 1462, 1387, 1361, 1342, 1294, 1251, 1152, 1062, 1036, 938, 837, 777, 668, 629, 596 cm-1 1 H-NMR (CDCl 3 , 300MHz) δppm: 0.10 (s, 3H), 0.12 (s, 3H), 0.84-0.97 (m, 3H), 0.90 (s, 9H), 1.25-1.70 (m, 16H) , 1.80-1.91 (m, 2H), 2.18 (dt, J = 1.9, 6.9Hz, 2H), 2.53 (t, J = 7.3Hz, 2H), 2.64 (t, J = 7.1Hz, 2H), 3.77 ( t, J = 6.1Hz, 2H), 4.31 (tt, J = 6.5, 1.9Hz, 1H)
IR (neat): 3231, 2930, 2857, 1630, 1462, 1387, 1361, 1342, 1294, 1251, 1152, 1062, 1036, 938, 837, 777, 668, 629, 596 cm -1
(2)上記(1)で得た化合物を用い、実施例 1 (3)と実質的に同様にして、(R)-[10-(3-ブロモプロピルスルファニル)-1-ブチルデカ-2-イニルオキシ]-tert-ブチルジメチルシランを得た。 (2) (R)-[10- (3-bromopropylsulfanyl) -1-butyldec-2-ynyloxy was used in substantially the same manner as in Example 1 (3) using the compound obtained in (1) above. ] -tert-butyldimethylsilane was obtained.
1H-NMR (CDCl3, 300MHz) δppm: 0.10 (s, 3H), 0.12 (s, 3H), 0.86-0.94 (m, 3H), 0.90 (s, 9H), 1.23-1.69 (m, 16H), 2.06-2.22 (m, 4H), 2.51 (t, J=7.4Hz, 2H), 2.66 (t, J=6.9Hz, 2H), 3.52 (t, J=6.5Hz, 2H), 4.31 (tt, J=6.5, 1.9Hz, 1H)
IR (neat): 3118, 2930, 2857, 1463, 1402, 1361, 1250, 1152, 1109, 1083, 1005, 938, 837, 777, 668, 565 cm-1 1 H-NMR (CDCl 3 , 300MHz) δppm: 0.10 (s, 3H), 0.12 (s, 3H), 0.86-0.94 (m, 3H), 0.90 (s, 9H), 1.23-1.69 (m, 16H) , 2.06-2.22 (m, 4H), 2.51 (t, J = 7.4Hz, 2H), 2.66 (t, J = 6.9Hz, 2H), 3.52 (t, J = 6.5Hz, 2H), 4.31 (tt, (J = 6.5, 1.9Hz, 1H)
IR (neat): 3118, 2930, 2857, 1463, 1402, 1361, 1250, 1152, 1109, 1083, 1005, 938, 837, 777, 668, 565 cm -1
(3)上記(2)で得た化合物を用い、実施例 1 (4) と実質的に同様にして、(R)-14-(3-ブロモプロピルスルファニル)テトラデカ-6-イン-5-オールを得た。 (3) (R) -14- (3-Bromopropylsulfanyl) tetradec-6-in-5-ol was used in substantially the same manner as in Example 1 (4) using the compound obtained in (2) above. Got.
1H-NMR (CDCl3, 300MHz) δppm: 0.92 (t, J=7.1Hz, 3H), 1.23-1.75 (m, 16H), 2.04-2.24 (m, 4H), 2.52 (t, J=7.4Hz, 2H), 2.66 (t, J=6.9Hz, 2H), 3.52 (t, J=6.5Hz, 2H), 4.30-4.39 (m, 1H)
IR (neat): 3231, 2930, 2857, 2230, 1630, 1461, 1434, 1384, 1333, 1294, 1242, 1148, 1104, 1036, 728, 629, 596, 563 cm-1 1 H-NMR (CDCl 3 , 300MHz) δppm: 0.92 (t, J = 7.1Hz, 3H), 1.23-1.75 (m, 16H), 2.04-2.24 (m, 4H), 2.52 (t, J = 7.4Hz , 2H), 2.66 (t, J = 6.9Hz, 2H), 3.52 (t, J = 6.5Hz, 2H), 4.30-4.39 (m, 1H)
IR (neat): 3231, 2930, 2857, 2230, 1630, 1461, 1434, 1384, 1333, 1294, 1242, 1148, 1104, 1036, 728, 629, 596, 563 cm -1
(4)上記(3)で得た化合物を用い、実施例 1 (6) と実質的に同様にして、標記化合物を得た。 (4) The title compound was obtained in substantially the same manner as in Example 1 (6) using the compound obtained in (3) above.
1H-NMR (DMSO-d6, 300MHz) δppm: 0.86 (t, J=7.1Hz, 3H), 1.20-1.58 (m, 16H), 1.73-1.85 (m, 2H), 2.16 (dt, J=2.0, 6.7Hz, 2H), 2.42-2.57 (m, 6H), 4.09-4.18 (m, 1H), 5.07 (d, J=5.6Hz, 1H)
IR (KBr): 3508, 3360, 2927, 2857, 1654, 1454, 1278, 1250, 1221, 1206, 1177, 1152, 1100, 1059, 1010, 891, 847, 811, 778, 748, 716, 609, 541, 526, 455 cm-1 1 H-NMR (DMSO-d 6 , 300MHz) δppm: 0.86 (t, J = 7.1Hz, 3H), 1.20-1.58 (m, 16H), 1.73-1.85 (m, 2H), 2.16 (dt, J = 2.0, 6.7Hz, 2H), 2.42-2.57 (m, 6H), 4.09-4.18 (m, 1H), 5.07 (d, J = 5.6Hz, 1H)
IR (KBr): 3508, 3360, 2927, 2857, 1654, 1454, 1278, 1250, 1221, 1206, 1177, 1152, 1100, 1059, 1010, 891, 847, 811, 778, 748, 716, 609, 541 , 526, 455 cm -1
(R)-(Z)-3-(10-ヒドロキシテトラデカ-8-エニルスルファニル)プロパン-1-スルホン酸 ナトリウム塩（化合物４７）
水素雰囲気下、Pd-CaCO3 (40 mg) の MeOH (5.0 mL)懸濁液にキノリン (18 mL)を室温で滴下し、45分間攪拌した。 これに、実施例 22 で得た化合物(100 mg, 0.259 mmol)の MeOH (1.0 mL)溶液を室温で滴下し、同温度で水素ガスの吸収がなくなるまで約1.5時間攪拌した。セライトパッドで濾過後、濃縮し、得られた粗生成物をシリカゲルカラムクロマトグラフィーで精製して、 標記化合物(90 mg)を得た。
(R)-(Z) -3- (10-Hydroxytetradec-8-enylsulfanyl) propane-1-sulfonic acid sodium salt (Compound 47)
Under a hydrogen atmosphere, quinoline (18 mL) was added dropwise to a suspension of Pd-CaCO 3 (40 mg) in MeOH (5.0 mL) at room temperature and stirred for 45 minutes. To this, a solution of the compound obtained in Example 22 (100 mg, 0.259 mmol) in MeOH (1.0 mL) was added dropwise at room temperature, and the mixture was stirred at the same temperature for about 1.5 hours until no hydrogen gas was absorbed. After filtration through a celite pad, concentration, the resulting crude product was purified by silica gel column chromatography to obtain the title compound (90 mg).
1H-NMR (DMSO-d6, 300MHz) δppm: 0.85 (t, J=6.7Hz, 3H), 1.14-1.56 (m, 16H), 1.72-1.85 (m, 2H), 1.93-2.09 (m, 2H), 2.41-2.57 (m, 6H), 4.10-4.27 (m, 1H), 4.47 (d, J=4.7Hz, 1H), 5.21-5.35 (m, 2H)
IR (KBr): 3330, 2924, 2852, 1656, 1467, 1378, 1203, 1080, 1057, 820, 752, 602, 528, 419 cm-1 1 H-NMR (DMSO-d 6 , 300MHz) δppm: 0.85 (t, J = 6.7Hz, 3H), 1.14-1.56 (m, 16H), 1.72-1.85 (m, 2H), 1.93-2.09 (m, 2H), 2.41-2.57 (m, 6H), 4.10-4.27 (m, 1H), 4.47 (d, J = 4.7Hz, 1H), 5.21-5.35 (m, 2H)
IR (KBr): 3330, 2924, 2852, 1656, 1467, 1378, 1203, 1080, 1057, 820, 752, 602, 528, 419 cm -1
(R)-3-(10-ヒドロキシテトラデカ-8-イニルオキシ)プロパン-1-スルホン酸 ナトリウム塩（化合物２１）
(1)水素化ナトリウム(324 mg, オイルフリー, 13.5 mmol) の DMF(N,N-ジメチルホルムアミド) (13.0 mL)懸濁液に、1,3-プロパンジオール (1.09 mL, 15.0 mmol) を 0oC で加え、同温度で10分間さらに室温で10分間攪拌した。この反応液に、実施例 11 (1)で得た化合物 (1.21 g, 3.00 mmol)の DMF (2.0 mL)溶液およびヨウ化ナトリウム (45 mg)を0oC で加え、室温で7時間攪拌した。反応液に飽和塩化アンモニウム水溶液 (70 mL) を加え、AcOEtおよびヘキサン (3:1) 混合液(70 mL x 2)で抽出した。有機層を水 (50 mL x 3) および飽和食塩水 (50mL) で洗浄、無水硫酸マグネシウム乾燥後、濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィーで精製して、(R)-3-[10-(tert-ブチルジメチルシロキシ)テトラデカ-8-イニルオキシ]プロパン-1-オール (660 mg)を得た。
(R) -3- (10-Hydroxytetradec-8-ynyloxy) propane-1-sulfonic acid sodium salt (Compound 21)
(1) To a suspension of sodium hydride (324 mg, oil-free, 13.5 mmol) in DMF (N, N-dimethylformamide) (13.0 mL), add 1,3-propanediol (1.09 mL, 15.0 mmol) to 0 o Added at C and stirred at the same temperature for 10 minutes and then at room temperature for 10 minutes. To this reaction solution, a DMF (2.0 mL) solution of the compound obtained in Example 11 (1) (1.21 g, 3.00 mmol) and sodium iodide (45 mg) were added at 0 ° C., and the mixture was stirred at room temperature for 7 hours. . Saturated aqueous ammonium chloride solution (70 mL) was added to the reaction mixture, and the mixture was extracted with a mixture of AcOEt and hexane (3: 1) (70 mL x 2). The organic layer was washed with water (50 mL × 3) and saturated brine (50 mL), dried over anhydrous magnesium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography to obtain (R) -3- [10- (tert-butyldimethylsiloxy) tetradec-8-ynyloxy] propan-1-ol (660 mg). .
1H-NMR (CDCl3, 300MHz) δppm: 0.10 (s, 3H), 0.12 (s, 3H), 0.85-0.94 (m, 3H), 0.90 (s, 9H), 1.24-1.67 (m, 16H), 1.75-1.87 (m, 2H), 2.18 (dt, J=1.9, 6.9Hz, 2H), 3.43 (t, J=6.6Hz, 2H), 3.61 (t, J=5.7Hz, 2H), 3.78 (t, J=5.5Hz, 2H), 4.31 (tt, J=6.6, 1.9Hz, 1H)
IR (neat): 3119, 2930, 2858, 1463, 1401, 1251, 1151, 1115, 1084, 938, 837, 777, 667 cm-1 1 H-NMR (CDCl 3 , 300MHz) δppm: 0.10 (s, 3H), 0.12 (s, 3H), 0.85-0.94 (m, 3H), 0.90 (s, 9H), 1.24-1.67 (m, 16H) , 1.75-1.87 (m, 2H), 2.18 (dt, J = 1.9, 6.9Hz, 2H), 3.43 (t, J = 6.6Hz, 2H), 3.61 (t, J = 5.7Hz, 2H), 3.78 ( t, J = 5.5Hz, 2H), 4.31 (tt, J = 6.6, 1.9Hz, 1H)
IR (neat): 3119, 2930, 2858, 1463, 1401, 1251, 1151, 1115, 1084, 938, 837, 777, 667 cm -1
(2)上記(1)で得た化合物を用い、実施例 1 (3) と実質的に同様にして、(R)-[10-(3-ブロモプロポキシ)-1-ブチルデカ-2-イニルオキシ]-tert-ブチルジメチルシランを得た。 (2) (R)-[10- (3-Bromopropoxy) -1-butyldec-2-ynyloxy] using the compound obtained in (1) above in substantially the same manner as in Example 1 (3) -tert-Butyldimethylsilane was obtained.
1H-NMR (CDCl3, 300MHz) δppm: 0.10 (s, 3H), 0.12 (s, 3H), 0.86-0.94 (m, 3H), 0.90 (s, 9H), 1.23-1.67 (m, 16H), 2.04-2.14 (m, 2H), 2.18 (dt, J=1.9, 6.9Hz, 2H), 3.42 (t, J=6.6Hz, 2H), 3.47-3.56 (m, 4H), 4.31 (tt, J=6.5, 1.9Hz, 1H)
IR (neat): 3228, 2931, 2858, 1630, 1463, 1362, 1294, 1255, 1212, 1150, 1116, 1081, 1036, 938, 837, 778, 666, 596 cm-1 1 H-NMR (CDCl 3 , 300MHz) δppm: 0.10 (s, 3H), 0.12 (s, 3H), 0.86-0.94 (m, 3H), 0.90 (s, 9H), 1.23-1.67 (m, 16H) , 2.04-2.14 (m, 2H), 2.18 (dt, J = 1.9, 6.9Hz, 2H), 3.42 (t, J = 6.6Hz, 2H), 3.47-3.56 (m, 4H), 4.31 (tt, J = 6.5, 1.9Hz, 1H)
IR (neat): 3228, 2931, 2858, 1630, 1463, 1362, 1294, 1255, 1212, 1150, 1116, 1081, 1036, 938, 837, 778, 666, 596 cm -1
(3)上記(2)で得た化合物を用い、実施例 1 (4) と実質的に同様にして、 (R)-14-(3-ブロモプロポキシ)テトラデカ-6-イン-5-オールを得た。 (3) (R) -14- (3-bromopropoxy) tetradec-6-in-5-ol was prepared in substantially the same manner as in Example 1 (4) using the compound obtained in (2) above. Obtained.
1H-NMR (CDCl3, 300MHz) δppm: 0.92 (t, J=7.1Hz, 3H), 1.22-1.78 (m, 16H), 2.04-2.14 (m, 2H), 2.21 (dt, J=1.9, 7.0Hz, 2H), 3.42 (t, J=6.6Hz, 2H), 3.48-3.56 (m, 4H), 4.30-4.39 (m, 1H)
IR (neat): 3400, 3118, 2933, 2859, 1673, 1466, 1401, 1286, 1257, 1212, 1148, 1116, 1037, 892, 768, 654, 573 cm-1 1 H-NMR (CDCl 3 , 300MHz) δppm: 0.92 (t, J = 7.1Hz, 3H), 1.22-1.78 (m, 16H), 2.04-2.14 (m, 2H), 2.21 (dt, J = 1.9, 7.0Hz, 2H), 3.42 (t, J = 6.6Hz, 2H), 3.48-3.56 (m, 4H), 4.30-4.39 (m, 1H)
IR (neat): 3400, 3118, 2933, 2859, 1673, 1466, 1401, 1286, 1257, 1212, 1148, 1116, 1037, 892, 768, 654, 573 cm -1
(4)上記(3)で得た化合物を用い、実施例 1 (6) と実質的に同様にして、標記化合物を得た。 (4) The title compound was obtained in substantially the same manner as in Example 1 (6) using the compound obtained in (3) above.
1H-NMR (DMSO-d6, 300MHz) δppm: 0.86 (t, J=7.1Hz, 3H), 1.20-1.58 (m, 16H), 1.70-1.82 (m, 2H), 2.12-2.21 (m, 2H), 2.37-2.45 (m, 2H), 3.28-3.40 (m, 4H), 4.09-4.19 (m, 1H), 5.08 (d, J=5.4Hz, 1H)
IR (KBr): 3360, 2932, 2857, 2799, 2230, 1656, 1468, 1376, 1210, 1192, 1117, 1055, 901, 793, 744, 621, 555, 530, 482 cm-1 1 H-NMR (DMSO-d 6 , 300MHz) δppm: 0.86 (t, J = 7.1Hz, 3H), 1.20-1.58 (m, 16H), 1.70-1.82 (m, 2H), 2.12-2.21 (m, 2H), 2.37-2.45 (m, 2H), 3.28-3.40 (m, 4H), 4.09-4.19 (m, 1H), 5.08 (d, J = 5.4Hz, 1H)
IR (KBr): 3360, 2932, 2857, 2799, 2230, 1656, 1468, 1376, 1210, 1192, 1117, 1055, 901, 793, 744, 621, 555, 530, 482 cm -1
(R)-(Z)-15-ヒドロキシノナデカ-13-エン-1-スルホン酸 リチウム塩（化合物３７）
アルゴン気流下、実施例 3で得た化合物 (100 mg, 0.254 mmol) の EtOH (5.0 mL)溶液に、アルコール性塩酸(1.0 mL, 0.5M)を滴下し、室温で2時間攪拌した。 不溶物を濾去し、濾液に LiOH (1.0 mL, 1.0M)水溶液を加え、室温で2時間攪拌した後濃縮した。得られた粗生成物を樹脂(HP-20, 日本連水)精製して、標記化合物 (96 mg)を得た。
(R)-(Z) -15-Hydroxynonadeca-13-ene-1-sulfonic acid lithium salt (Compound 37)
Under an argon stream, alcoholic hydrochloric acid (1.0 mL, 0.5M) was added dropwise to an EtOH (5.0 mL) solution of the compound obtained in Example 3 (100 mg, 0.254 mmol), and the mixture was stirred at room temperature for 2 hours. The insoluble material was removed by filtration, and an aqueous solution of LiOH (1.0 mL, 1.0M) was added to the filtrate. The obtained crude product was purified by resin (HP-20, Nipponrensui) to obtain the title compound (96 mg).
1H-NMR (DMSO-d6, 300MHz) δppm: 0.85 (t, J=6.7Hz, 3H), 1.12-1.59 (m, 26H), 1.94-2.05 (m, 2H), 2.30-2.39 (m, 2H), 4.15-4.28 (m, 1H), 4.47 (d, J=4.5Hz, 1H), 5.21-5.35 (m, 2H)
IR (KBr): 3342, 3014, 2958, 2932, 2922, 2848, 1656, 1464, 1407, 1291, 1222, 1186, 1077, 962, 872, 803, 726, 621, 566, 543, 472 cm-1 1 H-NMR (DMSO-d 6 , 300MHz) δppm: 0.85 (t, J = 6.7Hz, 3H), 1.12-1.59 (m, 26H), 1.94-2.05 (m, 2H), 2.30-2.39 (m, 2H), 4.15-4.28 (m, 1H), 4.47 (d, J = 4.5Hz, 1H), 5.21-5.35 (m, 2H)
IR (KBr): 3342, 3014, 2958, 2932, 2922, 2848, 1656, 1464, 1407, 1291, 1222, 1186, 1077, 962, 872, 803, 726, 621, 566, 543, 472 cm -1
(R)-(Z)-15-ヒドロキシノナデカ-13-エン-1-スルホン酸 カリウム塩（化合物３５）
実施例25において、LiOH水溶液の代わりに、KOH水溶液を用い、 実施例 25と実質的に同様にして、標記化合物を得た。
(R)-(Z) -15-Hydroxynonadeca-13-ene-1-sulfonic acid potassium salt (Compound 35)
In Example 25, the title compound was obtained in substantially the same manner as in Example 25 except that a KOH aqueous solution was used instead of the LiOH aqueous solution.
1H-NMR (DMSO-d6, 300MHz) δppm: 0.85 (t, J=6.6Hz, 3H), 1.15-1.60 (m, 26H), 1.93-2.07 (m, 2H), 2.30-2.39 (m, 2H), 4.13-4.25 (m, 1H), 4.47 (d, J=4.5Hz, 1H), 5.21-5.35 (m, 2H)
IR (KBr): 3347, 3007, 2924, 2918, 2852, 1470, 1379, 1200, 1191, 1053, 1020, 794, 721, 609, 550, 530 cm-1 1 H-NMR (DMSO-d 6 , 300MHz) δppm: 0.85 (t, J = 6.6Hz, 3H), 1.15-1.60 (m, 26H), 1.93-2.07 (m, 2H), 2.30-2.39 (m, 2H), 4.13-4.25 (m, 1H), 4.47 (d, J = 4.5Hz, 1H), 5.21-5.35 (m, 2H)
IR (KBr): 3347, 3007, 2924, 2918, 2852, 1470, 1379, 1200, 1191, 1053, 1020, 794, 721, 609, 550, 530 cm -1
(R)-(Z)-15-ヒドロキシノナデカ-13-エン-1-スルホン酸 アンモニウム塩（化合物３８）
実施例25において、LiOH水溶液の代わりに、28% アンモニア水を用い、実施例 25と実質的に同様にして、標記化合物を得た。
(R)-(Z) -15-Hydroxynonadeca-13-ene-1-sulfonic acid ammonium salt (Compound 38)
The title compound was obtained in substantially the same manner as in Example 25 except that 28% aqueous ammonia was used instead of the LiOH aqueous solution in Example 25.
1H-NMR (CD3OD, 300MHz) δppm: 0.91 (t, J=6.8Hz, 3H), 1.18-1.66 (m, 24H), 1.70-1.85 (m, 2H), 1.98-2.16 (m, 2H), 2.72-2.84 (m, 2H), 4.31-4.43 (m, 1H), 5.26-5.51 (m, 2H)
IR (neat): 3206, 2924, 2853, 1652, 1466, 1170, 1084, 1042, 792, 756, 722, 609, 529 cm-1 1 H-NMR (CD 3 OD, 300MHz) δppm: 0.91 (t, J = 6.8Hz, 3H), 1.18-1.66 (m, 24H), 1.70-1.85 (m, 2H), 1.98-2.16 (m, 2H ), 2.72-2.84 (m, 2H), 4.31-4.43 (m, 1H), 5.26-5.51 (m, 2H)
IR (neat): 3206, 2924, 2853, 1652, 1466, 1170, 1084, 1042, 792, 756, 722, 609, 529 cm -1
(R)-(Z)-15-ヒドロキシノナデカ-13-エン-1-スルホン酸 [トリス(ヒドロキシメチル)メチル]アミン塩（化合物３９）
実施例25において、LiOH水溶液の代わりに、トリス(ヒドロキシメチル)アミノメタンを用い、実施例 25と実質的に同様にして、標記化合物を得た。
(R)-(Z) -15-Hydroxynonadeca-13-ene-1-sulfonic acid [tris (hydroxymethyl) methyl] amine salt (Compound 39)
The title compound was obtained in substantially the same manner as in Example 25 except that tris (hydroxymethyl) aminomethane was used in place of the LiOH aqueous solution in Example 25.
1H-NMR (CD3OD, 300MHz) δppm: 0.91 (t, J=6.8Hz, 3H), 1.23-1.64 (m, 24H), 1.70-1.85 (m, 2H), 1.98-2.14 (m, 2H), 2.73-2.83 (m, 2H), 3.64 (s, 6H), 4.30-4.43 (m, 1H), 5.26-5.37 (m, 1H), 5.38-5.50 (m, 1H)
IR (KBr): 3340, 3232, 2919, 2851, 1630, 1516, 1468, 1294, 1188, 1051, 793, 756, 722, 610, 531 cm-1 1 H-NMR (CD 3 OD, 300MHz) δppm: 0.91 (t, J = 6.8Hz, 3H), 1.23-1.64 (m, 24H), 1.70-1.85 (m, 2H), 1.98-2.14 (m, 2H ), 2.73-2.83 (m, 2H), 3.64 (s, 6H), 4.30-4.43 (m, 1H), 5.26-5.37 (m, 1H), 5.38-5.50 (m, 1H)
IR (KBr): 3340, 3232, 2919, 2851, 1630, 1516, 1468, 1294, 1188, 1051, 793, 756, 722, 610, 531 cm -1
(R)-(Z)-15-ヒドロキシノナデカ-13-エン-1-スルホン酸 (L)-リジン塩（化合物４０）
実施例25において、LiOH水溶液の代わりに、(L)-リジンを用い、実施例 25と実質的に同様にして、標記化合物を得た。
(R)-(Z) -15-Hydroxynonadeca-13-ene-1-sulfonic acid (L) -lysine salt (compound 40)
The title compound was obtained in substantially the same manner as in Example 25 except that (L) -lysine was used instead of the LiOH aqueous solution in Example 25.
1H-NMR (CD3OD, 300MHz) δppm: 0.91 (t, J=6.5Hz, 3H), 1.16-1.91 (m, 32H), 1.98-2.14 (m, 2H), 2.73-2.82 (m, 2H), 2.88-2.97 (m, 2H), 3.50-3.58 (m, 1H), 4.30-4.42 (m, 1H), 5.24-5.36 (m, 1H), 5.38-5.50 (m, 1H)
IR (KBr): 2923, 1560, 1508, 1466, 1407, 1323, 1170, 1044, 900, 863, 797, 728, 668, 611, 538, 472, 459, 435, 428, 418 cm-1 1 H-NMR (CD 3 OD, 300MHz) δppm: 0.91 (t, J = 6.5Hz, 3H), 1.16-1.91 (m, 32H), 1.98-2.14 (m, 2H), 2.73-2.82 (m, 2H ), 2.88-2.97 (m, 2H), 3.50-3.58 (m, 1H), 4.30-4.42 (m, 1H), 5.24-5.36 (m, 1H), 5.38-5.50 (m, 1H)
IR (KBr): 2923, 1560, 1508, 1466, 1407, 1323, 1170, 1044, 900, 863, 797, 728, 668, 611, 538, 472, 459, 435, 428, 418 cm -1
(R)-(Z)-15-アセトキシノナデカ-13-エン-1-スルホン酸アミド（化合物４５）
実施例 19 で得た化合物(150 mg, 0.325 mmol) の DMF (0.2 mL)溶液を、塩化チオニル (0.20 mL)に 0oCで加え、同温度で2時間攪拌した。反応液に水(20 mL)を加え、AcOEt (30 mL x 2)抽出した。有機層を水 (30 mL)で洗浄、無水硫酸マグネシウムで乾燥後、濃縮した。得られたスルホニルクロリドのジクロロメタン(2 mL)溶液に、無水アンモニアガスを室温で30分間吹き込んだ。 沈殿物を濾去し、濾液を濃縮し、得られた粗生成物をシリカゲルカラムクロマトグラフィーで精製して、標記化合物(40 mg)を得た。
(R)-(Z) -15-Acetoxynonadeca-13-ene-1-sulfonic acid amide (Compound 45)
A solution of the compound obtained in Example 19 (150 mg, 0.325 mmol) in DMF (0.2 mL) was added to thionyl chloride (0.20 mL) at 0 ° C., and the mixture was stirred at the same temperature for 2 hours. Water (20 mL) was added to the reaction mixture, and AcOEt (30 mL x 2) was extracted. The organic layer was washed with water (30 mL), dried over anhydrous magnesium sulfate, and concentrated. Anhydrous ammonia gas was blown into the dichloromethane (2 mL) solution of the obtained sulfonyl chloride for 30 minutes at room temperature. The precipitate was removed by filtration, the filtrate was concentrated, and the resulting crude product was purified by silica gel column chromatography to obtain the title compound (40 mg).
1H-NMR (CDCl3, 300MHz) δppm: 0.89 (t, J=7.0Hz, 3H), 1.18-1.73 (m, 24H), 1.79-1.93 (m, 2H), 1.96-2.24 (m, 5H), 3.07-3.16 (m, 2H), 4.56 (bs, 2H), 5.23-5.34 (m, 1H), 5.48-5.59 (m, 2H)
IR (neat): 3255, 3014, 2925, 2854, 1736, 1556, 1466, 1401, 1371, 1332, 1241, 1149, 1084, 1019, 953, 723, 573, 498 cm-1 1 H-NMR (CDCl 3 , 300MHz) δppm: 0.89 (t, J = 7.0Hz, 3H), 1.18-1.73 (m, 24H), 1.79-1.93 (m, 2H), 1.96-2.24 (m, 5H) , 3.07-3.16 (m, 2H), 4.56 (bs, 2H), 5.23-5.34 (m, 1H), 5.48-5.59 (m, 2H)
IR (neat): 3255, 3014, 2925, 2854, 1736, 1556, 1466, 1401, 1371, 1332, 1241, 1149, 1084, 1019, 953, 723, 573, 498 cm -1
(R)-(Z)-15-ヒドロキシノナデカ-13-エン-1-スルホン酸アミド（化合物４６）
実施例 30 で得た化合物(40 mg, 0.0991 mmol) の MeOH (2.0 mL)溶液に、ナトリウムメトキシド(27 mg, 0.500 mmol)を室温で加え一夜攪拌した。反応液に水を加え、AcOEt (30 mL x 2)抽出し、無水硫酸マグネシウムで乾燥後、濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィーで精製して、標記化合物(27 mg)を得た。
(R)-(Z) -15-Hydroxynonadeca-13-ene-1-sulfonic acid amide (Compound 46)
Sodium methoxide (27 mg, 0.500 mmol) was added to a solution of the compound obtained in Example 30 (40 mg, 0.0991 mmol) in MeOH (2.0 mL) at room temperature and stirred overnight. Water was added to the reaction solution, extracted with AcOEt (30 mL x 2), dried over anhydrous magnesium sulfate and concentrated. The obtained crude product was purified by silica gel column chromatography to obtain the title compound (27 mg).
1H-NMR (CDCl3, 300MHz) δppm: 0.91 (t, J=6.9Hz, 3H), 1.20-1.65 (m, 24H), 1.80-1.93 (m, 2H), 1.98-2.18 (m, 2H), 3.07-3.15 (m, 2H), 4.37-4.56 (m, 3H), 5.31-5.42 (m, 1H), 5.43-5.54 (m, 1H)
IR (KBr): 3359, 2919, 2848, 1736, 1686, 1656, 1543, 1462, 1339, 1302, 1284, 1140, 1054, 899, 790, 724, 644, 591, 518, 489, 418 cm-1 1 H-NMR (CDCl 3 , 300MHz) δppm: 0.91 (t, J = 6.9Hz, 3H), 1.20-1.65 (m, 24H), 1.80-1.93 (m, 2H), 1.98-2.18 (m, 2H) , 3.07-3.15 (m, 2H), 4.37-4.56 (m, 3H), 5.31-5.42 (m, 1H), 5.43-5.54 (m, 1H)
IR (KBr): 3359, 2919, 2848, 1736, 1686, 1656, 1543, 1462, 1339, 1302, 1284, 1140, 1054, 899, 790, 724, 644, 591, 518, 489, 418 cm -1
(R)-(Z)-15-ヒドロキシノナデカ-13-エン-1-スルホン酸 メチルエステル（化合物７２）
実施例 3で得た化合物 (100 mg, 0.254 mmol) の EtOH (5.0 mL) 溶液に、アルコール性塩酸 (1.0 mL, 0.5M)を室温で滴下し、同温度で2時間攪拌した。沈殿物を濾去し、濾液に(トリメチルシリル)ジアゾメタン (1.0 mL, 2.0M THF溶液)を室温で加え、2時間攪拌した。反応液を水に注ぎ、AcOEt (50 mL x 2)抽出した。有機層を水および 飽和食塩水 (50 mL)で洗浄、無水硫酸マグネシウムデ乾燥後、濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィーで精製して、標記化合物(20 mg)を得た。
(R)-(Z) -15-Hydroxynonadeca-13-ene-1-sulfonic acid methyl ester (Compound 72)
Alcoholic hydrochloric acid (1.0 mL, 0.5M) was added dropwise at room temperature to a solution of the compound obtained in Example 3 (100 mg, 0.254 mmol) in EtOH (5.0 mL), and the mixture was stirred at the same temperature for 2 hours. The precipitate was removed by filtration, and (trimethylsilyl) diazomethane (1.0 mL, 2.0 M THF solution) was added to the filtrate at room temperature, followed by stirring for 2 hours. The reaction mixture was poured into water and extracted with AcOEt (50 mL x 2). The organic layer was washed with water and saturated brine (50 mL), dried over anhydrous magnesium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography to obtain the title compound (20 mg).
1H-NMR (CDCl3, 300MHz) δppm: 0.91 (t, J=6.8Hz, 3H), 1.19-1.66 (m, 24H), 1.78-1.92 (m, 2H), 1.98-2.18 (m, 2H), 3.05-3.14 (m, 2H), 3.89 (s, 3H), 4.37-4.48 (m, 1H), 5.32-5.41 (m, 1H), 5.43-5.54 (m, 1H)
IR (KBr): 3376, 2920, 2851, 1585, 1510, 1471, 1412, 1205, 1187, 1080, 1050, 863, 806, 721, 610, 528, 428 cm-1 1 H-NMR (CDCl 3 , 300MHz) δppm: 0.91 (t, J = 6.8Hz, 3H), 1.19-1.66 (m, 24H), 1.78-1.92 (m, 2H), 1.98-2.18 (m, 2H) , 3.05-3.14 (m, 2H), 3.89 (s, 3H), 4.37-4.48 (m, 1H), 5.32-5.41 (m, 1H), 5.43-5.54 (m, 1H)
IR (KBr): 3376, 2920, 2851, 1585, 1510, 1471, 1412, 1205, 1187, 1080, 1050, 863, 806, 721, 610, 528, 428 cm -1
試験例１
fMLP(N-formyl-Met-Leu-Phe)刺激によるエラスターゼ産生試験
ラット好中球は生理食塩水に溶解した１％カゼイン溶液を腹腔内投与（120mL/kg）15から18時間後に調製した。断頭後、腹腔洗浄により細胞を回収した。
洗浄液は冷PBSを使用する。腹腔洗浄液を回収し、遠心処理しHBSSを用いて細胞濃度、１×107細胞／mLに再懸濁する。細胞をプライミングする目的でサイトカラシンＢ（最終濃度５μg／mL）を添加した。96ウエル培養プレートにウエル当たり190μL加え、規定濃度（１×10-7Mから３×10-5M）の化合物を添加し５％ＣＯ2、37度で培養した。10分後、20μＭｆＭＬＰを10μＬを加えた。ｆＭＬＰを加えない群には0.4％エタノール溶液10μLを加えた。攪拌後、さらに10分間培養した。反応は氷上で停止し、培養上清は遠心により回収した。
Test example 1
Test for elastase production by stimulation with fMLP (N-formyl-Met-Leu-Phe) Rat neutrophils were prepared 15 to 18 hours after intraperitoneal administration (120 mL / kg) of a 1% casein solution dissolved in physiological saline. After decapitation, cells were collected by peritoneal washing.
Use cold PBS as the washing solution. The peritoneal lavage fluid is collected, centrifuged, and resuspended to a cell concentration of 1 × 10 7 cells / mL using HBSS. Cytochalasin B (final concentration 5 μg / mL) was added for the purpose of priming the cells. 190 μL per well was added to a 96-well culture plate, a compound at a specified concentration (1 × 10 −7 M to 3 × 10 −5 M) was added, and the cells were cultured at 37 ° C. with 5% CO 2 . Ten minutes later, 10 μL of 20 μM fMLP was added. 10 μL of 0.4% ethanol solution was added to the group to which no fMLP was added. After stirring, the cells were further cultured for 10 minutes. The reaction was stopped on ice, and the culture supernatant was collected by centrifugation.
培養上清中のエラスターゼ活性測定
培養上清中のエラスターゼ活性はエラスターゼ特異的な基質(N-succinyl-L-alanyl-L-alanyl-L-proline-valine-MCA；Peptide Institute, Inc. 大阪)0.12mMを用いて50mMとリス溶液（ｐH8.0）中で測定した。培養上清50μLと基質溶液50μLを加え、37度30分間インキュベートした。エラスターゼ活性は励起波長360nm、吸収波長480nmで測定した。エラスターゼ遊離抑制活性（阻害率）は以下の式によって算出した。
阻害率（％）＝｛1-(A-C）/(B-C)｝×100
AはfMLP（１μM）で刺激した時の蛍光強度を表す。BはfMLP（１μM）と化合物が添加した時の蛍光強度を表す。CはfMLPを添加しない時の蛍光強度を表す。50％阻害する濃度（IC50値）は濃度‐阻害曲線から算出した。結果は表４に示す。
Measurement of Elastase Activity in Culture Supernatant Elastase activity in culture supernatant is an elastase-specific substrate (N-succinyl-L-alanyl-L-alanyl-L-proline-valine-MCA; Peptide Institute, Inc. Osaka) 0.12 It measured in 50 mM and a squirrel solution (pH 8.0) using mM. 50 μL of the culture supernatant and 50 μL of the substrate solution were added and incubated at 37 ° C. for 30 minutes. The elastase activity was measured at an excitation wavelength of 360 nm and an absorption wavelength of 480 nm. The elastase release inhibitory activity (inhibition rate) was calculated by the following equation.
Inhibition rate (%) = {1- (AC) / (BC)} x 100
A represents the fluorescence intensity when stimulated with fMLP (1 μM). B represents the fluorescence intensity when fMLP (1 μM) and a compound are added. C represents the fluorescence intensity when no fMLP is added. The concentration that inhibits 50% (IC50 value) was calculated from the concentration-inhibition curve. The results are shown in Table 4.
上記表中、化合物23および33は化合物例に一致する。上記結果から発明化合物は強力なエラスターゼ生成阻害活性をもつことが証明された。 In the above table, compounds 23 and 33 correspond to compound examples. From the above results, it was proved that the compounds of the invention have strong elastase production inhibitory activity.
試験例２
ラット一過性中大脳動脈閉塞（t-MCAo）モデルにおける脳梗塞体積に対する作用方法
Wistar 雄性ラット（200-250 g）を２％ハロタン麻酔した。右内頸動脈（ICA）を注意深く単離した。シリコンーコーティングした栓子（長さ18mm）をICAに挿入した。体温はヒーティングパッドを用いて37℃に維持した。手術後、麻酔をはずし覚醒すると、虚血の成功した動物は前肢の重篤な方麻痺を呈した。１時間の中大脳動脈閉塞後、栓子を引いて虚血領域に血液を再灌流させた。ラットには溶媒（10% HP-b-CD）または溶媒に溶解した化合物33を再灌流直後から静脈内に１時間インフュージョン投与した。
Test example 2
Effects on cerebral infarct volume in rat transient middle cerebral artery occlusion (t-MCAo) model
Wistar male rats (200-250 g) were anesthetized with 2% halothane. The right internal carotid artery (ICA) was carefully isolated. A silicon-coated obturator (length 18 mm) was inserted into the ICA. Body temperature was maintained at 37 ° C. using a heating pad. After surgery, when anesthesia was removed and waking up, animals with successful ischemia exhibited severe paralysis of the forelimbs. After 1 hour of middle cerebral artery occlusion, an obturator was pulled to reperfuse blood into the ischemic area. Rats were infused intravenously for 1 hour immediately after reperfusion with vehicle (10% HP-b-CD) or compound 33 dissolved in vehicle.
梗塞体積の測定のために、ラットは再灌流から７１時間後に屠殺した。脳は生理的食塩水を経心灌流し、頭蓋から摘出し、２mmの厚さで冠状に薄切した。薄切切片は２％triphenyl-tetrazolium chloride（TTC）溶液に37℃で30分間浸して染色した。すべてのデータは平均±標準誤差で示した。統計学的解析は、Dunnett多重比較検定を行った。 Rats were sacrificed 71 hours after reperfusion for measurement of infarct volume. The brain was transcardially perfused with physiological saline, removed from the skull, and sliced into a coronal shape with a thickness of 2 mm. Thin slices were stained by soaking in a 2% triphenyl-tetrazolium chloride (TTC) solution at 37 ° C. for 30 minutes. All data are expressed as mean ± standard error. Statistical analysis was performed using Dunnett's multiple comparison test.
結果
ラット一過性中大脳動脈閉塞モデルにおける化合物33の脳梗塞体積に対する影響
10% HP-b-CDに溶解した化合物33（0.1 mg/kg/min）は再灌流直後から１時間持続投与した。化合物33は0.1 mg/kg/min１時間投与において溶媒群に比較して脳梗塞総体積、特に皮質における脳梗塞体積を有意差をもって縮小した（図１）。この結果は、化合物33が虚血性の脳障害に対して神経保護作用を有することを示唆する。
Results: Effects of compound 33 on cerebral infarct volume in a transient middle cerebral artery occlusion model in rats
Compound 33 (0.1 mg / kg / min) dissolved in 10% HP-b-CD was administered continuously for 1 hour immediately after reperfusion. Compound 33 significantly reduced the total volume of cerebral infarction, particularly the cerebral infarct volume in the cortex, compared with the solvent group when administered at 0.1 mg / kg / min for 1 hour (FIG. 1). This result suggests that compound 33 has a neuroprotective action against ischemic brain damage.
Claims (2)
A therapeutic agent for cerebral infarction comprising the elastase release inhibitor according to claim 1.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| JP2009509979A (en) * | 2005-09-29 | 2009-03-12 | ユニバーシティ オブ アルバータ | Compositions and methods for granzyme B inhibition |
| US8071098B2 (en) | 2006-05-19 | 2011-12-06 | National University Corporation Okayama University | Method of preventing cerebral vasospasm with anti-HMGB1 antibody |
| JP2017032581A (en) * | 2008-10-21 | 2017-02-09 | アスチュート メディカル，インコーポレイテッド | Methods and compositions for diagnosis and prognosis of renal injury and renal failure |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2009509979A (en) * | 2005-09-29 | 2009-03-12 | ユニバーシティ オブ アルバータ | Compositions and methods for granzyme B inhibition |
| US8071098B2 (en) | 2006-05-19 | 2011-12-06 | National University Corporation Okayama University | Method of preventing cerebral vasospasm with anti-HMGB1 antibody |
| JP2017032581A (en) * | 2008-10-21 | 2017-02-09 | アスチュート メディカル，インコーポレイテッド | Methods and compositions for diagnosis and prognosis of renal injury and renal failure |
| US10823733B2 (en) | 2008-10-21 | 2020-11-03 | Astute Medical, Inc. | Methods and compositions for diagnosis and prognosis of renal injury and renal failure |
| US11754566B2 (en) | 2008-10-21 | 2023-09-12 | Astute Medical, Inc. | Methods and compositions for diagnosis and prognosis of renal injury and renal failure |
| US10823742B2 (en) | 2010-06-23 | 2020-11-03 | Astute Medical, Inc. | Methods and compositions for diagnosis and prognosis of renal injury and renal failure |
| US11761967B2 (en) | 2010-06-23 | 2023-09-19 | Astute Medical, Inc. | Methods and compositions for diagnosis and prognosis of renal injury and renal failure |
| US11346846B2 (en) | 2017-02-06 | 2022-05-31 | Astute Medical, Inc. | Methods and compositions for diagnosis and prognosis of renal injury and renal failure |
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