JP3820070B2 - Reactor for previtamin D synthesis - Google Patents

Description

【０００６】
こうしたことから、低転化法では残存する原料（プロビタミンＤ類）を回収再反応することを前提としているので、低転化法での反応の良否は反応で消費されたプロビタミンＤ類に対する生成したプレビタミンＤ類の割合（選択率）で評価されることになる。一方、２段照射法を用いる場合は、タキステロール類をほとんど総てプレビタミンＤ類とする技術が既に知られているので（特開昭６０−２５９６５号公報参照）、プロビタミンＤ類の１段目の光照射においては、プレビタミンＤ類とタキステロール類の合計の収率が重要となる。
【０００７】
ところで、前述した反応装置によりプロビタミンＤ類の光照射を行う際に、プロビタミンＤ類の濃度を上げていくと、プレビタミンＤ類の選択率（低転化法の場合）にしても、プレビタミンＤ類とタキステロール類の合計の収率（２段照射法の場合）にしても、いずれも低下してしまう問題点があることが本発明者の実験により明らかになった。
【０００８】
医薬品の製造おいては、光照射されるプロビタミンＤ類の濃度が高いほど使用溶媒の量を減少できるので、コスト的に有利である。また、使用溶媒の量を減少できると廃棄物の処理といった環境の面でも好ましい。つまり、収率を考慮してプロビタミンＤ類濃度を低く設定せざるを得ないことは、この反応装置の欠点である。
【０００９】
本発明者らは、この反応装置では円周方向の攪拌がないため、ランプに近い側の液の過照射が進んでしまい、これがためにプロビタミンＤ類の濃度を高くできないのではないかと考察した。
【００１０】
円周方向の攪拌を向上する方法としては、流路上に邪魔板を設けて流れを分割し、流路を変更するスタティックミキサーが考えられるが、ほぼ直管部への導入に限られ、パイプ型反応装置への導入は困難である。また、スタティックミキサーを用いて反応装置自体を大幅に変更した場合には、光源に流路を近づけるため、流路を垂直方向に取らざるを得ず、パイプ型の反応装置ほど光の有効利用およびピストンフロー性が確保できない問題がある。
【００１１】
なお、パイプ型の反応管内に石英製の充填物を挿入した反応装置はこれまでに知られていない。
【００１２】
【発明が解決しようとする課題】
上記従来技術の状況のもとに、本発明の目的は、連続反応に適しているパイプ型反応装置のメリットを維持しつつ、医薬品たるビタミンＤ類の製造に適した光反応装置を提供することである。具体的には、従来よりも高い濃度でプロビタミンＤ類を反応させ、従来以上の選択率でプレビタミンＤ類を、または従来以上の収率でプレビタミン類とタキステロール類の混合物を得ることができる反応装置を提供することである。
【００１３】
さらに本発明の目的は、従来以上の選択率でプレビタミンＤ類を製造できる方法、または従来以上の収率でプレビタミン類とタキステロール類の混合物を製造できる方法を提供することである。
【００１４】
【課題を解決するための手段】
上述のように、本発明者らは、従来のパイプ型反応装置を用いた場合、投入するプロビタミンＤ類の濃度を上げていくとプレビタミンＤ類の選択率（低転化法の場合）にしても、プレビタミンＤ類とタキステロール類の合計の収率（２段照射法の場合）にしても、いずれも低下してしまうという問題点があることを知見した。
【００１５】
本発明者らはさらに、従来のパイプ型反応装置においてプロビタミンＤ類の濃度を高くすると選択率や収率が低下する原因として、円周方向の攪拌がないため、ランプに近い側の液の過照射が進んでしまうためと考察した。
【００１６】
そこで、本発明者らはかかる考察に基づいて、円周方向の撹拌を向上させるべく、石英管内に石英充填物を挿入することを検討した。その結果、石英充填物を挿入することで反応装置の容積は低下するものの、石英充填物の効果により光の利用効率はむしろ向上することを見出した。すなわち、同程度のプロビタミンＤの転化率を得るために石英充填物を挿入した反応装置は、挿入していない反応装置以上の流量で送液することが可能であることが判明した。また、石英充填物を挿入することでプレビタミンＤ類の選択率、あるいはプレビタミン類とタキステロール類の合計の収率が向上することも明らかとなった。つまり、処理能力を低下させることなく、従来より高濃度プロビタミンＤ類を投入しても同程度の収率が得られる反応装置を開発するに至った。
【００１７】
すなわち本発明は、螺旋状に巻いた石英管（反応管）の中央部の空間に光源を挿入したパイプ型反応装置において、その石英管内に石英の充填物を有することを特徴とするプロビタミン類からプレビタミンＤ類を製造するための反応装置である。
【００１８】
また、本発明は、かかる反応装置を用い、光を照射させつつプロビタミンＤ類の溶液を送液することにより、プレビタミンＤ類を効率的に製造する方法である。
【００１９】
【発明の実施の形態】
本発明のパイプ型反応装置における反応管たる石英管の太さは、光源のまわりに光源からの距離が離れすぎないように螺旋状に巻くことができる太さであればよい。通常はランプを冷却するための冷却管をランプとパイプ型反応管の間に置くので、その周りにできるだけ接するようにランプの発光部の長さをカバーするように石英管の螺旋が作成できればよい。例えば４５０Ｗ程度の高圧水銀灯であれば、内径が６ｍｍから１０ｍｍ程度が好ましい。また、石英管の肉厚についても、強度、工作性、光照射の効率等を考慮して適宜決定すればよい。
【００２０】
石英管に挿入する石英充填物の形状はビーズ、棒状、不定形等どのようなものでもよい。大きさは化学反応の点からは小さいほど好ましいが、送液に伴い充填物が流出しないようにする必要があり、さらに反応管の圧損を考慮すると１ｍｍ以上のものが好ましい。１ｍｍ以上であれば、単に石英管に括れを作るだけで充填物の飛び出しの抑制が可能である。また、管への充填のしやすさや反応の再現性を考慮すると、形状の揃っている石英ビーズが好ましく、なかでも充填物の作成の容易さ、つまり石英の細工の容易さを考慮すると、３ｍｍ程度のものが特に好ましい。
【００２１】
通常、石英充填物は管一杯につめる。そして、液の出側において管に括れを作るか、あるいはテフロン製のフィルターを取り付ける等により、充填物の流出を防ぐ必要がある。もっとも、低流量の場合には、これらの充填物飛び出し抑制は必ずしも要しない。
【００２２】
光源としては、通常、高圧水銀灯を用い、冷却管を石英管（反応管）との間に置く。この冷却管には必要に応じてフィルター溶液を循環させ、所望の波長の光のみを取り出すようにすることも可能である。
【００２３】
送液量は得るべき転化率、ランプの強度により調整される。送液量が少ない場合にはピストンフロー性を保つため、脈流が少ないポンプを使用することが望ましい。
【００２４】
以下に本発明の反応装置の具体例を示す。
図１は本発明の反応装置の概念図である。主要部分を説明すると、１１はプロビタミンＤ類送液用ポンプ、１２は石英充填物を挿入した石英コイル管、１３は石英充填物止め、１４はランプ冷却管、１５はランプ、１６はプロビタミンＤ類のフィードタンク、１７は反応液のリザーバーである。ランプ冷却管１４に冷却水を流し、ランプ１５を点灯し、フィードタンク１６から送液ポンプ１１によりプロビタミンＤ類の溶液を反応管１２に送液し、リザーバー１７で受けることで光反応を行う。波長を変え２段反応を実施する場合、あるいは処理能力を上げる場合は、石英充填物を挿入した石英コイル管１２、石英充填物止め１３、ランプ冷却管１４、ランプ１５からなるパイプ型反応装置を直列に連結することも可能である。ランプ冷却管には冷却水の他、所望の波長の光源を取り出すために冷却した溶液を循環させることができる。プロビタミンＤ類、プレビタミンＤ類、タキステロール類は酸素、光に敏感な場合が多いので、それらによる分解抑制のためフィードタンク１６およびリザーバー１７は遮光の上、窒素雰囲気下に保っておくことも容易にできる。また、プレビタミンＤ類からビタミンＤ類への熱異性化を防ぐため、フィードタンク１６、リザーバー１７あるいは石英コイル管１２を冷水浴等につけ、液温を低温に保つことも可能である。
【００２５】
なお、図１では石英管（反応管）の断面が円形となっていおり、螺旋の形状も最も単純なものが示されている。これらは本発明の実施のために好ましい形状ではあるが、本発明の目的が達成される範囲での変形である限り、これらの形状に限定されないことは当業者であれば容易に理解できるだろう。
【００２６】
図２は、管内部に石英充填物１８が挿入された石英コイル管の構造を示すものであり、これが円周方向の撹拌を生む。
【００２７】
本発明の反応装置または製造方法において用いられるプロビタミンＤ類は、下記式（Ｉ）
【００２８】
【化４】

【００２９】
［式中、Ｒ¹は水素原子または水酸基の保護基を示し、Ｒ²、Ｒ³およびＲ⁴はそれぞれ独立に、水素原子、水酸基、または保護された水酸基を示す。］
で表される化合物が好ましい。ここで、 Ｒ¹についての「水酸基の保護基」としては、例えばアシル基、トリアルキルシリル基が挙げられるが、本発明の製造方法で行われる反応についての保護基であれば他のものでもよい。同様に、 Ｒ²、Ｒ³およびＲ⁴についての「保護された水酸基」としては、例えばアシル基やトリアルキルシリル基により保護された水酸基が挙げられるが、本発明の製造方法で行われる反応に関して保護された水酸基である限り、他のものでもよい。
【００３０】
【実施例】
［実施例１］
【００３１】
【化５】

【００３２】
１α，３β，２４（Ｓ）−トリヒドロキシコレスタ−５，７−ジエン（１）のＴＨＦ溶液を転化率が９０％程度になるように流量を調整し、８ｍｍφの石英管に５ｍｍφの石英ビーズを詰めた反応管に高圧水銀灯（Ｈａｎｏｖｉａ製）を照射しつつ送液した。液温は１０−２０℃であった。得られた反応液のＨＰＬＣ分析（カラム：ＹＭＣ−ＡＭ３０３、溶離液：アセトニトリル／水＝６／５、流量：１．０ｍｌ／分、検出：２５４ｎｍ、温度：２５℃）を行い、１α，２４（Ｓ）−ジヒドロキシプレビタミンＤ₃（２）と対応するタキステロール（３）の収率を算出した。なお、比較のため石英ビーズを充填しない場合の実験も併せて行った。結果を表１に示す。
【００３３】
【表１】

【００３４】
［実施例２］
【００３５】
【化６】

【００３６】
１α，３β，２４（Ｒ）−トリヒドロキシコレスタ−５，７−ジエン（４）の２．０ｍｍｏｌ／ＬのＴＨＦ溶液を転化率が８０％程度になるように流量を調整し、１０ｍｍφの石英管に粒径の異なる石英ビーズを詰めた反応管に、高圧水銀灯（Ｈａｎｏｖｉａ製４５０Ｗ）を照射しつつ送液した。液温は１０−２０℃であった。得られた反応液のＨＰＬＣ分析（カラム：ＹＭＣ−ＡＭ３０３、溶離液：アセトニトリル／水＝６／５、流量：１．０ｍｌ／分、検出：２５４ｎｍ、温度：３５℃）を行い、１α，２４（Ｒ）−ジヒドロキシプレビタミンＤ₃（５）と対応するタキステロール（６）の収率を算出した。結果を表２に示す。
【００３７】
【表２】

【００３８】
［実施例３］
【００３９】
【化７】

【００４０】
１α，３β，２４（Ｒ）−トリヒドロキシコレスタ−５，７−ジエン（４）のＴＨＦ溶液を転化率が８５％程度になるように流量を調整し、８ｍｍφの石英管に５ｍｍφの石英ビーズまたは１ｍｍφの石英棒を１ｍｍに切ったもの（石英チップ）を充填した反応管に、高圧水銀灯（Ｈａｎｏｖｉａ製）を照射しつつ送液した。液温は１０−２０℃であった。得られた反応液のＨＰＬＣ分析（カラム：ＹＭＣ−ＡＭ３０３、溶離液：アセトニトリル／水＝６／５、流量：１．０ｍｌ／分、検出：２５４ｎｍ、温度：３５℃）を行い、１α，２４（Ｒ）−ジヒドロキシプレビタミンＤ₃（５）と対応するタキステロール（６）の収率を算出した。結果を表３に示す。
【００４１】
【表３】

【００４２】
［実施例４］
【００４３】
【化８】

【００４４】
１α，３β−ジエトキシカルボニルオキシコレスタ−５，７−ジエン（７）のトルエン溶液を転化率が２０％程度になるように流量を調整し、８ｍｍφの石英管に３ｍｍφの石英ビーズを充填した反応管に、高圧水銀灯（Ｈａｎｏｖｉａ製２００Ｗ）を照射しつつ送液した。液温は１０−２０℃であった。得られた反応液のＨＰＬＣ分析（カラム：ＤＥＶＥＬＯＳＩＬ ＯＤＳ Ａ−５、溶離液：アセトニトリル／水＝９５／５、流量：１．０ｍｌ／分、検出：２５４ｎｍ、温度：３５℃）を行い、（７）の転化率および１α−エトキシカルボニルオキシプレビタミンＤ₃ エトキシカルボニルエステル（８）の選択率（消費された（７）に対する（８）の収率の割合）を算出した。なお、比較のため石英ビーズを充填しない場合の実験も併せて行った。結果を表４に示す。
【００４５】
【表４】

【００４６】
【発明の効果】
本発明の反応装置または製造方法によれば、連続式でプレビタミンを製造する場合、低転化法においては従来以上の選択率でプレビタミンＤ類を得ることができる。また、２段照射法においては従来以上の収率でプレビタミン類とタキステロール類の混合物を得ることができる。したがって、光照射されるプロビタミンＤ類の濃度をその分高くすることができる。
【図面の簡単な説明】
【図１】本発明のプレビタミン類合成用反応装置の概念図を示す。
【図２】本発明のプレビタミン類合成用反応装置の石英管（反応管）部分を示す。
【図３】一般的なパイプ型反応装置の説明図である。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a reaction apparatus for producing vitamin D useful as a pharmaceutical product, and a production method using the same. More specifically, the present invention relates to a reactor used for synthesizing previtamins by light irradiation of provitamin Ds useful as a method for producing vitamin Ds, and a method for producing previtamins using the same.
[0002]
[Prior art]
The synthesis method of obtaining vitamin D by irradiating provitamin D with light to obtain previtamin D and then performing thermal isomerization of the previtamin D is one of the most reliable methods for synthesizing vitamin D One. When this method is applied to the manufacture of pharmaceuticals, a method of performing light irradiation while feeding a raw material solution (continuous type), a method of performing light irradiation without feeding a raw material solution (batch type), However, the former is preferable from the viewpoint of efficiency.
[0003]
As a continuous photoreaction apparatus, a reaction apparatus (pipe-type reaction apparatus) in which a quartz tube is spirally wound around a lamp is often used because of its excellent light utilization efficiency. This reactor also has the merit that the scale of the reaction can be easily changed by changing the output of the lamp or changing the number of reactors connected in series. It is a very useful reactor for photoreactions whose rate is said to vary (see FIG. 3). In addition, this reactor has an advantage of good piston flow and is less prone to over-irradiation due to residence.
[0004]
By the way, it is known that previtamin D obtained by light irradiation of a provitamin D with a high-pressure mercury lamp further absorbs light and changes to luminosterols, taxolols and the like. Therefore, in order to obtain previtamin D with a high yield, the previtamin D further stops the reaction before absorbing light (the conversion rate of provitamin D is kept low: a low conversion method), or once It is generally carried out to cause isomerization from a taxosterol to a previtamin D by irradiating the taxosterols generated by light irradiation with light having a shorter wavelength cut (two-stage irradiation method) ( (See the following formula).
[0005]
[Chemical 3]

[0006]
For this reason, the low conversion method is based on the premise that the remaining raw materials (provitamin Ds) are recovered and re-reacted. Therefore, the quality of the reaction in the low conversion method is generated for the provitamin Ds consumed in the reaction. It will be evaluated by the ratio (selectivity) of previtamin Ds. On the other hand, in the case of using the two-stage irradiation method, since the technology for almost all the taxosterols to be previtamin D is already known (see JP-A-60-25965), 1 of provitamin D In the light irradiation at the stage, the total yield of previtamin Ds and taxols is important.
[0007]
By the way, when provitamin Ds are irradiated with the above-mentioned reaction apparatus, if the concentration of provitamins D is increased, the previtamin Ds can be selected even if the previtamin Ds are selected (in the case of a low conversion method). The inventors' experiments have revealed that there is a problem that both the yields of vitamin Ds and taxols (in the case of the two-stage irradiation method) decrease.
[0008]
In the manufacture of pharmaceutical products, the higher the concentration of provitamin D irradiated with light, the more the amount of solvent used can be reduced, which is advantageous in terms of cost. Further, if the amount of the solvent used can be reduced, it is preferable from the viewpoint of environment such as waste disposal. That is, it is a drawback of this reactor that the concentration of provitamin Ds must be set low in consideration of the yield.
[0009]
The present inventors consider that in this reactor, there is no circumferential stirring, so that over-irradiation of the liquid on the side close to the lamp proceeds, which may not increase the concentration of provitamin Ds. did.
[0010]
As a method for improving the circumferential stirring, a static mixer can be considered in which a baffle plate is provided on the flow path to divide the flow and the flow path is changed. Introduction to the reactor is difficult. In addition, when the reactor itself is significantly changed using a static mixer, the flow path is brought closer to the light source, so the flow path must be taken in the vertical direction. There is a problem that piston flowability cannot be secured.
[0011]
A reaction apparatus in which a quartz packing is inserted into a pipe-type reaction tube has not been known so far.
[0012]
[Problems to be solved by the invention]
Under the circumstances of the above prior art, an object of the present invention is to provide a photoreaction apparatus suitable for the production of vitamin D as a pharmaceutical product while maintaining the merits of a pipe-type reaction apparatus suitable for continuous reaction. It is. Specifically, provitamin D is reacted at a higher concentration than before, and previtamin D is obtained at a selectivity higher than conventional, or a mixture of previtamin and taxosterol is obtained at a higher yield than conventional. It is providing the reaction apparatus which can do.
[0013]
Furthermore, the object of the present invention is to provide a method capable of producing previtamin Ds with a selectivity higher than conventional or a method capable of producing a mixture of previtamins and taxols in a yield higher than conventional.
[0014]
[Means for Solving the Problems]
As described above, the present inventors, when using a conventional pipe reactor, increase the selectivity of previtamin D (in the case of a low conversion method) by increasing the concentration of provitamin D to be added. However, even if it was the total yield (in the case of a two-stage irradiation method) of previtamin Ds and taxols, it was found that there was a problem that both were reduced.
[0015]
Furthermore, the inventors of the conventional pipe-type reactor increase the concentration of provitamin Ds as a cause of the decrease in selectivity and yield, because there is no circumferential stirring, so the liquid on the side closer to the lamp It was considered that over-irradiation would progress.
[0016]
Therefore, the present inventors have examined insertion of a quartz filler into a quartz tube in order to improve circumferential stirring based on such consideration. As a result, it was found that although the volume of the reaction apparatus is reduced by inserting the quartz packing, the light utilization efficiency is rather improved due to the effect of the quartz packing. That is, it has been found that a reaction apparatus in which a quartz packing is inserted in order to obtain the same conversion rate of provitamin D can be fed at a flow rate higher than that of a reaction apparatus in which no quartz vitamin is inserted. It was also found that the insertion of quartz fillers improves the previtamin D selectivity or the total yield of previtamins and taxols. That is, it has led to the development of a reactor capable of obtaining a similar yield even when a high-concentration provitamin D is introduced conventionally without reducing the processing capacity.
[0017]
That is, the present invention relates to a provitamin characterized in that in a pipe-type reactor in which a light source is inserted into a space in the center of a spirally wound quartz tube (reaction tube), the quartz tube has a quartz filling. Is a reactor for producing previtamin D from
[0018]
In addition, the present invention is a method for efficiently producing previtamin D by using such a reaction apparatus and feeding a solution of provitamin D while irradiating light.
[0019]
DETAILED DESCRIPTION OF THE INVENTION
The thickness of the quartz tube as the reaction tube in the pipe type reactor of the present invention may be any thickness that can be spirally wound around the light source so that the distance from the light source is not too far away. Normally, a cooling tube for cooling the lamp is placed between the lamp and the pipe-type reaction tube, so it is only necessary to create a spiral of the quartz tube so as to cover the length of the light emitting part of the lamp so as to contact as much as possible around it. . For example, in the case of a high pressure mercury lamp of about 450 W, the inner diameter is preferably about 6 mm to 10 mm. Further, the thickness of the quartz tube may be appropriately determined in consideration of strength, workability, light irradiation efficiency, and the like.
[0020]
The shape of the quartz filler to be inserted into the quartz tube may be any shape such as beads, rods, and irregular shapes. The size is preferably as small as possible from the point of chemical reaction, but it is necessary to prevent the packing from flowing out as the liquid is fed. If it is 1 mm or more, it is possible to suppress the popping out of the filler by simply forming a constriction in the quartz tube. Also, considering the ease of filling into the tube and the reproducibility of the reaction, quartz beads having a uniform shape are preferable, and in particular, considering the ease of creating a packing material, that is, the ease of quartz work, 3 mm A thing of a grade is especially preferable.
[0021]
Usually, the quartz filling is filled into a tube. Then, it is necessary to prevent the filling material from flowing out by, for example, forming a constriction on the tube on the outlet side of the liquid or attaching a Teflon filter. However, in the case of a low flow rate, it is not always necessary to suppress these packing pop-outs.
[0022]
As the light source, a high-pressure mercury lamp is usually used, and a cooling tube is placed between the quartz tube (reaction tube). It is also possible to circulate the filter solution in the cooling pipe as necessary to extract only light having a desired wavelength.
[0023]
The amount of liquid fed is adjusted by the conversion rate to be obtained and the intensity of the lamp. When the amount of liquid to be fed is small, it is desirable to use a pump with a small pulsating flow in order to keep the piston flow.
[0024]
Specific examples of the reaction apparatus of the present invention are shown below.
FIG. 1 is a conceptual diagram of the reaction apparatus of the present invention. The main parts are explained as follows: 11 is a pump for feeding provitamin Ds, 12 is a quartz coil tube with a quartz filler inserted therein, 13 is a quartz filler stopper, 14 is a lamp cooling tube, 15 is a lamp, 16 is a provitamin A D type feed tank, 17 is a reservoir for the reaction solution. Cooling water is supplied to the lamp cooling tube 14, the lamp 15 is turned on, and a solution of provitamin Ds is fed from the feed tank 16 to the reaction tube 12 by the liquid feeding pump 11 and received by the reservoir 17 to perform a photoreaction. . When carrying out a two-stage reaction by changing the wavelength or increasing the processing capacity, a pipe type reactor comprising a quartz coil tube 12, quartz filler stopper 13, lamp cooling tube 14, and lamp 15 inserted with a quartz filler is used. It is also possible to connect in series. In addition to cooling water, a cooled solution can be circulated in the lamp cooling tube to extract a light source having a desired wavelength. Provitamin Ds, pre-vitamin Ds and taxols are often sensitive to oxygen and light, so the feed tank 16 and the reservoir 17 should be kept in a nitrogen atmosphere with light shielding in order to suppress decomposition by them. Can also be easily done. In order to prevent thermal isomerization from pre-vitamin D to vitamin D, the feed tank 16, reservoir 17 or quartz coil tube 12 can be attached to a cold water bath or the like to keep the liquid temperature low.
[0025]
In FIG. 1, the quartz tube (reaction tube) has a circular cross section, and the simplest spiral shape is shown. Although these are preferred shapes for carrying out the present invention, those skilled in the art will readily understand that they are not limited to these shapes as long as they are variations within the scope of achieving the object of the present invention. .
[0026]
FIG. 2 shows the structure of a quartz coil tube with a quartz filler 18 inserted inside the tube, which produces circumferential agitation.
[0027]
The provitamin Ds used in the reaction apparatus or production method of the present invention are represented by the following formula (I)
[0028]
[Formula 4]

[0029]
[Wherein, R ¹ represents a hydrogen atom or a hydroxyl protecting group, and R ² , R ³ and R ⁴ each independently represents a hydrogen atom, a hydroxyl group or a protected hydroxyl group. ]
The compound represented by these is preferable. Here, examples of the “hydroxyl-protecting group” for R ¹ include an acyl group and a trialkylsilyl group, but other groups may be used as long as they are protective groups for the reaction performed in the production method of the present invention. . Similarly, as the “protected hydroxyl group” for R ² , R ³ and R ⁴ , for example, a hydroxyl group protected by an acyl group or a trialkylsilyl group can be mentioned. Regarding the reaction carried out in the production method of the present invention, Others may be used as long as they are protected hydroxyl groups.
[0030]
【Example】
[Example 1]
[0031]
[Chemical formula 5]

[0032]
The flow rate of THF solution of 1α, 3β, 24 (S) -trihydroxycholesta-5,7-diene (1) was adjusted so that the conversion was about 90%, and 5 mmφ quartz beads were placed in an 8 mmφ quartz tube. The reaction tube packed with was fed while irradiating with a high-pressure mercury lamp (manufactured by Hanovia). The liquid temperature was 10-20 ° C. The obtained reaction solution was subjected to HPLC analysis (column: YMC-AM303, eluent: acetonitrile / water = 6/5, flow rate: 1.0 ml / min, detection: 254 nm, temperature: 25 ° C.), and 1α, 24 ( The yield of S) -dihydroxy previtamin D ₃ (2) and the corresponding taxolol (3) was calculated. For comparison, an experiment in which the quartz beads were not filled was also performed. The results are shown in Table 1.
[0033]
[Table 1]

[0034]
[Example 2]
[0035]
[Chemical 6]

[0036]
The flow rate of a 2.0 mmol / L THF solution of 1α, 3β, 24 (R) -trihydroxycholesta-5,7-diene (4) was adjusted so that the conversion was about 80%, and 10 mmφ quartz Liquid was fed into a reaction tube in which quartz beads having different particle diameters were packed in a tube while being irradiated with a high-pressure mercury lamp (450 W manufactured by Hanovia). The liquid temperature was 10-20 ° C. The obtained reaction solution was subjected to HPLC analysis (column: YMC-AM303, eluent: acetonitrile / water = 6/5, flow rate: 1.0 ml / min, detection: 254 nm, temperature: 35 ° C.), and 1α, 24 ( The yield of R) -dihydroxy previtamin D ₃ (5) and the corresponding taxolol (6) was calculated. The results are shown in Table 2.
[0037]
[Table 2]

[0038]
[Example 3]
[0039]
[Chemical 7]

[0040]
The flow rate of THF solution of 1α, 3β, 24 (R) -trihydroxycholesta-5,7-diene (4) was adjusted so that the conversion was about 85%, and 5 mmφ quartz beads were placed in an 8 mmφ quartz tube. Alternatively, the solution was fed to a reaction tube filled with a 1 mmφ quartz rod cut into 1 mm (quartz chip) while irradiating a high-pressure mercury lamp (manufactured by Hanovia). The liquid temperature was 10-20 ° C. The obtained reaction solution was subjected to HPLC analysis (column: YMC-AM303, eluent: acetonitrile / water = 6/5, flow rate: 1.0 ml / min, detection: 254 nm, temperature: 35 ° C.), and 1α, 24 ( The yield of R) -dihydroxy previtamin D ₃ (5) and the corresponding taxolol (6) was calculated. The results are shown in Table 3.
[0041]
[Table 3]

[0042]
[Example 4]
[0043]
[Chemical 8]

[0044]
The flow rate of a toluene solution of 1α, 3β-diethoxycarbonyloxycholesta-5,7-diene (7) was adjusted so that the conversion was about 20%, and 3 mmφ quartz beads were filled in an 8 mmφ quartz tube. The reaction tube was fed while being irradiated with a high-pressure mercury lamp (200 W manufactured by Hanovia). The liquid temperature was 10-20 ° C. HPLC analysis of the resulting reaction solution (column: DEVELOSIL ODS A-5, eluent: acetonitrile / water = 95/5, flow rate: 1.0 ml / min, detection: 254 nm, temperature: 35 ° C.) was carried out (7 ) And 1α-ethoxycarbonyloxyprevitamin D ₃ ethoxycarbonyl ester (8) selectivity (ratio of yield of (8) to consumed (7)). For comparison, an experiment in which the quartz beads were not filled was also performed. The results are shown in Table 4.
[0045]
[Table 4]

[0046]
【The invention's effect】
According to the reaction apparatus or production method of the present invention, when previtamin is produced in a continuous manner, previtamin D can be obtained with a selectivity higher than that in the conventional conversion method. In addition, in the two-stage irradiation method, a mixture of previtamins and taxosterols can be obtained with a yield higher than conventional. Therefore, the concentration of provitamin Ds irradiated with light can be increased accordingly.
[Brief description of the drawings]
FIG. 1 shows a conceptual diagram of a previtamin synthesis reactor according to the present invention.
FIG. 2 shows a quartz tube (reaction tube) portion of the previtamin synthesis reactor according to the present invention.
FIG. 3 is an explanatory diagram of a general pipe reactor.

Claims (6)

A pre-vitamin is produced from provitamins, characterized in that in a pipe-type reactor in which a light source is inserted into the central space of a spirally wound quartz tube, the quartz tube has a quartz filling. Reactor for. Provitamin Ds are represented by the following formula (I)

[Wherein, R ¹ represents a hydrogen atom or a hydroxyl protecting group, and R ² , R ³ and R ⁴ each independently represents a hydrogen atom, a hydroxyl group or a protected hydroxyl group. ]
The reaction apparatus according to claim 1, which is a compound represented by the formula: The reaction apparatus according to claim 1 or 2, wherein the spirally wound quartz tube has an inner diameter of 6 to 10 mm, and the quartz packing is beads having a diameter of 1 to 5 mm. A method for producing previtamin D, wherein the solution of provitamin D is fed using the reaction apparatus according to claim 1 while irradiating light from a light source. Provitamin Ds are represented by the following formula (I)

[Wherein, R ¹ represents a hydrogen atom or a protecting group for a hydroxyl group, and R ² , R ³ and R ⁴ each independently represents a hydrogen atom, a hydroxyl group or a protected hydroxyl group. ]
The method for producing previtamin D according to claim 4, wherein the compound is represented by the formula: The method for producing previtamin D according to claim 4 or 5, wherein the spirally wound quartz tube has an inner diameter of 6 to 10 mm, and the quartz filler is a bead having a diameter of 1 to 5 mm.

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