JP4952208B2 - Method for producing Praelputrin A - Google Patents
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- JP4952208B2 JP4952208B2 JP2006310595A JP2006310595A JP4952208B2 JP 4952208 B2 JP4952208 B2 JP 4952208B2 JP 2006310595 A JP2006310595 A JP 2006310595A JP 2006310595 A JP2006310595 A JP 2006310595A JP 4952208 B2 JP4952208 B2 JP 4952208B2
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- 238000004519 manufacturing process Methods 0.000 title claims description 19
- 238000006243 chemical reaction Methods 0.000 claims description 69
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical group CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 22
- 150000002596 lactones Chemical class 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 14
- 240000007124 Brassica oleracea Species 0.000 claims description 12
- 235000003899 Brassica oleracea var acephala Nutrition 0.000 claims description 12
- 235000012905 Brassica oleracea var viridis Nutrition 0.000 claims description 12
- UIERETOOQGIECD-UHFFFAOYSA-N Angelic acid Natural products CC=C(C)C(O)=O UIERETOOQGIECD-UHFFFAOYSA-N 0.000 claims description 11
- UIERETOOQGIECD-ARJAWSKDSA-N angelic acid Chemical compound C\C=C(\C)C(O)=O UIERETOOQGIECD-ARJAWSKDSA-N 0.000 claims description 11
- 239000003054 catalyst Substances 0.000 claims description 7
- 229910052706 scandium Inorganic materials 0.000 claims description 6
- SIXSYDAISGFNSX-UHFFFAOYSA-N scandium atom Chemical compound [Sc] SIXSYDAISGFNSX-UHFFFAOYSA-N 0.000 claims description 6
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 claims description 6
- ADPMHRDERZTFIN-UHFFFAOYSA-N epinastine hydrobromide Chemical compound Br.C1C2=CC=CC=C2C2CN=C(N)N2C2=CC=CC=C21 ADPMHRDERZTFIN-UHFFFAOYSA-N 0.000 claims description 4
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- 150000001875 compounds Chemical class 0.000 description 20
- 239000000203 mixture Substances 0.000 description 16
- 239000000047 product Substances 0.000 description 16
- 239000007810 chemical reaction solvent Substances 0.000 description 8
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 238000006317 isomerization reaction Methods 0.000 description 6
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 6
- 238000000746 purification Methods 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- QSILYWCNPOLKPN-UHFFFAOYSA-N 3-chloro-3-methylbut-1-yne Chemical compound CC(C)(Cl)C#C QSILYWCNPOLKPN-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- -1 aliphatic organic base Chemical class 0.000 description 4
- 229940125904 compound 1 Drugs 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 150000007530 organic bases Chemical class 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 125000002827 triflate group Chemical group FC(S(=O)(=O)O*)(F)F 0.000 description 4
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 3
- CJIJXIFQYOPWTF-UHFFFAOYSA-N 7-hydroxycoumarin Natural products O1C(=O)C=CC2=CC(O)=CC=C21 CJIJXIFQYOPWTF-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 229940126214 compound 3 Drugs 0.000 description 3
- 238000006482 condensation reaction Methods 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- ORHBXUUXSCNDEV-UHFFFAOYSA-N umbelliferone Chemical compound C1=CC(=O)OC2=CC(O)=CC=C21 ORHBXUUXSCNDEV-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 238000005917 acylation reaction Methods 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 230000000996 additive effect Effects 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 238000005906 dihydroxylation reaction Methods 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 description 2
- 229910000489 osmium tetroxide Inorganic materials 0.000 description 2
- 239000012285 osmium tetroxide Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 230000000707 stereoselective effect Effects 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 238000006257 total synthesis reaction Methods 0.000 description 2
- AVFZOVWCLRSYKC-UHFFFAOYSA-N 1-methylpyrrolidine Chemical compound CN1CCCC1 AVFZOVWCLRSYKC-UHFFFAOYSA-N 0.000 description 1
- TVZDIFXOIOIPJG-UHFFFAOYSA-N 2,3,4-trichlorobenzoyl chloride Chemical compound ClC(=O)C1=CC=C(Cl)C(Cl)=C1Cl TVZDIFXOIOIPJG-UHFFFAOYSA-N 0.000 description 1
- OZGSEIVTQLXWRO-UHFFFAOYSA-N 2,4,6-trichlorobenzoyl chloride Chemical compound ClC(=O)C1=C(Cl)C=C(Cl)C=C1Cl OZGSEIVTQLXWRO-UHFFFAOYSA-N 0.000 description 1
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 description 1
- BWGRDBSNKQABCB-UHFFFAOYSA-N 4,4-difluoro-N-[3-[3-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octan-8-yl]-1-thiophen-2-ylpropyl]cyclohexane-1-carboxamide Chemical compound CC(C)C1=NN=C(C)N1C1CC2CCC(C1)N2CCC(NC(=O)C1CCC(F)(F)CC1)C1=CC=CS1 BWGRDBSNKQABCB-UHFFFAOYSA-N 0.000 description 1
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- LFZAGIJXANFPFN-UHFFFAOYSA-N N-[3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-thiophen-2-ylpropyl]acetamide Chemical compound C(C)(C)C1=NN=C(N1C1CCN(CC1)CCC(C=1SC=CC=1)NC(C)=O)C LFZAGIJXANFPFN-UHFFFAOYSA-N 0.000 description 1
- AHVYPIQETPWLSZ-UHFFFAOYSA-N N-methyl-pyrrolidine Natural products CN1CC=CC1 AHVYPIQETPWLSZ-UHFFFAOYSA-N 0.000 description 1
- LFTLOKWAGJYHHR-UHFFFAOYSA-N N-methylmorpholine N-oxide Chemical compound CN1(=O)CCOCC1 LFTLOKWAGJYHHR-UHFFFAOYSA-N 0.000 description 1
- 230000021736 acetylation Effects 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 150000004982 aromatic amines Chemical class 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 230000000711 cancerogenic effect Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 231100000315 carcinogenic Toxicity 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- GGSUCNLOZRCGPQ-UHFFFAOYSA-N diethylaniline Chemical compound CCN(CC)C1=CC=CC=C1 GGSUCNLOZRCGPQ-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 238000011403 purification operation Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Description
本発明は、プラエルプトリンＡの製造方法に関し、詳しくはプラエルプトリンＡを高収率かつ選択的に製造する方法に関する。 The present invention relates to a method for producing Praeleptrin A, and more particularly, to a method for selectively producing Praeleptrin A in high yield.
プラエルプトリンＡは、ゼンコ由来の成分であり、カルシウム拮抗作用や発癌プロモーター抑制作用などに加え、近年見出された抗エイズ活性など種々の興味深い薬理活性を示しており、多くの研究者から薬効成分として非常に注目されている（例えば、非特許文献１〜４等参照）。 Praeruptoline A is a component derived from zenko and exhibits various interesting pharmacological activities such as anti-AIDS activity recently found in addition to calcium antagonism and carcinogenic promoter suppression. It has attracted a great deal of attention (see, for example, Non-Patent Documents 1 to 4).
今日、かかるプラエルプトリンＡの全合成については種々の方法が提案されている（非特許文献５〜９参照）。
しかしながら、未だ効率的な合成方法による製造方法が確立されていないため、これまでは研究者自らの天然物からの単離製造に依存しているのが現状である。合成法としても、例えば、スエイト（Ｓｗａｉｔ）ら（非特許文献５参照）により提案されているプラエルプトリンＡの既知の全合成法は、アンゲリカ酸をジシクロヘキシルカルボジイミド（ＤＣＣ）により活性化エステルとした後、４’−アセチルケールラクトンとの縮合を行うものであり、この方法では最終工程の収率が４％と非常に低いものであった。また、この反応では立体的に障害の大きい４’−アンゲロイル（Ａｎｇ）化反応が進行しにくく、通常条件（ＡｎｇＣｌまたはＡｎｇ２Ｏ、ピリジン、Ｎ，Ｎ−ジメチル−４−アミノピリジン（ＤＭＡＰ）など）では、反応が進行しないか、あるいは複雑な立体異性体の混合物として得られることが報告されている。文献上の最適な反応条件を用いた合成においても、反応中に４’−Ａｎｇの二重結合に対して異性化を起こした４’−ティグロイル（Ｔｉｇ）体を生じることから、収率の低下を招いている。 However, since a production method by an efficient synthesis method has not yet been established, the present situation is that until now, the researcher relies on an isolated production from a natural product. As a synthesis method, for example, a known total synthesis method of praeputrin A proposed by Swate et al. (See Non-Patent Document 5) is a method in which angelic acid is converted into an activated ester with dicyclohexylcarbodiimide (DCC), Condensation with 4′-acetylkalelactone was performed, and in this method, the yield of the final step was as low as 4%. In this reaction, a sterically hindered 4′-angeloyl (Ang) reaction is difficult to proceed, and normal conditions (AngCl or Ang 2 O, pyridine, N, N-dimethyl-4-aminopyridine (DMAP), etc.) ), It is reported that the reaction does not proceed or is obtained as a complex mixture of stereoisomers. Even in the synthesis using the optimal reaction conditions in the literature, the yield is reduced because a 4′-tigloyl (Tig) isomer is generated during the reaction to isomerize the double bond of 4′-Ang. Is invited.
さらに、非特許文献５記載の方法を改善した続報（非特許文献６参照）も出ているが、反応自体は非特許文献５記載の方法に準じており、無溶媒条件で冷蔵庫に放置して反応を追跡するものであった。この方法では収率は４２％と改善したが、この反応条件では継続的に再現性を取ることが難しく、また、カラムクロマトグラフィー精製などで容易には分離困難な異性体も同程度副生するという問題があった。 Furthermore, there is a follow-up report (see Non-Patent Document 6) that improves the method described in Non-Patent Document 5, but the reaction itself is in accordance with the method described in Non-Patent Document 5, and it is left in a refrigerator under solvent-free conditions. The reaction was followed. Although this method improved the yield to 42%, it is difficult to continuously obtain reproducibility under these reaction conditions, and isomers that are difficult to separate by column chromatography purification and the like are also by-produced to the same extent. There was a problem.
一方、立体障害の大きい種々水酸基への高収率なアシル化反応を利用したプラエルプトリンＡの製造方法も幾つか報告されており（非特許文献７および８参照）、また、トリクロロベンゾイルクロライドを用いた立体障害の大きいアルコールのアンゲロイル化反応も、エー．イー．グリーンら（非特許文献９参照）によって報告されているが、いずれの合成反応も反応に長時間を要し、また生成物は目的物とその位置異性体の等量混合物からなり、収率が低く、かつ、この混合物もカラムクロマトグラフィー精製での分離が困難であった。 On the other hand, several production methods of praeputrin A using high yield acylation reaction to various hydroxyl groups with large steric hindrance have been reported (see Non-Patent Documents 7 and 8), and trichlorobenzoyl chloride was used. The angeloylation reaction of alcohol with large steric hindrance is also described in A. E. As reported by Green et al. (See Non-Patent Document 9), all of the synthesis reactions take a long time for the reaction, and the product is composed of an equal mixture of the target product and its positional isomer, and the yield is high. It was low and this mixture was also difficult to separate by column chromatography purification.
そこで本発明の目的は、プラエルプトリンＡを高収率かつ選択的に製造する方法を提供することにある。 Accordingly, an object of the present invention is to provide a method for selectively producing Praeruptoline A in high yield.
本発明者は、上記課題を解決するために鋭意研究した結果、シス−４’−アセチルケールラクトンを所定の条件下でアンゲリカ酸またはアンゲリカ酸無水物と反応させることにより上記目的を達成し得ることを見出し、本発明を完成するに至った。 As a result of diligent research to solve the above problems, the present inventor can achieve the above object by reacting cis-4′-acetyl kale lactone with angelic acid or angelic anhydride under predetermined conditions. As a result, the present invention has been completed.
即ち、本発明のプラエルプトリンＡの製造方法は、シス−４’−アセチルケールラクトンをアンゲリカ酸と、無水トリフラートおよび塩基の存在下で反応させることを特徴とするものである。 That is, the method for producing Praeruptoline A of the present invention is characterized in that cis-4'-acetyl kale lactone is reacted with angelic acid in the presence of triflate anhydride and a base.
前記塩基は、好ましくはジイソプロピルエチルアミンであり、また、反応温度は、好ましくは−８０〜−４０℃である。 The base is preferably diisopropylethylamine, and the reaction temperature is preferably −80 to −40 ° C.
また、本発明の他のプラエルプトリンＡの製造方法は、シス−４’−アセチルケールラクトンをアンゲリカ酸無水物と、トリフラートのスカンジウム触媒の存在下で反応させることを特徴とするものである。また、この反応温度は、好ましくは０〜２０℃である。 In addition, another method for producing Praerptoline A according to the present invention is characterized in that cis-4'-acetyl kale lactone is reacted with angelic anhydride in the presence of a triflate scandium catalyst. Moreover, this reaction temperature becomes like this. Preferably it is 0-20 degreeC.
本発明によれば、プラエルプトリンＡを高収率かつ選択的に製造することができる。 According to the present invention, plaeroptin A can be selectively produced in high yield.
以下、本発明の実施の形態につき具体的に説明する。
（実施形態１）
本発明の実施形態１においては、シス−４’−アセチルケールラクトンをアンゲリカ酸（ＡｎｇＯＨ）と、無水トリフラート（Ｔｆ２Ｏ）および塩基の存在下で反応させるものである。
Hereinafter, embodiments of the present invention will be specifically described.
(Embodiment 1)
In Embodiment 1 of the present invention, cis-4′-acetylkallactone is reacted with angelic acid (AngOH) in the presence of triflate anhydride (Tf 2 O) and a base.
本発明において使用する出発物質のシス−４’−アセチルケールラクトンは、既知の製造方法により得ることができる。例えば、前記非特許文献７に記載の製造方法に従い、市場で容易に入手し得る７-ヒドロキシクマリンを原料とし、これを３−クロロ−３−メチル−１−ブチンとの置換反応により中間体Ａを得、この中間体Ａを、例えば、触媒量の四酸化オスミウムを用いてオレフィンのジヒドロキシル化反応により中間体Ｂとし、この中間体Ｂを無水酢酸と反応させてシス−４’−アセチルケールラクトンを立体選択的に得ることができる。 The starting cis-4'-acetyl kale lactone used in the present invention can be obtained by a known production method. For example, according to the production method described in Non-Patent Document 7, 7-hydroxycoumarin which can be easily obtained in the market is used as a raw material, and this is converted into intermediate A by substitution reaction with 3-chloro-3-methyl-1-butyne. This intermediate A is converted to intermediate B by, for example, dihydroxylation of olefins using a catalytic amount of osmium tetroxide, and this intermediate B is reacted with acetic anhydride to give cis-4′-acetyl kale. Lactone can be obtained stereoselectively.
出発物質であるシス−４’−アセチルケールラクトンとアンゲリカ酸（ＡｎｇＯＨ）との縮合反応は、活性化能の強い無水トリフラートを用い、系内で非常に強力なアシル化活性種であるＡｎｇＯＴｆを発生させることが肝要である。また、この反応は、低温かつ短時間で完結させることが好ましい。具体的には−８０〜−６０℃、１〜３時間でＡｎｇＯＴｆを生成させ、同温度でシス−４’−アセチルケールラクトンの溶液を滴下後、０．５〜２４時間で−８０〜−４０℃まで昇温する方法や、シス−４’−アセチルケールラクトン、アンゲリカ酸（ＡｎｇＯＨ）および塩基の混合物に、無水トリフラートを−８０〜−６０℃で滴下し、同温度で０．５〜１時間反応させる方法が好ましい。このうち、シス−４’−アセチルケールラクトン、アンゲリカ酸（ＡｎｇＯＨ）および塩基の混合物に、無水トリフラートを−８０℃で滴下し、同温度で０．５〜１時間反応させる方法が特に好ましい。これにより反応過程で二重結合の異性化が抑えられ、収率および立体選択性を顕著に向上させることが可能となる。 The condensation reaction between the starting material cis-4'-acetylkallactone and angelic acid (AngOH) generates AngOTf, which is a very strong acylation active species in the system, using an active triflate anhydride. It is important to make it happen. Further, this reaction is preferably completed at a low temperature and in a short time. Specifically, AngOTf is produced at −80 to −60 ° C. for 1 to 3 hours, and a solution of cis-4′-acetylkallactone is added dropwise at the same temperature, and then −80 to −40 at 0.5 to 24 hours. To the mixture of cis-4′-acetyl kale lactone, angelic acid (AngOH) and base, at a temperature of from −80 to −60 ° C., and at the same temperature for 0.5 to 1 hour. A reaction method is preferred. Among these, the method of dripping an anhydrous triflate at -80 degreeC to the mixture of cis-4'-acetyl kale lactone, angelic acid (AngOH), and a base, and making it react at the same temperature for 0.5 to 1 hour is especially preferable. This suppresses isomerization of double bonds during the reaction process, and can significantly improve yield and stereoselectivity.
また、本発明においては、塩基の存在下で反応を行うことが肝要である。かかる塩基としては、好ましくは脂肪族系有機塩基であり、より好ましくはジイソプロピルエチルアミン（ＤＩＥＡ）である。かかるＤＩＥＡを用いる場合、高立体選択性と高収率とを高度に両立させることが可能となる。 In the present invention, it is important to carry out the reaction in the presence of a base. Such a base is preferably an aliphatic organic base, and more preferably diisopropylethylamine (DIEA). When such DIEA is used, high stereoselectivity and high yield can be made highly compatible.
出発物質のシス−４’−アセチルケールラクトンに対するＡｎｇＯＨの好適当量範囲は１．５〜１０である。また、Ｔｆ２Ｏの好適当量範囲は１．５〜１０である。さらに、塩基の好適当量範囲は１．５〜１０である。いずれも、これら範囲内において高立体選択性と高収率とを得ることができる。 The preferred equivalent range of AngOH to the starting cis-4′-acetyl kale lactone is 1.5-10. Also, good appropriate weight range of Tf 2 O is 1.5 to 10. Furthermore, the suitable equivalent range of a base is 1.5-10. In either case, high stereoselectivity and high yield can be obtained within these ranges.
本発明においては、反応溶媒として一般に知られているものを使用することができるが、高い立体選択性を実現するためには、塩化メチレンが好ましい。 In the present invention, a generally known reaction solvent can be used, but methylene chloride is preferable in order to realize high stereoselectivity.
（実施形態２）
本発明の実施形態２においては、シス−４’−アセチルケールラクトンをアンゲリカ酸無水物（Ａｎｇ２Ｏ）と、トリフラートのスカンジウム触媒（Ｓｃ（ＯＴｆ）３）の存在下で反応させるものである。なお、出発物質は、前記実施形態１で述べた方法と同様にして得ることができる。
(Embodiment 2)
In Embodiment 2 of the present invention, cis-4′-acetylkallactone is reacted with angelic anhydride (Ang 2 O) in the presence of a triflate scandium catalyst (Sc (OTf) 3 ). The starting material can be obtained in the same manner as described in the first embodiment.
この反応は、好ましくは０〜２０℃、特には０〜５℃において速やかに進行し、高い立体選択性で、かつ満足できる収率を得ることができる。 This reaction preferably proceeds rapidly at 0 to 20 ° C., particularly at 0 to 5 ° C., and a high stereoselectivity and a satisfactory yield can be obtained.
出発物質のシス−４’−アセチルケールラクトンに対するＡｎｇ２Ｏの好適当量範囲は２〜３である。また、Ｓｃ（ＯＴｆ）３の好適範囲は２〜５ｍｏｌ％である。いずれも、これら範囲内において高立体選択性と高収率とを得ることができる。 The preferred equivalent range of Ang 2 O relative to the starting cis-4′-acetyl kale lactone is 2-3. Moreover, the suitable range of Sc (OTf) 3 is 2-5 mol%. In either case, high stereoselectivity and high yield can be obtained within these ranges.
本発明においては、前記実施形態１と同様に反応溶媒として一般に知られているものを使用することができるが、高い立体選択性を実現するためには、塩化メチレンが好ましい。 In the present invention, generally known reaction solvents can be used as in the first embodiment, but methylene chloride is preferred in order to achieve high stereoselectivity.
以下、本発明を実験例に基づき説明する。
出発物質（シス−４’−アセチルケールラクトン）の製造例
下記の反応式および条件に従い、シス−４’−アセチルケールラクトン（化合物４）の製造工程を、増炭反応、分子内環化反応、ジヒドロキシレーション、立体選択的アセチル化の順に説明する。
Production Example of Starting Material (cis-4′-Acetyl Kale Lactone) According to the following reaction formula and conditions, the production process of cis-4′-acetyl kale lactone (compound 4) is changed to a carbon increase reaction, an intramolecular cyclization reaction, The description will be made in the order of dihydroxylation and stereoselective acetylation.
１）化合物１の合成
炭酸カリウム存在下、反応溶媒としてアセトン／水、触媒としてヨウ化カリウムをそれぞれ用い、原料の７-ヒドロキシクマリンと３−クロロ−３−メチル−１−ブチンとの置換反応を行った。７-ヒドロキシクマリンに対して５当量の３−クロロ−３−メチル−１−ブチンを用いた場合、６７．８％と良好な収率で目的とする化合物１を得ることができた。
1) Synthesis of Compound 1 In the presence of potassium carbonate, acetone / water as a reaction solvent and potassium iodide as a catalyst were used, respectively, and a substitution reaction between 7-hydroxycoumarin and 3-chloro-3-methyl-1-butyne as raw materials was performed. went. When 5 equivalents of 3-chloro-3-methyl-1-butyne was used with respect to 7-hydroxycoumarin, the target compound 1 could be obtained with a good yield of 67.8%.
なお、３−クロロ−３−メチル−１−ブチンの当量を半減するとヨウ化カリウムを増量しても収率の改善は認められなかった。また、反応溶媒として無水ジメチルホルムアミド（ＤＭＦ）を用いた場合には、顕著な収率の低下が観察された。 When the equivalent of 3-chloro-3-methyl-1-butyne was halved, no improvement in yield was observed even when potassium iodide was increased. Moreover, when anhydrous dimethylformamide (DMF) was used as a reaction solvent, a significant decrease in yield was observed.
２）化合物２の合成
化合物１のジエチルアニリン懸濁液を１８０℃で反応させることにより、分子内環化反応は速やかに進行し、８０％以上の良好な収率で目的とする化合物２を得ることができた。
2) Synthesis of Compound 2 By reacting a diethylaniline suspension of Compound 1 at 180 ° C., the intramolecular cyclization reaction proceeds rapidly, and the desired Compound 2 is obtained with a good yield of 80% or more. I was able to.
３）化合物３の合成
この反応では、化合物２および１当量のＮ−メチルモルホリンオキシドを反応溶媒に溶解し、触媒量の四酸化オスミウムを添加し室温で反応させることによって速やかに化合物３を良好な収率（収率８８％）で得ることができた。
3) Synthesis of Compound 3 In this reaction, Compound 2 and 1 equivalent of N-methylmorpholine oxide were dissolved in a reaction solvent, and a catalytic amount of osmium tetroxide was added and reacted at room temperature to rapidly improve Compound 3 Yield (88% yield) was obtained.
４）化合物４の合成
氷冷下、化合物３の無水テトラヒドロフラン溶液に１．１当量のＢＦ３・Ｅｔ２Ｏと１．６当量の無水酢酸の無水テトラヒドロフラン溶液を滴下し、室温で３時間攪拌することにより化合物４を立体選択的に得ることができた。
4) Synthesis of Compound 4 Under ice-cooling, 1.1 equivalent of BF 3 .Et 2 O and 1.6 equivalent of acetic anhydride in tetrahydrofuran are added dropwise to Compound 3 in tetrahydrofuran and stirred at room temperature for 3 hours. Thus, compound 4 could be obtained stereoselectively.
なお、カラム精製中に４’から３’−アセチル（Ａｃ）体への異性化が進行することが明らかとなっていたことから、速やかな精製操作の下で実際に反応を行ったところ、ＴＬＣでの反応追跡では中程度の立体選択性が観察された。後処理の後、速やかなフラッシュカラムクロマトグラフィー精製で得られた混合物を再結晶することによって、中程度の収率ながら化合物４を単一の立体異性体として得ることができた。 In addition, since it was clear that isomerization from 4 ′ to 3′-acetyl (Ac) proceeded during column purification, the reaction was actually performed under a rapid purification operation. A moderate stereoselectivity was observed in the reaction tracking at. After workup, compound 4 could be obtained as a single stereoisomer with moderate yield by recrystallizing the mixture obtained by rapid flash column chromatography purification.
また、この反応の副生成物は加水分解によって再利用可能であり、１）Ａｃ化、２）副生成物の加水分解、３）再Ａｃ化反応と一連の工程を繰り返すことによって、２．１ｇの原料の化合物３から約６６％の収率で目的の化合物４（１．８ｇ）を得ることができた。 Further, the by-product of this reaction can be reused by hydrolysis. By repeating 1) Ac conversion, 2) By-product hydrolysis, 3) Re-Ac conversion reaction and a series of steps, 2.1 g The target compound 4 (1.8 g) was obtained from the starting compound 3 in a yield of about 66%.
文献例１，２および実験例１〜３
出発物質である化合物４とアンゲリカ酸（ＡｎｇＯＨ）との縮合反応につき検討を行った。その結果を下記の表１に示す。なお、この反応はＡｎｇＯＨを適当な活性剤を用いて４’位へ導入するものであるが、反応条件により、下記反応式に示すように、生成可能な４種類の立体異性体の混合物が得られた。尚、混合物の割合は４００ＭＨｚＮＭＲにて決定した。
The condensation reaction between the starting material compound 4 and angelic acid (AngOH) was examined. The results are shown in Table 1 below. In this reaction, AngOH is introduced into the 4′-position using an appropriate activator. Depending on the reaction conditions, a mixture of four types of stereoisomers that can be produced is obtained as shown in the following reaction formula. It was. The ratio of the mixture was determined by 400 MHz NMR.
上記表１の文献例１および文献例２のように、前記非特許文献５および６の製造方法に基づくプラエルプトリンＡの製造方法でも、目的とする生成物５ａのほか二重結合により異性化した生成物５ｄが生成した。この立体異性体の混合物は、通常のカラムクロマトグラフィー精製では分離困難であることが知られていた。 As in Reference Example 1 and Reference Example 2 in Table 1 above, the production of praeroptrin A based on the production methods of Non-Patent Documents 5 and 6 is also isomerized by a double bond in addition to the target product 5a. Product 5d was produced. This mixture of stereoisomers was known to be difficult to separate by ordinary column chromatography purification.
そこで、生成可能な４種類の立体異性体の中で本発明の所望の生成物５ａのみを生成できるような反応条件の探索を開始した。まず、前記非特許文献８の製造方法のように、実験例１ではスカンジウム触媒を用い、系内でＡｎｇＯＨとｐ−トリフルオロ安息香酸無水物から発生させたＡｎｇ２Ｏと化合物４との反応を検討した。その結果、反応はほとんど進行しなかった。 Therefore, the search for reaction conditions that can produce only the desired product 5a of the present invention among the four types of stereoisomers that can be produced was started. First, as in the production method of Non-Patent Document 8, in Example 1, a scandium catalyst was used, and the reaction of Ang 2 O generated from AngOH and p-trifluorobenzoic anhydride in the system with Compound 4 was performed. investigated. As a result, the reaction hardly proceeded.
次に、実験例２では、前記非特許文献９における立体障害の大きい水酸基へのためのＡｎｇ化の報告例にあった２，４，６−トリクロロベンゾイルクロライドを用いた条件を検討した。その結果、反応は進行したものの長時間を要し、しかも生成物５ａと５ｂの１：１の混合物を低収率で得たに過ぎなかった。 Next, in Experimental Example 2, the conditions using 2,4,6-trichlorobenzoyl chloride, which was reported in the example of Ang conversion for a hydroxyl group having a large steric hindrance in Non-Patent Document 9, were examined. As a result, although the reaction proceeded, it took a long time and only a 1: 1 mixture of the products 5a and 5b was obtained in a low yield.
文献例１，２および実験例１，２の条件から、立体選択的な反応を満足させるためには、短時間かつ低温化で反応が進行できる強力なカルボキシル基の活性化が必要であることが示唆されたことから、実験例３では、活性化能の強い無水トリフラート（Ｔｆ２Ｏ）を用い、系内で非常に強力なアシル化活性種であるＡｎｇＯＴｆを発生させることによって反応が低温かつ短時間で完結するのではないかとの考えの下に、以下の条件で反応を行った。 From the conditions of Reference Examples 1 and 2 and Experimental Examples 1 and 2, in order to satisfy a stereoselective reaction, it is necessary to activate a strong carboxyl group that can proceed in a short time and at a low temperature. From this suggestion, in Experimental Example 3, an anhydrous triflate (Tf 2 O) having a strong activating ability was used to generate AngOTf, which is a very strong acylating active species in the system. The reaction was carried out under the following conditions with the idea that it would be completed in time.
即ち、反応は、氷冷下、化合物４に対して１０当量のＡｎｇＯＨと１０当量の２，６−ルチジンの塩化メチレン溶液にＴｆ２Ｏを加え、同温度で３０分間攪拌した後、化合物４の塩化メチレン溶液を−８０℃で滴下し、０℃まで昇温して行った。反応は、実験例３に示すように、反応温度を−８０℃から０℃の間で変化させたとき速やかに完結したが、目的とする生成物５ａは全く得られずに、ほぼ定量的な収率で生成物５ｃと５ｄの１：１の混合物を得た。これは、１）氷冷条件では最初に行ったＡｎｇＯＴｆの生成過程で既に二重結合の異性化が進行しており、なおかつ、２）化合物４においては系内で発生する酸性雰囲気で昇温することによって４’−ＡｃＯから３’−ＡｃＯへの異性化が進行したものであると考えられた。 That is, the reaction was carried out by adding Tf 2 O to a methylene chloride solution of 10 equivalents of AngOH and 10 equivalents of 2,6-lutidine with respect to compound 4 under ice cooling, followed by stirring at the same temperature for 30 minutes. The methylene chloride solution was added dropwise at -80 ° C, and the temperature was raised to 0 ° C. As shown in Experimental Example 3, the reaction was completed quickly when the reaction temperature was changed between −80 ° C. and 0 ° C., but the target product 5a was not obtained at all, and was almost quantitative. A 1: 1 mixture of products 5c and 5d was obtained in yield. This is because 1) the isomerization of double bonds has already progressed in the process of forming AngOTf first performed under ice-cooling conditions, and 2) Compound 4 is heated in an acidic atmosphere generated in the system. Thus, it was considered that isomerization from 4′-AcO to 3′-AcO progressed.
実験例４〜６
（反応条件（温度および時間）の検討）
選択性は得られなかったものの、高収率で生成物が得られた実験例３の反応を低温下で行うことによって上記の異性化メカニズムが抑えられ、立体選択的に生成物５ａが得られるのではないかとの考えの下に、下記の反応式の反応温度と反応時間を変化させて条件検討を行った。その結果を下記の表２に示す。尚、表中、混合物の割合は４００ＭＨｚＮＭＲで決定した。
(Examination of reaction conditions (temperature and time))
Although the selectivity was not obtained, the above isomerization mechanism was suppressed by performing the reaction of Experimental Example 3 in which the product was obtained in high yield at a low temperature, and the product 5a was obtained stereoselectively. Based on the idea that it may be, the conditions were examined by changing the reaction temperature and reaction time of the following reaction formula. The results are shown in Table 2 below. In the table, the ratio of the mixture was determined by 400 MHz NMR.
上記表２のように、実験例４において、−８０℃でＡｎｇＯＴｆを生成させ、同温度で化合物４の塩化メチレンを滴下後、−４０℃に昇温した条件では、９４％という高収率で目的とする生成物５ａを主生成物として得ることができた。この反応では、対応するＴｉｇ化合物（生成物５ｃ，５ｄ）は、ＮＭＲ上確認できなかった。 As shown in Table 2, in Example 4, AngOTf was produced at −80 ° C., methylene chloride of Compound 4 was added dropwise at the same temperature, and then the temperature was raised to −40 ° C., with a high yield of 94%. The target product 5a could be obtained as the main product. In this reaction, the corresponding Tig compound (product 5c, 5d) could not be confirmed on NMR.
また、表２に示すように−５０℃まで昇温した条件の実験例５においては、反応温度の立体選択性への影響が顕著に認められ、生成物５ａと５ｂの生成比が６．７：１となり、目的とする生成物５ａの割合が向上した。 Further, as shown in Table 2, in Experimental Example 5 under the condition where the temperature was raised to −50 ° C., the effect of the reaction temperature on the stereoselectivity was remarkably observed, and the production ratio of the products 5a and 5b was 6.7. The ratio of the target product 5a was improved.
化合物４の塩化メチレンを滴下後、−８０℃のまま反応を行った条件の実験例６においては、高い立体選択性を維持することができたものの、収率が低かった。 In Experimental Example 6 under the condition where the reaction was carried out at −80 ° C. after the dropwise addition of methylene chloride of Compound 4, high stereoselectivity could be maintained, but the yield was low.
実験例３〜６から、反応を低温下で行うことにより反応過程で二重結合の異性化が抑えられていることが明らかとなった。また、化合物４の添加後、昇温することで収率が向上することから、化合物４に対してＴｆ２Ｏが反応過程で副反応を誘発する可能性が低いことなどが考えられた。尚、表中、混合物の割合は４００ＭＨｚＮＭＲで決定した。 From Experimental Examples 3 to 6, it was revealed that isomerization of double bonds was suppressed during the reaction process by performing the reaction at a low temperature. In addition, since the yield was improved by increasing the temperature after the addition of Compound 4, it was considered that Tf 2 O was less likely to induce a side reaction in the reaction process with respect to Compound 4. In the table, the ratio of the mixture was determined by 400 MHz NMR.
実験例７〜１１
（添加剤（有機塩基）の影響）
次に、下記の反応式において脂肪族および芳香族有機塩基の添加効果につき評価した。その結果を下記の表３に示す。
(Influence of additive (organic base))
Next, the addition effect of aliphatic and aromatic organic bases was evaluated in the following reaction formula. The results are shown in Table 3 below.
上記実験例３〜６の結果より、低温下では化合物４に対してＴｆ２Ｏが反応過程で副反応を誘発する可能性が低いことから、ＡｎｇＯＨの活性化の段階で化合物４が反応系内で存在しても問題ないとの考えの下に、化合物４とＡｎｇＯＨおよび有機塩基の混合物の塩化メチレン溶液に−８０℃でＴｆ２Ｏを添加する反応条件で検討したところ、実験例７に示すように、有機塩基を添加しない条件では反応は全く進行しなかった。 From the results of the above experimental examples 3 to 6, it is unlikely that Tf 2 O induces a side reaction during the reaction process with respect to compound 4 at low temperatures. Under the idea that there is no problem even if it is present in the above, the reaction conditions in which Tf 2 O is added at −80 ° C. to a methylene chloride solution of a mixture of Compound 4, AngOH and an organic base are shown in Experimental Example 7. Thus, the reaction did not proceed at all under the condition where no organic base was added.
これに対し、脂肪族系の有機塩基を添加した条件では反応は速やかに進行した。特に、実験例８のジイソプロピルエチルアミン（ＤＩＥＡ）を用いた条件では、他の異性体との立体選択性は５０：１以上であり、かつ高収率で生成物５ａを得ることができた。 On the other hand, the reaction proceeded rapidly under the conditions where an aliphatic organic base was added. In particular, under the conditions using diisopropylethylamine (DIEA) of Experimental Example 8, the stereoselectivity with other isomers was 50: 1 or more, and the product 5a could be obtained in a high yield.
実験例９のトリエチルアミンを用いた場合には高い立体選択性を維持していたものの、収率の低下が確認された。 When the triethylamine of Experimental Example 9 was used, a high stereoselectivity was maintained, but a decrease in yield was confirmed.
実験例１０の環状の有機塩基であるＮ−メチルピロリジンを用いた場合、立体選択性ならびに収率の低下が確認された。 When N-methylpyrrolidine, which is the cyclic organic base of Experimental Example 10, was used, stereoselectivity and a decrease in yield were confirmed.
実験例１１の芳香族アミンであるピリジンを添加した場合には、反応は全く進行せずに、ほぼ定量的な原料回収に終わった。これは、ピリジンを塩基とした場合、Ｔｆ２Ｏの活性化で生成したＡｎｇＯＴｆに、さらにＡｎｇＯ−が反応したＡｎｇ２Ｏが主に生成しており、反応が進行しなくなったためではないかと考えられる。 When pyridine, which is the aromatic amine of Experimental Example 11, was added, the reaction did not proceed at all, and the raw material recovery was almost quantitative. This is thought to be because, when pyridine was used as the base, Ang OTf produced by the activation of Tf 2 O mainly produced Ang 2 O, which was further reacted with AngO − , and the reaction did not proceed. .
実験例７〜１１の結果から、立体選択性および収率を向上させるには添加する有機塩基としてＤＩＥＡが最も適していることが分かった。 From the results of Experimental Examples 7 to 11, it was found that DIEA was most suitable as an organic base to be added in order to improve stereoselectivity and yield.
実験例１２〜１７
（添加量と反応溶媒検討）
実験例７〜１１の結果から、次に、下記の反応式においてＡｎｇＯＨとＴｆ２ＯおよびＤＩＥＡの添加量を変化させたときの立体選択性と反応収率に及ぼす影響を検討した。その結果を下記の表４に示す。尚、表中、＊は上記式のａ、ｂ各々の当量であり、＊＊はａが１０当量であり、ｂが６．０当量である。また、表中、混合物の割合は４００ＭＨｚＮＭＲで決定した。
(Addition amount and reaction solvent study)
From the results of Experimental Examples 7 to 11, next, the effects on the stereoselectivity and the reaction yield when the addition amounts of AngOH, Tf 2 O and DIEA were changed in the following reaction formulas were examined. The results are shown in Table 4 below. In the table, * is the equivalent of each of a and b in the above formula, ** is 10 equivalents of a, and b is 6.0 equivalents. In the table, the ratio of the mixture was determined by 400 MHz NMR.
上記表４の実験例１２〜１４に見られるように、反応溶液の濃度を２０ｍｇ／ｍｌとして、ＡｎｇＯＨならびにＤＩＥＡの添加量を化合物４に対し１．５、３．０、５．０当量に変化させたとき、添加量の増加にともなって収率は改善するが、立体選択性の低下が見られた。 As seen in Experimental Examples 12 to 14 in Table 4 above, the concentration of the reaction solution was 20 mg / ml, and the addition amounts of AngOH and DIEA were changed to 1.5, 3.0, and 5.0 equivalents with respect to Compound 4. When the amount was increased, the yield improved as the amount added increased, but a decrease in stereoselectivity was observed.
次いで、上記表４の実験例１６に見られるように、反応溶液の濃度を１０ｍｇ／ｍｌとした場合では、添加物を１０当量用いても高い立体選択性を維持していた。 Next, as seen in Experimental Example 16 in Table 4 above, when the concentration of the reaction solution was 10 mg / ml, high stereoselectivity was maintained even when 10 equivalents of additive were used.
また、実験例１５に示すように、Ｔｆ２Ｏの添加量のみを１０当量から６当量に減量した場合でも良好な立体選択性および収率が得られた。以上のことから、反応は基質濃度とＴｆ２Ｏの添加速度に大きく影響を受ける可能性が示唆され、反応溶液の濃度は１０ｍｇ／ｍｌが適していると考えられた。なお、Ｔｆ２Ｏの添加量を１０当量とし、１．３ｇの化合物４とＡｎｇＯＨの縮合反応を行った場合、１．４２ｇの５ａ，プラエルプトリンＡを合成することができ、その生成物は、ゼンコの日局試薬試液薄層クロマトグラフィー用プラエルプトリンＡの規格に適合するものであった。 Further, as shown in Experimental Example 15, even when only the amount of Tf 2 O added was reduced from 10 equivalents to 6 equivalents, good stereoselectivity and yield were obtained. From the above, it was suggested that the reaction may be greatly influenced by the substrate concentration and the addition rate of Tf 2 O, and it was considered that the concentration of the reaction solution was 10 mg / ml. In addition, when the amount of Tf 2 O added was 10 equivalents and 1.3 g of compound 4 and AngOH were subjected to a condensation reaction, 1.42 g of 5a, preraputrin A could be synthesized. In accordance with the specifications of Praelputrin A for thin-layer chromatography of JP
尚、実験例１７に示すように、反応溶媒にトルエンを用いた場合には、顕著な立体選択性の低下が見られた。よって、反応溶媒としては塩化メチレンが適当であることが確認された。 In addition, as shown in Experimental Example 17, when toluene was used as the reaction solvent, a significant reduction in stereoselectivity was observed. Therefore, it was confirmed that methylene chloride was suitable as the reaction solvent.
実験例１８，１９
（Ａｎｇ２Ｏを用いた反応検討）
次いで、アンゲリカ酸（ＡｎｇＯＨ）に代え、無水アンゲリカ酸（Ａｎｇ２Ｏ）を用いて、検討を行った。すなわち、前述したＴｆ２Ｏによる活性化では系内に発生したＡｎｇＯＴｆが活性種として考えられるが、さらに反応の進んだＡｎｇ２Ｏが活性種の可能性も否定できないため、下記反応式に従い、Ｔｆ２Ｏを用いジイソプロピルエチルアミンの存在下、化合物４との反応を行った。その結果を下記の表５に示す。尚、表中、混合物の割合は４００ＭＨｚＮＭＲで決定した。
(Examination of reaction using Ang 2 O)
Next, angelic acid (Ang 2 O) was used in place of angelic acid (AngOH) for investigation. That is, AngOTf generated in the system can be considered as an active species in the above-described activation with Tf 2 O, but the possibility that Ang 2 O that has progressed further is an active species cannot be denied. Reaction with compound 4 was carried out using 2 O in the presence of diisopropylethylamine. The results are shown in Table 5 below. In the table, the ratio of the mixture was determined by 400 MHz NMR.
上記表５の実験例１９から分かるように、−８０℃から室温まで昇温して計６時間反応させても、反応は全く進行しなかった。このことから、本反応においての活性種はＡｎｇＯＴｆであることが明らかとなった。 As can be seen from Experimental Example 19 in Table 5 above, even when the temperature was raised from −80 ° C. to room temperature and the reaction was performed for a total of 6 hours, the reaction did not proceed at all. From this, it became clear that the active species in this reaction is AngOTf.
一方、実験例１８に示すように、化合物４とＡｎｇ２Ｏに対してスカンジウム触媒を用いたＡｎｇ化反応について検討したところ、反応は、氷冷下、速やかに進行し、高い立体選択性で、かつ満足できる収率が得られることが分かった。この結果から、Ａｎｇ２Ｏとトリフラートのスカンジウム触媒（Ｓｃ（ＯＴｆ）３）の組み合わせも有効な製造実施条件として挙げることができることが確かめられた。 On the other hand, as shown in Experimental Example 18, when an Angation reaction using a scandium catalyst with respect to Compound 4 and Ang 2 O was examined, the reaction proceeded rapidly under ice cooling, with high stereoselectivity, And it was found that a satisfactory yield was obtained. From this result, it was confirmed that a combination of Ang 2 O and a triflate scandium catalyst (Sc (OTf) 3 ) can also be mentioned as an effective production condition.
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