JP6071715B2 - Process for producing danidazole constituent optical isomers - Google Patents
Process for producing danidazole constituent optical isomers Download PDFInfo
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- JP6071715B2 JP6071715B2 JP2013080747A JP2013080747A JP6071715B2 JP 6071715 B2 JP6071715 B2 JP 6071715B2 JP 2013080747 A JP2013080747 A JP 2013080747A JP 2013080747 A JP2013080747 A JP 2013080747A JP 6071715 B2 JP6071715 B2 JP 6071715B2
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- 238000000034 method Methods 0.000 title description 11
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- 150000001875 compounds Chemical class 0.000 claims description 54
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- 125000003118 aryl group Chemical group 0.000 claims description 13
- 238000004519 manufacturing process Methods 0.000 claims description 11
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- 125000005041 acyloxyalkyl group Chemical group 0.000 claims description 2
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- 125000000654 isopropylidene group Chemical group C(C)(C)=* 0.000 description 4
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- FIITXXIVUIXYMI-NKWVEPMBSA-N Doranidazole Chemical compound OC[C@H](O)[C@@H](CO)OCN1C=CN=C1[N+]([O-])=O FIITXXIVUIXYMI-NKWVEPMBSA-N 0.000 description 2
- 239000002841 Lewis acid Substances 0.000 description 2
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- 229910021627 Tin(IV) chloride Inorganic materials 0.000 description 2
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- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 description 2
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- WOJACAOXAXXSLA-UHFFFAOYSA-N trimethyl-(2-nitro-1h-imidazol-5-yl)silane Chemical compound C[Si](C)(C)C1=CN=C([N+]([O-])=O)N1 WOJACAOXAXXSLA-UHFFFAOYSA-N 0.000 description 2
- SIOVKLKJSOKLIF-HJWRWDBZSA-N trimethylsilyl (1z)-n-trimethylsilylethanimidate Chemical compound C[Si](C)(C)OC(/C)=N\[Si](C)(C)C SIOVKLKJSOKLIF-HJWRWDBZSA-N 0.000 description 2
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 1
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- XJUZRXYOEPSWMB-UHFFFAOYSA-N Chloromethyl methyl ether Chemical compound COCCl XJUZRXYOEPSWMB-UHFFFAOYSA-N 0.000 description 1
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- 102000004142 Trypsin Human genes 0.000 description 1
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- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
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- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 1
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Description
本発明は、ラセミ体である放射線増感剤ドラニダゾールを構成する、２つの光学異性体の製造方法と、当該製造に用いられる中間体に関する。 The present invention relates to a method for producing two optical isomers constituting the racemic radiosensitizer dranidazole, and an intermediate used for the production.
ドラニダゾールは、低酸素性放射線増感剤として、開発されているラセミ体の２−ニトロイミダゾール誘導体であり、３つの水酸基を側鎖に有し、当該側鎖に２つの不斉炭素が存在する化合物である。光学異性体は、ドラニダゾールを構成する２Ｓ３Ｒ体（（２Ｓ，３Ｒ）−３−［（２−Ｎｉｔｒｏｉｍｉｄａｚｏｌ−１−ｙｌ）ｍｅｔｈｏｘｙ］ｂｕｔａｎｅ−１，２，４−ｔｒｉｏｌ）、２Ｒ３Ｓ体（（２Ｒ，３Ｓ）−３−［（２−Ｎｉｔｒｏｉｍｉｄａｚｏｌ−１−ｙｌ）ｍｅｔｈｏｘｙ］ｂｕｔａｎｅ−１，２，４−ｔｒｉｏｌ）以外に、ＳＳ体、ＲＲ体が存在し、これらの内、ＳＳ体とＲＲ体については製造方法が確立され、それぞれの物性、作用、効果については検討が為されているが、２Ｒ３Ｓ体、２Ｓ３Ｒ体についてはドラニダゾールを光学分割するしか入手手段が存せず、構成光学活性体については詳細な検討が困難な状況に存した。（例えば、特許文献１、２、非特許文献１を参照）これは、エリスリトール骨格で２位、３位がＳＲ或いはＲＳの配座になるような、２−ニトロイミダゾールとの縮合可能な前駆体が見出されていなかったためである。トリオール或いは、テトラオールの立体を維持し、末端基を修飾して行く方法としては、アスコルビン酸或いはイソアスコルビン酸を利用した方法が種々知られている（例えば、非特許文献２、３、４を参照）が、これらに開示された化合物からは、前記２Ｒ３Ｓ体、２Ｓ３Ｒ体を不斉合成することは出来ない。又、後記一般式（２）、（３）、（６）、（７）、（８）、（９）に表される化合物もこれらの文献には開示されていない。 Doranidazole is a racemic 2-nitroimidazole derivative that has been developed as a hypoxic radiosensitizer, a compound having three hydroxyl groups in the side chain and two asymmetric carbons in the side chain It is. The optical isomers are the 2S3R form ((2S, 3R) -3-[(2-Nitroimidazol-1-yl) methoxy] butane-1,2,4-triol), 2R3S form ((2R, 3S), which constitutes dranidazole. ) -3-[(2-Nitroimidazol-1-yl) method] butane-1,2,4-triol), there are SS and RR isomers, of which SS and RR isomers are manufactured. A method has been established, and the physical properties, actions, and effects of each have been studied. However, for 2R3S and 2S3R, there is only a means for obtaining optical resolution of dranidazole. The situation was difficult to consider. (For example, refer to Patent Documents 1 and 2 and Non-Patent Document 1) This is a condensable precursor with 2-nitroimidazole such that the 2nd and 3rd positions of the erythritol skeleton are in the conformation of SR or RS. This is because no has been found. Various methods using ascorbic acid or isoascorbic acid are known as methods for maintaining the triol or tetraol stericity and modifying the terminal group (for example, Non-Patent Documents 2, 3, and 4). However, the 2R3S form and 2S3R form cannot be asymmetrically synthesized from the compounds disclosed therein. Moreover, the compounds represented by the following general formulas (2), (3), (6), (7), (8), and (9) are not disclosed in these documents.
一方、ドラニダゾール、２Ｓ３Ｒ体、２Ｒ３Ｓ体、ＲＲ体、ＳＳ体には如実な薬効、物性の差が存し（例えば、非特許文献５を参照）ている。特に注目すべきは、放射線増感比において、ドラニダゾールが１．４５であるのに対し、２Ｓ３Ｒ体は１．６３、２Ｒ３Ｓ体は１．３６と大きく異なっていることであり、不斉合成を可能ならしめることにより、大幅な薬効の向上が望めることである。即ち、ドラニダゾールの開発の完遂には構成光学活性体の精密な比較が必要であり、これらの不斉合成技術の開発が望まれていた。 On the other hand, dranidazole, 2S3R isomer, 2R3S isomer, RR isomer, and SS isomer have practical drug efficacy and physical property differences (see, for example, Non-Patent Document 5). Of particular note is that in the radiation sensitization ratio, dranidazole is 1.45, whereas 2S3R is significantly different from 1.63 and 2R3S is 1.36, and asymmetric synthesis is possible. It is hoped that a significant improvement in medicinal effect can be expected by making it smooth. That is, in order to complete the development of dranidazole, precise comparison of constituent optically active substances is necessary, and development of these asymmetric synthesis techniques has been desired.
本発明は、この様な状況下為されたものであり、ドラニダゾールの構成光学活性体を不斉合成し、それぞれの光学活性体の薬理学的特徴、物理化学的特徴を明らかにすることを課題とする。 The present invention has been made under such circumstances, and it is an object to asymmetrically synthesize the constituent optically active substances of dranidazole and clarify the pharmacological characteristics and physicochemical characteristics of each optically active substance. And
この様な状況に鑑みて、本発明者らは、ドラニダゾールの構成光学活性体を不斉合成する手段を求めて、鋭意研究努力を重ねた結果、アスコルビン酸乃至はイソアスコルビン酸から誘導した、立体保存のされたアルキルオキシメチル誘導体を用いて、アシル化剤によりアシルオキシメチルオキシ化したものを用いることにより、不斉合成が可能であることを見出し、発明を完成させるに至った。即ち、本発明は、以下に示すとおりである。
＜１＞次に示す、構造式（１）に表される２−ニトロイミダゾール誘導体の製造方法であって、一般式（２）に表される化合物に、無水酢酸を反応せしめ、一般式（３）に表される化合物となし、しかる後に、一般式（４）に表される化合物と反応せしめ、しかる後に脱保護することを特徴とする、製造方法。In view of such a situation, the present inventors have sought for means for asymmetric synthesis of the constituent optically active substance of dranidazole and, as a result of intensive research efforts, By using a conserved alkyloxymethyl derivative and acyloxymethyloxylated with an acylating agent, it was found that asymmetric synthesis was possible, and the present invention was completed. That is, the present invention is as follows.
<1> A method for producing a 2-nitroimidazole derivative represented by the structural formula (1) shown below, wherein the compound represented by the general formula (2) is reacted with acetic anhydride, and the general formula (3) ) And then reacting with the compound represented by the general formula (4), followed by deprotection.
（但し、式中Ｒ １ 、Ｒ ２ 、Ｒ ４ はそれぞれ独立に芳香族アシル基を表し、Ｒ ３ は水素原子又はアルキル基を表す。）
(However, in the formula, R 1 , R 2 and R 4 each independently represents an aromatic acyl group , and R 3 represents a hydrogen atom or an alkyl group.)
（但し、式中Ｒ １ 、Ｒ ２ 、Ｒ ４ はそれぞれ独立に芳香族アシル基を表し、Ｒ ５ は水素原子又はアルキル基を表す。）
(However, in the formula, R 1 , R 2 and R 4 each independently represents an aromatic acyl group , and R 5 represents a hydrogen atom or an alkyl group.)
（但し、式中Ｒ６、Ｒ７、Ｒ８はそれぞれ独立にアルキル基を表す。）
(However, in the formula, R6, R7 and R8 each independently represents an alkyl group.)
＜２＞一般式（２）に表される化合物。
＜３＞一般式（３）に表される化合物。
＜４＞次に示す、構造式（５）に表される２−ニトロイミダゾール誘導体の製造方法であって、一般式（６）に表される化合物に、無水酢酸を反応せしめ、一般式（７）に表される化合物となし、しかる後に、前記一般式（４）に表される化合物と反応せしめ、しかる後に脱保護することを特徴とする、製造方法。<2> A compound represented by the general formula (2).
<3> A compound represented by the general formula (3).
<4> A method for producing a 2-nitroimidazole derivative represented by the structural formula (5) shown below, wherein the compound represented by the general formula (6) is reacted with acetic anhydride to give a general formula (7 ), And then reacting with the compound represented by the general formula (4), followed by deprotection.
（但し、式中Ｒ ９ 、Ｒ １０ 、Ｒ １２ はそれぞれ独立に芳香族アシル基を表し、Ｒ １１ は水素原子又はアルキル基を表す。）
(However, R < 9 >, R < 10 >, R < 12 > represents an aromatic acyl group each independently, and R < 11 > represents a hydrogen atom or an alkyl group.)
（但し、式中Ｒ ９ 、Ｒ １０ 、Ｒ １２ はそれぞれ独立に芳香族アシル基を表し、Ｒ １３ は水素原子又はアルキル基を表す。）
(However, R < 9 >, R < 10 >, R < 12 > represents an aromatic acyl group each independently, and R < 13 > represents a hydrogen atom or an alkyl group.)
＜５＞一般式（６）に表される化合物。
＜６＞一般式（７）に表される化合物。
＜７＞一般式（８）又は（９）に表される化合物。<5> A compound represented by the general formula (6).
<6> A compound represented by the general formula (7).
<7> A compound represented by the general formula (8) or (9).
（但し、式中Ｒ １４ はアシルオキシアルキル基を表す。）
(However, wherein R 14 represents an A sill oxyalkyl group.)
本発明によれば、ドラニダゾールの構成光学活性体を不斉合成し、それぞれの光学活性体の薬理学的特徴、物理化学的特徴を明らかにすることができる。 According to the present invention, a constituent optically active substance of dranidazole can be asymmetrically synthesized, and pharmacological characteristics and physicochemical characteristics of each optically active substance can be clarified.
＜１＞２Ｒ３Ｓ体の製造
２Ｒ３Ｓ体は、イソアスコルビン酸をイソプロピリデン等のケトニドで隣接する２つの水酸基を保護し、しかる後に開環して得られる、下記の化合物（（２Ｒ３Ｒ）−３，４−Ｏ−イソプロピリデン−２，３，４−トリヒドロキシブタン酸エチル）を出発物質とし、これをジメトキシメタンの様なジアルキルオキシメタン中で五酸化リンなどの酸で脱水縮合させ、しかる後に還元し、ジイソプロピリデンなどのケトニドを脱保護し、水酸基をベンゾイルクロライドなどのアシル化剤でアシル化して一般式（２）の化合物に変換したのち、無水酢酸を酸触媒存在下反応させ、一般式（３）の化合物に誘導し、トリメチルシリル−２−ニトロイミダゾールのような一般式（４）の化合物と、塩化第二錫などのルイス酸を触媒として縮合し、しかる後にアシル基を脱保護することにより製造することが出来る。<1> Manufacture of 2R3S Form The 2R3S form is obtained by protecting two adjacent hydroxyl groups with ketonide such as isopropylidene and then opening the ring with isoascorbic acid, and then obtaining the following compound ((2R3R) -3,4 -O-isopropylidene-2,3,4-trihydroxybutanoate) as a starting material, which is dehydrated and condensed with an acid such as phosphorus pentoxide in a dialkyloxymethane such as dimethoxymethane, and then reduced. , Deprotecting a ketonide such as diisopropylidene, acylating a hydroxyl group with an acylating agent such as benzoyl chloride and converting it to a compound of the general formula (2), and then reacting acetic anhydride in the presence of an acid catalyst, 3) The compound of the general formula (4) such as trimethylsilyl-2-nitroimidazole is contacted with a Lewis acid such as stannic chloride. It can be produced by condensing as a medium and then deprotecting the acyl group.
又、２Ｒ３Ｓ体は、アスコルビン酸を出発物質として、イソプロピリデン等のケトニドで隣接する２つの水酸基を保護し、しかる後に開環してから水酸基の立体を反転させて得られる、下記の化合物（（２Ｓ３Ｓ）−３，４−Ｏ−イソプロピリデン−２，３，４−トリヒドロキシブタン酸エチル）を出発物質とし、これを還元し、（２Ｒ３Ｓ）−３，４−Ｏ−イソプロピリデン−１，２，３，４−テトラヒドロキシブタンとし、遊離の水酸基をベンゾイルクロリドなどでアシル化し、しかる後にケトニドを外し、緩和な条件下で１級水酸基のみをベンゾイルクロリドなどでアシル化し、（２Ｓ３Ｒ）−１，３，４−トリベンゾイルオキシ−２−ブタノールとなし、２位水酸基にジメトキシメタンを反応させて一般式（６）の化合物となし、これに無水酢酸を反応させて一般式（７）の化合物に誘導させ、前項の手技によって２Ｒ３Ｓ体へ誘導することも出来る。即ち、アスコルビン酸を出発物質としても、イソアスコルビン酸を出発物質としても、いずれも一般式（６）の化合物、一般式（７）の化合物を経由して、２Ｒ３Ｓ体を製造することが出来る。 In addition, the 2R3S compound is obtained by protecting two adjacent hydroxyl groups with a ketonide such as isopropylidene using ascorbic acid as a starting material, and then opening the ring and then reversing the steric groups of the hydroxyl groups (( 2S3S) -3,4-O-isopropylidene-2,3,4-trihydroxybutanoate), which is reduced to (2R3S) -3,4-O-isopropylidene-1,2 , 3,4-tetrahydroxybutane, acylating the free hydroxyl group with benzoyl chloride and the like, and then removing the ketonide and acylating only the primary hydroxyl group with benzoyl chloride and the like under mild conditions, and (2S3R) -1, 3,4-tribenzoyloxy-2-butanol, and the 2-hydroxyl group is reacted with dimethoxymethane to form a compound of the general formula (6). The reacted acetic anhydride is derived to the compound of the general formula (7) can also be induced to 2R3S member by preceding procedure. That is, both ascorbic acid as a starting material and isoascorbic acid as a starting material can be used to produce a 2R3S compound via a compound of general formula (6) and a compound of general formula (7).
＜２＞２Ｓ３Ｒ体の製造
２Ｓ３Ｒ体は、２Ｒ３Ｓ体の製造法における出発物質を、イソアスコルビン酸をアスコルビン酸に、アスコルビン酸をイソアスコルビン酸に変えて、前述の２Ｒ３Ｓ体と同様に処理することにより得ることが出来る。即ち、アスコルビン酸をイソプロピリデン等のケトニドで隣接する２つの水酸基を保護し、しかる後に開環してから水酸基の立体を反転させて得られる化合物（（２Ｓ３Ｓ）−３，４−Ｏ−イソプロピリデン−２，３，４−トリヒドロキシブタン酸エチル）を出発物質とし、これをジメトキシメタンの様なジアルキルオキシメタン中で五酸化リンなどの酸で脱水縮合させ、しかる後に還元し、ジイソプロピリデンなどのケトニドを脱保護し、水酸基をベンゾイルクロライドなどのアシル化剤でアシル化して一般式（２）の化合物に変換したのち、無水酢酸を酸触媒存在下反応させ、一般式（３）の化合物に誘導し、トリメチルシリル−２−二トロイミダゾールのような一般式（４）の化合物と、塩化第二錫などのルイス酸を触媒として縮合し、しかる後にアシル基を脱保護することにより製造することが出来る。
これらの反応はいずれも常温乃至は１００℃の加熱条件下で行うことが出来、常温で行うことが副生成物の量が少ないので特に好ましい。
<2> Production of 2S3R Form The 2S3R form is obtained by treating the starting material in the production method of the 2R3S form in the same manner as the above-mentioned 2R3S form by changing isoascorbic acid to ascorbic acid and ascorbic acid to isoascorbic acid. Can be obtained. That is, a compound ((2S3S) -3,4-O-isopropylidene obtained by protecting two adjacent hydroxyl groups with ascorbic acid with a ketonide such as isopropylidene and then opening the ring and then reversing the stereotype of the hydroxyl group. -2,3,4-trihydroxybutanoic acid ethyl ester) as a starting material, which is dehydrated and condensed with an acid such as phosphorus pentoxide in a dialkyloxymethane such as dimethoxymethane, and then reduced to diisopropylidene, etc. After the ketonide was deprotected, the hydroxyl group was acylated with an acylating agent such as benzoyl chloride and converted to the compound of the general formula (2), and then the acetic anhydride was reacted in the presence of an acid catalyst to give the compound of the general formula (3). And condensed with a compound of the general formula (4) such as trimethylsilyl-2-ditroimidazole and a Lewis acid such as stannic chloride as a catalyst. It can be prepared by deprotecting the acyl group thereafter.
Any of these reactions can be carried out under ordinary temperature or 100 ° C. heating conditions, and it is particularly preferred to carry out the reaction at room temperature since the amount of by-products is small.
又、２Ｒ３Ｓ体と同様に、イソアスコルビン酸を出発物質として、イソプロピリデン等のケトニドで隣接する２つの水酸基を保護し、しかる後に開環して得られる化合物（（２Ｒ３Ｒ）−３，４−Ｏ−イソプロピリデン−２，３，４−トリヒドロキシブタン酸エチル）を出発物質とし、これを還元し、（２Ｒ３Ｒ）−３，４−Ｏ−イソプロピリデン−１，２，３，４−テトラヒドロキシブタンとし、遊離の水酸基をベンゾイルクロリドなどでアシル化し、しかる後にケトニドを外し、緩和な条件下で１級水酸基のみをベンゾイルクロリドなどでアシル化し、（２Ｒ３Ｓ）−１，３，４−トリベンゾイルオキシ−２−ブタノールとなし、２位水酸基にジメトキシメタンを反応させて一般式（２）の化合物となし、これに無水酢酸を反応させて一般式（３）の化合物に誘導させ、前項の手技によって２Ｓ３Ｒ体へ誘導することも出来る。即ち、アスコルビン酸を出発物質としても、イソアスコルビン酸を出発物質としても、いずれも一般式（２）の化合物、一般式（３）の化合物を経由して、２Ｓ３Ｒ体を製造することが出来る。 Similarly to the 2R3S compound, a compound ((2R3R) -3,4-O obtained by protecting two adjacent hydroxyl groups with a ketonide such as isopropylidene and then opening the ring using isoascorbic acid as a starting material. -Ethyl isopropylidene-2,3,4-trihydroxybutanoate), which is reduced and reduced to (2R3R) -3,4-O-isopropylidene-1,2,3,4-tetrahydroxybutane Then, the free hydroxyl group is acylated with benzoyl chloride and the like, and then ketonide is removed, and only the primary hydroxyl group is acylated with benzoyl chloride and the like under mild conditions to give (2R3S) -1,3,4-tribenzoyloxy- No 2-butanol was reacted with the 2-hydroxyl group to form a compound of the general formula (2), which was then reacted with acetic anhydride. It is derived to the compound of formula (3) can also be induced to 2S3R member by preceding procedure. That is, both ascorbic acid as a starting material and isoascorbic acid as a starting material can be used to produce a 2S3R form via a compound of general formula (2) and a compound of general formula (3).
＜３＞一般式（２）に表される化合物
一般式（２）において、式中Ｒ１、Ｒ２、Ｒ４はそれぞれ独立にアシル基又は水素原子を表し、Ｒ３はアルキル基を表す。Ｒ１、Ｒ２、Ｒ４はそれぞれ異なっていても良いし、同じでも良い。但し、水素原子であることは多くてもＲ１、Ｒ２、Ｒ４の内のいずれか１個のみに限られる。好ましいアシル基としては、ホルミル基、アセチル基、ラウロイル基、オレオイル基等の脂肪族アシル基やベンゾイル基等の芳香族アシル基が好適に例示でき、中でもベンゾイル基が、生成物の結晶性を向上せしめ、精製を容易にすることから特に好ましい。又Ｒ３に表されるアルキル基は、短鎖長のメチル基、エチル基、プロピル基、イソプロピル基等が好適に例示でき、メチル基が引き続いてのアセチル化が容易なことから特に好ましい。<3> Compound Represented by General Formula (2) In General Formula (2), R1, R2, and R4 each independently represent an acyl group or a hydrogen atom, and R3 represents an alkyl group. R1, R2, and R4 may be different or the same. However, the number of hydrogen atoms is limited to only one of R1, R2, and R4. Preferred examples of the acyl group include aliphatic acyl groups such as formyl group, acetyl group, lauroyl group, and oleoyl group, and aromatic acyl groups such as benzoyl group. Among them, benzoyl group is preferred for the crystallinity of the product. It is particularly preferred because it improves and facilitates purification. The alkyl group represented by R3 is preferably a short chain length methyl group, ethyl group, propyl group, isopropyl group or the like, and the methyl group is particularly preferred because subsequent acetylation is easy.
＜４＞一般式（３）に表される化合物
一般式（３）において、式中Ｒ１、Ｒ２、Ｒ４はそれぞれ独立に水素原子又はアシル基を表し、Ｒ５は水素原子又はアルキル基を表す。Ｒ１、Ｒ２、Ｒ４については、一般式（２）の条件が適用される。Ｒ５としては、続くトリメチルシリル−２−ニトロイミダゾールとの反応において、離脱しやすい、短鎖長のアルキル基、例えば、メチル基、エチル基、プロピル基、イソプロピル基、ブチル基等が好ましく、メチル基が特に好ましい。<4> Compound Represented by General Formula (3) In General Formula (3), R1, R2, and R4 each independently represent a hydrogen atom or an acyl group, and R5 represents a hydrogen atom or an alkyl group. About R1, R2, R4, the conditions of General formula (2) are applied. R5 is preferably a short-chain alkyl group, such as a methyl group, an ethyl group, a propyl group, an isopropyl group, or a butyl group, which is easily removed in the subsequent reaction with trimethylsilyl-2-nitroimidazole. Particularly preferred.
＜５＞一般式（４）に表される化合物
一般式（４）において、式中Ｒ６、Ｒ７、Ｒ８はそれぞれ独立にアルキル基を表す。当該アルキル基としては、短鎖長のアルキル基が好ましく、メチル基が特に好ましい。この様な一般式（４）の化合物は、２−ニトロイミダゾールに、シリル化剤を反応せしめることによって製造できる。シリル化剤としては、当該アルキル基がメチル基の場合には、トリメチルシリルクロリド、ヘキサメチルジシラザン、Ｎ，Ｏ−ビス（トリメチルシリル）アセトニドなどが好適に例示できる。かかるシリル化剤を２−ニトロイミダゾールと当量加え、室温で数分から３０分混合することにより、一般式（４）に表される化合物を調製することが出来る。<5> Compound Represented by General Formula (4) In General Formula (4), R6, R7 and R8 each independently represents an alkyl group. The alkyl group is preferably a short chain alkyl group, and particularly preferably a methyl group. Such a compound of the general formula (4) can be produced by reacting 2-nitroimidazole with a silylating agent. Preferred examples of the silylating agent include trimethylsilyl chloride, hexamethyldisilazane, N, O-bis (trimethylsilyl) acetonide and the like when the alkyl group is a methyl group. The compound represented by the general formula (4) can be prepared by adding an equivalent amount of this silylating agent to 2-nitroimidazole and mixing at room temperature for several minutes to 30 minutes.
＜６＞一般式（６）に表される化合物
一般式（６）に表される化合物については、２位水酸基と３位水酸基の立体配置が異なる他は一般式（２）に表される化合物の条件が好ましく適用される。<6> The compound represented by the general formula (6) The compound represented by the general formula (6) is represented by the general formula (2) except that the configuration of the 2-position hydroxyl group and the 3-position hydroxyl group is different. The following conditions are preferably applied.
＜７＞一般式（７）に表される化合物
一般式（７）に表される化合物については、２位水酸基と３位水酸基の立体配置が異なる他は一般式（３）に表される化合物の条件が好ましく適用される。<7> The compound represented by the general formula (7) The compound represented by the general formula (7) is represented by the general formula (3) except that the configuration of the 2-position hydroxyl group and the 3-position hydroxyl group is different. The following conditions are preferably applied.
一般式（８）および（９）において、Ｒ１４で表される基としては、最初の原料となるエステル体としての、エトキシカルボニル基、メトキシカルボニル基等の低鎖長アルキルオキシカルボニル基、アルコール体としてのヒドロキシメチル基、アルコール体のアシル化体としてのアセトキシメチル基、ラウロイルオキシメチル基、ベンゾイルオキシメチル基等が好適に例示できる。特に好ましいものはエステル体ではエトキシカルボニル基、アルコールのアシル化体としては、ベンゾイルオキシメチル基が例示できる。 In the general formulas (8) and (9), the group represented by R14 is a low-chain-length alkyloxycarbonyl group such as an ethoxycarbonyl group or a methoxycarbonyl group as an ester body as the first raw material, or an alcohol body. A hydroxymethyl group, an acetoxymethyl group, an lauroyloxymethyl group, a benzoyloxymethyl group, etc. as an acylated form of an alcohol can be preferably exemplified. Particularly preferred examples include an ethoxycarbonyl group in an ester form and a benzoyloxymethyl group as an acylated form of an alcohol.
以下に、実施例を示しながら更に詳細に本発明について説明を加える。 Hereinafter, the present invention will be described in more detail with reference to examples.
水素化リチウムアルミニウム１４．７３ｇにＴＨＦ２００ｍｌを加え、氷冷下撹拌した。化合物（（２Ｒ３Ｒ）−３，４−Ｏ−イソプロピリデン−２，３，４−トリヒドロキシブタン酸エチル）４８．２７ｇをＴＨＦ１００ｍｌに溶かし、徐々に反応液中に滴下した。滴下には約３時間を要した。滴下後室温にて１時間撹拌し、更に１時間加熱還流した。放冷後、反応液の様子を見ながらＨ ２ Ｏ ２５ｍｌを徐々に加えた。その後、ＮａＯＨ ａｑ２５ｍｌ、Ｈ ２ Ｏ ７０ｍｌを加えた。反応液を吸引濾過し、濾液を濃縮した。固体は熱エタノール（３００ｍｌ×５回）で抽出した。オイル状物質が得られた。
オイル状物質にピリジン３００ｍｌを加え溶解し、氷冷下撹拌した。その中に、塩化ベンゾイル１０６．５０ｇを徐々に滴下した。ＴＬＣ上原料がなくなったところでエタノール２００ｍｌを加え濃縮した。酢酸エチルーベンゼン（５：２）７００ｍｌを加え、Ｈ ２ Ｏ（２００ｍｌ×２回）、ｓａｔＮａＨＣＯ ３ ａｑ（２００ｍｌ×１回）、Ｈ ２ Ｏ（２００ｍｌ×１回）、ｓａｔＮａＣｌａｑ（２００ｍｌ×１回）で洗浄した。無水Ｎａ ２ ＳＯ ４ にて乾燥後、濾過、溶媒留去し、オイルを得た。しばらく放置したら、結晶化したのでこれを濾取した。濾液はシリカゲルカラムクロマトグラフィー（ｎーヘキサンー酢酸エチル）にて精製した。濾取した物とあわせて、６３．０２ｇ（収率７２．０％）の白色結晶を得た。（（２Ｓ３Ｒ）−１，２−ジベンゾイル−３，４−Ｏ−イソプロピリデン−１，２，３，４−テトラヒドロキシブタン）
１Ｈ−ＮＭＲ（ＣＤＣｌ ３ ）；δ１．３８（ｓ ３Ｈ）δ１．４４（ｓ ３Ｈ）δ４．０４（ｄｄ １Ｈ）
δ４．１６（ｄｄ １Ｈ）δ４．４６（ｑ １Ｈ）δ４．５６（ｄｄ １Ｈ）
δ４．７８（ｄｄ １Ｈ）δ５．４７〜５．５３（ｍ １Ｈ）
δ７．３８〜７．４６（ｍ ４Ｈ）δ７．５１〜７．５９（ｍ ２Ｈ）
δ７．９８〜８．０６（ｍ ４Ｈ）
200 ml of THF was added to 14.73 g of lithium aluminum hydride and stirred under ice cooling. 48.27 g of the compound ((2R3R) -3,4-O-isopropylidene-2,3,4-trihydroxybutanoic acid ethyl) was dissolved in 100 ml of THF and gradually dropped into the reaction solution. The dripping took about 3 hours. After dropping, the mixture was stirred at room temperature for 1 hour, and further heated to reflux for 1 hour. After allowing to cool, 25 ml of H 2 O was gradually added while watching the state of the reaction solution. Thereafter, NaOH aq 25 ml and H 2 O 70 ml were added. The reaction solution was suction filtered, and the filtrate was concentrated. The solid was extracted with hot ethanol (300 ml × 5 times). An oily substance was obtained.
To the oily substance, 300 ml of pyridine was added and dissolved, and the mixture was stirred under ice cooling. Into this, 106.50 g of benzoyl chloride was gradually added dropwise. When the raw material disappeared on TLC, 200 ml of ethanol was added and concentrated. 700 ml of ethyl acetate-benzene (5: 2) was added, H 2 O (200 ml × 2 times), satNaHCO 3 aq (200 ml × 1 time), H 2 O (200 ml × 1 time), satNaClaq (200 ml × 1 time) Washed with. After drying over anhydrous Na 2 SO 4 , filtration and evaporation of the solvent gave an oil. After standing for a while, it crystallized and was collected by filtration. The filtrate was purified by silica gel column chromatography (n-hexane-ethyl acetate). Together with the filtered product, 63.02 g (yield 72.0%) of white crystals was obtained. ((2S3R) -1,2-dibenzoyl-3,4-O-isopropylidene-1,2,3,4-tetrahydroxybutane)
1H-NMR (CDCl 3 ); δ 1.38 (s 3H) δ 1.44 (s 3H) δ 4.04 (dd 1H)
δ 4.16 (dd 1H) δ 4.46 (q 1H) δ 4.56 (dd 1H)
δ 4.78 (dd 1H) δ 5.47 to 5.53 (m 1H)
δ 7.38-7.46 (m 4H) δ 7.51-7.59 (m 2H)
δ 7.98-8.06 (m 4H)
得られた化合物（（２Ｓ３Ｒ）−１，２−ジベンゾイル−３，４−Ｏ−イソプロピリデン−１，２，３，４−テトラヒドロキシブタン）６２．１５ｇにＴＨＦを加えて溶かし、そこへ８０％酢酸水溶液を加えた。ＴＬＣで反応の進行状態を見ながら、酢酸水溶液を追加した。このとき、反応を速く進行させるために６０℃位に加熱した。ＴＬＣ上原料がほとんど消失したところで反応溶液を濃縮し、酢酸エチルーベンゼン（５：２）７００ｍｌで希釈し、Ｈ ２ Ｏ（１００ｍｌ×１回）、ｓａｔＮａＨＣＯ ３ ａｑ（１００ｍｌ×１回）、Ｈ ２ Ｏ（１００ｍｌ×１回）、ｓａｔＮａＣｌａｑ（１００ｍｌ×１回）で洗浄した。無水Ｎａ ２ ＳＯ ４ にて乾燥後、濾過、溶媒留去し、オイルを６２．１８ｇ得た。得られたオイルをシリカゲルカラムクロマトグラフィー（ｎーヘキサンー酢酸エチル）にて精製し、微黄色オイル５３．３６ｇ（収率９６．３％）を得た。
１Ｈ−ＮＭＲ（ＣＤＣｌ ３ ）；δ２．５３（ｄｄ １Ｈ）δ３．１１（ｄ １Ｈ）
δ３．６９（ｄｄｄ １Ｈ）δ３．８０（ｄｄｄ １Ｈ）
δ３．９１〜３．９９（ｍ １Ｈ）δ４．７８（ｄｄ １Ｈ）
δ４．８５（ｄｄ １Ｈ）δ５．３４〜５．４０（ｍ １Ｈ）
δ７．４０〜７．４８（ｍ ４Ｈ）δ７．５３〜７．６３（ｍ ２Ｈ）
δ８．０１〜８．０９（ｍ ４Ｈ）
得られたジオール５．０７ｇにピリジン５０ｍｌを加えて溶かし、氷冷下撹拌した。塩化ベンゾイル２．３９ｇをジエチルエーテル５ｍｌに溶かしたものを反応容器中に徐々に滴下した。約３．５時間後、エタノール５ｍｌを加えて反応を終了させてから濃縮した。酢酸エチルーベンゼン（４：１）５００ｍｌで希釈し、Ｈ ２ Ｏ（１００ｍｌ×１回）、ｄ−ＨＣｌ（１００ｍｌ×１回）、ｓａｔＮａＨＣＯ ３ ａｑ（１００ｍｌ×１回）、Ｈ ２ Ｏ（１００ｍｌ×１回）、ｓａｔＮａＣｌａｑ（１００ｍｌ×１回）で洗浄した。無水Ｎａ ２ ＳＯ ４ にて乾燥後、濾過、溶媒留去し、白色固体を６．４９ｇ（収率９７．３％）得た。
１Ｈ−ＮＭＲ（ＣＤＣｌ ３ ）；δ３．１５（ｄ １Ｈ）δ４．３２〜４．４２（ｍ １Ｈ）
δ４．４８（ｄｄ １Ｈ）δ４．６７（ｄｄ １Ｈ）
δ４．７６〜４．８７（ｍ ２Ｈ）δ５．５３〜５．５９（ｍ １Ｈ）
δ７．４０〜７．４５（ｍ ６Ｈ）δ７．５３〜７．５９（ｍ ３Ｈ）
δ７．９９〜８．０５（ｍ ６Ｈ）
上記で得られたベンゾエート６．４９ｇにベンゼン１０ｍｌを加えて溶かし、そこへジメトキシメタン３０ｍｌを加え、室温にて撹拌した。五酸化二リンを適当量加えた。ＴＬＣ上の原料が消失したところで撹拌を止め、酢酸エチルーベンゼン（４：１）５００ｍｌで希釈し、ｓａｔＮａＨＣＯ ３ ａｑ（１００ｍｌ×１回）、Ｈ ２ Ｏ（１００ｍｌ×１回）、ｓａｔＮａＣｌａｑ（１００ｍｌ×１回）で洗浄した。無水Ｎａ ２ ＳＯ ４ にて乾燥後、濾過、溶媒留去し、黄色オイルを得た。しばらく放置したら結晶化し、６．５３ｇの固体を得た。（収率９１．４％；（２Ｓ３Ｒ）−１，２，４−トリベンゾイルオキシ−３−メトキシメトキシブタン）
１Ｈ−ＮＭＲ（ＣＤＣｌ ３ ）；δ３．３９（ｓ ３Ｈ）δ４．３７〜４．５１（ｍ ２Ｈ）
δ４．６１〜４．８７（ｍ ５Ｈ）δ５．７２〜５．７８（ｍ １Ｈ）
δ７．３８〜７．４６（ｍ ６Ｈ）δ７．５１〜７．５８（ｍ ３Ｈ）
δ７．９９〜８．０７（ｍ ６Ｈ）
THF was added to 62.15 g of the obtained compound ((2S3R) -1,2-dibenzoyl-3,4-O-isopropylidene-1,2,3,4-tetrahydroxybutane), and 80% was dissolved there. Acetic acid aqueous solution was added. While observing the progress of the reaction by TLC, an aqueous acetic acid solution was added. At this time, it was heated to about 60 ° C. in order to advance the reaction quickly. When the raw material almost disappeared on TLC, the reaction solution was concentrated, diluted with 700 ml of ethyl acetate-benzene (5: 2), H 2 O (100 ml × 1), satNaHCO 3 aq (100 ml × 1), H 2. Washed with O (100 ml x 1), satNaClaq (100 ml x 1). After drying over anhydrous Na 2 SO 4 , filtration and evaporation of the solvent gave 62.18 g of oil. The obtained oil was purified by silica gel column chromatography (n-hexane-ethyl acetate) to obtain 53.36 g (yield 96.3%) of a slightly yellow oil.
1H-NMR (CDCl 3 ); δ 2.53 (dd 1H) δ 3.11 (d 1H)
δ 3.69 (ddd 1H) δ 3.80 (ddd 1H)
δ 3.91 to 3.99 (m 1H) δ 4.78 (dd 1H)
δ 4.85 (dd 1H) δ 5.34-5.40 (m 1H)
δ 7.40-7.48 (m 4H) δ 7.53-7.63 (m 2H)
δ 8.01 to 8.09 (m 4H)
To 5.07 g of the obtained diol, 50 ml of pyridine was added and dissolved, followed by stirring under ice cooling. A solution prepared by dissolving 2.39 g of benzoyl chloride in 5 ml of diethyl ether was gradually added dropwise to the reaction vessel. After about 3.5 hours, 5 ml of ethanol was added to terminate the reaction, followed by concentration. Dilute with 500 ml of ethyl acetate-benzene (4: 1), H 2 O (100 ml × 1 time), d-HCl (100 ml × 1 time), satNaHCO 3 aq (100 ml × 1 time), H 2 O (100 ml × Once) and washed with satNaClaq (100 ml × 1). After drying over anhydrous Na 2 SO 4 , filtration and solvent distillation were performed to obtain 6.49 g (yield 97.3%) of a white solid.
1H-NMR (CDCl 3 ); δ 3.15 (d 1H) δ 4.32 to 4.42 (m 1H)
δ 4.48 (dd 1H) δ 4.67 (dd 1H)
δ 4.76 to 4.87 (m 2H) δ 5.53 to 5.59 (m 1H)
δ 7.40 to 7.45 (m 6H) δ 7.53 to 7.59 (m 3H)
δ 7.9 to 8.05 (m 6H)
To 6.49 g of the benzoate obtained above, 10 ml of benzene was added and dissolved, 30 ml of dimethoxymethane was added thereto, and the mixture was stirred at room temperature. Appropriate amount of diphosphorus pentoxide was added. Stirring was stopped when the raw material on TLC disappeared, diluted with 500 ml of ethyl acetate-benzene (4: 1), satNaHCO 3 aq (100 ml × 1), H 2 O (100 ml × 1), satNaClaq (100 ml × Washed once). After drying over anhydrous Na 2 SO 4 , filtration and evaporation of the solvent gave a yellow oil. After standing for a while, it crystallized to give 6.53 g of solid. (Yield 91.4%; (2S3R) -1,2,4-tribenzoyloxy-3-methoxymethoxybutane)
1H-NMR (CDCl 3 ); δ 3.39 (s 3H) δ 4.37 to 4.51 (m 2H)
δ 4.61 to 4.87 (m 5H) δ 5.72 to 5.78 (m 1H)
δ 7.38-7.46 (m 6H) δ 7.51-7.58 (m 3H)
δ 7.9 to 8.07 (m 6H)
（２Ｓ３Ｒ）−１，２，４−トリベンゾイルオキシ−３−メトキシメトキシブタン６．５３ｇにベンゼン２０ｍｌを加えて溶かし、そこへ無水酢酸 １．５ｍｌを加えて氷冷下で撹拌した。三ふっ化ほう素ジエチルエーテル錯体１ｍｌを加えた。添加と同時に、（２Ｓ３Ｒ）−３−アセトキシメトキシ−１，２，４−ベンゾイルオキシブタンが生成し、反応液は黒色へと変化した。この（２Ｓ３Ｒ）−３−アセトキシメトキシ−１，２，４−ベンゾイルオキシブタンを取り出すことなく、６０分後、ｓａｔＮａＨＣＯ ３ ａｑ１００ｍｌと氷を反応液へ加えた。酢酸エチルーベンゼン（４：１）５００ｍｌで抽出し、Ｈ ２ Ｏ（１００ｍｌ×１回）、ｓａｔＮａＣｌａｑ（１００ｍｌ×１回）で洗浄した。無水Ｎａ ２ ＳＯ ４ にて乾燥後、濾過、溶媒留去し、茶色オイル７．４２ｇを得た。
１Ｈ−ＮＭＲ（ＣＤＣｌ ３ ）；δ１．９１（ｓ ３Ｈ）δ４．４３〜４．５２（ｍ ２Ｈ）
δ４．６６（ｄｄ １Ｈ）δ４．７２〜５．２７（ｍ ２Ｈ）
δ５．３９（ｄ １Ｈ）δ５．４８（ｄ １Ｈ）
δ５．６７〜５．７２（ｍ １Ｈ）δ７．３７〜７．４６（ｍ ６Ｈ）
δ７．５１〜７．６０（ｍ ３Ｈ）δ７．９７〜８．０７（ｍ ６Ｈ）
２ーニトロイミダゾール１．８６ｇにＮ，Ｏービス（トリメチルシリル）アセタミド７ｍｌを加え室温にて撹拌した。反応液が黄色澄明液になったのを確認してから濃縮した。
ベンゾエート７．４２ｇをベンゼン１０ｍｌで溶かして、２ーニトロイミダゾールに加えた。更に、トリメチルシリルトリフルオロメタンスルホネート１ｍｌを加え室温にて撹拌した。ＴＬＣ上原料の消失が認められたところで撹拌を止めた。酢酸エチルーベンゼン（４：１）５００ｍｌで希釈し、ｓａｔＮａＨＣＯ ３ ａｑ（１００ｍｌ×１０回）で洗浄し、未反応の２ーニトロイミダゾールを除いた。更に、Ｈ ２ Ｏ（１００ｍｌ×１回）、ｓａｔＮａＣｌａｑ（１００ｍｌ×１回）で洗浄し、無水Ｎａ ２ ＳＯ ４ にて乾燥後、濾過、溶媒留去し、茶色オイルを得た。少量のエタノールを加えて結晶化させ、５．０６ｇの白色結晶を得た。（収率６６．３％；（２Ｓ３Ｒ）−３−（２−ニトロイミダゾール−１−イルメトキシ）−１，２，４−トリベンゾイルオキシブタン）
１Ｈ−ＮＭＲ（ＣＤＣｌ ３ ）；δ４．４４〜４．５１（ｍ ２Ｈ）δ４．６０（ｄｄ １Ｈ）
δ４．７５（ｄｄ １Ｈ）δ４．８１〜４．８５（ｍ １Ｈ）
δ５．６９〜５．７２（ｍ １Ｈ）δ５．９７（ｄ １Ｈ）
δ６．０７（ｄ １Ｈ）δ７．００（ｓ １Ｈ）δ７．２８（ｓ １Ｈ）
δ７．４０〜７．４９（ｍ ６Ｈ）δ７．５４〜７．６３（ｍ ３Ｈ）
δ７．９３〜８．０５（ｍ ６Ｈ）
20 ml of benzene was dissolved in 6.53 g of (2S3R) -1,2,4-tribenzoyloxy-3-methoxymethoxybutane, 1.5 ml of acetic anhydride was added thereto, and the mixture was stirred under ice cooling. 1 ml of boron trifluoride diethyl ether complex was added. Simultaneously with the addition, (2S3R) -3-acetoxymethoxy-1,2,4-benzoyloxybutane was produced, and the reaction solution turned black. Without taking out this (2S3R) -3-acetoxymethoxy-1,2,4-benzoyloxybutane, 60 minutes later, 100 ml of sat NaHCO 3 aq and ice were added to the reaction solution. The mixture was extracted with 500 ml of ethyl acetate-benzene (4: 1) and washed with H 2 O (100 ml × 1) and satNaClaq (100 ml × 1). After drying over anhydrous Na 2 SO 4 , filtration and evaporation of the solvent gave 7.42 g of a brown oil.
1H-NMR (CDCl 3 ); δ 1.91 (s 3H) δ 4.43 to 4.52 (m 2H)
δ 4.66 (dd 1H) δ 4.72-5.27 (m 2H)
δ 5.39 (d 1H) δ 5.48 (d 1H)
δ 5.67 to 5.72 (m 1H) δ 7.37 to 7.46 (m 6H)
δ 7.51 to 7.60 (m 3H) δ 7.97 to 8.07 (m 6H)
7 ml of N, O-bis (trimethylsilyl) acetamide was added to 1.86 g of 2-nitroimidazole and stirred at room temperature. After confirming that the reaction liquid became a yellow clear liquid, it was concentrated.
7.42 g of benzoate was dissolved in 10 ml of benzene and added to 2-nitroimidazole. Furthermore, 1 ml of trimethylsilyl trifluoromethanesulfonate was added and stirred at room temperature. Stirring was stopped when disappearance of the raw material was observed on TLC. The reaction mixture was diluted with 500 ml of ethyl acetate-benzene (4: 1) and washed with sat NaHCO 3 aq (100 ml × 10 times) to remove unreacted 2-nitroimidazole. Further, it was washed with H 2 O (100 ml × 1 time) and satNaClaq (100 ml × 1 time), dried over anhydrous Na 2 SO 4 , filtered and evaporated to obtain a brown oil. A small amount of ethanol was added for crystallization to obtain 5.06 g of white crystals. (Yield 66.3%; (2S3R) -3- (2-nitroimidazol-1-ylmethoxy) -1,2,4-tribenzoyloxybutane)
1H-NMR (CDCl 3 ); δ 4.44 to 4.51 (m 2H) δ 4.60 (dd 1H)
δ 4.75 (dd 1H) δ 4.81 to 4.85 (m 1H)
δ 5.69 to 5.72 (m 1H) δ 5.97 (d 1H)
δ6.07 (d 1H) δ7.00 (s 1H) δ7.28 (s 1H)
δ 7.40-7.49 (m 6H) δ 7.54-7.63 (m 3H)
δ 7.93 to 8.05 (m 6H)
（２Ｓ３Ｒ）−３−（２−ニトロイミダゾール−１−イルメトキシ）−１，２，４−トリベンゾイルオキシブタン５．０６ｇにメタノール５０ｍｌを加え、室温にて撹拌した。反応液は白濁していたが、その中へナトリウムメトキシド０．０５ｇを加えた。４８時間後に酢酸０．５ｍｌを反応液に加えてから、溶媒を留去した。少量のエタノールを加え、結晶化させた。エタノールから再結晶し、白色針状晶１．３３ｇを得た。（収率５９．５％；（２Ｓ３Ｒ）−３−（２−ニトロイミダゾール−１−イルメトキシ）ブタン−１，２，４−トリオール）
１Ｈ−ＮＭＲ（ＤＭＳＯ）；δ３．１６〜３．２４（ｍ １Ｈ）δ３．３０〜３．６４（ｍ ５Ｈ）
δ４．４３（ｔ １Ｈ）δ４．６４（ｔ １Ｈ）δ４．７５（ｄ １Ｈ）
δ５．８４（ｓ ２Ｈ）δ７．１９（ｓ １Ｈ）δ７．８１（ｓ １Ｈ）
ＩＲ（ｃｍ−１）；３３１４、１５４４、１４９８、１３６４50 ml of methanol was added to 5.06 g of (2S3R) -3- (2-nitroimidazol-1-ylmethoxy) -1,2,4-tribenzoyloxybutane and stirred at room temperature. Although the reaction solution was cloudy, 0.05 g of sodium methoxide was added therein. After 48 hours, 0.5 ml of acetic acid was added to the reaction solution, and then the solvent was distilled off. A small amount of ethanol was added to allow crystallization. Recrystallization from ethanol gave 1.33 g of white needle crystals. (Yield 59.5%; (2S3R) -3- (2-nitroimidazol-1-ylmethoxy) butane-1,2,4-triol)
1H-NMR (DMSO); δ 3.16-3.24 (m 1H) δ 3.30-3.64 (m 5H)
δ 4.43 (t 1H) δ 4.64 (t 1H) δ 4.75 (d 1H)
δ 5.84 (s 2H) δ 7.19 (s 1H) δ 7.81 (s 1H)
IR (cm-1); 3314, 1544, 1498, 1364
（２Ｒ３Ｒ）−３，４−Ｏ−イソプロピリデン−２，３，４−トリヒドロキシブタン酸エチル４．９７ｇを氷冷下撹拌した中に、Ｎ，Ｎ−ジイソプロピルエチルアミン１０ｍｌ、クロルメチルメチルエーテル７ｍｌを加えた。１時間氷冷下撹拌した後、室温で撹拌したが、溶液が固化してしまったので、塩化メチレン２０ｍｌを加えた。ＴＬＣ上の原料がほぼ消失したところで撹拌を止め、溶液を濃縮した。酢酸エチルーベンゼン（５：２）７００ｍｌで希釈し、Ｈ ２ Ｏ（１００ｍｌ×１回）、ｓａｔＮａＨＣＯ ３ ａｑ（１００ｍｌ×１回）、Ｈ ２ Ｏ（１００ｍｌ×１回）、ｓａｔＮａＣｌａｑ（１００ｍｌ×１回）で洗浄した。無水Ｎａ ２ ＳＯ ４ にて乾燥後、濾過、溶媒留去して、茶色オイル６．００ｇを得た。（収率９９．３％；（２Ｒ３Ｒ）−３，４−Ｏ−イソプロピリデン−３，４−ジヒドロキシ−２−メトキシメトキシブタン酸エチル）
１Ｈ−ＮＭＲ（ＣＤＣｌ ３ ）；δ１．３６（ｓ ３Ｈ）δ１．４１（ｓ ３Ｈ）δ２．０９（ｓ ３Ｈ）
δ３．３９（ｓ ３Ｈ）δ３．７８〜３．８３（ｍ １Ｈ）
δ３．９５（ｄｄ １Ｈ）δ４．０６〜４．２０（ｍ ３Ｈ）
δ４．４４（ｄｄ １Ｈ）δ４．６８（ｄ １Ｈ）δ４．７６（ｄ １Ｈ）
水素化リチウムアルミニウム１．００ｇにＴＨＦ３０ｍｌを加え、氷冷下にて撹拌した。（２Ｒ３Ｒ）−３，４−Ｏ−イソプロピリデン−３，４−ジヒドロキシ−２−メトキシメトキシブタン酸エチル６．００ｇをＴＨＦ１０ｍｌに溶かしそれを反応容器の中に徐々に滴下した。氷冷下にて１時間撹拌した後、加熱還流した。滴下終了から７時間後に加熱を止め、放冷してからＨ ２ Ｏ ２ｍｌを加え、続いて５０％ＮａＯＨａｑ ２ｍｌ、Ｈ ２ Ｏ ５ｍｌを加えた。
酢酸エチルで抽出し、抽出液を合わせて濃縮した。微黄色オイル４．９９ｇを得た。（（２Ｓ３Ｒ）−３，４−Ｏ−イソプロピリデン−１，３，４−トリヒドロキシ−２−メトキシメトキシブタン）
１Ｈ−ＮＭＲ（ＣＤＣｌ ３ ）；δ１．３５（ｓ ３Ｈ）δ１．４２（ｓ ３Ｈ）
δ２．７９（ｂｒ ｓ １Ｈ）δ３．４５（ｓ ３Ｈ）
δ３．５５〜３．６１（ｍ １Ｈ）δ３．６４〜３．６９（ｍ １Ｈ）
δ３．８０〜３．８６（ｍ １Ｈ）δ３．８６〜３．９５（ｍ １Ｈ）
δ４．０６〜４．１４（ｍ ２Ｈ）δ４．７１（ｄ １Ｈ）
δ４．７６（ｄ １Ｈ）
（２Ｓ３Ｒ）−３，４−Ｏ−イソプロピリデン−１，３，４−トリヒドロキシ−２−メトキシメトキシブタン４．９９ｇにピリジン３０ｍｌを加えて溶かし、氷冷下撹拌した。そこへ塩化ベンゾイル５．２６ｇを徐々に滴下した。４時間後、エタノールを加え濃縮した。酢酸エチルーベンゼン（４：１）５００ｍｌにて希釈後、Ｈ ２ Ｏ（１００ｍｌ×１回）、ｓａｔＮａＨＣＯ ３ ａｑ（１００ｍｌ×１回）、Ｈ ２ Ｏ（１００ｍｌ×１回）、ｓａｔＮａＣｌａｑ（１００ｍｌ×１回）で洗浄した。無水Ｎａ ２ ＳＯ ４ にて乾燥後、濾過、溶媒留去して黄色オイルを得た。シリカゲルカラムクロマトグラフィー（酢酸エチルーｎーヘキサン）で精製し、無色透明オイル５．２１ｇ（収率６９．５％；（２Ｓ３Ｒ）−１−ベンゾイルオキシ−３，４−Ｏ−イソプロピリデン−３，４−ジヒドロキシ−２−メトキシメトキシブタン）を得た。
１Ｈ−ＮＭＲ（ＣＤＣｌ ３ ）；δ１．３７（ｓ ３Ｈ）δ１．４４（ｓ ３Ｈ）δ３．３８（ｓ ３Ｈ）
δ３．９２〜３．９８（ｍ １Ｈ）δ４．０１（ｄｄ １Ｈ）
δ４．１３（ｄｄ １Ｈ）δ４．２５（ｑ １Ｈ）
δ４．３６（ｄｄ １Ｈ）δ４．６７（ｄｄ １Ｈ）
δ４．７２（ｄ １Ｈ）δ４．８２（ｄ １Ｈ）
δ７．４１〜７．４７（ｍ ２Ｈ）δ７．５３〜７．５９（ｍ １Ｈ）
δ８．０５（ｄ ２Ｈ）
While stirring 4.97 g of ethyl (2R3R) -3,4-O-isopropylidene-2,3,4-trihydroxybutanoate under ice cooling, 10 ml of N, N-diisopropylethylamine and 7 ml of chloromethyl methyl ether were added. added. After stirring for 1 hour under ice-cooling, the mixture was stirred at room temperature, but the solution was solidified, so 20 ml of methylene chloride was added. Stirring was stopped when the raw material on TLC almost disappeared, and the solution was concentrated. Dilute with 700 ml of ethyl acetate-benzene (5: 2), H 2 O (100 ml × 1), satNaHCO 3 aq (100 ml × 1), H 2 O (100 ml × 1), satNaClaq (100 ml × 1) ). After drying over anhydrous Na 2 SO 4 , filtration and evaporation of the solvent gave 6.00 g of a brown oil. (Yield 99.3%; (2R3R) -3,4-O-isopropylidene-3,4-dihydroxy-2-methoxymethoxybutanoate)
1H-NMR (CDCl 3 ); δ 1.36 (s 3H) δ 1.41 (s 3H) δ 2.09 (s 3H)
δ 3.39 (s 3H) δ 3.78-3.83 (m 1H)
δ 3.95 (dd 1H) δ 4.06 to 4.20 (m 3H)
δ 4.44 (dd 1H) δ 4.68 (d 1H) δ 4.76 (d 1H)
30 ml of THF was added to 1.00 g of lithium aluminum hydride and stirred under ice cooling. 6.00 g of ethyl (2R3R) -3,4-O-isopropylidene-3,4-dihydroxy-2-methoxymethoxybutanoate was dissolved in 10 ml of THF and gradually dropped into the reaction vessel. The mixture was stirred for 1 hour under ice cooling and then heated to reflux. After 7 hours from the end of dropping, the heating was stopped, the mixture was allowed to cool, 2 ml of H 2 O was added, followed by 2 ml of 50% NaOHaq and 5 ml of H 2 O.
Extraction was performed with ethyl acetate, and the extracts were combined and concentrated. 4.99 g of a slightly yellow oil was obtained. ((2S3R) -3,4-O-isopropylidene-1,3,4-trihydroxy-2-methoxymethoxybutane)
1H-NMR (CDCl 3 ); δ 1.35 (s 3H) δ 1.42 (s 3H)
δ 2.79 (br s 1H) δ 3.45 (s 3H)
δ3.55-3.61 (m 1H) δ3.64-3.69 (m 1H)
δ 3.80 to 3.86 (m 1H) δ 3.86 to 3.95 (m 1H)
δ 4.06-4.14 (m 2H) δ 4.71 (d 1H)
δ4.76 (d 1H)
(2S3R) -3,4-O-isopropylidene-1,3,4-trihydroxy-2-methoxymethoxybutane was dissolved in 4.99 g by adding 30 ml of pyridine and stirred under ice cooling. Thereto was gradually added dropwise 5.26 g of benzoyl chloride. After 4 hours, ethanol was added and concentrated. After dilution with 500 ml of ethyl acetate-benzene (4: 1), H 2 O (100 ml × 1 time), satNaHCO 3 aq (100 ml × 1 time), H 2 O (100 ml × 1 time), satNaClaq (100 ml × 1) Washed). After drying over anhydrous Na 2 SO 4 , filtration and evaporation of the solvent gave a yellow oil. Purified by silica gel column chromatography (ethyl acetate-n-hexane), colorless transparent oil 5.21 g (yield 69.5%; (2S3R) -1-benzoyloxy-3,4-O-isopropylidene-3,4- Dihydroxy-2-methoxymethoxybutane) was obtained.
1H-NMR (CDCl 3 ); δ 1.37 (s 3H) δ 1.44 (s 3H) δ 3.38 (s 3H)
δ 3.92-3.98 (m 1H) δ 4.01 (dd 1H)
δ 4.13 (dd 1H) δ 4.25 (q 1H)
δ 4.36 (dd 1H) δ 4.67 (dd 1H)
δ 4.72 (d 1H) δ 4.82 (d 1H)
δ 7.41-7.47 (m 2H) δ 7.53-7.59 (m 1H)
δ 8.05 (d 2H)
（２Ｓ３Ｒ）−１−ベンゾイルオキシ−３，４−Ｏ−イソプロピリデン−３，４−ジヒドロキシ−２−メトキシメトキシブタン５．２１ｇに８０％酢酸５０ｍｌを加え、約５０℃に加熱して撹拌した。３時間後撹拌を止め、酢酸エチルーベンゼン（４：１）５００ｍｌで希釈した。ｄ−ＮａＯＨａｑ（１００ｍｌ×３回）、ｓａｔＮａＨＣＯ ３ ａｑ（１００ｍｌ×１回）、Ｈ ２ Ｏ（１００ｍｌ×１回）、ｓａｔＮａＣｌａｑ（１００ｍｌ×１回）で洗浄した。無水Ｎａ ２ ＳＯ ４ にて乾燥後、濾過、溶媒留去して淡黄色オイル３．９６ｇ（収率８７．３％）を得た。
１Ｈ−ＮＭＲ（ＣＤＣｌ ３ ）；δ２．３２（ｂｒ ｓ １Ｈ）δ３．０２（ｄ １Ｈ）
δ３．４２（ｓ ３Ｈ）δ３．８１（ｂｒ ｓ ３Ｈ）
δ３．９２〜３．９８（ｍ １Ｈ）δ４．５８（ｄ ２Ｈ）
δ４．７４（ｄ １Ｈ）δ４．８０（ｄ １Ｈ）δ７．４６（ｔ ２Ｈ）
δ７．５４〜７．６１（ｍ １Ｈ）δ８．０５（ｄ ２Ｈ）
ベンゾエート３．９６ｇをピリジン５０ｍｌに溶かし、氷冷下で撹拌した。その中へ塩化ベンゾイル５．１３ｇを徐々に滴下した。途中室温撹拌に戻した。ＴＬＣ上の原料がほぼ消失したところでエタノールを加え溶媒を留去した。酢酸エチルーベンゼン（４：１）５００ｍｌで希釈した後、Ｈ ２ Ｏ（１００ｍｌ×１回）、ｓａｔＮａＨＣＯ ３ ａｑ（１００ｍｌ×１回）、Ｈ ２ Ｏ（１００ｍｌ×１回）、ｓａｔＮａＣｌａｑ（１００ｍｌ×１回）で洗浄した。無水Ｎａ ２ ＳＯ ４ で乾燥後、濾過、溶媒留去した所、結晶が析出したのでこれを濾取した。白色結晶４．９８ｇ（収率７１．０％；（２Ｒ３Ｓ）−１，２，４−トリベンゾイルオキシ−３−メトキシメトキシブタン）を得た。
１Ｈ−ＮＭＲ（ＣＤＣｌ ３ ）；δ３．３９（ｓ ３Ｈ）δ４．３７〜４．５１（ｍ ２Ｈ）
δ４．６３〜４．８８（ｍ ５Ｈ）δ５．７３〜５．７９（ｍ １Ｈ）
δ７．３９〜７．４６（ｍ ６Ｈ）δ７．５２〜７．５９（ｍ ３Ｈ）
δ７．９９〜８．０７（ｍ ６Ｈ）
50% 80% acetic acid was added to 5.21 g of (2S3R) -1-benzoyloxy-3,4-O-isopropylidene-3,4-dihydroxy-2-methoxymethoxybutane, and the mixture was heated to about 50 ° C. and stirred. After 3 hours, stirring was stopped and the mixture was diluted with 500 ml of ethyl acetate-benzene (4: 1). Washed with d-NaOHaq (100 ml × 3 times), sat NaHCO 3 aq (100 ml × 1 time), H 2 O (100 ml × 1 time), satNaClaq (100 ml × 1 time). After drying over anhydrous Na 2 SO 4 , filtration and evaporation of the solvent gave 3.96 g (yield 87.3%) of a pale yellow oil.
1H-NMR (CDCl 3 ); δ 2.32 (br s 1H) δ 3.02 (d 1H)
δ 3.42 (s 3H) δ 3.81 (br s 3H)
δ 3.92 to 3.98 (m 1H) δ 4.58 (d 2H)
δ 4.74 (d 1H) δ 4.80 (d 1H) δ 7.46 (t 2H)
δ 7.54 to 7.61 (m 1H) δ 8.05 (d 2H)
3.96 g of benzoate was dissolved in 50 ml of pyridine and stirred under ice cooling. Into this, 5.13 g of benzoyl chloride was gradually added dropwise. The mixture was returned to room temperature stirring halfway. When the raw material on TLC almost disappeared, ethanol was added and the solvent was distilled off. After diluting with 500 ml of ethyl acetate-benzene (4: 1), H 2 O (100 ml × 1 time), satNaHCO 3 aq (100 ml × 1 time), H 2 O (100 ml × 1 time), satNaClaq (100 ml × 1) Washed). After drying over anhydrous Na 2 SO 4 , filtration and evaporation of the solvent resulted in crystals that were collected by filtration. 4.98 g of white crystals (yield 71.0%; (2R3S) -1,2,4-tribenzoyloxy-3-methoxymethoxybutane) was obtained.
1H-NMR (CDCl 3 ); δ 3.39 (s 3H) δ 4.37 to 4.51 (m 2H)
δ 4.63 to 4.88 (m 5H) δ 5.73 to 5.79 (m 1H)
δ 7.39-7.46 (m 6H) δ 7.52-7.59 (m 3H)
δ 7.9 to 8.07 (m 6H)
実施例１と同様に、２−ニトロイミダゾール１．８６ｇにＮ，Ｏービス（トリメチルシリル）アセタミド７ｍｌを加え室温にて撹拌した。反応液が黄色澄明液になったのを確認してから濃縮した。
（２Ｒ３Ｓ）−１，２，４−トリベンゾイルオキシ−３−メトキシメトキシブタン７．４２ｇをベンゼン１０ｍｌで溶かして、２ーニトロイミダゾールに加えた。更に、トリメチルシリルトリフルオロメタンスルホネート１ｍｌを加え室温にて撹拌した。ＴＬＣ上原料の消失が認められたところで撹拌を止めた。酢酸エチルーベンゼン（４：１）５００ｍｌで希釈し、ｓａｔＮａＨＣＯ ３ ａｑ（１００ｍｌ×１０回）で洗浄し、未反応の２ーニトロイミダゾールを除いた。更に、Ｈ ２ Ｏ（１００ｍｌ×１回）、ｓａｔＮａＣｌａｑ（１００ｍｌ×１回）で洗浄し、無水Ｎａ ２ ＳＯ ４ にて乾燥後、濾過、溶媒留去し、茶色オイルを得た。少量のエタノールを加えて結晶化させ、５．０６ｇの白色結晶を得た。（収率６６．３％；（２Ｒ３Ｓ）−３−（２−ニトロイミダゾール−１−イルメトキシ）−１，２，４−トリベンゾイルオキシブタン）
１Ｈ−ＮＭＲ（ＣＤＣｌ ３ ）；δ４．４３〜４．５２（ｍ ２Ｈ）δ４．６０（ｄｄ １Ｈ）
δ４．７５（ｄｄ １Ｈ）δ４．７９〜４．８８（ｍ １Ｈ）
δ５．６８〜５．７３（ｍ １Ｈ）δ５．９７（ｄ １Ｈ）
δ６．０６（ｄ １Ｈ）δ７．００（ｓ １Ｈ）δ７．２８（ｓ １Ｈ）
δ７．４０〜７．４８（ｍ ６Ｈ）δ７．５４〜７．６３（ｍ ３Ｈ）
δ７．９３〜８．０７（ｍ ６Ｈ）
In the same manner as in Example 1, 7 ml of N, O-bis (trimethylsilyl) acetamide was added to 1.86 g of 2-nitroimidazole and stirred at room temperature. After confirming that the reaction liquid became a yellow clear liquid, it was concentrated.
7.42 g of (2R3S) -1,2,4-tribenzoyloxy-3-methoxymethoxybutane was dissolved in 10 ml of benzene and added to 2-nitroimidazole. Furthermore, 1 ml of trimethylsilyl trifluoromethanesulfonate was added and stirred at room temperature. Stirring was stopped when disappearance of the raw material was observed on TLC. The reaction mixture was diluted with 500 ml of ethyl acetate-benzene (4: 1) and washed with sat NaHCO 3 aq (100 ml × 10 times) to remove unreacted 2-nitroimidazole. Further, it was washed with H 2 O (100 ml × 1 time) and satNaClaq (100 ml × 1 time), dried over anhydrous Na 2 SO 4 , filtered and evaporated to obtain a brown oil. A small amount of ethanol was added for crystallization to obtain 5.06 g of white crystals. (Yield 66.3%; (2R3S) -3- (2-nitroimidazol-1-ylmethoxy) -1,2,4-tribenzoyloxybutane)
1H-NMR (CDCl 3 ); δ 4.43 to 4.52 (m 2H) δ 4.60 (dd 1H)
δ 4.75 (dd 1H) δ 4.79 to 4.88 (m 1H)
δ 5.68 to 5.73 (m 1H) δ 5.97 (d 1H)
δ 6.06 (d 1H) δ 7.00 (s 1H) δ 7.28 (s 1H)
δ 7.40-7.48 (m 6H) δ 7.54-7.63 (m 3H)
δ 7.93 to 8.07 (m 6H)
（２Ｒ３Ｓ）−３−（２−ニトロイミダゾール−１−イルメトキシ）−１，２，４−トリベンゾイルオキシブタン３．０４ｇにメタノール５０ｍｌを加え、室温にて撹拌した。その中へナトリウムメトキシド０．０３ｇを加えた。反応溶液の黄色が濃くなった。３．５時間後に酢酸１ｍｌを反応液に加えてから、溶媒を留去した。放置後、結晶化したので濾取し、エタノールから再結晶し、白色針状晶０．９４ｇを得た。（収率７０．０％；（２Ｒ３Ｓ）−３−（２−ニトロイミダゾール−１−イルメトキシ）ブタン−１，２，４−トリオール）
１Ｈ−ＮＭＲ（ＤＭＳＯ）；δ３．１５〜３．２４（ｍ １Ｈ）δ３．３０〜３．６４（ｍ ５Ｈ）
δ４．４２（ｔ １Ｈ）δ４．６４（ｔ １Ｈ）δ４．７５（ｄ １Ｈ）
δ５．８４（ｓ ２Ｈ）δ７．１９（ｓ １Ｈ）δ７．８１（ｓ １Ｈ）
ＩＲ（ｃｍ−１）；３３１４、１５４４、１４９８、１３６４50 ml of methanol was added to 3.04 g of (2R3S) -3- (2-nitroimidazol-1-ylmethoxy) -1,2,4-tribenzoyloxybutane and stirred at room temperature. Sodium methoxide 0.03g was added in it. The reaction solution became darker in yellow. After 3.5 hours, 1 ml of acetic acid was added to the reaction solution, and then the solvent was distilled off. After standing, it crystallized and was collected by filtration and recrystallized from ethanol to obtain 0.94 g of white needle crystals. (Yield 70.0%; (2R3S) -3- (2-nitroimidazol-1-ylmethoxy) butane-1,2,4-triol)
1H-NMR (DMSO); δ 3.15-3.24 (m 1H) δ 3.30-3.64 (m 5H)
δ 4.42 (t 1H) δ 4.64 (t 1H) δ 4.75 (d 1H)
δ 5.84 (s 2H) δ 7.19 (s 1H) δ 7.81 (s 1H)
IR (cm-1); 3314, 1544, 1498, 1364
（２Ｒ３Ｓ）−１，２，４−トリベンゾイルオキシ−３−メトキシメトキシブタンについて、別法での製造を試みた。即ち、Ｌ−アスコルビン酸より誘導した、（２Ｒ３Ｓ）−３，４−Ｏ−イソプロピリデン−２，３，４−トリヒドロキシブタン酸エチル６．８６ｇにトリフェニルホスフィン１７．７３ｇ、安息香酸８．３０ｇ、ＴＨＦ１００ｍｌを加え、室温で撹拌し溶解させた。ＴＨＦ２０ｍｌにジエチルアゾジカルボキシレート１２．６４ｇを溶かし、それを反応溶液の中に滴下した。若干発熱したが、そのまま撹拌した。７２時間後、溶液を濃縮し、酢酸エチルーベンゼン（５：２）７００ｍｌで希釈した。Ｈ ２ Ｏ（１００ｍｌ×１回）、ｓａｔＮａＨＣＯ ３ ａｑ（１００ｍｌ×１回）、Ｈ ２ Ｏ（１００ｍｌ×１回）、ｓａｔＮａＣｌａｑ（１００ｍｌ×１回）で洗浄した。無水Ｎａ ２ ＳＯ ４ にて乾燥後、濾過、溶媒留去し、赤茶色オイルを得た。得られたオイルをシリカゲルカラムクロマトグラフィー（酢酸エチル−ｎ−ヘキサン）で精製した。得られた分画には不純物として安息香酸の混入が認められたため、酢酸エチルーベンゼン（５：２）７００ｍｌで希釈した後、ｓａｔＮａＨＣＯ ３ ａｑ（１００ｍｌ×３回）、Ｈ ２ Ｏ（１００ｍｌ×１回）、ｓａｔＮａＣｌａｑ（１００ｍｌ×１回）で洗浄した。無水Ｎａ ２ ＳＯ ４ にて乾燥後、濾過、溶媒留去し、目的のベンゾエート５．４３ｇを微黄色オイルとして得た。（収率５２．４％；（２Ｓ３Ｓ）−３，４−Ｏ−イソプロピリデン−２−ベンゾイルオキシ−３，４−ジヒドロキシブタン酸エチル）
１Ｈ−ＮＭＲ（ＣＤＣｌ ３ ）；δ１．２９（ｔ ３Ｈ）δ１．３８（ｓ ３Ｈ）δ１．４３（ｓ ３Ｈ）
δ４．１１〜４．２１（ｍ ２Ｈ）δ４．２６（ｑ ２Ｈ）
δ４．５８〜４．６４（ｍ １Ｈ）δ５．３５（ｄ １Ｈ）
δ７．４３〜７．５１（ｍ ２Ｈ）δ７．５６〜７．６５（ｍ １Ｈ）
δ８．１０（ｄ ２Ｈ）
水素化リチウムアルミニウム１．０１ｇにＴＨＦ１５ｍｌを加え、氷冷下撹拌した。ベンゾエート５．４３ｇをＴＨＦ１０ｍｌに溶かし、徐々に反応液中に滴下した。滴下終了後室温にて１時間撹拌し、更に加熱還流を４．５時間した。放冷後、反応液の様子を見ながらＨ ２ Ｏ １ｍｌを加え、更に、５０％ＮａＯＨａｑ１ｍｌ、Ｈ ２ Ｏ ５ｍｌを加えた。反応液を濃縮してから、酢酸エチル、メタノールで抽出し、無色透明オイル５．０７ｇを得た。
得られた無色透明オイルにピリジン５０ｍｌを加え溶解し、氷冷下撹拌した。その中に、塩化ベンゾイル１０ｍｌを徐々に滴下した。約１７時間後、エタノール１０ｍｌを加え濃縮した。酢酸エチルーベンゼン（５：２）７００ｍｌを加え、Ｈ ２ Ｏ（１００ｍｌ×１回）、ｓａｔＮａＨＣＯ ３ ａｑ（１００ｍｌ×１回）、Ｈ ２ Ｏ（１００ｍｌ×１回）、ｓａｔＮａＣｌａｑ（１００ｍｌ×１回）で洗浄した。無水Ｎａ ２ ＳＯ ４ にて乾燥後、濾過、溶媒留去し、茶色オイルを得た。これをシリカゲルカラムクロマトグラフィー（ｎーヘキサン：酢酸エチル＝９：１）にて精製し、白色結晶３．６０ｇを得た。（収率５５．２％，総収率２８．９％；（２Ｒ３Ｓ）−１，２−ジベンゾイルオキシ−３，４−イソプロピリデン−３，４−ジヒドロキシブタン）
１Ｈ−ＮＭＲ（ＣＤＣｌ ３ ）；δ１．３８（ｓ ３Ｈ）δ１．４４（ｓ ３Ｈ）
δ４．０６（ｄｄ １Ｈ）δ４．１７（ｄｄ １Ｈ）
δ４．４８（ｑ １Ｈ）δ４．５６（ｄｄ １Ｈ）
δ４．７９（ｄｄ １Ｈ）δ５．４９〜５．５４（ｍ １Ｈ）
δ７．３８〜７．４７（ｍ ４Ｈ）δ７．５０〜７．６２（ｍ ２Ｈ）
δ７．９９〜８．０７（ｍ ４Ｈ）
(2R3S) -1,2,4-tribenzoyloxy-3-methoxymethoxybutane was tried to be produced by another method. That is, derived from L-ascorbic acid, 6.86 g of ethyl (2R3S) -3,4-O-isopropylidene-2,3,4-trihydroxybutanoate, 17.73 g of triphenylphosphine and 8.30 g of benzoic acid , 100 ml of THF was added and dissolved by stirring at room temperature. 12.64 g of diethyl azodicarboxylate was dissolved in 20 ml of THF, and this was dropped into the reaction solution. Slightly exothermic but stirred as is. After 72 hours, the solution was concentrated and diluted with 700 ml of ethyl acetate-benzene (5: 2). Washed with H 2 O (100 ml × 1), satNaHCO 3 aq (100 ml × 1), H 2 O (100 ml × 1), satNaClaq (100 ml × 1). After drying over anhydrous Na 2 SO 4 , filtration and evaporation of the solvent gave a reddish brown oil. The obtained oil was purified by silica gel column chromatography (ethyl acetate-n-hexane). Since contamination of benzoic acid was observed as an impurity in the obtained fraction, it was diluted with 700 ml of ethyl acetate-benzene (5: 2), then sat NaHCO 3 aq (100 ml × 3 times), H 2 O (100 ml × 1 ) And satNaClaq (100 ml × 1). After drying over anhydrous Na 2 SO 4 , filtration and evaporation of the solvent gave 5.43 g of the desired benzoate as a pale yellow oil. (Yield 52.4%; (2S3S) -3,4-O-isopropylidene-2-benzoyloxy-3,4-dihydroxybutanoate ethyl)
1H-NMR (CDCl 3 ); δ 1.29 (t 3H) δ 1.38 (s 3H) δ 1.43 (s 3H)
δ 4.11 to 4.21 (m 2H) δ 4.26 (q 2H)
δ4.58 to 4.64 (m 1H) δ5.35 (d 1H)
δ7.43 to 7.51 (m 2H) δ7.56 to 7.65 (m 1H)
δ 8.10 (d 2H)
15 ml of THF was added to 1.01 g of lithium aluminum hydride and stirred under ice cooling. 5.43 g of benzoate was dissolved in 10 ml of THF and gradually dropped into the reaction solution. After completion of the dropwise addition, the mixture was stirred at room temperature for 1 hour and further heated to reflux for 4.5 hours. After allowing to cool, 1 ml of H 2 O was added while observing the state of the reaction solution, and further 1 ml of 50% NaOHaq and 5 ml of H 2 O were added. The reaction mixture was concentrated and extracted with ethyl acetate and methanol to obtain 5.07 g of a colorless transparent oil.
50 mL of pyridine was added to the obtained colorless transparent oil for dissolution, and the mixture was stirred under ice cooling. Into this, 10 ml of benzoyl chloride was gradually added dropwise. After about 17 hours, 10 ml of ethanol was added and concentrated. Add 700 ml of ethyl acetate-benzene (5: 2), H 2 O (100 ml × 1 time), satNaHCO 3 aq (100 ml × 1 time), H 2 O (100 ml × 1 time), satNaClaq (100 ml × 1 time) Washed with. After drying over anhydrous Na 2 SO 4 , filtration and evaporation of the solvent gave a brown oil. This was purified by silica gel column chromatography (n-hexane: ethyl acetate = 9: 1) to obtain 3.60 g of white crystals. (Yield 55.2%, total yield 28.9%; (2R3S) -1,2-dibenzoyloxy-3,4-isopropylidene-3,4-dihydroxybutane)
1H-NMR (CDCl 3 ); δ 1.38 (s 3H) δ 1.44 (s 3H)
δ4.06 (dd 1H) δ4.17 (dd 1H)
δ 4.48 (q 1H) δ 4.56 (dd 1H)
δ4.79 (dd 1H) δ 5.49 to 5.54 (m 1H)
δ 7.38-7.47 (m 4H) δ 7.50-7.62 (m 2H)
δ 7.9 to 8.07 (m 4H)
（２Ｒ３Ｓ）−１，２−ジベンゾイルオキシ−３，４−イソプロピリデン−３，４−ジヒドロキシブタン４．２２ｇにＴＨＦ５０ｍｌを加え溶解した。そこへ８０％酢酸５０ｍｌを加え、室温にて撹拌した。反応液中に結晶が析出していたのでＴＨＦ５０ｍｌを追加した。ＴＬＣで反応の進行状況を見て、ＴＬＣ上原料がほとんど消失した時点で撹拌を止めた。酢酸エチルーベンゼン（４：１）５００ｍｌで希釈し、Ｈ ２ Ｏ（１００ｍｌ×１回）、ｓａｔＮａＨＣＯ ３ ａｑ（１００ｍｌ×５回）、Ｈ ２ Ｏ（１００ｍｌ×１回）、ｓａｔＮａＣｌａｑ（１００ｍｌ×１回）で洗浄した。尚、ｓａｔＮａＨＣＯ ３ ａｑで洗浄した時には、水層がアルカリ性になったことを確認した。続いて、無水Ｎａ ２ ＳＯ ４ にて乾燥し、濾過、溶媒留去し、オレンジ色オイルを３．３０ｇ得た。（収率８７．７％）
１Ｈ−ＮＭＲ（ＣＤＣｌ ３ ）；δ２．５９（ｂｒ ｓ １Ｈ）δ３．１７（ｄ １Ｈ）
δ３．６８〜３．７６（ｍ ２Ｈ）δ３．９５（ｍ １Ｈ）
δ４．７５〜４．８８（ｍ ２Ｈ）δ５．３５〜５．４１（ｍ １Ｈ）
δ７．４０〜７．４７（ｍ ４Ｈ）δ７．５３〜７．６２（ｍ ２Ｈ）
δ８．０１〜８．０５（ｍ ４Ｈ）
ジオール３．３０ｇをピリジン５０ｍｌに溶かし、氷冷下撹拌した。塩化ベンゾイル２．９３ｇを反応容器中に徐々に滴下した。約２．５時間後、メタノール１０ｍｌを加えて反応を終了させてから濃縮した。酢酸エチルーベンゼン（４：１）５００ｍｌで希釈し、Ｈ ２ Ｏ（１００ｍｌ×１回）、ｓａｔＮａＨＣＯ ３ ａｑ（１００ｍｌ×１回）、Ｈ ２ Ｏ（１００ｍｌ×１回）、ｓａｔＮａＣｌａｑ（１００ｍｌ×１回）で洗浄した。無水Ｎａ ２ ＳＯ ４ にて乾燥後、濾過、溶媒留去した。シリカゲルカラムクロマトグラフィー（酢酸エチルーｎーヘキサン）にて精製し白色結晶３．８３ｇを得た。（収率８８．２％）
１Ｈ−ＮＭＲ（ＣＤＣｌ ３ ）；δ３．２１（ｂｒ ｓ １Ｈ）δ４．３６（ｂｒ ｓ １Ｈ）
δ４．４７（ｄｄ １Ｈ）δ４．６７（ｄｄ １Ｈ）
δ４．７５〜４．８８（ｍ ２Ｈ）δ５．５３〜５．５９（ｍ １Ｈ）
δ７．４１〜７．４６（ｍ ６Ｈ）δ７．５４〜７．６０（ｍ ３Ｈ）
δ８．０１〜８．０６（ｍ ６Ｈ）
ベンゾエート１．８１ｇにジメトキシメタン３０ｍｌを加えて溶かし、室温にて撹拌した。そこへ五酸化二リンを適当量加えた。ＴＬＣ上の原料が消失したところで撹拌を止め、酢酸エチルーベンゼン（５：１）３００ｍｌで希釈し、Ｈ ２ Ｏ（５０ｍｌ×１回）、ｓａｔＮａＨＣＯ ３ ａｑ（５０ｍｌ×１回）、Ｈ ２ Ｏ（５０ｍｌ×１回）、ｓａｔＮａＣｌａｑ（５０ｍｌ×１回）で洗浄した。無水Ｎａ ２ ＳＯ ４ にて乾燥後、濾過、溶媒留去し、茶色オイルを得た。しばらく放置し結晶化させ、１．９３ｇの固体を得た。（収率９５．８％；（２Ｒ３Ｓ）−１，２，４−トリベンゾイルオキシ−３−メトキシメトキシブタン）
１Ｈ−ＮＭＲ（ＣＤＣｌ ３ ）；δ３．３９（ｓ ３Ｈ）δ４．３７〜４．５１（ｍ ２Ｈ）
δ４．６３〜４．８８（ｍ ５Ｈ）δ５．７３〜５．７９（ｍ １Ｈ）
δ７．３９〜７．４６（ｍ ６Ｈ）δ７．５２〜７．５９（ｍ ３Ｈ）
δ７．９９〜８．０７（ｍ ６Ｈ）
50 ml of THF was dissolved in 4.22 g of (2R3S) -1,2-dibenzoyloxy-3,4-isopropylidene-3,4-dihydroxybutane. Thereto, 50 ml of 80% acetic acid was added and stirred at room temperature. Since crystals were precipitated in the reaction solution, 50 ml of THF was added. The progress of the reaction was observed by TLC, and stirring was stopped when the raw material on TLC almost disappeared. Dilute with 500 ml of ethyl acetate-benzene (4: 1), H 2 O (100 ml × 1), satNaHCO 3 aq (100 ml × 5), H 2 O (100 ml × 1), satNaClaq (100 ml × 1) ). Incidentally, when washed with satNaHCO 3 aq, the aqueous layer was confirmed to become alkaline. Subsequently, dried over anhydrous Na 2 SO 4, filtered, evaporated to give 3.30g of an orange oil. (Yield 87.7%)
1H-NMR (CDCl 3 ); δ 2.59 (br s 1H) δ 3.17 (d 1H)
δ 3.68-3.76 (m 2H) δ 3.95 (m 1H)
δ 4.75 to 4.88 (m 2H) δ 5.35 to 5.41 (m 1H)
δ 7.40-7.47 (m 4H) δ 7.53-7.62 (m 2H)
δ 8.01-8.05 (m 4H)
3.30 g of diol was dissolved in 50 ml of pyridine and stirred under ice cooling. 2.93 g of benzoyl chloride was gradually dropped into the reaction vessel. After about 2.5 hours, 10 ml of methanol was added to terminate the reaction, and then concentrated. Dilute with 500 ml of ethyl acetate-benzene (4: 1), H 2 O (100 ml × 1 time), satNaHCO 3 aq (100 ml × 1 time), H 2 O (100 ml × 1 time), satNaClaq (100 ml × 1 time) ). After drying over anhydrous Na 2 SO 4 , filtration and solvent distillation were performed. Purification by silica gel column chromatography (ethyl acetate-n-hexane) gave 3.83 g of white crystals. (Yield 88.2%)
1H-NMR (CDCl 3 ); δ 3.21 (br s 1H) δ 4.36 (br s 1H)
δ 4.47 (dd 1H) δ 4.67 (dd 1H)
δ 4.75 to 4.88 (m 2H) δ 5.53 to 5.59 (m 1H)
δ 7.41-7.46 (m 6H) δ 7.54-7.60 (m 3H)
δ 8.01-8.06 (m 6H)
30 ml of dimethoxymethane was dissolved in 1.81 g of benzoate and stirred at room temperature. An appropriate amount of diphosphorus pentoxide was added thereto. When the raw material on TLC disappeared, the stirring was stopped, diluted with 300 ml of ethyl acetate-benzene (5: 1), H 2 O (50 ml × 1 time), satNaHCO 3 aq (50 ml × 1 time), H 2 O ( 50 ml × 1) and satNaClaq (50 ml × 1). After drying over anhydrous Na 2 SO 4 , filtration and evaporation of the solvent gave a brown oil. It was left to crystallize for a while to obtain 1.93 g of a solid. (Yield 95.8%; (2R3S) -1,2,4-tribenzoyloxy-3-methoxymethoxybutane)
1H-NMR (CDCl 3 ); δ 3.39 (s 3H) δ 4.37 to 4.51 (m 2H)
δ 4.63 to 4.88 (m 5H) δ 5.73 to 5.79 (m 1H)
δ 7.39-7.46 (m 6H) δ 7.52-7.59 (m 3H)
δ 7.9 to 8.07 (m 6H)
（２Ｓ３Ｒ）−３−（２−ニトロイミダゾール−１−イルメトキシ）ブタン−１，２，４−トリオール、（２Ｒ３Ｓ）−３−（２−ニトロイミダゾール−１−イルメトキシ）ブタン−１，２，４−トリオール）及びドラニダゾールについて、ＥＭＴ−６に対する低酸素性細胞放射線増感効果をイン・ビボ−イン・ビトロアッセイで比較した。即ち、特開平０３−２２３２５８号公報に記載の方法に従い、１０ ５ 個のＥＭＴ−６細胞をＢａｌｂ／ｃ雌性マウス（５週齢）の後ろ肢大腿部に移植し、１週間飼育し、固形腫瘍を形成させ、しかる後にγ線２０Ｇｙを照射し、腫瘍を取り出し、トリプシン処理して浮遊細胞となし、これを、５％ＦＢＳ加ＭＥＭ培地で培養し、コロニー形成法により、生存率を求め、これより増感係数を求めた。（増感剤を投与しない場合を１とし、どの程度増感したかをしめす指標）結果を表１に示す。この値は、特開平０３−２２３２５８号公報の結果と良く一致するものであることか判る。 (2S3R) -3- (2-nitroimidazol-1-ylmethoxy) butane-1,2,4-triol, (2R3S) -3- (2-nitroimidazol-1-ylmethoxy) butane-1,2,4- Triol) and dranidazole were compared by in vivo-in vitro assay for hypoxic cell radiosensitization effect on EMT-6. That is, according to the method described in JP-A-03-223258, 10 5 EMT-6 cells were transplanted into the hind limb thigh of a Balb / c female mouse (5 weeks old), reared for 1 week, and solid. A tumor is formed, and then irradiated with 20 Gy of γ-rays, the tumor is removed, treated with trypsin to form a floating cell, this is cultured in a 5% FBS-added MEM medium, and the survival rate is obtained by a colony formation method. The sensitization coefficient was obtained from this. Table 1 shows the results (an index indicating how much the sensitizer is not administered and 1 indicating how much sensitization is performed). It can be seen that this value is in good agreement with the result of JP-A-03-223258.
細胞腫を、種々変えて、コロニー法（ｃｏｌｏｎｙ ａｓｓａｙ）を用いて、低酸素性細胞放射線増感作用を調べた。即ち、細胞をトリプシン処理し、浮遊細胞とし、２０分間９５％Ｎ２＋５％ＣＯ ２ で通気し低酸素状態にした後、ＰＢＳ及び検体のＰＢＳ溶液の存在下で、Ｘ線（０、１、２、３Ｇｙ）を照射した。その後５％ＦＢＳ加ＭＥＭ培地で７２時間培養し、形成したコロニー数を計数し、線量・生存率曲線を引き、この線量−生存率曲線より被験化合物無添加時の低酸素性細胞の生存率を１％下げる放射線量を、被験化合物添加時の低酸素性細胞の生存率を１％下げさせる放射線量で除した値を求めて増感係数を求めた。ここで、ＳＣＣＶＩＩはＢａｌｂ／ｃに自然発生した扁平上皮癌から樹立された細胞であり、Ｖ７９はチャイニーズハムスターの肺由来のフィブロブラスト様細胞であり、Ｌ５１７８Ｙはリンパ種由来のガン細胞である。結果を表２に示す。これより、（２Ｒ３Ｓ）−２−（２−ニトロイミダゾール−１−イルメトキシ）−１，３，４−トリヒドロキシブタン）は特異的に、肺癌、リンパ腫に優れた増感効果を示すことが判る。 Hypoxic cell radiosensitization was examined using a colony assay with various changes in cell tumors. That is, the cells were trypsinized to become floating cells, aerated with 95% N 2 + 5% CO 2 for 20 minutes to be hypoxic, and then subjected to X-rays (0, 1, 2) in the presence of PBS and the sample PBS solution. 2, 3 Gy). Thereafter, the cells were cultured in MEM medium supplemented with 5% FBS for 72 hours, the number of formed colonies was counted, a dose / viability curve was drawn, and the survival rate of hypoxic cells when no test compound was added was determined from this dose-survival curve. The sensitization coefficient was determined by determining the value obtained by dividing the radiation dose decreased by 1% by the radiation dose that decreased the survival rate of hypoxic cells upon addition of the test compound by 1%. Here, SCCVII is a cell established from a squamous cell carcinoma naturally occurring in Balb / c, V79 is a fibroblast-like cell derived from Chinese hamster lung, and L5178Y is a lymphoid-derived cancer cell. The results are shown in Table 2. From this, it can be seen that (2R3S) -2- (2-nitroimidazol-1-ylmethoxy) -1,3,4-trihydroxybutane) specifically exhibits an excellent sensitizing effect in lung cancer and lymphoma.
本発明は、医薬品の製造に応用できる。 The present invention can be applied to the manufacture of pharmaceutical products.
Claims (7)
（但し、式中Ｒ １ 、Ｒ ２ 、Ｒ ４ はそれぞれ独立に芳香族アシル基を表し、Ｒ ３ は水素原子又はアルキル基を表す。）
（但し、式中Ｒ １ 、Ｒ ２ 、Ｒ ４ はそれぞれ独立に芳香族アシル基を表し、Ｒ ５ は水素原子又はアルキル基を表す。）
（但し、式中Ｒ ６ 、Ｒ ７ 、Ｒ ８ はそれぞれ独立にアルキル基を表す。） A method for producing a 2-nitroimidazole derivative represented by the following structural formula (1), wherein the compound represented by the general formula (2) is reacted with acetic anhydride, and is represented by the general formula (3). And then reacting with the compound represented by the general formula (4), followed by deprotection.
(However, in the formula, R 1 , R 2 and R 4 each independently represents an aromatic acyl group , and R 3 represents a hydrogen atom or an alkyl group.)
(However, in the formula, R 1 , R 2 and R 4 each independently represents an aromatic acyl group , and R 5 represents a hydrogen atom or an alkyl group.)
(However, in the formula, R 6 , R 7 and R 8 each independently represents an alkyl group.)
（但し、式中Ｒ １ 、Ｒ ２ 、Ｒ ４ はそれぞれ独立に芳香族アシル基を表し、Ｒ ３ は水素原子又はアルキル基を表す。） A compound represented by the general formula (2).
(However, in the formula, R 1 , R 2 and R 4 each independently represents an aromatic acyl group , and R 3 represents a hydrogen atom or an alkyl group.)
（但し、式中Ｒ １ 、Ｒ ２ 、Ｒ ４ はそれぞれ独立に芳香族アシル基を表し、Ｒ ５ は水素原子又はアルキル基を表す。） The compound represented by General formula (3).
(However, in the formula, R 1 , R 2 and R 4 each independently represents an aromatic acyl group , and R 5 represents a hydrogen atom or an alkyl group.)
（但し、式中Ｒ ９ 、Ｒ １０ 、Ｒ １２ はそれぞれ独立に芳香族アシル基を表し、Ｒ １１ は水素原子又はアルキル基を表す。）
（但し、式中Ｒ ９ 、Ｒ １０ 、Ｒ １２ はそれぞれ独立に芳香族アシル基を表し、Ｒ １３ は水素原子又はアルキル基を表す。）
（但し、式中Ｒ ６ 、Ｒ ７ 、Ｒ ８ はそれぞれ独立にアルキル基を表す。） A method for producing a 2-nitroimidazole derivative represented by the structural formula (5) shown below, wherein the compound represented by the general formula (6) is reacted with acetic anhydride, and is represented by the general formula (7). the compounds and without, thereafter, a reacted with a compound represented by one general formula (4), wherein the deprotecting thereafter, production method.
(However, R < 9 >, R < 10 >, R < 12 > represents an aromatic acyl group each independently, and R < 11 > represents a hydrogen atom or an alkyl group.)
(However, R < 9 >, R < 10 >, R < 12 > represents an aromatic acyl group each independently, and R < 13 > represents a hydrogen atom or an alkyl group.)
(However, in the formula, R 6 , R 7 and R 8 each independently represents an alkyl group.)
（但し、式中Ｒ ９ 、Ｒ １０ 、Ｒ １２ はそれぞれ独立に芳香族アシル基を表し、Ｒ １１ は水素原子又はアルキル基を表す。） The compound represented by General formula (6).
(However, R < 9 >, R < 10 >, R < 12 > represents an aromatic acyl group each independently, and R < 11 > represents a hydrogen atom or an alkyl group.)
（但し、式中Ｒ ９ 、Ｒ １０ 、Ｒ １２ はそれぞれ独立に芳香族アシル基を表し、Ｒ １３ は水素原子又はアルキル基を表す。） The compound represented by General formula (7).
(However, R < 9 >, R < 10 >, R < 12 > represents an aromatic acyl group each independently, and R < 13 > represents a hydrogen atom or an alkyl group.)
（但し、式中Ｒ １４ はアシルオキシアルキル基を表す。） The compound represented by General formula (8) or (9).
(However, wherein R 14 represents an A sill oxyalkyl group.)
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| KR102241954B1 (en) * | 2020-02-07 | 2021-04-19 | 두산중공업 주식회사 | Apparatus for automatic welding for rectanglar structure |
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| DK0632028T3 (en) * | 1992-12-18 | 2003-07-21 | Pola Chem Ind Inc | Optically active 2-nitroimidazole derivative, process for producing same and intermediate for preparation of same |
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| KR102103529B1 (en) * | 2018-10-04 | 2020-04-22 | 월드시스템주식회사 | protective vinyl attachment device using numerical control |
| KR102241954B1 (en) * | 2020-02-07 | 2021-04-19 | 두산중공업 주식회사 | Apparatus for automatic welding for rectanglar structure |
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