JP4412279B2 - Process for producing optically active α-amino nitrile compound - Google Patents

Description

  The present invention relates to a process for producing an optically active α-amino nitrile compound. In particular, the present invention relates to a method for producing a biotin synthesis intermediate which is an optically active α-amino nitrile compound and a biotin production method using the intermediate production method.

で示されるチエノイミダゾール化合物を合成中間体として用いる製法（ケミカル・レビューズ（Ｃｈｅｍｉｃａｌ Ｒｅｖｉｅｗｓ），９７巻，６号，１７５５−１７９２頁，１９９７年、特公昭４９−３２５５１号、特公昭５３−２７２７９号、特公平３−６６３１２号、特公平５−９０６４号）等が知られている。
しかしながら、これら公知のビオチン製法は、その製造工程が長く、また、その途中の工程で煩雑な光学分割を要するというような欠点がある。The optically active α-amino nitrile compound is useful as a synthetic intermediate for pharmaceuticals and optically active α-amino acids.
U.S. Pat. No. 2,164,781, JP-A-50-94122, JP-A-50-101526, West German Patent Publication No. 157909, West German Patent Publication No. 157910, US Patent Publication No. 5,268,498 Chemical Reviews, Vol. 42, p. 189-283, 1948, Russian Chemical Reviews, Vol. 58, No. 2, p. 148-162, 1989, etc. After making an aldehyde compound into a bisulfite adduct, there is a disclosure of a process for producing an α-amino nitrile compound by reacting an amine compound and a cyano compound.
Regarding the production method of optically active α-amino nitrile compounds, Journal of Organic Chemistry [Vol. 48, 5369-5373, 1983] includes aldehyde compounds, optically active amine compounds and cyanides. JP-A-2001-89434 discloses a production method using an aldehyde compound, an amine compound, a cyanide, and an optically active binaphthol compound as an asymmetric catalyst. Furthermore, Japanese Patent Application Laid-Open No. 11-25381 discloses a method for producing an optically active α-amino nitrile compound using an imine compound and Japanese Patent Application Laid-Open No. 11-189578 as an oxime ester compound.
However, the α carbon of the aldehyde compound, which is the raw material compound, is an asymmetric carbon, and a method for introducing an asymmetric center at the carbonyl carbon position while maintaining the absolute configuration of this asymmetric center has been found up to now. Not.
In addition, biotin is a vitamin useful as a feed additive, a pharmaceutical, and the like.

(Chemical Reviews, 97, 6, 1755-1792, 1997, Japanese Patent Publication No. 49-32551, Japanese Patent Publication No. 53-27279) No. 3-66312 and No. 5-9064) are known.
However, these known biotin production methods have a drawback that the production process is long and complicated optical resolution is required in the middle of the process.

式中、Ｒ^５は、水素原子、ベンゼン環上に置換基を有していてもよいベンジル基、ベンゼン環上に置換基を有していてもよいベンズヒドリル基、又はベンゼン環上に置換基を有していてもよいトリチル基を表す、
で示される光学活性なアルデヒド化合物を原料化合物として用いる、一般式（ＩＶ−ａ）：

式中、Ｒ^３１は、ベンゼン環上に置換基を有していてもよいベンジル基、ベンゼン環上に置換基を有していてもよいベンズヒドリル基、又はベンゼン環上に置換基を有していてもよいトリチル基を表し、Ｒ^５は、前記と同一意味を表す、
で示される光学活性α−アミノニトリルであるビオチン合成中間体の工業的に有利な製造方法及び当該中間体を用いたビオチンの製造方法を提供することにある。
課題を解決するために本発明者等は鋭意研究の結果、α位に不斉炭素を有する光学活性アルデヒド化合物を原料化合物として用い、当該アルデヒド化合物の重亜硫酸付加体を経由し、置換基を有するアミン化合物及びシアン化物を用いる製法が、当該アルデヒド化合物のα炭素の絶対配置を維持しながら医薬品やアミノ酸等の合成中間体として用いられる光学活性α−アミノニトリル化合物の工業的に優れた製法であることを見出して本発明を完成した。
すなわち、本発明は、α位に不斉炭素を有する光学活性アルデヒド化合物又はその塩を、含水溶媒中、重亜硫酸化物と反応させて、当該アルデヒド化合物の重亜硫酸付加体を得る工程、得られた重亜硫酸付加体に、置換基を有する一級アミン化合物若しくは二級アミン化合物及びシアン化物を反応させる工程を含む、光学活性α−アミノニトリル化合物又はその塩の製法に関する。
さらに本発明は、ビオチン製造において、上記方法を用いて光学活性アルデヒド化合物（ＩＩＩ）から化合物（ＩＶ−ａ）を合成中間体として経由する製法が、工業的に優れた製法であることを見出して本発明を完成した。
すなわち、本発明は、一般式（ＩＩＩ−ａ）：

式中、記号は前記と同一意味を有する、
で示される化合物又はその塩を、含水溶媒中、重亜硫酸化物と反応させて、化合物（ＩＩＩ−ａ）の重亜硫酸付加体を得る工程、得られた重亜硫酸付加体に、一般式（ＩＩ−ａ）：

式中、記号は前記と同一意味を表す、
で示される化合物とシアン化物を反応させる工程を含む、一般式（ＩＶ−ｂ）：

式中、記号は前記と同一意味を表す、
で示される化合物又はその塩の製法に関する。
また、本発明は、一般式（ＩＩＩ−ａ）：

式中、記号は前記と同一意味を有する、
で示される化合物又はその塩を、含水溶媒中、重亜硫酸化物と反応させて、化合物（ＩＩＩ−ａ）の重亜硫酸付加体を得る工程、得られた重亜硫酸付加体に、一般式（ＩＩ−ａ）：

式中、記号は前記と同一意味を表す、
で示される化合物とシアン化物を反応させる工程を含む、一般式（ＩＶ−ｃ）：

式中、記号は前記と同一意味を表す、
で示される化合物又はその塩の製法に関する。
さらに、本発明は、上記の方法により、一般式（ＩＶ−ｂ）：

式中、記号は前記と同一意味を表す、
で示される化合物又はその塩を製し、得られた化合物（ＩＶ−ｂ）を加水分解し、一般式（Ｖ）：

式中、記号は前記と同一意味を表す、
で示される化合物又はその塩を製し、次いで得られた化合物（Ｖ）を環変換し、一般式（ＶＩ）：

式中、記号は前記と同一意味を表す、
で示される化合物又はその塩を製し、さらに得られた化合物（ＶＩ）を加水分解し、一般式（ＶＩＩ）：

式中、記号は前記と同一意味を表す、
で示される化合物又はその塩を製し、次いで得られた化合物（ＶＩＩ）を環化及びエピ化し、一般式（ＶＩＩＩ）：

式中、記号は前記と同一意味を表す、
で示される化合物を製し、次いで得られた化合物（ＶＩＩＩ）に、一般式（ＩＸ）：

式中、Ｘ^１はハロゲン原子、Ｒ^６はエステル化されたカルボキシル基又はアミド化されたカルボキシル基を表す、
で示される化合物を反応させ、一般式（Ｘ）：

式中、記号は前記と同一意味を表す、
で示される化合物又はその塩を得、次いで得られた化合物（Ｘ）を、還元し、必要であれば加水分解し、さらに必要であればＲ^３１及び／又はＲ^５を水素原子へ変換することを特徴とする、式（ＸＩ）：

で示される化合物の製法に関する。The present invention is to provide a method for efficiently producing an optically active α-amino nitrile compound.
The present invention also provides a compound represented by the general formula (III):

In the formula, R ⁵ represents a hydrogen atom, a benzyl group which may have a substituent on the benzene ring, a benzhydryl group which may have a substituent on the benzene ring, or a substituent on the benzene ring. Represents a trityl group which may have,
A general formula (IV-a) using an optically active aldehyde compound represented by the formula:

In the formula, R ³¹ has a benzyl group which may have a substituent on the benzene ring, a benzhydryl group which may have a substituent on the benzene ring, or a substituent on the benzene ring. Represents an optional trityl group, and R ⁵ represents the same meaning as described above.
An industrially advantageous method for producing a biotin synthesis intermediate which is an optically active α-amino nitrile represented by formula (1) and a method for producing biotin using the intermediate.
In order to solve the problem, the present inventors, as a result of earnest research, use an optically active aldehyde compound having an asymmetric carbon at the α-position as a raw material compound, and have a substituent via a bisulfite adduct of the aldehyde compound. The production method using an amine compound and a cyanide is an industrially excellent production method of an optically active α-amino nitrile compound used as a synthetic intermediate for pharmaceuticals and amino acids while maintaining the absolute configuration of the α carbon of the aldehyde compound. As a result, the present invention was completed.
That is, the present invention was obtained by reacting an optically active aldehyde compound having an asymmetric carbon at the α-position or a salt thereof with bisulfite in a hydrous solvent to obtain a bisulfite adduct of the aldehyde compound. The present invention relates to a process for producing an optically active α-amino nitrile compound or a salt thereof, which comprises reacting a bisulfite adduct with a primary amine compound or secondary amine compound having a substituent and a cyanide.
Furthermore, the present invention has found that in the production of biotin, the production method using compound (IV-a) from optically active aldehyde compound (III) as a synthetic intermediate using the above method is an industrially excellent production method. The present invention has been completed.
That is, the present invention relates to the general formula (III-a):

Wherein the symbols have the same meaning as above.
Or a salt thereof in a water-containing solvent to react with bisulfite oxide to obtain a bisulfite adduct of compound (III-a). The resulting bisulfite adduct is converted to the general formula (II- a):

In the formula, the symbols have the same meaning as described above.
Comprising a step of reacting a compound represented by formula (I) with cyanide:

In the formula, the symbols have the same meaning as described above.
To a method for producing a compound represented by the formula:
The present invention also provides a compound represented by the general formula (III-a):

Wherein the symbols have the same meaning as above.
Or a salt thereof in a water-containing solvent to react with bisulfite oxide to obtain a bisulfite adduct of compound (III-a). The resulting bisulfite adduct is converted to the general formula (II- a):

In the formula, the symbols have the same meaning as described above.
Comprising a step of reacting a compound represented by formula (I) with cyanide:

In the formula, the symbols have the same meaning as described above.
To a method for producing a compound represented by the formula:
Furthermore, the present invention provides a compound of the general formula (IV-b):

In the formula, the symbols have the same meaning as described above.
Or a salt thereof, and the resulting compound (IV-b) is hydrolyzed to give a general formula (V):

In the formula, the symbols have the same meaning as described above.
Or a salt thereof, and then the obtained compound (V) is subjected to ring transformation to give a compound represented by the general formula (VI):

In the formula, the symbols have the same meaning as described above.
Or a salt thereof, and the obtained compound (VI) is hydrolyzed to give a compound represented by the general formula (VII):

In the formula, the symbols have the same meaning as described above.
Or a salt thereof, and then the obtained compound (VII) is cyclized and epimerized to obtain a compound represented by the general formula (VIII):

In the formula, the symbols have the same meaning as described above.
Then, the compound (VIII) thus obtained is converted into the general formula (IX):

In the formula, X ¹ represents a halogen atom, R ⁶ represents an esterified carboxyl group or an amidated carboxyl group,
And a compound represented by the general formula (X):

In the formula, the symbols have the same meaning as described above.
Or a salt thereof obtained, and then reducing the obtained compound (X), hydrolyzing if necessary, and further converting R ³¹ and / or R ⁵ to a hydrogen atom if necessary. Formula (XI), characterized by:

It relates to a process for producing a compound represented by

式中、Ｒ^３は、置換基を有していてもよいアルキル基、置換基を有していてもよいアルコキシ基、置換基を有していてもよいアルケニル基、又は置換基を有していてもよいアリール基を表し、Ｒ^４は、水素原子、置換基を有していてもよいアルキル基、置換基を有していてもよいアルコキシ基、置換基を有していてもよいアルケニル基、又は置換基を有していてもよいアリール基を表す、
で示される化合物が挙げられる。このうち一級アミン化合物が好ましく、特に、化合物（ＩＩ）のＲ^３が、ベンゼン環上に置換基を有していてもよいベンジル基、ベンゼン環上に置換基を有していてもよいベンズヒドリル基、又はベンゼン環上に置換基を有していてもよいトリチル基であり、Ｒ^４が水素原子である化合物（ＩＩ−ａ）が好ましい。
シアン化物としては、水により大きな影響を受けないものであればよく、シアン化を行う際に通常用いられる化合物であり、例えば、青酸、シアン化アルカリ金属または有機シアニド等が挙げられ、このうちシアン化アルカリ金属が好ましい。シアン化アルカリ金属化合物としては、例えば、シアン化リチウム、シアン化カリウム、シアン化ナトリウム等が挙げられ、有機シアニドとしては、例えば、トリブチルチンシアニド、ジメチルアルミニウムシアニド、テトラエチルアンモニウムシアニド、ジエチルホルホニルシアニド等が挙げられる。
また、本発明の製法は、β位に不斉炭素を有する光学活性アルコール化合物から、α位に不斉炭素を有するアルデヒド化合物を得た後に行うという連続工程でも用いることができる。当該光学活性アルコール化合物から光学活性アルデヒド化合物を得る工程は、後述するような常法により行うことができる。
本発明において用いられる、或いは得られる光学活性α−アミノニトリル化合物としては、α位及びβ位に不斉中心を有していればよく、例えば、化合物（ＩＶ）が挙げられる。このような光学活性α−アミノニトリル化合物のうち、ビオチン合成中間体としては、化合物（ＩＶ−ａ）が挙げられ、このうち、化合物（ＩＶ−ｂ）が好ましい。
本発明に用いられるα位に不斉炭素を有する光学活性アルデヒド化合物としては、当該アルデヒド化合物の重亜硫酸付加体になった場合に水溶性のものであって、例えば、一般式（Ｉ）：

式中、Ｒ^１及びＲ^２は、異なって、置換基を有していてもよいアルキル基、置換基を有していてもよいアルコキシ基、置換基を有していてもよいアルケニル基、置換基を有していてもよいアリール基、置換基を有していてもよいアミノ基、置換基を有していてもよい複素環式基、シアノ基、カルボキシル基、又は置換基を有していてもよいカルバモイル基を表すか、或いは、Ｒ^１及びＲ^２は末端で互いに結合して隣接する不斉炭素原子とともに置換基を有していてもよい複素環式基を形成している基を表す、
で示される化合物が挙げられる。このようなα位に不斉炭素を有する光学活性アルデヒド化合物（Ｉ）のうち、ビオチン合成中間体としては、化合物（ＩＩＩ）が挙げられ、このうち、化合物（ＩＩＩ−ａ）が好ましい。
本発明の製法のうち、好ましい組み合わせとしては、α位に不斉炭素を有する光学活性アルデヒド化合物が化合物（Ｉ）であり、置換基を有する一級アミン化合物若しくは二級アミン化合物が化合物（ＩＩ）であり、光学活性α−アミノニトリル化合物が一般式（ＩＶ）：

式中、Ｒ^３は、置換基を有していてもよいアルキル基、置換基を有していてもよいアルコキシ基、置換基を有していてもよいアルケニル基、又は置換基を有していてもよいアリール基を表し、Ｒ^４は、水素原子、置換基を有していてもよいアルキル基、置換基を有していてもよいアルコキシ基、置換基を有していてもよいアルケニル基、又は置換基を有していてもよいアリール基を表し、他の記号は前記と同一意味を表す、
で示される化合物であるものが挙げられる。このうち、さらに好ましい組み合わせとしては、α位に不斉炭素を有する光学活性アルデヒド化合物が化合物（ＩＩＩ）であり、置換基を有する一級アミン化合物若しくは二級アミン化合物が化合物（ＩＩ−ａ）であり、光学活性α−アミノニトリル化合物が化合物（ＩＶ−ａ）であるものが挙げられ、特に好ましい組み合わせとしては、α位に不斉炭素を有する光学活性アルデヒド化合物が化合物（ＩＩＩ−ａ）であり、置換基を有する一級アミン化合物若しくは二級アミン化合物が化合物（ＩＩ−ａ）であり、光学活性α−アミノニトリル化合物が化合物（ＩＶ−ｂ）であるものが挙げられる。これら好ましい組み合わせにおいて、重亜硫酸化物がアルカリ金属重亜硫酸塩、シアン化物がシアン化アルカリ金属のものが好適に用いられる。
本発明により得られた化合物（ＩＶ）及び化合物（ＩＶ−ａ）のシアノ基をアミド化する工程並びに本発明により得られた化合物（ＩＶ−ｂ）から化合物（Ｖ）を得る工程は、対応するシアノ化合物を酸の存在下、溶媒中又は無溶媒中で反応させ、さらに塩基で中和することにより行うことができる。酸としては、塩酸、硫酸、リン酸、メタンスルホン酸等を好適に用いることができる。塩基としては、アンモニア、モノメチルアミン、ジメチルアミン、水酸化ナトリウム、炭酸水素ナトリウム、炭酸ナトリウム、水酸化カリウム、炭酸水素カリウム、炭酸カリウム、リン酸カリウム、リン酸水素二カリウム等を好適にもちいることができる。溶媒としては、反応に悪影響を及ぼさない溶媒であればよく、例えば、トルエン、ジクロロメタン、テトラヒドロフラン、Ｎ，Ｎ−ジメチルホルムアミド、１，４−ジオキサン、メチルエチルケトン、アセトン、クロロホルム、１，２−ジクロロエタン、キシレン、メシチレン、ｔｅｒｔ−ブチルメチルエーテル等が挙げられる。本反応は、０℃〜１００℃、とりわけ３０℃〜５０℃で好適に進行する。
また、本発明により得られた化合物（ＩＶ）及び化合物（ＩＶ−ａ）のシアノ基をアミド化する工程並びに本発明により得られた化合物（ＩＶ−ｂ）から化合物（Ｖ）を得る工程は、シンセシス（Ｓｙｎｔｈｅｓｉｓ）、９４９−９５０頁（１９８９年）記載の方法に準じて、実施することができる。すなわち、対応するシアノ化合物を塩基及びジメチルスルホキシド溶媒の存在下、酸化剤を用いることにより、実施することができる。塩基としては、炭酸カリウム、炭酸水素カリウム、炭酸ナトリウム、炭酸水素ナトリウム、炭酸リチウム、炭酸セシウム、水酸化ナトリウム、水酸化カリウム、水酸化アンモニウム及び水酸化リチウム等が挙げられ、このうち、炭酸カリウム及び水酸化ナトリウムが好ましい。ジメチルスルホキシド溶媒は、ジメチルスルホキシド単独でも用いることができるが、水、メタノール、アセトン、Ｎ，Ｎ−ジメチルホルムアミド、ジクロロメタン、トルエン等の溶媒と混合して用いてもよい。酸化剤としては、過酸化水素、過酸化ナトリウム、過酸化水素炭酸ナトリウム付加物、過酸化リチウム及び過酸化カリウム等が挙げられ、このうち過酸化水素が好ましい。本反応は、−３０℃〜１２０℃、とりわけ１０℃〜６０℃で好適に進行する。本反応において、塩基としては炭酸カリウム及び溶媒としてジメチルスルホキシド、酸化剤としては過酸化水素水の組み合わせが好ましい。
また、得られた光学活性α−アミノニトリル化合物から対応する光学活性α−アミノ酸への変換は、常法により、例えば、当該シアノ基の加水分解反応やエステル化反応などによりカルボキシル基やエステル基などに変換することによって行うことができる。例えば、カルボキシル基への変換は、酸又は塩基の存在下、溶媒中又は無溶媒中で行うことができる。酸としては、硫酸、塩酸等を好適に用いることができる。塩基としては、水酸化アルカリ金属、アルカリ金属アルコキシド等を好適に用いることができる。溶媒としては、反応に悪影響を及ぼさない溶媒であればよく、例えば、ジクロロメタン、水、テトラヒドロフラン、エタノール等が挙げられる。本反応は、−３０℃〜２００℃、とりわけ０℃〜１００℃で好適に進行する。エステル化の反応は、上記のようにして得たカルボキシル基を有する化合物に対応するアルコール類を脱水剤の存在下、適当な溶媒中又は無溶媒中、反応することにより行うことができる。脱水剤としては、硫酸、塩化チオニル、塩酸等を好適に用いることができる。溶媒としては、反応に悪影響を及ぼさない溶媒であればよく、例えば、トルエン、キシレン、Ｎ，Ｎ−ジメチルホルムアミド、ジオキサン、テトラヒドロフラン等が挙げられる。本反応は、−２０℃〜２００℃、とりわけ２０℃〜１２０℃で好適に進行する。
本発明において用いられる、或いは得られる化合物（ＶＩ）は化合物（Ｖ）を、環変換させることにより製造することができる。本反応は、酸素の不存在下、例えば、窒素またはアルゴン等の気流下で実施することができる。本反応は、適当な溶媒中又は無溶媒で実施することができる。溶媒としては、反応に悪影響を及ぼさない溶媒であればよく、例えば、Ｎ，Ｎ−ジメチルホルムアミド、ジメチルスルホキシド、Ｎ，Ｎ−ジメチルアセトアミド、Ｎ−メチル−２−ピロリドン又はこれらの混合溶媒を適宜用いることができる。本反応は、０℃〜２００℃、とりわけ８０℃〜１００℃で好適に進行する。
また、本発明において得られた化合物（ＩＶ−ａ）を用いるか、或いは、上記方法によって化合物（ＩＶ−ａ）のシアノ基をアミド化した化合物を用いて、塩基の存在下、環変換することにより、一般式（ＸＩＩ）：

式中、Ｒ^７はシアノ基又カルバモイル基を表し、他の記号は上記と同一意味を表す、
で示されるジスルフィド化合物を製造することができる。
塩基としては、炭酸アルカリ金属（炭酸ナトリウム、炭酸カリウムなど）、炭酸水素アルカリ金属（炭酸水素ナトリウムなど）、有機酸アルカリ金属塩（酢酸ナトリウムなど）、水酸化アルカリ金属（水酸化ナトリウム、水酸化カリウムなど）、水素化アルカリ金属（水素化ナトリウムなど）、アルカリ金属アミド（ナトリウムアミド、リチウムアミドなど）、アルカリ金属アルコキシド（ナトリウムメトキシドなど）、リン酸アルカリ金属、アルカリ金属（ナトリウムなど）又は有機塩基（トリエチルアミン、ジイソプロピルエチルアミン、モルホリン、Ｎ−メチルモルホリン、ピリジン、ピペリジン、ジメチルアニリン、ジメチルアミノピリジンなど）等を好適に用いることができる。このうち炭酸水素ナトリウム、酢酸ナトリウムが特に好ましい。
塩基の使用量は、化合物（ＩＶ−ａ）又は化合物（ＩＶ−ａ）のシアノ基をアミド基に変換した化合物に対し、０．１モル当量〜１００モル当量、とりわけ１モル当量〜３モル当量使用するのが好ましい。
本反応は、適当な溶媒中又は無溶媒で実施することができる。溶媒としては、反応に悪影響を及ぼさない溶媒であればよく、例えばＮ，Ｎ−ジメチルホルムアミド、ジメチルスルホキシド、Ｎ，Ｎ−ジメチルアセトアミド、Ｎ−メチルピロリジン又はこれらの混合溶媒を適宜用いることができる。本反応は、０〜２００℃、とりわけ８０〜１００℃で好適に進行する。
化合物（ＸＩＩ）には、不斉炭素に基づく光学異性体が存在するが、光学的に活性な（＋）−ビオチンのみが生物学的に活性であることから、（＋）−ビオチンに効率的に導くためには、イミダゾリジン環の５位が（−ＣＨ_２Ｓ−が結合している位置）がＲ配置の光学活性体（例えば、下記化合物（ＸＩＩ−ａ））が好ましい。
また、（＋）−ビオチンへは、化合物（ＸＩＩ−ａ）又は化合物（ＶＩＩ）を化合物（ＶＩＩＩ）へ変換し、次いで特開平８−２３１５５３号、特開２０００−１９１６６５号、ケミカル・レビューズ（Ｃｈｅｍｉｃａｌ Ｒｅｖｉｅｗｓ），９７巻，６号，１７５５−１７９２頁，１９９７年等に記載の公知製法又はそれらに準じた製法によって製造できるが、例えば以下のようにして製造することもできる。

式中、記号は前記と同一意味を有する。
さらに化合物（ＶＩ）から化合物（ＶＩＩ）への変換は、常法により、例えば泉屋信夫他著、「ペプチド合成の基礎と実験」（丸善（株）１９８５年）や、グリーン他（Ｇｒｅｅｎｅ）著「プロテクティブ グループス イン オーガニック シンセシス（ＰＲＯＴＥＣＴＩＶＥ ＧＲＯＵＰＳ ＩＮ ＯＲＧＡＮＩＣ ＳＹＮＴＨＥＳＩＳ）」第２版（ジョーン・ウィリー・アンド・サンズ社１９９１年）に記載された方法又はそれらに準じた方法で、加水分解により実施できる。具体的には、例えば、水酸化アルカリ金属、アルカリ金属アルコキシド等の塩基、鉱酸（塩酸、硫酸等）等の酸を用いた加水分解によって、カルボキシル基に変換することができる。溶媒としては、反応に悪影響を及ぼさない溶媒であればよく、例えば、酢酸、水、エタノール、テトラヒドロフラン、ジクロロメタン等が挙げられる。本加水分解反応は、０℃〜２００℃、とりわけ５０℃〜８０℃で好適に進行する。
化合物（ＶＩＩ）は、化合物（ＸＩＩ−ａ）を還元剤及び酸、或いは金属ナトリウム／液体アンモニアの存在下、溶媒中又は無溶媒で反応させ、さらにカルバモイル基をカルボキシル基へ変換させることにより製造できる。還元剤としては、亜鉛、鉄等を好適に用いることができる。酸としては、酢酸、塩酸、硫酸等の希酸等を好適に用いることができる。溶媒としては、反応に悪影響を及ぼさない溶媒であればよく、例えば、ジクロロメタン、ベンゼン、トルエン、テトラヒドロフラン等が挙げられる。本還元反応は、０℃〜２００℃、とりわけ８０℃〜１００℃で好適に進行する。カルバモイル基からカルボキシル基への変換は、常法により行うことができる。
化合物（ＶＩＩＩ）は、化合物（ＩＶ−ｃ）を酸素の不存在下、例えば、窒素又はアルゴン等の気流下、溶媒中若しくは無溶媒で環変換及び環化するか、又は化合物（ＶＩＩ）を、溶媒中若しくは無溶媒で環化及びエピ化することにより製造できる。
化合物（ＩＶ−ｃ）の環変換及び環化の工程に用いる溶媒としては、反応に悪影響を及ぼさない溶媒であればよく、例えば、Ｎ，Ｎ−ジメチルホルムアミド、ジメチルスルホキシド、Ｎ，Ｎ−ジメチルアセトアミド、Ｎ−メチル−２−ピロリドン等が挙げられる。本反応は、０℃〜２００℃、とりわけ８０℃〜１００℃で好適に進行する。
本発明における化合物（ＶＩＩ）の環化及びエピ化は、環化してからエピ化する工程（化合物（ＶＩＩＩ−ａ）を経由する工程）及びエピ化してから環化する工程（化合物（ＶＩＩ−ａ）を経由する工程）のいずれの工程も含むものである。
化合物（ＶＩＩ）の環化工程は活性化剤の存在下、好適に実施することができる製造できる。活性化剤としては、ＤＣＣ（ジシクロヘキシルカルボジイミド）、ＥＤＣ・ＨＣｌ（１−〔３−（ジメチルアミノ）プロピル〕−３−エチルカルボジイミド塩酸塩）、シアヌリッククロリド等を好適に用いることができる。また環化工程は、必要に応じ、下記エピ化工程で用いられる塩基の存在下に実施することができる。エピ化工程は、塩基の存在下、或いは添加物なしで加熱のみにより好適に実施することができる。塩基としては、ピリジン、ＤＢＵ（１，８−ジアザビシクロ［５．４．０］ウンデカ−７−エン）、トリエチルアミン等の有機塩基等を好適に用いることができる。またエピ化工程は、必要に応じ、酸（ｐ−トルエンスルホン酸、塩化水素等）の存在下に実施することができる。
環化及びエピ化工程に用いる溶媒としては、反応に悪影響を及ぼさない溶媒であればよく、例えば、ピリジン、トルエン、テトラヒドロフラン、アセトン、アセトニトリル、エタノール等が挙げられる。本反応は、−２０℃〜１２０℃、とりわけ０℃〜７０℃で好適に進行する。
化合物（Ｘ）は、化合物（ＶＩＩＩ）と化合物（ＩＸ）を触媒の存在下、溶媒中又は無溶媒で反応させ、その後加水分解させることにより製造できる。触媒としては、水酸化パラジウム、パラジウム炭素、パラジウムブラック、テトラキストリフェニルホスフィンパラジウム、ジクロロビストリフェニルホスフィンパラジウム等を好適に用いることができる。加水分解反応は、水又は酸（ｐ−トルエンスルホン酸、塩酸、硫酸等）の存在下に好適に実施することができる。溶媒としては、反応に悪影響を及ぼさない溶媒であればよく、例えば、テトラヒドロフラン、Ｎ，Ｎ−ジメチルホルムアミド、トルエン等が挙げられる。本反応は、−２０℃〜２００℃、とりわけ３０℃〜５０℃で好適に進行する。
（＋）−ビオチンである化合物（ＸＩ）は、化合物（Ｘ）を溶媒中又は無溶媒で還元後、加水分解し、さらに化合物（Ｘ）のＲ^３１及び／又はＲ^５が水素原子以外の基である場合、該Ｒ^３１及び／又はＲ^５を水素原子へ変換（保護基の脱保護反応）させることにより製造できる。
還元反応は、例えば水酸化パラジウム、パラジウム炭素、パラジウムブラック、塩化パラジウム、酢酸パラジウム等の触媒の存在下、水素添加することにより好適に実施できる。加水分解反応は、例えば水酸化ナトリウム等の塩基を用いることにより好適に実施できる。溶媒としては、反応に悪影響を及ぼさない溶媒であればよく、例えば、メタノール、エタノール、テトラヒドロフラン、水又はこれらの混合溶媒等が挙げられる。本反応は、０℃〜２００℃、とりわけ５０℃〜８０℃で好適に進行する。
さらに化合物（Ｘ）のＲ^３１及び／又はＲ^５が、水素原子以外の基である場合、該Ｒ^３１及び／又はＲ^５を水素原子へ変換させる工程（保護基の脱保護反応）は、常法により、例えばグリーン他（Ｇｒｅｅｎｅ）著「プロテクティブ グループス イン オーガニックシンセシス（ＰＲＯＴＥＣＴＩＶＥ ＧＲＯＵＰＳ ＩＮ ＯＲＧＡＮＩＣ ＳＹＮＴＨＥＳＩＳ）」第２版（ジョーン・ウィリー・アンド・サンズ社１９９１年）に記載された方法又はそれに準じた方法により行うことができる。具体例としては、臭化水素酸等のハロゲン化水素酸で処理するか、又はメシチレンと酸（メタンスルホン酸、硫酸等）とで処理することにより、好適に実施できる。溶媒としては、反応に悪影響を及ぼさない溶媒であればよく、例えば、水、ベンゼン、トルエン、ジクロロメタン等が挙げられる。本反応は、０℃〜２００℃、とりわけ８０℃〜１００℃で好適に進行する。
化合物（ＩＩＩ）は、ブレティン オブ ケミカル ソサエティ オブ ジャパン（Ｂｕｌｌｅｔｉｎ ｏｆ Ｃｈｅｍｉｃａｌ Ｓｏｃｉｅｔｙ ｏｆ Ｊａｐａｎ），３７巻，２号，２４２−２４４頁，１９６４年、アナリティカル バイオケミストリー（Ａｎａｌｙｔｉｃａｌ Ｂｉｏｃｈｅｍｉｓｔｒｙ），１３８巻，４４９−４５０頁，１９８４年、ヘテロサイクルズ（Ｈｅｔｅｒｏｃｙｃｌｅｓ），１８巻，２５９−２６３頁，１９８２年等に記載の公知の製法又はそれらに準じた製法によって製造できるが、例えば以下のようにして製造することができる。

式中、Ｘ^２はハロゲン原子を表し、他の記号は前記と同一意味を表す。
化合物（１）とクロロギ酸フェニル（又はクロロギ酸アルキル）から化合物（２）を製造する工程は、塩基の存在下、溶媒中又は無溶媒で実施することができる。塩基としては、水酸化アルカリ金属、炭酸アルカリ金属、炭酸水素アルカリ金属、アルカリ金属アルコキシド、有機塩基等を好適に用いることができる。溶媒としては、反応に悪影響を及ぼさない溶媒であればよく、例えば、トルエン、ベンゼン、キシレン、テトラヒドロフラン、１，４−ジオキサン、ジエチルエーテル、ジクロロメタン、水等が挙げられる。本反応は、−３０℃〜１２０℃、とりわけ２０℃〜５０℃で好適に進行する。
化合物（３）においてＲ^５が水素原子以外の置換基を有する化合物は、化合物（２）とＲ^５−Ｘ^２（Ｒ^５のクロリド、ブロミド等）とを、塩基及びジメチルスルホキシド等の高極性溶媒の存在下、溶媒中又は無溶媒で反応させて製造できる。塩基としては、水酸化アルカリ金属、炭酸アルカリ金属、炭酸水素アルカリ金属、アルカリ金属アルコキシド、有機塩基等を好適に用いることができる。溶媒としては、反応に悪影響を及ぼさない溶媒であればよく、例えば、水、Ｎ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメチルアセトアミド、Ｎ−メチル−２−ピロリドン、メタノール等が挙げられる。本反応は、−２０℃〜１２０℃、とりわけ１５℃〜４０℃で好適に進行する。
化合物（４）は、化合物（３）を還元剤と、酸又はアルキル化剤の存在下、溶媒中又は無溶媒で反応させて製造できる。還元剤としては、水素化ホウ素ナトリウム、水素化ホウ素リチウム、水素化リチウムアルミニウム、Ｒｅｄ−Ａｌ（水素化ビス（２−メトキシエトキシ）アルミニウムナトリウム）、ジボラン、ボランメチルスルフィド錯体等を好適に用いることができる。酸としては、硫酸、塩化水素、ルイス酸（トリメチルシリルクロリド、ヨウ素、塩素、ボラントリフルオリドエーテル錯体等）等を好適に用いることができる。アルキル化剤としては、ジメチル硫酸、ヨウ化メチル、ベンジルハライド等を好適に用いることができる。溶媒としては、反応に悪影響を及ぼさない溶媒であればよく、例えば、テトラヒドロフラン、エタノール等が挙げられる。本反応は、−３０℃〜１２０℃、とりわけ０℃〜４０℃で好適に進行する。
化合物（ＩＩＩ）は、化合物（４）を酸化剤の存在下、溶媒中又は無溶媒で反応させて製造できる。酸化剤としては、（１）ジメチルスルホキシド、三酸化イオウピリジン錯塩及びアミン（ジイソプロピルエチルアミン、トリエチルアミン等）からなるもの、（２）ジメチルスルホキシド、オキサリルクロリド及びアミン（ジイソプロピルエチルアミン、トリエチルアミン等）からなるもの、（３）ジメチルスルフィド、塩素及びアミン（ジイソプロピルエチルアミン、トリエチルアミン等）からなるもの、（４）次亜塩素酸ソーダ、炭酸水素ナトリウム、臭化ナトリウム、及び４−ヒドロキシテトラメチルピペリジンオキシド若しくはその誘導体（４−アミノテトラメチルピペリジンオキシド、４−カルボキシテトラメチルピペリジンオキシド、４−シアノテトラメチルピペリジンオキシド等）からなるもの、（５）クロム酸及びその塩、（６）金属触媒（白金、パラジウム等）及び酸素、（７）過酸及び過酸化物、或いは（８）ジメチルスルホキシド、ジシクロヘキシルカルボジイミド、塩基（ピリジン等）、酸（トリフルオロ酢酸、リン酸等）（Ｐｆｉｔｚｎｅｒ−Ｍｏｆｆａｔｔ酸化）等を好適に用いることができる。溶媒としては、反応に悪影響を及ぼさない溶媒であればよく、例えば、ジメチルスルホキシド、ジクロロメタン、水、ベンゼン、トルエン等が挙げられる。本反応は、−７８℃〜１００℃、とりわけ−７８℃〜２５℃で好適に進行する。
また化合物（ＩＩＩ）は、化合物（３）のカルボキシル基をチオニルクロリド、塩化オキサリル等でハロゲン化した後、金属触媒（白金、パラジウム等）及び水素を用いて接触還元することにより、化合物（４）を経由することなく製造することもできる。
本発明に用いられる化合物（１）、化合物（２）、化合物（３）、化合物（４）及び化合物（ＩＩＩ）については、不斉炭素に基づく光学異性体が存在するが、光学的に活性な（＋）−ビオチンのみが生物学的に活性があることから、本発明方法により（＋）−ビオチンに効率よく導くためには、以下の各光学活性体が好ましい。

式中、記号は前記と同一意味を表す。
また化合物（４）は、ヘテロサイクルズ（Ｈｅｔｅｒｏｃｙｃｌｅｓ），１８巻，２５９−２６３頁，１９８２年等に記載の公知の製法又はそれらに準じた製法によって製造できるが、例えば以下のようにして製造することもできる。

式中、記号は前記と同一意味を表す。
化合物（５）は、システインとトリホスゲン（又はホスゲン、クロロギ酸フェニル、クロロギ酸アルキル等）とを塩基（水酸アルカリ金属、炭酸アルカリ金属、炭酸水素アルカリ金属等）の存在下、溶媒中又は無溶媒で反応させ、さらにエタノールと活性化剤（チオニルクロリド、硫酸、塩化水素、オキサリルクロリド等）の存在下、反応させて製造できる。溶媒としては、反応に悪影響を及ぼさない溶媒であればよく、例えば、水、１，４−ジオキサン、テトラヒドロフラン、ジエチルエーテル等が挙げられる。本反応は、−２０℃〜１００℃、とりわけ０℃〜４０℃で好適に進行する。
化合物（６）において、Ｒ^１が水素原子以外の置換基を有する化合物は、化合物（５）とＲ^５−Ｘ^２（Ｒ^５のクロリド、ブロミド等）とを塩基の存在下、溶媒中又は無溶媒で反応させて製造できる。塩基としては、炭酸アルカリ金属、水素化アルカリ金属、アルカリ金属アミド等を好適に用いることができる。溶媒としては、反応に悪影響を及ぼさない溶媒であればよく、例えば、Ｎ，Ｎ−ジメチルアセトアミド、アセトン、アセトニトリル、テトラヒドロフラン等が挙げられる。本反応は、−２０℃〜１００℃、とりわけ１５℃〜３５℃で好適に進行する。
化合物（４）は、化合物（６）を還元剤の存在下、溶媒中又は無溶媒で反応させて製造できる。還元剤としては、水素化ホウ素ナトリウム、水素化ホウ素リチウム、水素化リチウムアルミニウム、Ｒｅｄ−Ａｌ、ＤＩＢＡＬ（ジイソブチルアルミニウムヒドリド）、水素化ホウ素カルシウム、水素化ホウ素亜鉛等を好適に用いることができる。溶媒としては、反応に悪影響を及ぼさない溶媒であればよく、例えば、エタノール、メタノール、水、ジエチルエーテル、テトラヒドロフラン、１，４−ジオキサン等が挙げられる。本反応は、−７８℃〜５０℃、とりわけ−２０℃〜２０℃で好適に進行する。
また化合物（ＩＩＩ）は、ジャーナル・オブ・アメリカン・ケミカル・ソサエティ（Ｊｏｕｒｎａｌ ｏｆ Ａｍｅｒｉｃａｎ Ｃｈｅｍｉｃａｌ Ｓｏｃｉｅｔｙ）、１１２巻、７０５０−７０５１頁、１９９０年等に記載の公知の製法又はそれらに準じた製法によって製造できるが、例えば以下のようにして製造することもできる。

式中、記号は前記と同一意味を表す。
化合物（７）は、化合物（３）とエタンチオールとを、活性化剤の存在下、溶媒中又は無溶媒で反応させて製造できる。活性化剤としては、ＤＣＣ、ＥＤＣ・ＨＣｌ、クロロ炭酸エステル類、イソシアヌリッククロリド、ＣＤＩ（カルボニルジイミダゾール）等を好適に用いることができる。本反応において、さらにＤＭＡＰ（１，４−ジメチルアミノピリジン）を添加すると反応が迅速に進行するため好ましい。溶媒としては、反応に悪影響を及ぼさない溶媒であればよく、例えば、アセトニトリル、アセトン、テトラヒドロフラン、ベンゼン、トルエン等が挙げられる。本反応は、−５０℃〜１００℃、とりわけ０℃〜２０℃で好適に進行する。
化合物（ＩＩＩ）は、化合物（７）を還元剤及び触媒の存在下、溶媒中又は無溶媒で反応させて製造できる。還元剤としては、トリエチルシラン、トリクロロシラン、トリフェニルシラン等のシラン類等を好適に用いることができる。触媒としては、水酸化パラジウム、パラジウム炭素、パラジウムブラック等のパラジウム触媒等を好適に用いることができる。溶媒としては、反応に悪影響を及ぼさない溶媒であればよく、例えば、ジクロロメタン、アセトン、テトラヒドロフラン等が挙げられる。本反応は、−２０℃〜１００℃、とりわけ０℃〜２０℃で好適に進行する。
さらに本発明で用いられる化合物（ＩＸ）を製造する方法は、ハンドブック・オブ・グリニャアード・リエージェンツ（ＨＡＮＤＢＯＯＫ ＯＦ ＧＲＩＧＮＡＲＤ ＲＥＡＧＥＮＴＳ）５３−７７頁、１９９６年、オーガノジンク・リエージェンツ・イン・オーガニック・シンセシス（ＯＲＧＡＮＯＺＩＮＣ ＲＥＡＧＥＮＴＳ ｉｎ ＯＲＧＡＮＩＣ ＳＹＮＴＨＥＳＩＳ）、１８−６７頁、１９９６年等に記載されているが、例えば、下記のような方法を用いて製造することもできる。
化合物（ＩＸ）は、亜鉛又はマグネシウムを溶媒中にけん濁し、塩素、臭素、塩化水素又は臭化水素を加えた後、一般式（ＸＩＩＩ）：

式中、記号は前記と同一意味を表す、
で示される化合物と反応させて製造することができる。溶媒としては、反応に悪影響を及ぼさない溶媒であればよく、例えば、テトラヒドロフラン、トルエン、ジエチルエーテル、１，２−ジメトキシエタン、アセトニトリル、１，４−ジオキサン等があげられ、これらの混合溶媒も用いることができる。本反応は、−５０℃〜１５０℃、とりわけ５℃〜８０℃で好適に進行する。特に、本方法においては、亜鉛を用いて臭素の存在下反応するのが好ましい。
また、化合物（ＩＸ）は、亜鉛又はマグネシウムを溶媒中にけん濁し、一般式（ＸＩＶ）：

式中、Ｍは金属原子を表し、Ｙはヨウ素、臭素、塩素を表す、
で示される塩（ＸＩＶ）を加えた後、化合物（ＸＩＩＩ）と反応させて製造することができる。溶媒としては、反応に悪影響を及ぼさない溶媒であればよく、例えば、テトラヒドロフラン、トルエン、ジエチルエーテル、１，２−ジメトキシエタン、アセトニトリル、１，４−ジオキサン等があげられ、これらの混合溶媒も用いることができる。本反応は、−５０℃〜１５０℃、とりわけ５℃〜８０℃で好適に進行する。塩（ＸＩＶ）の金属原子（Ｍ）としては、典型金属又は遷移金属等が挙げられる。典型金属としては、リチウム、ナトリウム、カリウム、セシウム、マグネシウム、カルシウム、バリウム、アルミニウム、亜鉛、ケイ素、スズ等が挙げられ、遷移元素としては、チタン、クロム、モリブデン、タングステン、マンガン、鉄、ルテニウム、コバルト、ロジウム、ニッケル、パラジウム、白金、銅等が挙げられる。
本発明において用いられる、或いは得られる化合物（Ｉ）及び化合物（ＩＶ）のＲ^１及びＲ^２としては、それぞれ異なって、置換基を有していてもよいアルキル基、置換基を有していてもよいアルコキシ基、置換基を有していてもよいアルケニル基、置換基を有していてもよいアリール基、置換基を有していてもよいアミノ基、置換基を有していてもよい複素環式基、シアノ基、カルボキシル基、又は置換基を有していてもよいカルバモイル基を表すか、或いは、Ｒ^１及びＲ^２は末端で互いに結合して隣接する不斉炭素原子とともに置換基を有していてもよい複素環式基を形成している基を表わす。
Ｒ^１及びＲ^２における置換基を有していてもよいアルキル基の置換基としては、フェニル基、アルコキシ基、ジアルキルアミノ基、アルキルアミノ基、アルコキシカルボニル基、アルカノイル基、アルカノイルオキシ基、カルバモイル基、ジアルキルアミノカルボニル基、アルキルアミノカルボニル基、ハロゲン原子、水酸基、シアノ基、アルキルチオ基、アルキルスルフィル基、アルキルスルホニル基、アルカノイルアミノ基等が挙げられる。当該置換基は、同一又は異なって１〜３個置換していてもよい。
Ｒ^１及びＲ^２における置換基を有していてもよいアルコキシ基の置換基としては、フェニル基、アルコキシ基、ジアルキルアミノ基、アルキルアミノ基、アルコキシカルボニル基、アルカノイル基、アルカノイルオキシ基、カルバモイル基、ジアルキルアミノカルボニル基、アルキルアミノカルボニル基、ハロゲン原子、水酸基、シアノ基、アルキルチオ基、アルキルスルフィル基、アルキルスルホニル基等が挙げられる。当該置換基は、同一又は異なって１〜３個置換していてもよい。
Ｒ^１及びＲ^２における置換基を有していてもよいアルケニル基の置換基としては、フェニル基、アルコキシ基、ジアルキルアミノ基、アルキルアミノ基、アルコキシカルボニル基、アルカノイル基、アルカノイルオキシ基、カルバモイル基、ジアルキルアミノカルボニル基、アルキルアミノカルボニル基、ハロゲン原子、水酸基、シアノ基、アルキルチオ基、アルキルスルフィル基、アルキルスルホニル基等が挙げられる。当該置換基は、同一又は異なって１〜３個置換していてもよい。
Ｒ^１及びＲ^２における置換基を有していてもよいアリール基の置換基としては、水酸基、ハロゲン原子、アルコキシ基、アルキル基、アミノ基、ニトロ基、シアノ基、ジアルキルアミノ基、アルキルアミノ基、ハロゲノアルキル基、ホルミル基、フェニル基、カルボキシル基、アルコキシカルボニル基、アルカノイル基等が挙げられる。当該置換基は、同一又は異なって１〜３個置換していてもよい。当該アリール基としては、フェニル基、ナフチル基、アントラセニル基、フェナントレニル基等が挙げられる。
Ｒ^１及びＲ^２における置換基を有していてもよいアミノ基の置換基としては、アルキル基、アルケニル基、アルキニル基、アルカノイル基、アルコキシカルボニル基、カルバモイル基、チオカルバモイル基等が挙げられる。当該置換基は、同一又は異なって１〜２個置換していてもよい。
Ｒ^１及びＲ^２における置換基を有していてもよい複素環式基の複素環式基としては、ヘテロ原子として硫黄原子、窒素原子および酸素原子から選ばれる原子を１乃至４個含有する複素環式基（当該複素環式基は置換基を有していてもよい。）が挙げられる。当該複素環式基としては、飽和もしくは不飽和単環または二環複素芳香環式基が挙げられ、例えば、チエニル基、フリル基、テトラヒドロフリル基、ピラニル基、ピロリル基、イミダゾリル基、ピラゾリル基、イソチアゾリル基、イソオキサゾリル基、ピリジル基、ピラジニル基、ピリミジニル基、ピリダジニル基、ピロリジニル基、ピロリニル基、イミダゾリジニル基、イミダゾリニル基、ピラゾリジニル基、ピラゾリニル基、ピペリジル基、ピペラジニル基、モルホリニル基、チオモルホリニル基、ベンゾチエニル基、ベンゾフリル基、イソベンゾフラニル基、クロメニル基、インドリル基、イソインドリル基、インダゾリル基、プリニル基、キノリジニル基、ナフチリジニル基、キノキサリニル基、シンノリニル基、キノリル基、イソキノリル基、ベンゾチアゾリル基、ベンズイソチアゾリル基、キナゾリニル基、フタラジニル基、ベンゾオキサゾリル基、ベンズイミダゾリル基、プテリジニル基、ピリドピリミジニル基、イソクロマニル基、クロマニル基、インドリニル基、イソインドリニル基、テトラヒドロキノリル基、テトラヒドロイソキノリル基、テトラヒドロキノキサリニル基、ジヒドロフタラジニル基などが挙げられる。また、当該複素環式基の置換基としては、ハロゲン原子、アルコキシ基、アルカノイルオキシ基、カルバモイル基、ハロゲノアルキル基、ジアルキルアミノ基、アルコキシカルボニル基、モルホリノアルキル基、ヒドロキシアルキル基、アルキル基、ベンジルオキシ基、アルコキシカルボニル基、アルカノイル基、水酸基、オキソ基またはホルミル基が挙げられる。当該置換基は、同一又は異なって１〜３個置換していてもよい。
Ｒ^１及びＲ^２における置換基を有していてもよいカルバモイル基の置換基としては、アルキル基、アルケニル基、アルキニル基、アルカノイル基、アルコキシカルボニル基、カルバモイル基、チオカルバモイル基等が挙げられる。
また、Ｒ^１及びＲ^２は末端で互いに結合して隣接する不斉炭素原子とともに置換基を有していてもよい複素環式基の複素環式基としては、ヘテロ原子として硫黄原子、窒素原子および酸素原子から選ばれる原子を１乃至４個含有する複素環式基が挙げられ、例えば、ピロリジニル基、ピペリジニル基、チアゾリジニル基、ピペラジニル基、モルホリニル基、チオモルホリニル基、イミダゾリニル基、ピラゾリジニル基、テトラヒドロフラニル基、ピラゾリニル基、テトラヒドロピラニル基、イソクロマニル基、クロマニル基、インドリニル基、イソインドリニル基等が挙げられる。当該複素環式基の置換基としては、ハロゲン原子、アルコキシ基、アルカノイルオキシ基、カルバモイル基、ハロゲノアルキル基、ジアルキルアミノ基、アルコキシカルボニル基、モルホリノアルキル基、ヒドロキシアルキル基、ベンジルオキシ基、アルコキシカルボニル基、アルカノイル基、水酸基、オキソ基、ホルミル基、または置換基を有していてもよいフェニル基で１〜３置換されていてもよいアルキル基が挙げられる。当該複素環式基の置換基は、同一又は異なって１〜３個置換していてもよい。アルキル基の置換基であるフェニル基の置換基としては、同一又は異なるハロゲン原子、アルキル基及びアルコキシ基から選ばれる基が挙げられ、これら置換基は、同一又は異なって１〜３個置換していてもよい。
このうち、Ｒ^１がベンジル基を表し、Ｒ^２がブトキシカルボニルアミノ基を表すか、Ｒ^１及びＲ^２は末端で互いに結合して隣接する不斉炭素原子とともに、少なくともオキソ基で置換されているチアゾリジン環を形成しているものが好ましい。
本発明において用いられる、或いは得られる化合物（ＩＩ）及び化合物（ＩＶ）のＲ^３としては、置換基を有していてもよいアルキル基、置換基を有していてもよいアルコキシ基、置換基を有していてもよいアルケニル基、置換基を有していてもよいアリール基が挙げられる。
Ｒ^３における置換基を有していてもよいアルキル基の置換基としては、フェニル基、アルコキシ基、ジアルキルアミノ基、アルキルアミノ基、アルコキシカルボニル基、アルカノイル基、アルカノイルオキシ基、カルバモイル基、ジアルキルアミノカルボニル基、アルキルアミノカルボニル基、ハロゲン原子、水酸基、シアノ基、アルキルチオ基、アルキルスルフィル基、アルキルスルホニル基、アルカノイルアミノ基等が挙げられる。当該置換基は、同一又は異なって１〜３個置換していてもよい。当該置換基のうち、フェニル基が好ましい。
Ｒ^３における置換基を有していてもよいアルコキシ基の置換基としては、フェニル基、アルコキシ基、ジアルキルアミノ基、アルキルアミノ基、アルコキシカルボニル基、アルカノイル基、アルカノイルオキシ基、カルバモイル基、ジアルキルアミノカルボニル基、アルキルアミノカルボニル基、ハロゲン原子、水酸基、シアノ基、アルキルチオ基、アルキルスルフィル基、アルキルスルホニル基等が挙げられる。当該置換基は、同一又は異なって１〜３個置換していてもよい。
Ｒ^３における置換基を有していてもよいアルケニル基の置換基としては、フェニル基、アルコキシ基、ジアルキルアミノ基、アルキルアミノ基、アルコキシカルボニル基、アルカノイル基、アルカノイルオキシ基、カルバモイル基、ジアルキルアミノカルボニル基、アルキルアミノカルボニル基、ハロゲン原子、水酸基、シアノ基、アルキルチオ基、アルキルスルフィル基、アルキルスルホニル基等が挙げられる。当該置換基は、同一又は異なって１〜３個置換していてもよい。
Ｒ^３における置換基を有していてもよいアリール基の置換基としては、水酸基、ハロゲン原子、アルコキシ基、アルキル基、アミノ基、ニトロ基、シアノ基、ジアルキルアミノ基、アルキルアミノ基、ハロゲノアルキル基、ホルミル基、フェニル基、カルボキシル基、アルコキシカルボニル基、アルカノイル基等が挙げられる。当該置換基は、同一又は異なって１〜３個置換していてもよい。当該アリール基としては、フェニル基、ナフチル基、アントラセニル基、フェナントレニル基等が挙げられる。
Ｒ^３としては、ベンゼン環上に置換基を有していてもよいベンジル基、ベンゼン環上に置換基を有していてもよいベンズヒドリル基、又はベンゼン環上に置換基を有していてもよいトリチル基が好ましく、ベンズヒドリル基のベンゼン環上の置換基としては、同一又は異なるハロゲン原子、アルキル基及びアルコキシ基から選ばれる基が挙げられ、トリチル基のベンゼン環上の置換基としては、同一又は異なるハロゲン原子、アルキル基及びアルコキシ基から選ばれる基が挙げられる。上記のベンジル基、ベンズヒドリル基又はトリチル基における各々のベンゼン環上には、同一又は異なる１〜３個の上記置換基を有していてもよい。
さらに、Ｒ^３が（１）ベンゼン環がハロゲン原子、アルキル基及びアルコキシ基から選ばれる基で置換されていてもよいベンジル基、（２）ベンゼン環がハロゲン原子、アルキル基及びアルコキシ基から選ばれる基で置換されていてもよいベンズヒドリル基、又は（３）ベンゼン環がハロゲン原子、アルキル基及びアルコキシ基から選ばれる基で置換されていてもよいトリチル基であるものが好ましく、特に、ベンジル基、ベンズヒドリル基又はトリチル基であるものが好ましい。
本発明において用いられる、或いは得られる化合物（ＩＩ）及び化合物（ＩＶ）のＲ^４としては、水素原子、置換基を有していてもよいアルキル基、置換基を有していてもよいアルコキシ基、置換基を有していてもよいアルケニル基、置換基を有していてもよいアリール基が挙げられる。
Ｒ^４における置換基を有していてもよいアルキル基の置換基としては、フェニル基、アルコキシ基、ジアルキルアミノ基、アルキルアミノ基、アルコキシカルボニル基、アルカノイル基、アルカノイルオキシ基、カルバモイル基、ジアルキルアミノカルボニル基、アルキルアミノカルボニル基、ハロゲン原子、水酸基、シアノ基、アルキルチオ基、アルキルスルフィル基、アルキルスルホニル基、アルカノイルアミノ基等が挙げられる。当該置換基は、同一又は異なって１〜３個置換していてもよい。当該置換基のうち、フェニル基が好ましい。
Ｒ^４における置換基を有していてもよいアルコキシ基の置換基としては、フェニル基、アルコキシ基、ジアルキルアミノ基、アルキルアミノ基、アルコキシカルボニル基、アルカノイル基、アルカノイルオキシ基、カルバモイル基、ジアルキルアミノカルボニル基、アルキルアミノカルボニル基、ハロゲン原子、水酸基、シアノ基、アルキルチオ基、アルキルスルフィル基、アルキルスルホニル基等が挙げられる。当該置換基は、同一又は異なって１〜３個置換していてもよい。
Ｒ^４における置換基を有していてもよいアルケニル基の置換基としては、フェニル基、アルコキシ基、ジアルキルアミノ基、アルキルアミノ基、アルコキシカルボニル基、アルカノイル基、アルカノイルオキシ基、カルバモイル基、ジアルキルアミノカルボニル基、アルキルアミノカルボニル基、ハロゲン原子、水酸基、シアノ基、アルキルチオ基、アルキルスルフィル基、アルキルスルホニル基等が挙げられる。当該置換基は、同一又は異なって１〜３個置換していてもよい。
Ｒ^４における置換基を有していてもよいアリール基の置換基としては、水酸基、ハロゲン原子、アルコキシ基、アルキル基、アミノ基、ニトロ基、シアノ基、ジアルキルアミノ基、アルキルアミノ基、ハロゲノアルキル基、ホルミル基、フェニル基、カルボキシル基、アルコキシカルボニル基、アルカノイル基等が挙げられる。当該置換基は、同一又は異なって１〜３個置換していてもよい。当該アリール基としては、フェニル基、ナフチル基、アントラセニル基、フェナントレニル基等が挙げられる。
Ｒ^４としては、水素原子、ベンゼン環上に置換基を有していてもよいベンジル基、ベンゼン環上に置換基を有していてもよいベンズヒドリル基、又はベンゼン環上に置換基を有していてもよいトリチル基であるものが好ましく、ベンズヒドリル基のベンゼン環上の置換基としては、同一又は異なるハロゲン原子、アルキル基及びアルコキシ基から選ばれる基が挙げられ、トリチル基のベンゼン環上の置換基としては、同一又は異なるハロゲン原子、アルキル基及びアルコキシ基から選ばれる基が挙げられる。上記のベンジル基、ベンズヒドリル基又はトリチル基における各々のベンゼン環上には、同一又は異なる１〜３個の上記置換基を有していてもよい。
さらに、Ｒ^４が（１）水素原子、（２）ベンゼン環がハロゲン原子、アルキル基及びアルコキシ基から選ばれる基で置換されていてもよいベンジル基、（３）ベンゼン環がハロゲン原子、アルキル基及びアルコキシ基から選ばれる基で置換されていてもよいベンズヒドリル基、又は（４）ベンゼン環がハロゲン原子、アルキル基及びアルコキシ基から選ばれる基で置換されていてもよいトリチル基が好ましく、特に、水素原子、ベンジル基、ベンズヒドリル基又はトリチル基であるものが好ましい。
本発明において用いられる、或いは得られる化合物（ＩＸ）及び化合物（Ｘ）のＲ^６としては、エステル化されたカルボキシル基又はアミド化されたカルボキシル基が挙げられ、このうち、アルコキシカルボニル基又はアルキルカルバモイル基が好ましく、さらにアルコキシカルボニル基が好ましい。
本発明において用いられる、或いは得られる化合物（ＩＩ−ａ）、化合物（ＩＶ−ａ）、化合物（ＩＶ−ｂ）、化合物（ＩＶ−ｃ）、化合物（Ｖ）、化合物（ＶＩ）、化合物（ＶＩＩ）、化合物（ＶＩＩ−ａ）、化合物（ＶＩＩＩ）、化合物（ＶＩＩＩ−ａ）、化合物（Ｘ）、化合物（ＸＩＩ）及び化合物（ＸＩＩ−ａ）のＲ^３１としては、ベンゼン環上に置換基を有していてもよいベンジル基、ベンゼン環上に置換基を有していてもよいベンズヒドリル基、又はベンゼン環上に置換基を有していてもよいトリチル基であるものが挙げられ、ベンジル基のベンゼン環上の置換基としては、ハロゲン原子、アルキル基及びアルコキシ基から選ばれる基が挙げられ、ベンズヒドリル基のベンゼン環上の置換基としては、同一又は異なるハロゲン原子、アルキル基及びアルコキシ基から選ばれる基が挙げられ、トリチル基のベンゼン環上の置換基としては、同一又は異なるハロゲン原子、アルキル基及びアルコキシ基から選ばれる基が挙げられる。上記のベンジル基、ベンズヒドリル基又はトリチル基における各々のベンゼン環上には、同一又は異なる１〜３個の上記置換基を有していてもよい。このうち、Ｒ^３１が（１）ベンゼン環がハロゲン原子、アルキル基及びアルコキシ基から選ばれる基で置換されていてもよいベンジル基、（２）ベンゼン環がハロゲン原子、アルキル基及びアルコキシ基から選ばれる基で置換されていてもよいベンズヒドリル基、又は（３）ベンゼン環がハロゲン原子、アルキル基及びアルコキシ基から選ばれる基で置換されていてもよいトリチル基が好ましく、さらに、ベンジル基、ベンズヒドリル基又はトリチル基であるものが好ましく、特にベンジル基が好ましい。
本発明において用いられる、或いは得られる化合物（ＩＩＩ）、化合物（ＩＩＩ−ａ）、化合物（ＩＶ−ａ）、化合物（ＩＶ−ｂ）、化合物（ＩＶ−ｃ）、化合物（Ｖ）、化合物（ＶＩ）、化合物（ＶＩＩ）、化合物（ＶＩＩ−ａ）、化合物（ＶＩＩＩ）、化合物（ＶＩＩＩ−ａ）、化合物（Ｘ）、化合物（ＸＩＩ）、化合物（ＸＩＩ−ａ）、化合物（３）、化合物（３−ａ）、化合物（４）、化合物（４−ａ）、化合物（６）及び化合物（７）のＲ^５としては、水素原子、ベンゼン環上に置換基を有していてもよいベンジル基、ベンゼン環上に置換基を有していてもよいベンズヒドリル基、又はベンゼン環上に置換基を有していてもよいトリチル基であるものが挙げられ、このうち、（１）水素原子、（２）ベンゼン環がハロゲン原子、アルキル基及びアルコキシ基から選ばれる基で置換されていてもよいベンジル基、（３）ベンゼン環がハロゲン原子、アルキル基及びアルコキシ基から選ばれる基で置換されていてもよいベンズヒドリル基、又は（４）ベンゼン環がハロゲン原子、アルキル基及びアルコキシ基から選ばれる基で置換されていてもよいトリチル基が好ましく、さらに、ベンジル基、ベンズヒドリル基又はトリチル基であるものが好ましく、特にベンジル基が好ましい。
本発明において、化合物（ＩＩＩ−ａ）から化合物（ＩＶ−ｂ）を製する場合、Ｒ^３１としては、ベンゼン環上に置換基を有していてもよいベンジル基、ベンゼン環上に置換基を有していてもよいベンズヒドリル基、又はベンゼン環上に置換基を有していてもよいトリチル基のものが挙げられ、Ｒ^５としては、水素原子、ベンゼン環上に置換基を有していてもよいベンジル基、ベンゼン環上に置換基を有していてもよいベンズヒドリル基、又はベンゼン環上に置換基を有していてもよいトリチル基のものが挙げられ、これらＲ^３１及びＲ^５のベンズヒドリル基のベンゼン環上の置換基としては、同一又は異なるハロゲン原子、アルキル基及びアルコキシ基から選ばれる基が挙げられ、トリチル基のベンゼン環上の置換基としては、同一又は異なるハロゲン原子、アルキル基及びアルコキシ基から選ばれる基が挙げられる。上記のベンジル基、ベンズヒドリル基又はトリチル基における各々のベンゼン環上には、同一又は異なる１〜３個の上記置換基を有していてもよい。このうち、Ｒ^３１が、（１）ベンゼン環がハロゲン原子、アルキル基及びアルコキシ基から選ばれる基で置換されていてもよいベンジル基、（２）ベンゼン環がハロゲン原子、アルキル基及びアルコキシ基から選ばれる基で置換されていてもよいベンズヒドリル基、又は（３）ベンゼン環がハロゲン原子、アルキル基及びアルコキシ基から選ばれる基で置換されていてもよいトリチル基であるもの、Ｒ^５が（１）水素原子、（２）ベンゼン環がハロゲン原子、アルキル基及びアルコキシ基から選ばれる基で置換されていてもよいベンジル基、（３）ベンゼン環がハロゲン原子、アルキル基及びアルコキシ基から選ばれる基で置換されていてもよいベンズヒドリル基、又は（４）ベンゼン環がハロゲン原子、アルキル基及びアルコキシ基から選ばれる基で置換されていてもよいトリチル基であるものが好ましく、さらに、Ｒ^３１がベンジル基、ベンズヒドリル基又はトリチル基であり、Ｒ^５が水素原子、ベンジル基、ベンズヒドリル基又はトリチル基であるものが好ましく、またさらに、Ｒ^３１及びＲ^５が同一又は異なって、ベンジル基、ベンズヒドリル基又はトリチル基であるものが好ましく、特に、Ｒ^３１及びＲ^５がともにベンジル基のものが好ましい。
本発明において、化合物（ＩＶ−ｂ）から化合物（ＸＩ）を製する場合、Ｒ^{３ １}としては、ベンゼン環上に置換基を有していてもよいベンジル基、ベンゼン環上に置換基を有していてもよいベンズヒドリル基、又はベンゼン環上に置換基を有していてもよいトリチル基のものが挙げられ、Ｒ^５としては、水素原子、ベンゼン環上に置換基を有していてもよいベンジル基、ベンゼン環上に置換基を有していてもよいベンズヒドリル基、又はベンゼン環上に置換基を有していてもよいトリチル基のものが挙げられ、Ｒ^６としては、エステル化されたカルボキシル基又はアミド化されたカルボキシル基のものが挙げられ、Ｒ^３１及びＲ^５のベンジル基のベンゼン環上の置換基としては、同一又は異なるハロゲン原子、アルキル基及びアルコキシ基から選ばれる基が挙げられ、ベンズヒドリル基のベンゼン環上の置換基としては、同一又は異なるハロゲン原子、アルキル基及びアルコキシ基から選ばれる基が挙げられ、トリチル基のベンゼン環上の置換基としては、同一又は異なるハロゲン原子、アルキル基及びアルコキシ基から選ばれる基が挙げられる。上記のベンジル基、ベンズヒドリル基又はトリチル基における各々のベンゼン環上には、同一又は異なる１〜３個の上記置換基を有していてもよい。このうち、Ｒ^３１が、（１）ベンゼン環がハロゲン原子、アルキル基及びアルコキシ基から選ばれる基で置換されていてもよいベンジル基、（２）ベンゼン環がハロゲン原子、アルキル基及びアルコキシ基から選ばれる基で置換されていてもよいベンズヒドリル基、又は（３）ベンゼン環がハロゲン原子、アルキル基及びアルコキシ基から選ばれる基で置換されていてもよいトリチル基であるもの、Ｒ^５が（１）水素原子、（２）ベンゼン環がハロゲン原子、アルキル基及びアルコキシ基から選ばれる基で置換されていてもよいベンジル基、（３）ベンゼン環がハロゲン原子、アルキル基及びアルコキシ基から選ばれる基で置換されていてもよいベンズヒドリル基、又は（４）ベンゼン環がハロゲン原子、アルキル基及びアルコキシ基から選ばれる基で置換されていてもよいトリチル基であるもの、Ｒ^６がアルコキシカルボニル基又はアルキルカルバモイル基であるものが好ましく、さらに、Ｒ^３１及びＲ^５が同一又は異なって、ベンジル基、ベンズヒドリル基又はトリチル基であるもの、Ｒ^６がアルコキシカルボニル基のものが好ましく、特に、Ｒ^３１及びＲ^５がともにベンジル基のもの、Ｒ^６がアルコキシカルボニル基のものが好ましい。
本発明において用いられる、或いは得られる化合物（ＩＩ）、化合物（ＩＩ−ａ）、化合物（ＩＶ）、化合物（ＩＶ−ａ）、化合物（ＩＶ−ｂ）、化合物（ＩＶ−ｃ）、化合物（Ｖ）、化合物（ＶＩＩ）、化合物（ＶＩＩ−ａ）又は化合物（ＩＸ）で示される化合物の塩としては、例えば、無機塩（塩酸塩、リン酸塩、臭化水素酸塩、硫酸塩など）或いは有機酸（酢酸塩、ギ酸塩、プロピオン酸塩、フマル酸塩、マレイン酸塩、コハク酸塩、酒石酸塩、クエン酸塩、リンゴ酸塩、蓚酸塩、安息香酸塩、メタンスルホン酸塩、ベンゼンスルホン酸塩、トシル酸塩など）との塩が挙げられる。さらに本発明の化合物がカルボン酸などの酸性基を有している場合、本発明の化合物は、例えば無機塩基（ナトリウム塩、カリウム塩などのアルカリ金属塩、カルシウム塩、マグネシウム塩などのアルカリ土類金属塩、アンモニウム塩など）或いは有機塩基（トリエチルアミン塩、リシン塩の如きアミノ酸塩など）との塩を形成していてもよい。遊離体と塩とは、公知の方法或いはそれに準じる方法により相互に変換することができる。
本明細書において、アルキル基又はアルコキシ基としては、炭素数１〜６の直鎖又は分岐鎖のもの、とりわけ炭素数１〜４の直鎖又は分岐鎖のものが挙げられる。アルケニル基、アルキニル基、アルカノイル基、アルコキシカルボニル基又はアルキルチオカルボニル基としては、炭素数２〜７の直鎖又は分岐鎖のもの、とりわけ炭素数２〜５の直鎖又は分岐鎖のものが挙げられる。ハロゲン原子としては、フッ素原子、塩素原子、臭素原子又はヨウ素原子が挙げられる。
次に、本発明を実施例に基づいてさらに詳細に説明するが、本発明はかかる実施例のみに限定されるものではない。  The optically active α-amino nitrile compound used or obtained in the present invention is obtained by reacting an optically active aldehyde compound having an asymmetric carbon at the α-position or a salt thereof with bisulfite oxide in a water-containing solvent. After the bisulfite adduct is obtained, it can be produced by reacting the obtained bisulfite adduct with a primary amine compound or secondary amine compound having a substituent and a cyanide.
  As the water-containing solvent in this reaction, a mixed solvent of water and an organic solvent can be used. The organic solvent may be any solvent that does not adversely affect the reaction. For example, ethyl acetate, dimethyl sulfoxide, N, N-dimethylformamide, N, N-dimethylacetamide, hexamethylphosphoramide, toluene, dichloromethane, chloroform, 1,2-dimethoxyethane, N-methylpyrrolidone, diethyl ether, 1,4-dioxane and the like may be mentioned, and these organic solvents may be mixed and used. Of these, ethyl acetate, dichloromethane, toluene, dimethyl sulfoxide and the like are preferable.
  When the primary amine compound or secondary amine compound having a substituent and the cyanide are reacted, each can be carried out sequentially, but after adding the primary amine compound or secondary amine compound having a substituent, The cyanide may be reacted after the sulfurous oxide is added again. This reaction suitably proceeds at −20 ° C. to 70 ° C., particularly 0 ° C. to 30 ° C.
  Examples of the bisulfite oxide include alkali metal bisulfites (for example, sodium bisulfite, potassium bisulfite, lithium bisulfite), alkaline earth bisulfites (for example, calcium bisulfite, magnesium bisulfite, etc.) and transitions. Metal bisulfites such as elemental metal bisulfites (eg, iron bisulfite, iron dinitrite bisulfite, etc.) can be mentioned. Of these, alkali metal bisulfite is preferable, and sodium bisulfite is particularly preferable.
  Examples of the primary amine compound or secondary amine compound having a substituent include peptides (for example, peptides described in Journal of Organic Chemistry, Vol. 58, page 5186-5191, 1993). Amino acids (for example, amino acid derivatives such as the intermediate of enalapril described in Journal of Medicinal Chemistry, 28, 434-442, 1985, abnormalities such as kainic acid, etc. Amino acid derivatives, natural amino acid derivatives, etc.) and general formula (II):

        Where R³Is an alkyl group which may have a substituent, an alkoxy group which may have a substituent, an alkenyl group which may have a substituent, or an aryl group which may have a substituent Represents R⁴Is a hydrogen atom, an alkyl group which may have a substituent, an alkoxy group which may have a substituent, an alkenyl group which may have a substituent, or a substituent. Represents a good aryl group,
The compound shown by these is mentioned. Of these, primary amine compounds are preferred, and in particular R of compound (II)³Is a benzyl group which may have a substituent on the benzene ring, a benzhydryl group which may have a substituent on the benzene ring, or a trityl group which may have a substituent on the benzene ring And R⁴Compound (II-a) in which is a hydrogen atom is preferred.
  Any cyanide may be used as long as it is not significantly affected by water, and is a compound usually used for cyanation, and examples thereof include cyanic acid, alkali metal cyanide, and organic cyanide. Alkali metal halides are preferred. Examples of the alkali metal cyanide compound include lithium cyanide, potassium cyanide, sodium cyanide, and the like, and examples of the organic cyanide include tributyltin cyanide, dimethylaluminum cyanide, tetraethylammonium cyanide, diethylformyl cyanide. Nido etc. are mentioned.
  The production method of the present invention can also be used in a continuous process in which an aldehyde compound having an asymmetric carbon at the α-position is obtained from an optically active alcohol compound having an asymmetric carbon at the β-position. The step of obtaining the optically active aldehyde compound from the optically active alcohol compound can be performed by a conventional method as described later.
  The optically active α-amino nitrile compound used or obtained in the present invention is only required to have an asymmetric center at the α-position and β-position, and examples thereof include compound (IV). Among such optically active α-amino nitrile compounds, the biotin synthesis intermediate includes compound (IV-a), and among these, compound (IV-b) is preferable.
  The optically active aldehyde compound having an asymmetric carbon at the α-position used in the present invention is water-soluble when it becomes a bisulfite adduct of the aldehyde compound. For example, the general formula (I):

        Where R¹And R²Are different, may have an alkyl group which may have a substituent, an alkoxy group which may have a substituent, an alkenyl group which may have a substituent, and a substituent. Represents an aryl group, an optionally substituted amino group, an optionally substituted heterocyclic group, a cyano group, a carboxyl group, or an optionally substituted carbamoyl group Or R¹And R²Represents a group which is bonded to each other at a terminal to form a heterocyclic group which may have a substituent together with the adjacent asymmetric carbon atom,
The compound shown by these is mentioned. Among such optically active aldehyde compounds (I) having an asymmetric carbon at the α-position, examples of the biotin synthesis intermediate include compound (III), and among these, compound (III-a) is preferable.
  Among the production methods of the present invention, as a preferred combination, an optically active aldehyde compound having an asymmetric carbon at the α-position is compound (I), and a primary amine compound or secondary amine compound having a substituent is compound (II). The optically active α-amino nitrile compound is represented by the general formula (IV):

        Where R³Is an alkyl group which may have a substituent, an alkoxy group which may have a substituent, an alkenyl group which may have a substituent, or an aryl group which may have a substituent Represents R⁴Is a hydrogen atom, an alkyl group which may have a substituent, an alkoxy group which may have a substituent, an alkenyl group which may have a substituent, or a substituent. Represents a good aryl group, and other symbols represent the same meaning as described above.
What is a compound shown by is mentioned. Among these, as a more preferable combination, an optically active aldehyde compound having an asymmetric carbon at the α-position is the compound (III), and a primary amine compound or secondary amine compound having a substituent is the compound (II-a). , An optically active α-amino nitrile compound is compound (IV-a), and a particularly preferred combination is an optically active aldehyde compound having an asymmetric carbon at the α-position as compound (III-a). The primary amine compound or secondary amine compound having a substituent is the compound (II-a), and the optically active α-amino nitrile compound is the compound (IV-b). In these preferred combinations, those in which bisulfite is an alkali metal bisulfite and cyanide is an alkali metal cyanide are preferably used.
  The step of amidating the cyano group of compound (IV) and compound (IV-a) obtained by the present invention and the step of obtaining compound (V) from compound (IV-b) obtained by the present invention correspond to The reaction can be carried out by reacting the cyano compound in the presence of an acid in a solvent or in the absence of a solvent, and further neutralizing with a base. As the acid, hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid and the like can be suitably used. As the base, ammonia, monomethylamine, dimethylamine, sodium hydroxide, sodium hydrogen carbonate, sodium carbonate, potassium hydroxide, potassium hydrogen carbonate, potassium carbonate, potassium phosphate, dipotassium hydrogen phosphate, etc. are preferably used. Can do. The solvent may be any solvent that does not adversely influence the reaction. For example, toluene, dichloromethane, tetrahydrofuran, N, N-dimethylformamide, 1,4-dioxane, methyl ethyl ketone, acetone, chloroform, 1,2-dichloroethane, xylene , Mesitylene, tert-butyl methyl ether and the like. This reaction suitably proceeds at 0 ° C to 100 ° C, particularly 30 ° C to 50 ° C.
  The step of amidating the cyano group of compound (IV) and compound (IV-a) obtained according to the present invention and the step of obtaining compound (V) from compound (IV-b) obtained according to the present invention include Synthesis can be performed according to the method described in Synthesis, pages 949-950 (1989). That is, the corresponding cyano compound can be carried out by using an oxidizing agent in the presence of a base and a dimethyl sulfoxide solvent. Examples of the base include potassium carbonate, potassium hydrogen carbonate, sodium carbonate, sodium hydrogen carbonate, lithium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, ammonium hydroxide and lithium hydroxide. Among these, potassium carbonate and Sodium hydroxide is preferred. As the dimethyl sulfoxide solvent, dimethyl sulfoxide can be used alone, but may be used by mixing with a solvent such as water, methanol, acetone, N, N-dimethylformamide, dichloromethane, toluene and the like. Examples of the oxidizing agent include hydrogen peroxide, sodium peroxide, hydrogen peroxide sodium carbonate adduct, lithium peroxide, and potassium peroxide. Of these, hydrogen peroxide is preferable. This reaction suitably proceeds at −30 ° C. to 120 ° C., particularly 10 ° C. to 60 ° C. In this reaction, potassium carbonate as the base, dimethyl sulfoxide as the solvent, and hydrogen peroxide water as the oxidizing agent are preferable.
  Further, the conversion of the obtained optically active α-amino nitrile compound into the corresponding optically active α-amino acid is carried out by a conventional method, for example, carboxyl group or ester group by hydrolysis reaction or esterification reaction of the cyano group. Can be done by converting to For example, the conversion to a carboxyl group can be performed in the presence of an acid or a base, in a solvent or in the absence of a solvent. As the acid, sulfuric acid, hydrochloric acid and the like can be preferably used. As the base, alkali metal hydroxide, alkali metal alkoxide and the like can be preferably used. The solvent may be any solvent that does not adversely influence the reaction, and examples thereof include dichloromethane, water, tetrahydrofuran, ethanol and the like. This reaction suitably proceeds at −30 ° C. to 200 ° C., particularly 0 ° C. to 100 ° C. The esterification reaction can be carried out by reacting the alcohol corresponding to the carboxyl group-containing compound obtained as described above in the presence of a dehydrating agent in an appropriate solvent or in the absence of a solvent. As the dehydrating agent, sulfuric acid, thionyl chloride, hydrochloric acid and the like can be suitably used. The solvent may be any solvent that does not adversely influence the reaction, and examples thereof include toluene, xylene, N, N-dimethylformamide, dioxane, tetrahydrofuran and the like. This reaction suitably proceeds at -20 ° C to 200 ° C, particularly 20 ° C to 120 ° C.
  The compound (VI) used or obtained in the present invention can be produced by subjecting the compound (V) to ring conversion. This reaction can be carried out in the absence of oxygen, for example, under an air stream such as nitrogen or argon. This reaction can be carried out in a suitable solvent or without a solvent. The solvent may be any solvent that does not adversely affect the reaction. For example, N, N-dimethylformamide, dimethyl sulfoxide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, or a mixed solvent thereof is appropriately used. be able to. This reaction suitably proceeds at 0 ° C to 200 ° C, particularly 80 ° C to 100 ° C.
  Further, ring conversion is performed in the presence of a base using the compound (IV-a) obtained in the present invention or using a compound obtained by amidating the cyano group of the compound (IV-a) by the above method. According to general formula (XII):

        Where R⁷Represents a cyano group or a carbamoyl group, and the other symbols have the same meaning as described above.
The disulfide compound shown by can be manufactured.
  Bases include alkali metal carbonates (sodium carbonate, potassium carbonate, etc.), alkali metal hydrogen carbonates (sodium bicarbonate, etc.), organic acid alkali metal salts (sodium acetate, etc.), alkali metal hydroxides (sodium hydroxide, potassium hydroxide, etc.) Etc.), alkali metal hydrides (such as sodium hydride), alkali metal amides (such as sodium amide, lithium amide), alkali metal alkoxides (such as sodium methoxide), alkali metal phosphates, alkali metals (such as sodium) or organic bases (Triethylamine, diisopropylethylamine, morpholine, N-methylmorpholine, pyridine, piperidine, dimethylaniline, dimethylaminopyridine, etc.) can be suitably used. Of these, sodium hydrogen carbonate and sodium acetate are particularly preferred.
  The amount of the base used is 0.1 molar equivalent to 100 molar equivalents, particularly 1 molar equivalent to 3 molar equivalents, relative to compound (IV-a) or a compound obtained by converting the cyano group of compound (IV-a) into an amide group. It is preferred to use.
  This reaction can be carried out in a suitable solvent or without a solvent. The solvent may be any solvent that does not adversely influence the reaction. For example, N, N-dimethylformamide, dimethyl sulfoxide, N, N-dimethylacetamide, N-methylpyrrolidine, or a mixed solvent thereof can be appropriately used. This reaction suitably proceeds at 0 to 200 ° C, particularly 80 to 100 ° C.
  Compound (XII) has optical isomers based on asymmetric carbon, but since only optically active (+)-biotin is biologically active, (+)-biotin is efficient. The 5 position of the imidazolidine ring is (-CH₂The optically active substance (for example, the following compound (XII-a)) in which the S configuration is bonded to the R configuration is preferable.
  In addition, to (+)-biotin, the compound (XII-a) or the compound (VII) is converted into the compound (VIII), and then disclosed in JP-A-8-231553, JP-A-2000-191665, Chemical Reviews ( Chemical Reviews), Vol. 97, No. 6, pp. 1755-1792, 1997, and the like, or a production method based thereon, for example, can also be produced as follows.

        In the formula, the symbols have the same meaning as described above.
  Furthermore, the conversion from compound (VI) to compound (VII) can be carried out by conventional methods, for example, by Nobuo Izumiya et al., “Basics and Experiments of Peptide Synthesis” (Maruzen Co., Ltd. 1985), Green et al. It can be carried out by hydrolysis by the method described in Protective Groups in Organic Synthesis (2nd edition) (Joan Willie & Sons 1991) or a method analogous thereto. Specifically, it can be converted into a carboxyl group by hydrolysis using a base such as an alkali metal hydroxide or alkali metal alkoxide, or an acid such as a mineral acid (hydrochloric acid, sulfuric acid or the like). The solvent may be any solvent that does not adversely influence the reaction, and examples thereof include acetic acid, water, ethanol, tetrahydrofuran, and dichloromethane. This hydrolysis reaction suitably proceeds at 0 ° C to 200 ° C, particularly 50 ° C to 80 ° C.
  Compound (VII) can be produced by reacting compound (XII-a) in the presence of a reducing agent and an acid, or sodium metal / liquid ammonia in a solvent or without solvent, and further converting a carbamoyl group to a carboxyl group. . As the reducing agent, zinc, iron or the like can be suitably used. As the acid, dilute acids such as acetic acid, hydrochloric acid and sulfuric acid can be preferably used. The solvent may be any solvent that does not adversely influence the reaction, and examples thereof include dichloromethane, benzene, toluene, tetrahydrofuran and the like. This reduction reaction suitably proceeds at 0 ° C to 200 ° C, particularly 80 ° C to 100 ° C. Conversion from a carbamoyl group to a carboxyl group can be performed by a conventional method.
  Compound (VIII) is obtained by subjecting compound (IV-c) to ring conversion and cyclization in the absence of oxygen, for example, in a stream of nitrogen or argon in a solvent or without solvent, or compound (VII) It can be produced by cyclization and epimerization in a solvent or without solvent.
  The solvent used in the step of ring conversion and cyclization of compound (IV-c) may be any solvent that does not adversely influence the reaction. For example, N, N-dimethylformamide, dimethyl sulfoxide, N, N-dimethylacetamide N-methyl-2-pyrrolidone and the like. This reaction suitably proceeds at 0 ° C to 200 ° C, particularly 80 ° C to 100 ° C.
  The cyclization and epimerization of compound (VII) in the present invention includes a step of cyclization and then epimerization (step via compound (VIII-a)) and a step of cyclization after epimerization (compound (VII-a) Any step of step)) is included.
  The cyclization step of compound (VII) can be preferably carried out in the presence of an activating agent. As the activator, DCC (dicyclohexylcarbodiimide), EDC.HCl (1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride), cyanuric chloride and the like can be preferably used. Moreover, a cyclization process can be implemented in presence of the base used at the following epimerization process as needed. The epimerization step can be preferably carried out only by heating in the presence of a base or without an additive. As the base, organic bases such as pyridine, DBU (1,8-diazabicyclo [5.4.0] undec-7-ene), triethylamine and the like can be preferably used. Moreover, an epimerization process can be implemented in presence of an acid (p-toluenesulfonic acid, hydrogen chloride, etc.) as needed.
  The solvent used in the cyclization and epimerization step may be any solvent that does not adversely influence the reaction, and examples thereof include pyridine, toluene, tetrahydrofuran, acetone, acetonitrile, ethanol and the like. This reaction suitably proceeds at -20 ° C to 120 ° C, particularly 0 ° C to 70 ° C.
  Compound (X) can be produced by reacting compound (VIII) and compound (IX) in the presence of a catalyst in a solvent or without a solvent, and then hydrolyzing the compound. As the catalyst, palladium hydroxide, palladium carbon, palladium black, tetrakistriphenylphosphine palladium, dichlorobistriphenylphosphine palladium, or the like can be suitably used. The hydrolysis reaction can be preferably carried out in the presence of water or an acid (p-toluenesulfonic acid, hydrochloric acid, sulfuric acid, etc.). The solvent may be any solvent that does not adversely influence the reaction, and examples thereof include tetrahydrofuran, N, N-dimethylformamide, toluene and the like. This reaction suitably proceeds at -20 ° C to 200 ° C, particularly 30 ° C to 50 ° C.
  Compound (XI), which is (+)-biotin, is obtained by reducing Compound (X) in a solvent or without a solvent and then hydrolyzing the compound (X).³¹And / or R⁵When is a group other than a hydrogen atom, the R³¹And / or R⁵Can be converted to a hydrogen atom (protection group deprotection reaction).
  The reduction reaction can be preferably carried out by hydrogenation in the presence of a catalyst such as palladium hydroxide, palladium carbon, palladium black, palladium chloride, palladium acetate and the like. The hydrolysis reaction can be suitably carried out by using a base such as sodium hydroxide. The solvent may be any solvent that does not adversely influence the reaction, and examples thereof include methanol, ethanol, tetrahydrofuran, water, or a mixed solvent thereof. This reaction suitably proceeds at 0 ° C to 200 ° C, particularly 50 ° C to 80 ° C.
  Further, R of compound (X)³¹And / or R⁵Is a group other than a hydrogen atom, the R³¹And / or R⁵The step of converting a hydrogen atom into a hydrogen atom (protection group deprotection reaction) can be carried out in a conventional manner, for example, Green et al. -It can carry out by the method described in And Sons 1991) or the method according to it. As a specific example, it can be suitably carried out by treating with hydrohalic acid such as hydrobromic acid or treating with mesitylene and an acid (methanesulfonic acid, sulfuric acid, etc.). The solvent may be any solvent that does not adversely influence the reaction, and examples thereof include water, benzene, toluene, dichloromethane and the like. This reaction suitably proceeds at 0 ° C to 200 ° C, particularly 80 ° C to 100 ° C.
  Compound (III) is a product of Bulletin of Chemical Society of Japan, Vol. 37, No. 2, pages 242-244, 1964, Analytical Biochemistry, Vol. Page, 1984, Heterocycles, Vol. 18, pages 259-263, 1982, etc., and can be produced by a known production method or a production method based thereon, for example, as follows. it can.

        Where X²Represents a halogen atom, and the other symbols have the same meaning as described above.
  The step of producing compound (2) from compound (1) and phenyl chloroformate (or alkyl chloroformate) can be carried out in the presence of a base or in the absence of a solvent. As the base, alkali metal hydroxide, alkali metal carbonate, alkali metal hydrogen carbonate, alkali metal alkoxide, organic base, and the like can be preferably used. The solvent may be any solvent that does not adversely influence the reaction, and examples thereof include toluene, benzene, xylene, tetrahydrofuran, 1,4-dioxane, diethyl ether, dichloromethane, water and the like. This reaction suitably proceeds at −30 ° C. to 120 ° C., particularly 20 ° C. to 50 ° C.
  R in the compound (3)⁵The compound having a substituent other than a hydrogen atom is a compound (2) and R⁵-X²(R⁵In the presence of a base and a highly polar solvent such as dimethyl sulfoxide in a solvent or without a solvent. As the base, alkali metal hydroxide, alkali metal carbonate, alkali metal hydrogen carbonate, alkali metal alkoxide, organic base, and the like can be preferably used. The solvent may be any solvent that does not adversely affect the reaction, and examples thereof include water, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, methanol and the like. This reaction suitably proceeds at -20 ° C to 120 ° C, particularly 15 ° C to 40 ° C.
  Compound (4) can be produced by reacting compound (3) with a reducing agent in the presence of an acid or an alkylating agent in a solvent or without a solvent. As the reducing agent, it is preferable to use sodium borohydride, lithium borohydride, lithium aluminum hydride, Red-Al (sodium bis (2-methoxyethoxy) aluminum hydride), diborane, borane methyl sulfide complex, and the like. it can. As the acid, sulfuric acid, hydrogen chloride, Lewis acid (trimethylsilyl chloride, iodine, chlorine, borane trifluoride ether complex, etc.) and the like can be suitably used. As the alkylating agent, dimethyl sulfate, methyl iodide, benzyl halide and the like can be suitably used. The solvent may be any solvent that does not adversely influence the reaction, and examples thereof include tetrahydrofuran and ethanol. This reaction suitably proceeds at -30 ° C to 120 ° C, particularly 0 ° C to 40 ° C.
  Compound (III) can be produced by reacting compound (4) in the presence of an oxidizing agent in a solvent or without a solvent. The oxidizing agent includes (1) dimethyl sulfoxide, sulfur trioxide pyridine complex salt and amine (diisopropylethylamine, triethylamine, etc.), (2) dimethyl sulfoxide, oxalyl chloride and amine (diisopropylethylamine, triethylamine, etc.), (3) Consisting of dimethyl sulfide, chlorine and amine (diisopropylethylamine, triethylamine, etc.), (4) sodium hypochlorite, sodium hydrogen carbonate, sodium bromide, and 4-hydroxytetramethylpiperidine oxide or derivatives thereof (4 -Aminotetramethylpiperidine oxide, 4-carboxytetramethylpiperidine oxide, 4-cyanotetramethylpiperidine oxide, etc.), (5) chromic acid and its salts, 6) Metal catalyst (platinum, palladium, etc.) and oxygen, (7) Peracid and peroxide, or (8) Dimethyl sulfoxide, dicyclohexylcarbodiimide, base (pyridine, etc.), acid (trifluoroacetic acid, phosphoric acid, etc.) ( Pfitzner-Moffatt oxidation) or the like can be preferably used. The solvent may be any solvent that does not adversely influence the reaction, and examples thereof include dimethyl sulfoxide, dichloromethane, water, benzene, toluene and the like. This reaction suitably proceeds at -78 ° C to 100 ° C, particularly at -78 ° C to 25 ° C.
  Compound (III) is obtained by halogenating the carboxyl group of compound (3) with thionyl chloride, oxalyl chloride, etc., and then catalytically reducing the compound (4) with a metal catalyst (platinum, palladium, etc.) and hydrogen. It can also be manufactured without going through.
  Compound (1), compound (2), compound (3), compound (4) and compound (III) used in the present invention have optical isomers based on asymmetric carbon, but are optically active. Since only (+)-biotin is biologically active, the following optically active substances are preferable in order to efficiently lead to (+)-biotin by the method of the present invention.

        In the formula, the symbols have the same meaning as described above.
  Compound (4) can be produced by a known production method described in Heterocycles, Vol. 18, pp. 259-263, 1982 or the like, or a production method analogous thereto, for example, as follows. You can also.

        In the formula, the symbols have the same meaning as described above.
  Compound (5) is prepared by combining cysteine and triphosgene (or phosgene, phenyl chloroformate, alkyl chloroformate, etc.) in the presence of a base (alkali metal hydroxide, alkali metal carbonate, alkali metal hydrogen carbonate, etc.) in a solvent or without solvent. In the presence of ethanol and an activator (thionyl chloride, sulfuric acid, hydrogen chloride, oxalyl chloride, etc.). As a solvent, what is necessary is just a solvent which does not exert a bad influence on reaction, For example, water, 1, 4- dioxane, tetrahydrofuran, diethyl ether etc. are mentioned. This reaction suitably proceeds at −20 ° C. to 100 ° C., particularly 0 ° C. to 40 ° C.
  In compound (6), R¹In which R 1 has a substituent other than a hydrogen atom, the compound (5) and R⁵-X²(R⁵In the presence of a base in a solvent or in the absence of a solvent. As the base, alkali metal carbonate, alkali metal hydride, alkali metal amide and the like can be preferably used. The solvent may be any solvent that does not adversely influence the reaction, and examples thereof include N, N-dimethylacetamide, acetone, acetonitrile, tetrahydrofuran and the like. This reaction suitably proceeds at −20 ° C. to 100 ° C., particularly 15 ° C. to 35 ° C.
  Compound (4) can be produced by reacting compound (6) in the presence of a reducing agent in a solvent or without a solvent. As the reducing agent, sodium borohydride, lithium borohydride, lithium aluminum hydride, Red-Al, DIBAL (diisobutylaluminum hydride), calcium borohydride, zinc borohydride and the like can be suitably used. The solvent may be any solvent that does not adversely influence the reaction, and examples thereof include ethanol, methanol, water, diethyl ether, tetrahydrofuran, 1,4-dioxane and the like. This reaction suitably proceeds at −78 ° C. to 50 ° C., particularly −20 ° C. to 20 ° C.
  Compound (III) can be produced by a known production method described in Journal of American Chemical Society, Vol. 112, pages 7050-7051, 1990, etc., or a production method according thereto. However, it can also be produced as follows, for example.

        In the formula, the symbols have the same meaning as described above.
  Compound (7) can be produced by reacting compound (3) with ethanethiol in the presence of an activator in a solvent or without solvent. As the activator, DCC, EDC · HCl, chlorocarbonates, isocyanuric chloride, CDI (carbonyldiimidazole) and the like can be suitably used. In this reaction, addition of DMAP (1,4-dimethylaminopyridine) is preferred because the reaction proceeds rapidly. The solvent may be any solvent that does not adversely influence the reaction, and examples thereof include acetonitrile, acetone, tetrahydrofuran, benzene, toluene and the like. This reaction suitably proceeds at −50 ° C. to 100 ° C., particularly 0 ° C. to 20 ° C.
  Compound (III) can be produced by reacting compound (7) in the presence or absence of a solvent in the presence of a reducing agent and a catalyst. As the reducing agent, silanes such as triethylsilane, trichlorosilane, and triphenylsilane can be suitably used. As the catalyst, palladium catalysts such as palladium hydroxide, palladium carbon, palladium black and the like can be suitably used. The solvent may be any solvent that does not adversely influence the reaction, and examples thereof include dichloromethane, acetone, tetrahydrofuran, and the like. This reaction suitably proceeds at −20 ° C. to 100 ° C., particularly 0 ° C. to 20 ° C.
  Furthermore, the method for producing the compound (IX) used in the present invention is described in HANDBOOK OF GRIGNAD REAGENTS, pages 53-77, 1996, ORGANOZINC REAGENTS in Organic Synthesis. ORGANIC SYNTHESIS), pages 18-67, 1996, etc., for example, it can also be produced using the following method.
  Compound (IX) is obtained by suspending zinc or magnesium in a solvent, adding chlorine, bromine, hydrogen chloride or hydrogen bromide, and then adding the compound represented by the general formula (XIII):

        In the formula, the symbols have the same meaning as described above.
It can be made to react with the compound shown by. Any solvent may be used as long as it does not adversely affect the reaction. Examples thereof include tetrahydrofuran, toluene, diethyl ether, 1,2-dimethoxyethane, acetonitrile, 1,4-dioxane, and a mixed solvent thereof is also used. be able to. This reaction suitably proceeds at −50 ° C. to 150 ° C., particularly 5 ° C. to 80 ° C. In particular, in this method, it is preferable to react using zinc in the presence of bromine.
  In addition, compound (IX) suspends zinc or magnesium in a solvent, and is represented by the general formula (XIV):

        In the formula, M represents a metal atom, Y represents iodine, bromine or chlorine.
And then reacting with compound (XIII). Any solvent may be used as long as it does not adversely affect the reaction. Examples thereof include tetrahydrofuran, toluene, diethyl ether, 1,2-dimethoxyethane, acetonitrile, 1,4-dioxane, and a mixed solvent thereof is also used. be able to. This reaction suitably proceeds at −50 ° C. to 150 ° C., particularly 5 ° C. to 80 ° C. Examples of the metal atom (M) of the salt (XIV) include typical metals and transition metals. Typical metals include lithium, sodium, potassium, cesium, magnesium, calcium, barium, aluminum, zinc, silicon, tin, etc., and transition elements include titanium, chromium, molybdenum, tungsten, manganese, iron, ruthenium, Examples include cobalt, rhodium, nickel, palladium, platinum, copper, and the like.
  R of Compound (I) and Compound (IV) used or obtained in the present invention¹And R²Are different from each other, may have an alkyl group which may have a substituent, an alkoxy group which may have a substituent, an alkenyl group which may have a substituent, and a substituent. An aryl group which may have a substituent, an amino group which may have a substituent, a heterocyclic group which may have a substituent, a cyano group, a carboxyl group, or a carbamoyl group which may have a substituent. Represent or R¹And R²Represents a group which is bonded to each other at the terminal to form a heterocyclic group which may have a substituent together with the adjacent asymmetric carbon atom.
  R¹And R²Examples of the substituent of the alkyl group which may have a substituent include: phenyl group, alkoxy group, dialkylamino group, alkylamino group, alkoxycarbonyl group, alkanoyl group, alkanoyloxy group, carbamoyl group, dialkylaminocarbonyl group An alkylaminocarbonyl group, a halogen atom, a hydroxyl group, a cyano group, an alkylthio group, an alkylsulfyl group, an alkylsulfonyl group, an alkanoylamino group, and the like. The substituents may be the same or different, and 1 to 3 substituents may be substituted.
  R¹And R²As the substituent of the alkoxy group which may have a substituent, a phenyl group, an alkoxy group, a dialkylamino group, an alkylamino group, an alkoxycarbonyl group, an alkanoyl group, an alkanoyloxy group, a carbamoyl group, a dialkylaminocarbonyl group , Alkylaminocarbonyl group, halogen atom, hydroxyl group, cyano group, alkylthio group, alkylsulfyl group, alkylsulfonyl group and the like. The substituents may be the same or different, and 1 to 3 substituents may be substituted.
  R¹And R²As the substituent of the alkenyl group that may have a substituent, a phenyl group, an alkoxy group, a dialkylamino group, an alkylamino group, an alkoxycarbonyl group, an alkanoyl group, an alkanoyloxy group, a carbamoyl group, a dialkylaminocarbonyl group , Alkylaminocarbonyl group, halogen atom, hydroxyl group, cyano group, alkylthio group, alkylsulfyl group, alkylsulfonyl group and the like. The substituents may be the same or different, and 1 to 3 substituents may be substituted.
  R¹And R²As the substituent of the aryl group which may have a substituent in the group, a hydroxyl group, a halogen atom, an alkoxy group, an alkyl group, an amino group, a nitro group, a cyano group, a dialkylamino group, an alkylamino group, a halogenoalkyl group, Examples include formyl group, phenyl group, carboxyl group, alkoxycarbonyl group, alkanoyl group and the like. The substituents may be the same or different, and 1 to 3 substituents may be substituted. Examples of the aryl group include a phenyl group, a naphthyl group, an anthracenyl group, and a phenanthrenyl group.
  R¹And R²Examples of the substituent of the amino group that may have a substituent include an alkyl group, an alkenyl group, an alkynyl group, an alkanoyl group, an alkoxycarbonyl group, a carbamoyl group, a thiocarbamoyl group, and the like. The substituents may be the same or different and may be substituted one to two.
  R¹And R²As the heterocyclic group of the heterocyclic group which may have a substituent, a heterocyclic group containing 1 to 4 atoms selected from a sulfur atom, a nitrogen atom and an oxygen atom as a hetero atom ( The heterocyclic group may have a substituent.). Examples of the heterocyclic group include saturated or unsaturated monocyclic or bicyclic heteroaromatic groups such as thienyl group, furyl group, tetrahydrofuryl group, pyranyl group, pyrrolyl group, imidazolyl group, pyrazolyl group, Isothiazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl Group, benzofuryl group, isobenzofuranyl group, chromenyl group, indolyl group, isoindolyl group, indazolyl group, purinyl group, quinolidinyl group, naphthyridinyl group, quinoxalinyl group, cinnolinyl group, quinolyl group, iso Noryl group, benzothiazolyl group, benzisothiazolyl group, quinazolinyl group, phthalazinyl group, benzoxazolyl group, benzimidazolyl group, pteridinyl group, pyridopyrimidinyl group, isochromanyl group, chromanyl group, indolinyl group, isoindolinyl group, tetrahydroquino group Examples include a ryl group, a tetrahydroisoquinolyl group, a tetrahydroquinoxalinyl group, and a dihydrophthalazinyl group. In addition, the substituent of the heterocyclic group includes a halogen atom, an alkoxy group, an alkanoyloxy group, a carbamoyl group, a halogenoalkyl group, a dialkylamino group, an alkoxycarbonyl group, a morpholinoalkyl group, a hydroxyalkyl group, an alkyl group, and benzyl. Examples thereof include an oxy group, an alkoxycarbonyl group, an alkanoyl group, a hydroxyl group, an oxo group, and a formyl group. The substituents may be the same or different, and 1 to 3 substituents may be substituted.
  R¹And R²Examples of the substituent of the carbamoyl group that may have a substituent include an alkyl group, an alkenyl group, an alkynyl group, an alkanoyl group, an alkoxycarbonyl group, a carbamoyl group, a thiocarbamoyl group, and the like.
  R¹And R²The heterocyclic group of the heterocyclic group which may have a substituent together with the adjacent asymmetric carbon atom bonded to each other at the terminal is an atom selected from a sulfur atom, a nitrogen atom and an oxygen atom as a hetero atom And includes, for example, pyrrolidinyl group, piperidinyl group, thiazolidinyl group, piperazinyl group, morpholinyl group, thiomorpholinyl group, imidazolinyl group, pyrazolidinyl group, tetrahydrofuranyl group, pyrazolinyl group, tetrahydropyrani group. Group, isochrominyl group, chromanyl group, indolinyl group, isoindolinyl group and the like. Examples of the substituent of the heterocyclic group include halogen atom, alkoxy group, alkanoyloxy group, carbamoyl group, halogenoalkyl group, dialkylamino group, alkoxycarbonyl group, morpholinoalkyl group, hydroxyalkyl group, benzyloxy group, alkoxycarbonyl. Group, an alkanoyl group, a hydroxyl group, an oxo group, a formyl group, or an alkyl group optionally substituted by 1 to 3 with a phenyl group which may have a substituent. The substituents of the heterocyclic group may be the same or different and may be substituted by 1 to 3. Examples of the substituent of the phenyl group which is a substituent of the alkyl group include groups selected from the same or different halogen atoms, alkyl groups and alkoxy groups, and these substituents are the same or different and are substituted by 1 to 3 groups. May be.
  Of these, R¹Represents a benzyl group, R²Represents a butoxycarbonylamino group or R¹And R²Are preferably bonded to each other at the terminal to form a thiazolidine ring substituted with at least an oxo group together with the adjacent asymmetric carbon atom.
  R of Compound (II) and Compound (IV) used or obtained in the present invention³As an alkyl group which may have a substituent, an alkoxy group which may have a substituent, an alkenyl group which may have a substituent, an aryl group which may have a substituent Is mentioned.
  R³Examples of the substituent of the alkyl group which may have a substituent include: phenyl group, alkoxy group, dialkylamino group, alkylamino group, alkoxycarbonyl group, alkanoyl group, alkanoyloxy group, carbamoyl group, dialkylaminocarbonyl group An alkylaminocarbonyl group, a halogen atom, a hydroxyl group, a cyano group, an alkylthio group, an alkylsulfyl group, an alkylsulfonyl group, an alkanoylamino group, and the like. The substituents may be the same or different, and 1 to 3 substituents may be substituted. Of these substituents, a phenyl group is preferred.
  R³As the substituent of the alkoxy group which may have a substituent, a phenyl group, an alkoxy group, a dialkylamino group, an alkylamino group, an alkoxycarbonyl group, an alkanoyl group, an alkanoyloxy group, a carbamoyl group, a dialkylaminocarbonyl group , Alkylaminocarbonyl group, halogen atom, hydroxyl group, cyano group, alkylthio group, alkylsulfyl group, alkylsulfonyl group and the like. The substituents may be the same or different, and 1 to 3 substituents may be substituted.
  R³As the substituent of the alkenyl group that may have a substituent, a phenyl group, an alkoxy group, a dialkylamino group, an alkylamino group, an alkoxycarbonyl group, an alkanoyl group, an alkanoyloxy group, a carbamoyl group, a dialkylaminocarbonyl group , Alkylaminocarbonyl group, halogen atom, hydroxyl group, cyano group, alkylthio group, alkylsulfyl group, alkylsulfonyl group and the like. The substituents may be the same or different, and 1 to 3 substituents may be substituted.
  R³As the substituent of the aryl group which may have a substituent in the group, a hydroxyl group, a halogen atom, an alkoxy group, an alkyl group, an amino group, a nitro group, a cyano group, a dialkylamino group, an alkylamino group, a halogenoalkyl group, Examples include formyl group, phenyl group, carboxyl group, alkoxycarbonyl group, alkanoyl group and the like. The substituents may be the same or different, and 1 to 3 substituents may be substituted. Examples of the aryl group include a phenyl group, a naphthyl group, an anthracenyl group, and a phenanthrenyl group.
  R³As, a benzyl group optionally having a substituent on the benzene ring, a benzhydryl group optionally having a substituent on the benzene ring, or a trityl optionally having a substituent on the benzene ring Group is preferable, examples of the substituent on the benzene ring of the benzhydryl group include groups selected from the same or different halogen atom, alkyl group and alkoxy group, and the substituent on the benzene ring of the trityl group is the same or different. Examples include groups selected from halogen atoms, alkyl groups, and alkoxy groups. On each benzene ring in the benzyl group, benzhydryl group or trityl group, 1 to 3 substituents may be the same or different.
  In addition, R³(1) The benzene ring may be substituted with a group selected from a halogen atom, an alkyl group and an alkoxy group, and (2) the benzene ring is substituted with a group selected from a halogen atom, an alkyl group and an alkoxy group. Preferred is a benzhydryl group which may be substituted, or (3) a trityl group in which the benzene ring may be substituted with a group selected from a halogen atom, an alkyl group and an alkoxy group, and in particular, a benzyl group, a benzhydryl group or a trityl group. What is group is preferable.
  R of Compound (II) and Compound (IV) used or obtained in the present invention⁴As a hydrogen atom, an alkyl group which may have a substituent, an alkoxy group which may have a substituent, an alkenyl group which may have a substituent, or a substituent. Good aryl groups are mentioned.
  R⁴Examples of the substituent of the alkyl group which may have a substituent include: phenyl group, alkoxy group, dialkylamino group, alkylamino group, alkoxycarbonyl group, alkanoyl group, alkanoyloxy group, carbamoyl group, dialkylaminocarbonyl group An alkylaminocarbonyl group, a halogen atom, a hydroxyl group, a cyano group, an alkylthio group, an alkylsulfyl group, an alkylsulfonyl group, an alkanoylamino group, and the like. The substituents may be the same or different, and 1 to 3 substituents may be substituted. Of these substituents, a phenyl group is preferred.
  R⁴As the substituent of the alkoxy group which may have a substituent, a phenyl group, an alkoxy group, a dialkylamino group, an alkylamino group, an alkoxycarbonyl group, an alkanoyl group, an alkanoyloxy group, a carbamoyl group, a dialkylaminocarbonyl group , Alkylaminocarbonyl group, halogen atom, hydroxyl group, cyano group, alkylthio group, alkylsulfyl group, alkylsulfonyl group and the like. The substituents may be the same or different, and 1 to 3 substituents may be substituted.
  R⁴As the substituent of the alkenyl group that may have a substituent, a phenyl group, an alkoxy group, a dialkylamino group, an alkylamino group, an alkoxycarbonyl group, an alkanoyl group, an alkanoyloxy group, a carbamoyl group, a dialkylaminocarbonyl group , Alkylaminocarbonyl group, halogen atom, hydroxyl group, cyano group, alkylthio group, alkylsulfyl group, alkylsulfonyl group and the like. The substituents may be the same or different, and 1 to 3 substituents may be substituted.
  R⁴As the substituent of the aryl group which may have a substituent in the group, a hydroxyl group, a halogen atom, an alkoxy group, an alkyl group, an amino group, a nitro group, a cyano group, a dialkylamino group, an alkylamino group, a halogenoalkyl group, Examples include formyl group, phenyl group, carboxyl group, alkoxycarbonyl group, alkanoyl group and the like. The substituents may be the same or different, and 1 to 3 substituents may be substituted. Examples of the aryl group include a phenyl group, a naphthyl group, an anthracenyl group, and a phenanthrenyl group.
  R⁴As a hydrogen atom, a benzyl group which may have a substituent on the benzene ring, a benzhydryl group which may have a substituent on the benzene ring, or a substituent on the benzene ring. The substituent on the benzene ring of the benzhydryl group is preferably a group selected from the same or different halogen atoms, alkyl groups and alkoxy groups, and the substituent on the benzene ring of the trityl group is preferable. As for, the group chosen from the same or different halogen atom, an alkyl group, and an alkoxy group is mentioned. On each benzene ring in the benzyl group, benzhydryl group or trityl group, 1 to 3 substituents may be the same or different.
  In addition, R⁴(1) a hydrogen atom, (2) a benzyl group in which the benzene ring may be substituted with a group selected from a halogen atom, an alkyl group and an alkoxy group, and (3) a benzene ring from a halogen atom, an alkyl group and an alkoxy group. Preferred is a benzhydryl group optionally substituted with a selected group, or (4) a trityl group optionally substituted with a group selected from a halogen atom, an alkyl group and an alkoxy group, particularly a hydrogen atom, benzyl A group, a benzhydryl group or a trityl group is preferred.
  R of compound (IX) and compound (X) used or obtained in the present invention⁶Examples thereof include an esterified carboxyl group or an amidated carboxyl group, and among them, an alkoxycarbonyl group or an alkylcarbamoyl group is preferable, and an alkoxycarbonyl group is more preferable.
  Compound (II-a), Compound (IV-a), Compound (IV-b), Compound (IV-c), Compound (V), Compound (VI), Compound (VII) used or obtained in the present invention R of compound (VII-a), compound (VIII), compound (VIII-a), compound (X), compound (XII) and compound (XII-a)³¹As, a benzyl group optionally having a substituent on the benzene ring, a benzhydryl group optionally having a substituent on the benzene ring, or a trityl optionally having a substituent on the benzene ring The substituent on the benzene ring of the benzyl group includes a group selected from a halogen atom, an alkyl group and an alkoxy group, and the substituent on the benzene ring of the benzhydryl group is the same or A group selected from different halogen atoms, alkyl groups and alkoxy groups can be mentioned, and examples of the substituent on the benzene ring of the trityl group include groups selected from the same or different halogen atoms, alkyl groups and alkoxy groups. On each benzene ring in the benzyl group, benzhydryl group or trityl group, 1 to 3 substituents may be the same or different. Of these, R³¹(1) The benzene ring may be substituted with a group selected from a halogen atom, an alkyl group and an alkoxy group, and (2) the benzene ring is substituted with a group selected from a halogen atom, an alkyl group and an alkoxy group. A benzhydryl group which may be substituted, or (3) a trityl group in which the benzene ring may be substituted with a group selected from a halogen atom, an alkyl group and an alkoxy group is preferred, and further a benzyl group, a benzhydryl group or a trityl group. In particular, a benzyl group is preferred.
  Compound (III), Compound (III-a), Compound (IV-a), Compound (IV-b), Compound (IV-c), Compound (V), Compound (VI) used or obtained in the present invention ), Compound (VII), Compound (VII-a), Compound (VIII), Compound (VIII-a), Compound (X), Compound (XII), Compound (XII-a), Compound (3), Compound ( 3-a), R of compound (4), compound (4-a), compound (6) and compound (7)⁵As a hydrogen atom, a benzyl group which may have a substituent on the benzene ring, a benzhydryl group which may have a substituent on the benzene ring, or a substituent on the benzene ring. Among them, (1) a hydrogen atom, (2) a benzyl group in which the benzene ring may be substituted with a group selected from a halogen atom, an alkyl group and an alkoxy group, (3 ) The benzene ring may be substituted with a group selected from a halogen atom, an alkyl group and an alkoxy group, or (4) the benzene ring is substituted with a group selected from a halogen atom, an alkyl group and an alkoxy group. Preferred is a trityl group, more preferably a benzyl group, a benzhydryl group or a trityl group, and particularly preferably a benzyl group.
  In the present invention, when compound (IV-b) is produced from compound (III-a), R³¹As, a benzyl group optionally having a substituent on the benzene ring, a benzhydryl group optionally having a substituent on the benzene ring, or a trityl optionally having a substituent on the benzene ring Of the group R⁵As a hydrogen atom, a benzyl group which may have a substituent on the benzene ring, a benzhydryl group which may have a substituent on the benzene ring, or a substituent on the benzene ring. And those having a trityl group may be mentioned.³¹And R⁵Examples of the substituent on the benzene ring of the benzhydryl group include groups selected from the same or different halogen atoms, alkyl groups and alkoxy groups, and examples of the substituent on the benzene ring of the trityl group include the same or different halogen atoms, Examples include groups selected from alkyl groups and alkoxy groups. On each benzene ring in the benzyl group, benzhydryl group or trityl group, 1 to 3 substituents may be the same or different. Of these, R³¹(1) The benzene ring may be substituted with a group selected from a halogen atom, an alkyl group and an alkoxy group, and (2) the benzene ring is substituted with a group selected from a halogen atom, an alkyl group and an alkoxy group. A benzhydryl group which may be substituted, or (3) a trityl group in which the benzene ring may be substituted with a group selected from a halogen atom, an alkyl group and an alkoxy group, R⁵(1) a hydrogen atom, (2) a benzyl group in which the benzene ring may be substituted with a group selected from a halogen atom, an alkyl group and an alkoxy group, and (3) a benzene ring from a halogen atom, an alkyl group and an alkoxy group. Preferred is a benzhydryl group optionally substituted with a selected group, or (4) a trityl group optionally substituted with a group selected from a halogen atom, an alkyl group and an alkoxy group, and R³¹Is a benzyl group, a benzhydryl group or a trityl group, and R⁵Are preferably a hydrogen atom, a benzyl group, a benzhydryl group or a trityl group.³¹And R⁵Are the same or different and are preferably a benzyl group, a benzhydryl group or a trityl group.³¹And R⁵Are preferably benzyl groups.
  In the present invention, when compound (XI) is produced from compound (IV-b), R^{3 1}As, a benzyl group optionally having a substituent on the benzene ring, a benzhydryl group optionally having a substituent on the benzene ring, or a trityl optionally having a substituent on the benzene ring Of the group R⁵As a hydrogen atom, a benzyl group which may have a substituent on the benzene ring, a benzhydryl group which may have a substituent on the benzene ring, or a substituent on the benzene ring. May be those of a trityl group, and R⁶As examples thereof, those having an esterified carboxyl group or an amidated carboxyl group can be mentioned.³¹And R⁵Examples of the substituent on the benzene ring of the benzyl group include groups selected from the same or different halogen atoms, alkyl groups and alkoxy groups. Examples of the substituent on the benzene ring of the benzhydryl group include the same or different halogen atoms, Examples include a group selected from an alkyl group and an alkoxy group, and examples of the substituent on the benzene ring of the trityl group include groups selected from the same or different halogen atoms, alkyl groups, and alkoxy groups. On each benzene ring in the benzyl group, benzhydryl group or trityl group, 1 to 3 substituents may be the same or different. Of these, R³¹(1) The benzene ring may be substituted with a group selected from a halogen atom, an alkyl group and an alkoxy group, and (2) the benzene ring is substituted with a group selected from a halogen atom, an alkyl group and an alkoxy group. A benzhydryl group which may be substituted, or (3) a trityl group in which the benzene ring may be substituted with a group selected from a halogen atom, an alkyl group and an alkoxy group, R⁵(1) a hydrogen atom, (2) a benzyl group in which the benzene ring may be substituted with a group selected from a halogen atom, an alkyl group and an alkoxy group, and (3) a benzene ring from a halogen atom, an alkyl group and an alkoxy group. A benzhydryl group optionally substituted with a selected group, or (4) a trityl group optionally substituted with a group selected from a halogen atom, an alkyl group and an alkoxy group, R⁶Is preferably an alkoxycarbonyl group or an alkylcarbamoyl group, and further R³¹And R⁵Are the same or different and are a benzyl group, a benzhydryl group or a trityl group, R⁶Are preferably alkoxycarbonyl groups, particularly R³¹And R⁵Are both benzyl groups, R⁶Is preferably an alkoxycarbonyl group.
  Compound (II), Compound (II-a), Compound (IV), Compound (IV-a), Compound (IV-b), Compound (IV-c), Compound (V) used or obtained in the present invention ), Compound (VII), compound (VII-a) or a salt of the compound represented by compound (IX), for example, an inorganic salt (hydrochloride, phosphate, hydrobromide, sulfate, etc.) or Organic acids (acetate, formate, propionate, fumarate, maleate, succinate, tartrate, citrate, malate, succinate, benzoate, methanesulfonate, benzenesulfone Acid salts, tosylate salts, etc.). Further, when the compound of the present invention has an acidic group such as a carboxylic acid, the compound of the present invention may be an inorganic base (an alkali metal salt such as sodium salt or potassium salt, an alkaline earth such as calcium salt or magnesium salt). Metal salts, ammonium salts, etc.) or organic bases (amino acid salts such as triethylamine salts, lysine salts, etc.) may be formed. The educt and the salt can be converted into each other by a known method or a method analogous thereto.
  In the present specification, examples of the alkyl group or alkoxy group include linear or branched ones having 1 to 6 carbon atoms, particularly linear or branched ones having 1 to 4 carbon atoms. Examples of the alkenyl group, alkynyl group, alkanoyl group, alkoxycarbonyl group or alkylthiocarbonyl group include those having a linear or branched chain having 2 to 7 carbon atoms, particularly those having a linear or branched chain having 2 to 5 carbon atoms. . Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  Next, the present invention will be described in more detail based on examples, but the present invention is not limited to such examples.

(1) 40 g of (4R) -3-benzyl-4-hydroxymethylthiazolidine-2-one was dissolved in 90 ml of dimethyl sulfoxide and 70 ml of ethyl acetate, and 2.92 ml of pyridine and 2.78 ml of trifluoroacetic acid were added at room temperature. To this solution, 44.4 g of dicyclohexylcarbodiimide was added at room temperature, and 20 ml of ethyl acetate was further added so that the temperature of the solution did not exceed 43 ° C. After confirming that the temperature of the solution began to drop, the solution was stirred at 50 ° C. for 3 hours. 200 ml of ethyl acetate was further added to this solution, and after ice cooling for 1 hour, the precipitate was filtered off and washed with 40 ml of ice-cooled ethyl acetate. The filtrate was washed with 200 ml of 12% brine and separated, and the aqueous layer was re-extracted with 100 ml of ethyl acetate. The ethyl acetate layers were combined, and further washed with 200 ml of 12% brine to obtain (4R) -2-oxo-3-benzylthiazolidine-4-carbaldehyde in the ethyl acetate layer ((4R) -2- Oxo-3-benzylthiazolidine-4-carbaldehyde 90.3%: (4R) -3-benzyl-4-hydroxymethylthiazolidine-2-one 4.8%).
(HPLC conditions)
Column: Capcell Pack C18 (SG120A 4.6 × 150 mm) [manufactured by Shiseido], moving layer: 15 mM sodium diphosphate buffer: acetonitrile = 5: 1, flow rate: 1 ml / min, UV detection: 220 nm, column temperature 40 ° C. .
(2) Water (2 v / w) and 18.6 g of sodium bisulfite were added to an ethyl acetate solution of (4R) -2-oxo-3-benzylthiazolidine-4-carbaldehyde obtained in (1) above at 25 ° C. In addition, the mixture was stirred for 30 minutes. Ethyl acetate was evaporated under reduced pressure, ethyl acetate (2 v / w) was added, and the mixture was stirred at 25 ° C. for 17 hours and a half. The precipitate was separated by filtration, and the aqueous layer and the ethyl acetate layer were separated to obtain (4R) -2-oxo-3-benzylthiazolidine-4-carbaldehyde bisulfite adduct in the aqueous layer. When the aqueous layer was analyzed under the following HPLC conditions, the yield was 89.3%. In addition, (4R) -2-oxo-3-benzylthiazolidine-4-carbaldehyde bisulfite adduct was isolated from the aqueous layer, and (1R) -1-[(4S) -3-benzyl-2-oxo was isolated. Thiazolin-4-yl] -1-hydroxymethylsulfonic acid sodium salt was obtained.
Melting point: 121-123 ° C
[Α] _D ²⁶ : −75.5 ° (c = 1.0, N, N-dimethylformamide)
(HPLC conditions)
Column: Capcell Pack C18 (SG120A 4.6 × 150 mm) [manufactured by Shiseido], moving layer: 15 mM sodium diphosphate buffer: acetonitrile = 5: 1, flow rate: 1 ml / min, UV detection: 220 nm, column temperature 40 ° C. .
(3) Add 106 ml of dichloromethane to the aqueous solution of (4R) -2-oxo-3-benzylthiazolidine-4-carbaldehyde bisulfite adduct obtained in (2) above, and add 29.2 g of benzylamine at 10 ° C. or lower. added. The solution was gradually warmed and stirred at 20 ° C. for 2 hours, then the solution was cooled again to 8 ° C., 9.4 g of sodium cyanide was added, and the mixture was stirred at 20 ° C.-25 ° C. for 20 hours. Further, 6.34 g of sodium bisulfite and 2.35 g of sodium cyanide were added to the solution and stirred for 1 hour and a half. The solution was separated by adding 40 ml of water and 40 ml of dichloromethane. The aqueous layer was re-extracted again with 40 ml of dichloromethane, and the combined organic layer was dehydrated and filtered with magnesium sulfate and concentrated to give (4R) -4- [1- (N-benzylamino) -1-cyanomethyl] -3. -The syn-isomer 46.91g and anti-isomer 4.15g of benzyl thiazolidine-2-one were obtained, respectively.

The compound obtained in Example 1- (3) was suspended in 113 ml of toluene, and 5,4 ml of water and 56 ml of concentrated sulfuric acid were added under ice cooling, followed by stirring at 42 ° C. for 19 hours. 5 ml of concentrated sulfuric acid was added, and the mixture was further stirred for 5 hours. At 40 ° C. or lower, 28 ml of water, 163 ml of acetone, and 185 ml of water were sequentially added to the solution. Subsequently, 185 ml of concentrated aqueous ammonia was added to the solution at 40 ° C. or lower, and the mixture was stirred at 5 ° C. for 60 minutes. The precipitated crystals are collected by filtration, washed with acetone, water and acetone in this order, and dried to give (4R) -4-[(1R) -1- (N-benzylamino) -1-carbamoylmethyl] -3. -43.9 g of benzylthiazolidine-2-one was obtained as pale yellow crystals.
Melting point: 194-195 ° C
ESI · MS (m / z): 356 (M ⁺ +1)
[Α] ^{_{D 20: -38.8 ° (C =}} 0.45, N, N- dimethylformamide).

100 g of (4R) -4-[(1R) -1- (N-benzylamino) -1-carbamoylmethyl] -3-benzylthiazolidine-2-one was dissolved in 200 ml of N, N-dimethylformamide and flowed under a nitrogen stream. And stirred at 85 ° C. for 5 hours. At 90 ° C. to 95 ° C., 200 ml of 35% hydrochloric acid was added dropwise to the solution and stirred for 1 hour and 15 minutes. Furthermore, 100 ml of 35% hydrochloric acid was added dropwise and stirred for 2 hours. Subsequently, 200 ml of water was added dropwise at 85 ° C. The solution is ice-cooled, and the precipitated crystals are collected by filtration, washed with water, and dried at 50 ° C. for 17 hours to give (4R, 5R) -1,3-dibenzyl-2-oxo-5- (mercaptomethyl). ) 93.1 g of imidazolidine-4-carboxylic acid was obtained as colorless crystals.
Melting point: 159-160 ° C
ESI · MS (m / z): 357 (M ⁺ +1)
[Α] _D ²⁰ : + 48.8 ° (C = 0.62, N, N-dimethylformamide).

To a 240 ml chloroform solution of 30 g of (4R, 5R) -1,3-dibenzyl-2-oxo-5- (mercaptomethyl) imidazolidine-4-carboxylic acid, 22.7 g of pyridine and 2.6 ml of trifluoroacetic acid, dicyclohexylcarbodiimide was added. A solution of 17.4 g of chloroform in 60 ml was added dropwise at 5 ° C. over 30 minutes. The solution was refluxed for 5 hours and then concentrated under reduced pressure. After concentration by substitution twice with ethyl acetate, 300 ml of ethyl acetate was added to the residue, and the mixture was stirred at 50 ° C. for 30 minutes. After cooling to 25 ° C., insoluble matters were filtered off. After the filtrate was concentrated, 85 ml of methanol was added and dissolved by heating. After cooling the solution, the precipitated crystals were collected by filtration and washed with cold methanol. The precipitated crystals were blown and dried at 50 ° C. to give 21.3 g of (3aS, 6aR) -1,3-dibenzyl-hexahydro-4H-thieno [3,4-d] imidazole-2,4-dione as colorless crystals. Got as.
Melting point: 122-123 ° C
[Α] _D ²⁵ : + 90.5 ° (C = 1.0, chloroform).

  Under a nitrogen atmosphere, 30.4 g of zinc powder was suspended in 55 ml of tetrahydrofuran, 3.5 ml of trimethylsilyl chloride was added, and the mixture was stirred for 15 minutes. After heating to 40 ° C., 102.9 g of 5-iodovaleric acid ethyl ester was added dropwise. Although heat was generated simultaneously with the dropwise addition, the dropwise addition was continued so as to maintain a temperature of 60 ° C to 65 ° C. After completion of the dropwise addition, the mixture was washed with 5 ml of tetrahydrofuran, immersed in an outer bath at 55 ° C. and continuously stirred (total time for dropwise addition and stirring: 50 minutes). Cooled to 23 ° C. 125 ml of toluene, (3aS, 6aR) -1,3-dibenzyl-hexahydro-4H-thieno [3,4-d] imidazole-2,4-dione 52.5 g, 1.09 g of 10% palladium hydroxide carbon, Toluene 50 ml and N, N-dimethylformamide 11.5 ml were sequentially added, and the mixture was stirred at 24 ° C. to 35.5 ° C. for 50 minutes. The reaction solution was filtered using 12 g of activated carbon and 32.5 g of celite, and washed with 200 ml of tetrahydrofuran. The filtrate and washings were combined, washed with 2M hydrochloric acid, washed with water, and concentrated. The residue was dissolved in 390 ml of toluene, 2.95 g of p-toluenesulfonic acid monohydrate was added, and the mixture was stirred at 20 ° C. to 25 ° C. for 1.5 hours. About 100 ml of the solvent was distilled off at 40 ° C. to 45 ° C., and the remainder was washed with water, an aqueous solution of sodium thiosulfate and water in this order, and further concentrated to give (5Z) -5-[(3aS, 6aR) -1,3. 60.6 g of -dibenzyl-hexahydro-2-oxo-4H-thieno [3,4-d] imidazol-4-ylidene] pentanoic acid ethyl ester were obtained as an oil.

  400 ml of purified water, 12.85 g of 20% palladium hydroxide on carbon, (5Z) -5-[(3aS, 6aR) -1,3-dibenzyl-hexahydro-2-oxo-4H-thieno [3,4-d] imidazole -4-ylidene] pentanoic acid ethyl ester 249.5 g of methanol 900 ml solution was added in that order, and the mixture was replaced with hydrogen 490 kPa three times. Further, 627 kPa hydrogen pressure was applied at 6.5 ° C., and the mixture was stirred at 500 rpm. 50 minutes after the start of heating, 92.5 ° C. and 843 kPa, 4 hours later, 117 ° C. and 921 kPa, and 11 hours later, 116 ° C. and 853 kPa, so hydrogen was added to 882 kPa. After 24 hours, the reaction solution was cooled at 115 ° C. and 892 kPa, washed with methanol, and the catalyst was filtered. The filtrate was concentrated, and 400 ml of toluene was added to the residue, followed by displacement concentration three times at 65 ° C. in the outer bath. To the above residue, 1206 ml of methanol, 402 ml of water and 53.3 g of sodium hydroxide were added and stirred at 40 ° C. for 2 hours. 300 g of 10% aqueous hydrochloric acid was added to the reaction solution to neutralize the pH to 7, 6 g of activated carbon was added, and the mixture was stirred at room temperature for 40 minutes. The reaction solution was precoated and filtered with 6 g of activated carbon. Methanol was distilled off under reduced pressure, and 600 ml of ethyl acetate was added. 10% aqueous hydrochloric acid was added for extraction (pH of the aqueous layer was 0.7), and the organic layer was washed with 10% brine. The organic layer was dried over magnesium sulfate and filtered. The extract was concentrated under reduced pressure, and when ethyl acetate no longer flew off, it was substituted and concentrated twice with 170 ml of mesitylene, and (3aS, 4S, 6aR) -1,3-dibenzyl-hexahydro-2-oxo-4H-thieno [3,4- d] 170.1 g of imidazole-4-pentanoic acid was obtained as a colorless oil.

  3.0 g of (3aS, 4S, 6aR) -1,3-dibenzyl-hexahydro-2-oxo-4H-thieno [3,4-d] imidazol-4-pentanoic acid and 24 ml of 48% hydrobromic acid were added to 110 The mixture was heated at reflux from 48 to 120 ° C. for 48 hours. Hot extraction with 10 ml of toluene was performed 4 times to remove benzyl bromide. The aqueous layer was concentrated, and 15 ml of water and 11.5 ml of 6M aqueous sodium hydroxide solution were added to the residue. Subsequently, 3.36 g of ethoxycarbonyl chloride was added dropwise, the pH was kept at 8-10, and the reaction was performed at room temperature for 3 hours. . Thereafter, the reaction solution was heated to 70 ° C. to 80 ° C. and reacted for 20 hours (during this time, a 6M aqueous sodium hydroxide solution was added to maintain the pH at 12). The pH was adjusted to 7.4 to 7.8 with 7 ml of 16% hydrochloric acid, and filtration was performed using 1.0 g of activated carbon at 90 to 95 ° C. The filtrate was heated to 80 ° C. to 85 ° C., adjusted to pH 1.8 to 2.2 using 6 ml of 16% hydrochloric acid, and neutralized crystallization was performed. After cooling, it was collected by filtration, washed with water, and dried by blowing at 50 ° C. to obtain 1.38 g of (+)-biotin as colorless crystals.

20 g of (4R, 5R) -1,3-dibenzyl-2-oxo-5- (mercaptomethyl) imidazolidine-4-carboxylic acid was dissolved in 160 ml of chloroform, 6.2 g of pyridine was added, and dicyclohexylcarbodiimide 12 was added under ice cooling. A solution of 0.7 g of chloroform in 40 ml was added at 15 ° C. or lower. The mixture was stirred at room temperature for 1 hour, and ethyl acetate was added to the reaction solution, followed by filtration. The filtrate was washed with 2M hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate, and saturated brine. The organic layer was dried and concentrated. The residue was recrystallized with ethyl acetate to obtain 8.0 g of (3aR, 6aR) -1,3-dibenzyl-hexahydro-4H-thieno [3,4-d] imidazole-2,4-dione.
Melting point: 115-116 ° C
[Α] _D ²⁶ : + 10.6 ° (C = 1.0, chloroform).

100 mg of (3aR, 6aR) -1,3-dibenzyl-hexahydro-4H-thieno [3,4-d] imidazole-2,4-dione is dissolved in 1 ml of chloroform, 0.5 ml of pyridine is added, and the mixture is stirred at room temperature for 23 hours. did. The reaction mixture was washed with 2M hydrochloric acid, water, saturated sodium bicarbonate, and saturated brine. The organic layer was dried and concentrated. By adding isopropyl ether and filtering the precipitated crystals, 75.1 mg of (3aS, 6aR) -1,3-dibenzyl-hexahydro-4H-thieno [3,4-d] imidazole-2,4-dione was obtained. Obtained.
Melting point: 122-123 ° C
[Α] _D ²⁵ : + 90.5 ° (C = 1.0, chloroform).

  23.5 g of (4R) -4-[(1R) -1- (N-benzylamino) -1-cyanomethyl] -3-benzylthiazolin-2-one was dissolved in 210 ml of dimethyl sulfoxide, and potassium carbonate (fine powder) 1.35 g was added, and 12 ml of 30% hydrogen peroxide was added dropwise at 20 ° C. to 25 ° C., followed by stirring at room temperature for 1 hour. An additional 12 ml of 30% aqueous hydrogen peroxide was added to the solution and stirred at 20 ° C. for 13 hours, and then 210 ml of water was added at room temperature and stirred for 3 hours. The precipitated crystals were collected by filtration, washed with water and acetone, and then air-dried overnight at 50 ° C. to give colorless powder of (4R) -4-[(1R) -1- (N-benzylamino) -1 -Carbamoylmethyl] -3-benzylthiazolin-2-one 21.8 g was obtained. The physical property values of this product coincided with those of Example 2.

(1) 92.8 g of zinc powder was suspended in a mixed solution of 180 ml of tetrahydrofuran and 120 ml of toluene, 58 g of bromine was added at 10 ° C. to 37 ° C. over 15 minutes, and the solution was heated to 50 ° C. over 15 minutes. To the solution, 186.4 g of 5-iodovaleric acid ethyl ester was added dropwise at 50 ° C. to 55 ° C. over 3.5 hours.
(2) After cooling the solution obtained in Example 11- (1) to 30 ° C., 360 ml of toluene, (3aS, 6aR) -1,3-dibenzyl-hexahydro-4H-thieno [3,4-d] imidazole 176 g of 2,4-dione and 4.8 g of N, N-dimethylformamide 44 ml suspension in the order of 176 g of palladium catalyst (Degussa; E 1002 NN / D 10% Pd) were added at 28 ° C. to 40 ° C. for 17 hours. Stir. Hydrochloric acid (concentrated hydrochloric acid 157 ml + water 184 ml) was added to the solution at 10 ° C. to 30 ° C., and the mixture was stirred at 20 ° C. for 1 hour. After filtering the solution, the filtrate was heated to 40 ° C. over 40 minutes and separated. The organic layer was washed with water, an aqueous sodium hydrogen carbonate solution, an aqueous sodium bisulfite solution, and water in this order and concentrated. Toluene was added to the residue and further concentrated. After the residue was dissolved in 67 ml of methanol, 6.7 g of activated carbon was added, stirred and filtered. The residue was washed with 67 ml of methanol, combined with the filtrate and used in the next step.
The product obtained in the above reaction was partially saponified to give (5Z) -5-[(3aS, 6aR) -1,3-dibenzyl-hexahydro-2-oxo-4H-thieno [3,4-d] imidazole- 4-Ilidene] pentanoic acid was quantified by HPLC under the following conditions to obtain (5Z) -5-[(3aS, 6aR) -1,3-dibenzyl-hexahydro-2-oxo-4H- It was confirmed that 220 g of thieno [3,4-d] imidazol-4-ylidene] pentanoic acid ethyl ester was obtained.
(HPLC conditions)
Column: L-column ODS (4.6 × 150 mm) (manufactured by Shimadzu Corporation), moving bed: acetonitrile / potassium hydrogen diphosphate (pH 3) = 40/60, flow rate: 1.0 ml / min, UV detection: 254 nm, Column temperature 40 ° C
(3) 88 ml of the methanol solution obtained in Example 11- (2) was added with 313 ml of methanol, 110 ml of water and 9.06 g of palladium catalyst (Degussa; E 106 NN / W5% Pd), hydrogen pressure 9 khPa, internal temperature Stir at 110 ° C. for 16 hours. After cooling the solution, the catalyst was filtered and washed with 350 ml of methanol. A sodium hydroxide aqueous solution (14.6 g of sodium hydroxide + 55 ml of water) was added to the filtrate, and the mixture was stirred at 50 ° C. for 1 hour. To the solution was added 10% hydrochloric acid at 30 ° C. or lower until pH 7, and then concentrated. Toluene was added to the residue and further concentrated. The residue was dissolved in 300 ml of toluene and then washed with 10% hydrochloric acid and water while heating at 40 ° C. (3aS, 4S, 6aR) -1,3-dibenzyl-hexahydro-2-oxo-4H-thieno [3,4-d] imidazole obtained by the above reaction by quantifying the organic layer by HPLC under the following conditions It was confirmed that 52 g of -4-pentanoic acid was obtained.
(HPLC conditions)
Column: L-column ODS (4.6 × 150 mm) (manufactured by Shimadzu Corporation), moving bed: acetonitrile / potassium hydrogen diphosphate (pH 3) = 40/60, flow rate: 1.0 ml / min, UV detection: 254 nm, Column temperature 40 ° C.
(4) After concentrating the toluene solution obtained in Example 11- (3), it was substituted and concentrated with mesitylene. The residue was dissolved in 166 ml of mesitylene, 108 ml of methanesulfonic acid was added, and the mixture was stirred at 133 ° C. for 1 hour. The solution was cooled to 80 ° C., 15 ml of acetic acid was added, and the solution was added dropwise to 1040 ml of purified water at 30 ° C. or lower. The solution was cooled with ice for 1 hour, and the precipitated crystals were collected by filtration, washed with water and acetone, and dried under reduced pressure to obtain 25.7 g of crude biotin.
24.6 g of crude biotin was dissolved in an aqueous sodium hydroxide solution (4.42 g of sodium hydroxide + 330 ml of water) and adjusted to pH 8.5 with dilute hydrochloric acid at 50 ° C. to 60 ° C. The solution was added with 16 g of activated carbon at 50 ° C. to 60 ° C., stirred for 10 minutes, and then filtered. The filtrate was heated to 90 ° C. to 95 ° C., the solution was adjusted to pH 1.8-2.2 with concentrated hydrochloric acid, and neutralized crystallization was performed. The mixture was stirred at the same temperature for 30 minutes to grow crystals. The solution was slowly cooled and ice-cooled, and the precipitated crystals were filtered off. The crystals were air-dried at 50 ° C. overnight to obtain 22.4 g of (+)-biotin.
Reference example 1
(1) 175.6 g of L-cysteine-hydrochloride monohydrate was dissolved in a solution of 184.0 g of sodium hydroxide in 0.88 liters of water under ice-cooling, and phenyl chloroformate 313 was added within a range not exceeding 30 ° C. 0.2 g of a 0.35 liter solution of toluene was added dropwise. After stirring for 2 hours at room temperature, the solution was allowed to stand for liquid separation. The aqueous layer was washed with 0.35 liter of toluene, separated, and the aqueous layer was concentrated to obtain 139.84 g of (4R) -2-oxothiazolidine-4-carboxylic acid as colorless crystals.
Melting point: 168-170 ° C
MS · APCI (m / z): 148 (M ⁺ +1)
[Α] _D ²⁵ : −62.8 ° (C = 1.0, H ₂ O).
(2) To 1.47 g of the compound obtained in Reference Example 1- (1), a solution of 0.6 g of sodium hydroxide in 1.5 ml of water and 4.4 ml of dimethyl sulfoxide were sequentially added under ice cooling. Thereto was added 2.3 ml of benzyl chloride at room temperature, and the mixture was stirred for 15 hours. The mixture was neutralized with dilute hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, insolubles were filtered off and concentrated to give 2.24 g of (4R) -2-oxo-3-benzylthiazolidine-4-carboxylic acid. Was obtained as colorless crystals.
Melting point: 95-97 ° C
MS · APCI (m / z): 238 (M ⁺ +1)
[Α] _D ²⁵ : -102.2 ° (C = 1.0, chloroform).
(3) Sodium borohydride (1.53 g) was added to tetrahydrofuran (32 ml) at room temperature and cooled to 10 ° C. Thereto was added 8.0 g of the compound obtained in Reference Example 1- (2), further 2 g of tetrahydrofuran in 2.0 g of sulfuric acid was added, and the mixture was stirred at 40 ° C. to 50 ° C. for 3 hours. 2M hydrochloric acid was added until. The reaction solution was diluted with ethyl acetate and separated. The organic layer was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized with diisopropyl ether to obtain 6.82 g of (4R) -3-benzyl-4-hydroxymethylthiazolidin-2-one as colorless crystals.
Melting point: 87-90 ° C
MS · APCI (m / z): 224 (M ⁺ +1)
[Α] _D ²⁵ : −26.7 ° (C = 1.0, methanol)
Optical purity (HPLC):> 99% ee
(HPLC conditions)
Column: Chiralcel AD (4.6 × 250 mm) [manufactured by Daicel Chemical Industries, Ltd.], moving layer: ethanol / hexane = 10/90, flow rate: 0.8 ml / min, UV detection: 225 nm, column temperature: 40 ° C.
(4) 1.0 g of the compound obtained in Reference Example 1- (3) was dissolved in 5.0 ml of dimethyl sulfoxide, and 1.95 ml of diisopropylethylamine was added dropwise at room temperature. The reaction mixture was ice-cooled, 1.78 g of sulfur trioxide pyridine complex salt was added at 12 ° C. to 20 ° C., and the mixture was stirred at the same temperature for 30 min. The reaction solution was added to 30 ml of ice water and extracted with 20 ml of ethyl acetate. The aqueous layer was re-extracted with 10 ml of ethyl acetate. The ethyl acetate layers were combined and washed twice with 10 ml of 10% citric acid, and then washed with 10 ml of water and 10 ml of saturated saline. After drying over magnesium sulfate and concentration under reduced pressure, 985.9 mg of (4R) -2-oxo-3-benzylthiazolidine-4-carbaldehyde was obtained as a colorless oil.
MS.APCI (m / z): 222 (M ⁺⁺ 1).
Reference example 2
2.34 g of dimethyl sulfoxide was dissolved in 22 ml of dichloromethane, and 1.31 ml of oxalyl chloride was added thereto at −78 ° C. After stirring at the same temperature for 10 minutes, a solution of the compound 2.23 g obtained in Reference Example 1- (3) in 11 ml of dichloromethane was added dropwise at -60 ° C. or lower. After stirring at −78 ° C. for 20 minutes, 5.58 ml of triethylamine was added dropwise at −60 ° C. or lower. After raising the reaction temperature to −20 ° C. over 1.5 hours, the reaction mixture was added to 10% citric acid water and separated. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give 2.20 g of the same target product as in Reference Example 1- (4). The physical property values of this product coincided with those of Reference Example 1- (4).
Reference example 3
532 mg of chlorine was dissolved in 11 ml of dichloromethane, and 0.73 ml of N, N-dimethyl sulfide was added at -20 ° C to -10 ° C. After stirring at the same temperature for 10 minutes, a solution of 1.12 g of the compound obtained in Reference Example 1- (3) in 5.5 ml of dichloromethane was added dropwise at -25 ° C. After stirring at −25 ° C. for 20 minutes, 2.79 ml of triethylamine was added dropwise at −25 to −18 ° C. After stirring at −25 ° C. for 10 minutes, the reaction mixture was added to 10% citric acid water and separated. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give 1.17 g of the same target product as in Reference Example 1- (4). The physical property values of this product coincided with those of Reference Example 1- (4).
Reference example 4
447 mg of the compound obtained in Reference Example 1- (3), 6.9 mg of 4-hydroxytetramethylpiperidine oxide and 206 mg of sodium bromide were dissolved in a mixed solvent of 6 ml of dichloromethane and 1 ml of water, and ice-cooling was performed while bubbling nitrogen. Below, a mixture of 1.49 g of sodium hypochlorite water, 491 mg of sodium bicarbonate and 5 ml of water was slowly added dropwise. After stirring for 1 hour, the layers were separated, and the organic layer was washed with 16 mg of potassium iodide, 10% aqueous potassium hydrogen sulfate solution and hypo water, respectively. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to obtain 147.5 mg of the same object as Reference Example 1- (4). The physical property values of this product coincided with those of Reference Example 1- (4).
Reference Example 5
(1) 175.6 g of L-cysteine-hydrochloride monohydrate was dissolved in a 2 liter solution of 180 g of sodium hydroxide in an ice-cooled nitrogen stream. In this solution, a solution of 118.7 g of triphosgene in 700 ml of 1,4-dioxane was added dropwise at 25 ° C. to 29 ° C. over 1 hour and 30 minutes, and further stirred at the same temperature for 3 hours. Concentrated hydrochloric acid was added to this reaction mixture to adjust to weak acidity, and then the solvent was distilled off under reduced pressure. 200 ml of toluene was added to the concentrated residue, and the mixture was again distilled off under reduced pressure. After adding 700 ml of ethanol to this concentrated residue, 131 g of thionyl chloride was added over 40 minutes under ice cooling, followed by stirring for 19 hours while raising the temperature to room temperature. After evaporating the solvent under reduced pressure, the concentrated residue was dissolved in 1 liter of ethyl acetate, and washed with 700 ml of water, 300 ml of a saturated aqueous sodium hydrogen carbonate solution, and 500 ml of saturated brine in this order. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 162 g of (4R) -2-oxothiazolidine-4-carboxylic acid ethyl ester as an oil.
MS · APCI (m / z): 176 (M ⁺ +1)
[Α] _D ²⁵ : −52.7 ° (C = 1.0, chloroform).
(2) 1.79 g of sodium bromide, 5 ml of N, N-dimethylacetamide and 1 ml of benzyl chloride were stirred at 23 ° C. to 26 ° C. for 15 hours to obtain benzyl bromide. To this solution, 1.27 g of the compound obtained in Reference Example 5- (1), 2 ml of N, N-dimethylacetamide and 1.1 g of potassium carbonate were added, reacted at 23 ° C. to 30 ° C. for 93 hours, ethyl acetate and 10% aqueous citric acid was added and the aqueous layer was separated. The organic layer was washed with water, dried over magnesium sulfate, and concentrated to give 2.29 g of residue. The residue was purified by silica gel column chromatography (solvent: n-hexane: ethyl acetate = 5: 1) to give 1.67 g of (4R) -2-oxo-3-benzylthiazolidine-4-carboxylic acid ethyl ester as a colorless oil. Obtained as a thing.
MS · APCI (m / z): 266 (M ⁺ +1)
[Α] _D ²⁴ : −96.6 ° (C = 1.0, chloroform)
Optical purity (HPLC): 98.1% ee
(HPLC conditions)
Column: Chiralcel OD (4.6 × 250 mm) [manufactured by Daicel Chemical Industries, Ltd.], moving bed: ethanol / hexane = 5/95, flow rate: 0.8 ml / min, UV detection: 225 nm, column temperature: 40 ° C.
Reference Example 6
28.4 g of (4R) -2-oxo-3-benzylthiazolidine-4-carboxylic acid ethyl ester was dissolved in 227 ml of ethanol, 2.26 g of sodium borohydride was added, and the mixture was stirred at room temperature for 15 hours. Further, 0.76 g of sodium borohydride was added and stirred at room temperature for 2 hours. Concentrated hydrochloric acid was added thereto and neutralized so that the pH was 6-7, and then the solution was concentrated. The concentrated residue was dissolved in ethyl acetate and washed three times with water, and the aqueous layer was back extracted once with ethyl acetate. The ethyl acetate layers were combined, dried over magnesium sulfate, and concentrated to give 22.6 g of an oily residue. The residue is crystallized by adding isopropyl ether, further filtered, washed with isopropyl ether, and dried under reduced pressure to give 18.4 g of (4R) -3-benzyl-4-hydroxymethylthiazolidine-2-one as colorless crystals. Obtained. The physical properties of this product coincided with those of Reference Example 1- (3).
Reference Example 7
(1) 10 g of (4R) -2-oxo-3-benzylthiazolidine-4-carboxylic acid was dissolved in 200 ml of acetonitrile, and 9.2 g of DCC was added at room temperature. Subsequently, 3.3 ml of ethanethiol and 670 mg of 4-dimethylaminopyridine were sequentially added to the solution under ice cooling, and the mixture was stirred at room temperature for 2 hours. The insoluble material was removed by filtration and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (solvent: n-hexane: ethyl acetate = 10: 1) to give 10.8 g of (4S) -4-ethylthiocarbonyl-3-benzylthiazolidin-2-one as an oil. Got as.
MS · APCI (m / z): 282 (M ⁺ +1)
[Α] _D ²⁵ : -110.8 ° (C = 1.04, chloroform).
(2) 0.5 g of the compound obtained in Reference Example 7- (1) was dissolved in 5.0 ml of dichloromethane, and 284 mg of palladium hydroxide was added under a nitrogen stream. At room temperature, 0.85 ml of triethylsilane was added and stirred at the same temperature for 3 hours. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain 0.5 g of (4R) -2-oxo-3-benzylthiazolidine-4-carbaldehyde as an oil. The physical property values of this product coincided with those of Reference Example 1- (4).
Reference Example 8
35.34 g of the compound obtained in Example 5, 121 ml of mesitylene and 116.1 g of methanesulfonic acid were heated at an internal temperature of 130 ° C. The reaction starting time was reached at 125 ° C., stirred at 128 ° C. to 133 ° C. for 4 hours, and disappearance of monobenzylbiotin was confirmed by high performance liquid chromatography. The reaction solution was cooled to 80 ° C., 30 ml of acetic acid was added, and the methanesulfonic acid layer was dropped into 710 ml of purified water. The mesitylene layer was separated, and after 1 hour on ice, the crude crystals were collected by filtration, washed with 200 ml of water and then methanol until the washing liquid disappeared black. By air drying overnight at 50 ° C., 15.89 g of crude (+)-biotin was obtained.
The obtained crude (+)-biotin was dissolved in 160 ml of purified water (2.73 g) in purified water and the pH was adjusted to 7 with dilute hydrochloric acid at 90 ° C to 95 ° C. Charcoal powder 4 g was added to the system at 90 ° C. to 95 ° C., and after stirring for 10 minutes, charcoal powder precoat filtration was performed. The filtrate was reheated to 90 ° C. to 95 ° C., 4 g of charcoal powder was added to the system again, and after stirring for 10 minutes, charcoal powder precoat filtration was performed. The filtrate was reheated to 80 ° C. to 85 ° C., and the pH was adjusted to 1.8 to 2.2 with concentrated hydrochloric acid for neutralization crystallization. The mixture was stirred at the same temperature for 1 hour to grow crystals. After slow cooling and ice cooling, the crystals were filtered. The crystals were blown and dried overnight at 50 ° C. to obtain 13.86 g of (+)-biotin as colorless crystals.
Reference Example 9
(1) By treating 6.0 g of (4R) -4-[(1S) -1- (N-benzylamino) -1-cyanomethyl] -3-benzylthiazolidine-2-one in the same manner as in Example 2. A colorless oily (4R) -4-[(1S) -1- (N-benzylamino) -1-carbamoylmethyl] -3-benzylthiazolidine-2-one was obtained. Next, the resultant was dissolved in ethyl acetate, 6 ml of 4M hydrogen chloride-ethyl acetate solution was added, and the precipitated crystals were collected by filtration to give (4R) -4-[(1S) -1- (N-benzylamino) -1- 4.3 g of carbamoylmethyl] -3-benzylthiazolidine-2-one hydrochloride was obtained.
ESI · MS (m / z): 356 (M ⁺ +1)
[Α] _D ²³ : −32.6 ° (C = 1.0, methanol).
(2) 0.54 g of (4R) -4-[(1S) -1- (N-benzylamino) -1-carbamoylmethyl] -3-benzylthiazolidine-2-one hydrochloride was added to 10 ml of N, N-dimethylformamide. And stirred at 100 ° C. for 3 hours under a nitrogen stream. Ethyl acetate was added to the reaction mixture, washed with water and saturated brine, dried and concentrated. The residue was crystallized from hexane to obtain 342 mg of (3aS, 6aR) -1,3-dibenzyl-hexahydro-4H-thieno [3,4-d] imidazole-2,4-dione as colorless crystals.
Optical purity (HPLC):> 91% ee
(HPLC conditions)
Column: Chiralcel AD (4.6 × 250 mm) [manufactured by Daicel Chemical Industries, Ltd.], moving layer: ethanol / hexane = 15/85, flow rate: 0.8 ml / min, UV detection: 225 nm, column temperature: 40 ° C.
Reference Example 10
(4R) -4-[(1R) -1- (N-benzylamino) -1-carbamoylmethyl] -3-benzylthiazolidin-2-one in a solution of 14 g of N, N-dimethylformamide in 39 ml of sodium bicarbonate; 96g was added and it stirred at 80-85 degreeC for 17 hours. The reaction solution was concentrated under reduced pressure, 40 ml of methanol and 20 ml of water were added to the concentrated residue, and the mixture was stirred at 5 ° C. or lower for 1 hour. The precipitated crystals were collected by filtration, washed with a mixed solution of 80 ml of methanol and 40 ml of water, and then blown and dried at 50 ° C. for 17 hours to obtain (4S, 4 ′S, 5R, 5′R) -5, 5 ′-[ Dithiobis (methylene)] bis (1,3-dibenzyl-2-oxoimidazolidine-4-carboxamide) 12.14 g was obtained as pale yellow crystals.
Melting point: 208-211 ° C
ESI · MS (m / z): 709 (M ⁺ +1)
[Α] ^{_{D 20: + 55.4 ° (C}} = 0.29, N, N- dimethylformamide).
Reference Example 11
497 mg of (4S, 4 ′S, 5R, 5′R) -5,5 ′-[dithiobis (methylene)] bis (1,3-dibenzyl-2-oxoimidazolidine-4-carboxamide) was dissolved in 5 ml of acetic acid. , 249 mg of zinc powder was added, and the mixture was stirred at 90 ° C. for 1.5 hours. Ethyl acetate was added to the reaction solution and filtered through celite. The filtrate was concentrated under reduced pressure, and ether and hexane were added to the residue. The precipitated crystals were collected by filtration, washed with water and hexane, and then dried under reduced pressure to give 482 mg of (4R, 5R) -1,3-dibenzyl-2-oxo-5- (mercaptomethyl) imidazolidine-4-carboxamide as colorless matter. Obtained as crystals.
Melting point: 119-122 ° C
ESI · MS (m / z): 356 (M ⁺ +1)
[Α] _D ²⁰ : −1.2 ° (C = 0.33, N, N-dimethylformamide).
Reference Example 12
12 g of the compound obtained in Reference Example 10 was dissolved in 24 ml of acetic acid, 7.2 g of zinc powder was added, and the mixture was stirred at 55 ° C. to 60 ° C. for 1 hour. After cooling the reaction solution to 20 ° C., 72 ml of concentrated hydrochloric acid was added and stirred at 80 ° C. to 90 ° C. for 2 hours. 120 ml of water was added to the reaction solution, cooled to 25 ° C. over 1 hour, and stirred at 5 ° C. or lower for 1 hour. The precipitated crystals are collected by filtration, washed with 95 ml of water, and dried under reduced pressure to give (4R, 5R) -1,3-dibenzyl-2-oxo-5- (mercaptomethyl) imidazolidine-4-carboxylic acid. 05 g were obtained as colorless crystals. The physical property values of this product coincided with those of Example 3.

  In the present invention, an optically active aldehyde compound having an asymmetric carbon at the α-position is produced by introducing an asymmetric center at the α-position without racemizing the β-position (the α-position of the optically active aldehyde compound). The optically active α-amino nitrile compound is useful as an intermediate for pharmaceuticals and amino acids and can be produced without using an expensive reagent such as an asymmetric catalyst, so that it is an industrially advantageous production method. In addition, the biotin production method that uses the compound (IV-b) produced by the production method of the present invention as a synthetic intermediate can produce biotin at a lower cost than the known production methods, and therefore is industrially advantageous for biotin. It is a manufacturing method.

Claims (7)

Formula (III):

In the formula, R ⁵ represents a hydrogen atom, a benzyl group which may have a substituent on the benzene ring, a benzhydryl group which may have a substituent on the benzene ring, or a substituent on the benzene ring. Represents a trityl group which may have,
In a compound or a salt thereof represented, in the water-containing solvent, is reacted with bisulfite compound to obtain a bisulfite adduct of the aldehyde compound, the resulting bisulfite adduct of the general formula (II-a):
R ³¹ —NH ₂ (II-a)
In the formula, R ³¹ has a benzyl group which may have a substituent on the benzene ring, a benzhydryl group which may have a substituent on the benzene ring, or a substituent on the benzene ring. Represents an optionally trityl group,
Comprising a step of reacting a compound represented by formula (II) with cyanide :

In the formula, the symbols have the same meaning as described above.
Compound or preparation of a salt thereof represented in. Compound (III) is represented by the general formula (III-a):

In the formula, R ⁵ represents a hydrogen atom, a benzyl group which may have a substituent on the benzene ring, a benzhydryl group which may have a substituent on the benzene ring, or a substituent on the benzene ring. Represents a trityl group which may have,
Wherein the compound (IV-a) is represented by the general formula (IV-b):

In the formula, R ³¹ has a benzyl group which may have a substituent on the benzene ring, a benzhydryl group which may have a substituent on the benzene ring, or a substituent on the benzene ring. Represents a trityl group, and R ⁵ represents the same meaning as described above.
The process according to claim 1 , which is a compound represented by the formula: Compound (III) is represented by the general formula (III-a):

In the formula, R ⁵ represents a hydrogen atom, a benzyl group which may have a substituent on the benzene ring, a benzhydryl group which may have a substituent on the benzene ring, or a substituent on the benzene ring. Represents a trityl group which may have,
Wherein the compound (IV-a) is represented by the general formula (IV-c):

In the formula, R ³¹ has a benzyl group which may have a substituent on the benzene ring, a benzhydryl group which may have a substituent on the benzene ring, or a substituent on the benzene ring. Represents a trityl group, and R ⁵ represents the same meaning as described above.
The process according to claim 1 , which is a compound represented by the formula: The process according to any one of claims 1 to 3 , wherein the bisulfite oxide is an alkali metal bisulfite and the cyanide is an alkali metal cyanide. R ³¹ is (1) a benzyl group in which the benzene ring may be substituted with a group selected from a halogen atom, an alkyl group and an alkoxy group, and (2) a group in which the benzene ring is selected from a halogen atom, an alkyl group and an alkoxy group. A benzhydryl group which may be substituted, or (3) a trityl group in which the benzene ring may be substituted with a group selected from a halogen atom, an alkyl group and an alkoxy group, R ⁵ is (1) a hydrogen atom, (2) The benzene ring may be substituted with a group selected from a halogen atom, an alkyl group and an alkoxy group, and (3) the benzene ring may be substituted with a group selected from a halogen atom, an alkyl group and an alkoxy group. A benzhydryl group, or (4) a benzene ring is substituted with a group selected from a halogen atom, an alkyl group and an alkoxy group And is also good trityl group, bisulfite compound is an alkali metal bisulfite, ranges second or third term process according to claim cyanide is alkali metal cyanide. R ³¹ is a benzyl group, a benzhydryl group or trityl group, R ⁵ is a hydrogen atom, a benzyl group, benzhydryl group or process ranging fifth claim of claim trityl group. According to the method of claim 2, the general formula (IV-b):

In the formula, R ³¹ has a benzyl group which may have a substituent on the benzene ring, a benzhydryl group which may have a substituent on the benzene ring, or a substituent on the benzene ring. The trityl group, R ⁵ may be a hydrogen atom, a benzyl group optionally having a substituent on the benzene ring, a benzhydryl group optionally having a substituent on the benzene ring, or on the benzene ring; Represents a trityl group which may have a substituent,
Or a salt thereof, and the resulting compound (IV-b) is hydrolyzed to give a general formula (V):

In the formula, the symbols have the same meaning as described above.
Or a salt thereof, and then the obtained compound (V) is subjected to ring transformation to give a compound represented by the general formula (VI):

In the formula, the symbols have the same meaning as described above.
Or a salt thereof, and the obtained compound (VI) is hydrolyzed to give a compound represented by the general formula (VII):

In the formula, the symbols have the same meaning as described above.
Or a salt thereof, and then the obtained compound (VII) is cyclized and epimerized to obtain a compound represented by the general formula (VIII):

In the formula, the symbols have the same meaning as described above.
Then, the compound (VIII) thus obtained is converted into the general formula (IX):
_{^{X 1 Zn- (CH 2) 4}} R 6 (IX)
In the formula, X ¹ represents a halogen atom, R ⁶ represents an esterified carboxyl group or an amidated carboxyl group,
And a compound represented by the general formula (X):

In the formula, the symbols have the same meaning as described above.
Or a salt thereof obtained, and then reducing the obtained compound (X), hydrolyzing if necessary, and further converting R ³¹ and / or R ⁵ to a hydrogen atom if necessary. Formula (XI), characterized by:

The manufacturing method of the compound shown by these.