WO2010021093A1 - Asymmetric organic catalyst - Google Patents

Asymmetric organic catalyst Download PDF

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WO2010021093A1
WO2010021093A1 PCT/JP2009/003699 JP2009003699W WO2010021093A1 WO 2010021093 A1 WO2010021093 A1 WO 2010021093A1 JP 2009003699 W JP2009003699 W JP 2009003699W WO 2010021093 A1 WO2010021093 A1 WO 2010021093A1
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group
formula
asymmetric
added
compound
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French (fr)
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敬司 中山
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第一三共株式会社
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
    • C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C311/09—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton the carbon skeleton being further substituted by at least two halogen atoms
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
    • B01J31/04—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides containing carboxylic acids or their salts
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B53/00—Asymmetric syntheses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/45—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by at least one doubly—bound oxygen atom, not being part of a —CHO group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/56—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and doubly-bound oxygen atoms bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C07C45/72—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
    • C07D319/06—1,3-Dioxanes; Hydrogenated 1,3-dioxanes not condensed with other rings
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
    • B01J2231/30—Addition reactions at carbon centres, i.e. to either C-C or C-X multiple bonds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the present invention relates to an asymmetric organic catalyst for addition reaction or condensation reaction and a method for producing an optically active keto alcohol using the same.
  • a compound having an asymmetric carbon atom or the like includes a plurality of optically active substances having different steric configurations.
  • optically active substances there are compounds that are significantly different in physiological activity from other optically active substances, and it is extremely important to selectively produce such useful optically active substances.
  • optical resolution means in the selective production method of optically active substances a method of reacting with a compound having no asymmetric element and selectively synthesizing one enantiomer (enantioselective asymmetric) Synthesis) is useful without waste of raw materials.
  • metal complexes are widely known as such asymmetric catalysts.
  • metal complexes are generated as waste, and the metal at the center is often a rare metal (rare metal), which is problematic when considering earth resources and the like, and has environmental problems.
  • Non-Patent Documents 1 to 5 amino acids such as proline and diamines having a primary amino group, a secondary amino group, and a tertiary amino group have been reported (Non-Patent Documents 1 to 5).
  • these asymmetric organic catalysts have problems such as a large amount of use, an insufficient optical activity yield, and substrate specificity.
  • these catalysts are derived from the opposite optically active forms and require the opposite as an asymmetric source, and the induction is complicated.
  • An object of the present invention is to provide a new asymmetric organic catalyst capable of achieving a high optical activity yield with a small amount of use and an enantioselective asymmetric synthesis method using them.
  • the present inventor examined the asymmetric organic catalyst in the aldol reaction.
  • the aldol reaction was carried out using cyclohexanecarboxylic acids having the following primary amino group and secondary amino group, the enantiomer was obtained in a small amount and in a high yield.
  • the inventors have found that selective asymmetric synthesis is possible, and that the enantiomer of the resulting ketoalcohol compound can be selectively obtained by selecting an optically active form of the catalyst, and the present invention has been completed.
  • the present invention has the formula (1)
  • R 1 and R 2 represents a hydrogen atom and the other represents an acyl group
  • R 3 represents an alkoxy group, an aryloxy group, an aralkyloxy group, an amino group, an alkylamino group, or a dialkylamino group.
  • R 1 HN— and R 2 HN— have the same configuration on the asymmetric carbon atom.
  • An asymmetric organic catalyst for addition reaction or condensation reaction comprising an optically active diaminocyclohexanecarboxylic acid represented by the formula (1) or a Bronsted acid salt thereof is provided.
  • the asymmetric organic catalyst of the present invention is used, an enantiomer having high optical purity can be selectively obtained with a small amount of catalyst.
  • the enantioselectivity of the resulting keto alcohol is high, and the desired keto alcohol enantiomer can be selectively obtained by selecting the asymmetric organic catalyst to be used.
  • the asymmetric organic catalyst of the present invention comprises an optically active diaminocyclohexanecarboxylic acid ester and an amide represented by the formula (1).
  • one of R 1 and R 2 is a hydrogen atom and the other is an acyl group.
  • the acyl group is a group generated by removing one or more hydroxy groups of oxo acid, and examples thereof include a group generated by removing a hydroxy group from carboxylic acid or sulfonic acid.
  • the acyl group include an alkanoyl group, an aroyl group, an alkanesulfonyl group, a halogenoalkanesulfonyl group, and an arylsulfonyl group.
  • the alkanoyl group is preferably an alkanoyl group having 2 to 12 carbon atoms; more preferably an acetyl group, a propionyl group, or a butyryl group.
  • aroyl group a benzoyl group, a benzoyl group having a substituent, and the like are preferable.
  • the alkanesulfonyl group an alkanesulfonyl group having 1 to 6 carbon atoms is preferable; a methanesulfonyl group and an ethanesulfonyl group are more preferable.
  • the halogenoalkanesulfonyl group is preferably an alkanesulfonyl group having 1 to 6 carbon atoms substituted with 1 to 15 halogen atoms; a trifluoromethanesulfonyl group or a pentafluoroethanesulfonyl group is preferred.
  • a benzenesulfonyl group and a paratoluenesulfonyl group are preferable.
  • acyl groups represented by R 1 or R 2 an alkanesulfonyl group or a halogenoalkanesulfonyl group is particularly preferred.
  • R 1 and R 2 are hydrogen atom and the other is an acyl group in order for the compound of the formula (1) to function as an asymmetric organic catalyst. This is considered because the hydrogen atom acts as a Bronsted acid.
  • R 3 represents an alkoxy group, an aryloxy group, an aralkyloxy group, an amino group, an alkylamino group or a dialkylamino group.
  • alkoxy group include linear, branched or cyclic alkoxy groups having 1 to 12 carbon atoms, such as methoxy group, ethoxy group, n-propyloxy group, isopropyloxy group, isobutyloxy group, tert-butyloxy group. , Cyclopentyloxy group, cyclohexyloxy group and the like. Of these, alkoxy groups having 1 to 6 carbon atoms are particularly preferable.
  • aryloxy group examples include an aryloxy group having 6 to 14 carbon atoms, such as a phenoxy group, a naphthyloxy group, and an anthracenyloxy group.
  • aralkyloxy group examples include a group in which an alkoxy group having 1 to 6 carbon atoms is bonded to an aryl group having 6 to 14 carbon atoms, such as a phenyl C 1-6 alkoxy group, more specifically, a benzyloxy group, diphenyl A methyloxy group etc. are mentioned.
  • alkylamino group examples include alkylamino groups having 1 to 12 carbon atoms, such as a methylamino group, an ethylamino group, a propylamino group, and an isopropylamino group. Of these, an alkylamino group having 1 to 6 carbon atoms is particularly preferable.
  • dialkylamino group examples include a di (C 1-12 alkyl) amino group, such as a dimethylamino group, a diethylamino group, a dipropylamino group, and a dibutylamino group. Of these, a di (C 1-12 alkyl) amino group is particularly preferred.
  • an alkoxy group, an aralkyloxy group, an alkylamino group, and a dialkylamino group are particularly preferable.
  • asymmetric organic catalysts act as catalysts even in a salt form with Bronsted acid, and depending on the substrate, these salts may give better values.
  • the counter acid include inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid, organic carboxylic acids such as acetic acid, benzoic acid and tartaric acid, and organic sulfonic acids such as mesylic acid and paratoluenesulfonic acid. Of these, organic sulfonic acids such as mesylic acid are particularly preferred.
  • the compound of the formula (1) can be produced, for example, according to the following reaction formula.
  • the configuration of the following reaction formula is the case of Formula (1a), the compound of another configuration can be manufactured similarly.
  • R 3a represents an alkyl group, an aryl group or an aralkyl group
  • Boc represents a t-butoxycarbonyl group
  • Z represents a benzyloxycarbonyl group
  • R 1 is the same as above
  • a compound (B) is obtained by an iodolactone reaction using iodination of a readily available cyclohexene carboxylic acid (A).
  • This iodolactonization reaction can be performed by reacting compound (A) with iodine and potassium iodide in the presence of an alkali such as sodium bicarbonate.
  • Compound (C) is obtained by reacting compound (B) with an alkali such as sodium hydroxide to cause lactone ring opening and epoxidation.
  • Compound (D) is obtained by azidating compound (C) with sodium azide or the like.
  • Compound (E) is then obtained by reducing compound (D) in the presence of di-tert-butyl dicarbonate.
  • the reduction reaction is preferably catalytic reduction using palladium carbon or the like as a catalyst.
  • Compound (F) is obtained by azidating the hydroxy group of compound (E).
  • the compound (F) is then reduced, preferably catalytically reduced, to give the compound (G).
  • compound (H) is obtained.
  • Boc is eliminated by hydrolysis to obtain compound (I), which is reacted with acylating agent (R 1 ) to obtain compound (J), and then protecting group ( If Z) is eliminated by hydrogenation, compound (1a) is obtained.
  • the compound (H) is hydrogenated to remove the protecting group (Z) to obtain a compound (K), which is reacted with an acylating agent (R 2 ) to obtain a compound (L), and then protected. If the group (Boc) is eliminated by hydrolysis, the compound (1b) is obtained.
  • Boc and Z which are protecting groups for amino groups
  • the protective group include a combination of a hydrolytic leaving group such as a benzoyl group or 3,4,5-trimethoxyphenylmethyl group and a hydrogenation leaving group such as a benzyl group or a phenylethyl group.
  • a compound in which R 3 is an amino group, an alkylamino group or a dialkylamino group can be obtained by amidating an ester (—COOR 3a ) at any stage of the above reaction step.
  • the amidation reaction can be performed using, for example, ammonia, ammonium salt, alkylamine, or dialkylamine.
  • the compound (1) thus obtained is useful as an asymmetric organic catalyst for addition reaction or condensation reaction. That is, if an addition reaction or a condensation reaction is performed in the presence of the compound (1), an enantiomer can be obtained with high yield and high optical purity, and enantioselective asymmetric synthesis is possible.
  • examples of the addition reaction or condensation reaction include aldol reaction, Mannich reaction, Michael reaction, amination reaction, halogenation reaction and the like.
  • the catalyst of the present invention is particularly preferably applied to the aldol reaction.
  • the aldol reaction using the asymmetric organic catalyst of the present invention is represented by the following reaction formula.
  • R 4 and R 5 represent a hydrogen atom or an organic group
  • R 6 represents an organic group
  • * represents an asymmetric carbon atom, and has a specific configuration
  • the organic group represented by R 4, R 5 and R 6, are not limited to, hydrocarbon group, heterocyclic group, an alcohol, ether and the like.
  • hydrocarbon group both an aromatic hydrocarbon group and an aliphatic hydrocarbon group are included.
  • These hydrocarbon groups and heterocyclic groups, alcohols, ethers and the like may have a substituent such as a halogen atom, a nitro group, an amino group, a cyano group, a carboxyl group, an alkoxycarbonyl group, or a silyl group.
  • R 4 and R 5 may be combined to form a cycloalkane structure.
  • the catalyst of the formula (1) to be used may be used in an amount of 0.5 to 10 mol%, more preferably 1 to 10 mol%, relative to the raw material compound of the formula (2) or the formula (3).
  • the amount of catalyst used is small compared to the amount of conventional asymmetric organic catalysts used.
  • the reaction may be carried out in accordance with a normal aldol reaction, for example, at 0 to 20 ° C. for about 0.5 to 72 hours in the presence or absence of a solvent.
  • the configuration of the enantiomer of the target keto alcohol can be controlled by changing the configuration of the asymmetric organic catalyst of the formula (1) used. That is, the configuration of the enantiomer of the keto alcohol obtained is determined depending on whether the catalyst of the formula (1a) or the catalyst of the formula (1b) is used, so that two catalysts are synthesized from a common asymmetric source. By doing so, the target enantiomer can be selectively obtained.
  • the catalyst of the present invention can be recovered from the reaction mixture and reused.
  • Example 5 0.9 mL cyclohexanone and 45.3 mg p-nitrobenzaldehyde were added to a mixture of 0.9 mL tetrahydrofuran and 0.9 mL water. To this was added 5 mol% of compound (1a-1) or compound (1b-1) with respect to 1 mol of p-nitrobenzaldehyde, and the mixture was stirred at room temperature (25 ° C.) for 3 to 4 days. The reaction mixture was extracted with 3 mL of ethyl acetate, and after liquid separation, the organic layer was concentrated. The residue was purified by silica gel column chromatography to obtain 74.9 mg (yield 99%, diastereo ratio: 7/93 (syn / anti), 97% ee) of an aldol adduct.
  • Table 1 shows the results of the aldol reaction as in Example 5.
  • Example 6 0.9 mL of cyclopentanone and 45.3 mg of p-nitrobenzaldehyde were added to a mixture of 0.9 mL of tetrahydrofuran and 0.9 mL of water. To this was added 5 mol% of compound (1a-1) or compound (1b-1) with respect to 1 mol of p-nitrobenzaldehyde, and the mixture was stirred at room temperature (25 ° C.) for 16 to 22 hours. Thereafter, the same treatment as in Example 5 was performed to obtain 69.9 mg (yield 99%, diastereo ratio 92/8 (syn / anti), 93% ee) of an aldol adduct.
  • Table 2 shows the results of the aldol reaction performed in the same manner as in Example 6.
  • Example 7 The reaction was performed in substantially the same manner as in Example 5 except that 2,2-dimethyl-1,3-dioxa-5-one was used instead of cyclohexanone. The results are shown in Table 3.

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Abstract

Provided are a novel asymmetric organic catalyst with which it is possible to realize a high optically-active yield when said catalyst is used in a small amount, and a method for producing a compound using the same. The asymmetric organic catalyst is for addition reactions or condensation reactions and is formed from an optically active diaminocyclohexanecarboxylic acid represented by formula (1), or Brønsted acid salt thereof. (In the formula, one of R1 and R2 is a hydrogen atom and the other is an acyl group, and R3 is an alkoxy, aryloxy, aralkyloxy, amino, alkylamino, or dialkylamino group.  * is an asymmetric carbon atom, and R1HN- and R2HN- have the same configuration on the asymmetric carbon atom.)

Description

不斉有機触媒Asymmetric organic catalyst
　本発明は、付加反応又は縮合反応用不斉有機触媒及びこれを用いた光学活性ケトアルコールの製造法に関する。 The present invention relates to an asymmetric organic catalyst for addition reaction or condensation reaction and a method for producing an optically active keto alcohol using the same.
　不斉炭素原子等を有する化合物には、立体配置の異なる複数の光学活性体が存在する。このような光学活性な物質の中には、他の光学活性体とは生理活性等が大きく相違する化合物があり、その有用な光学活性体を選択的に製造することは極めて重要である。光学活性体の選択的な製造法には、光学分割手段もあるが、不斉の要素を持たない化合物に対して反応を行い、一方のエナンチオマーを選択的に合成する方法（エナンチオ選択的不斉合成）が原料の無駄がなく有用である。 A compound having an asymmetric carbon atom or the like includes a plurality of optically active substances having different steric configurations. Among such optically active substances, there are compounds that are significantly different in physiological activity from other optically active substances, and it is extremely important to selectively produce such useful optically active substances. Although there are optical resolution means in the selective production method of optically active substances, a method of reacting with a compound having no asymmetric element and selectively synthesizing one enantiomer (enantioselective asymmetric) Synthesis) is useful without waste of raw materials.
　エナンチオ選択的不斉合成にあたっては、選択性の高い不斉触媒が必要であり、そのような不斉触媒としては金属錯体が広く知られている。しかし金属錯体は、金属が廃棄物として発生する他、その中心となる金属が希少金属（レアメタル）であることが多く、地球資源等を考慮した場合に問題があり、環境上問題がある。 In enantioselective asymmetric synthesis, a highly selective asymmetric catalyst is required, and metal complexes are widely known as such asymmetric catalysts. However, metal complexes are generated as waste, and the metal at the center is often a rare metal (rare metal), which is problematic when considering earth resources and the like, and has environmental problems.
　かかる観点から、回収して再利用が可能である不斉有機触媒が注目されている。このような不斉有機触媒としては、プロリン等のアミノ酸及び一級アミノ基、二級アミノ基、及び三級アミノ基を有するジアミン類が報告されている（非特許文献１～５）。しかしながら、これらの不斉有機触媒は、使用量が多い、光学活性収率が十分でない、基質特異性等の問題がある。また、これらの触媒は、異なるエナンチオマーを合成する際には、反対の光学活性体から誘導され、不斉源として反対のものを必要としており、その誘導は煩雑であった。 From this point of view, asymmetric organic catalysts that can be recovered and reused are attracting attention. As such asymmetric organic catalysts, amino acids such as proline and diamines having a primary amino group, a secondary amino group, and a tertiary amino group have been reported (Non-Patent Documents 1 to 5). However, these asymmetric organic catalysts have problems such as a large amount of use, an insufficient optical activity yield, and substrate specificity. In addition, when synthesizing different enantiomers, these catalysts are derived from the opposite optically active forms and require the opposite as an asymmetric source, and the induction is complicated.
　本発明の課題は、少ない使用量で、高い光学活性収率を達成できる新たな不斉有機触媒及びそれらを用いたエナンチオ選択的不斉合成法を提供することにある。 An object of the present invention is to provide a new asymmetric organic catalyst capable of achieving a high optical activity yield with a small amount of use and an enantioselective asymmetric synthesis method using them.
　本発明者は、アルドール反応における不斉有機触媒について検討したところ、下記一級アミノ基及び二級アミノ基を有するシクロヘキサンカルボン酸類を用いてアルドール反応を行えば、少ない使用量で、高収率でエナンチオ選択的不斉合成が可能であること、さらには当該触媒の光学活性体の選択により、得られるケトアルコール化合物のエナンチオマーを選択的に得ることができることを見出し、本発明を完成した。 The present inventor examined the asymmetric organic catalyst in the aldol reaction. When the aldol reaction was carried out using cyclohexanecarboxylic acids having the following primary amino group and secondary amino group, the enantiomer was obtained in a small amount and in a high yield. The inventors have found that selective asymmetric synthesis is possible, and that the enantiomer of the resulting ketoalcohol compound can be selectively obtained by selecting an optically active form of the catalyst, and the present invention has been completed.
　すなわち、本発明は、式（１） That is, the present invention has the formula (1)
Figure JPOXMLDOC01-appb-C000001
Figure JPOXMLDOC01-appb-C000001
（式中、Ｒ１及びＲ２は、一方が水素原子、他方がアシル基を示し、Ｒ３はアルコキシ基、アリールオキシ基、アラルキルオキシ基、アミノ基、アルキルアミノ基又はジアルキルアミノ基を示す。＊は不斉炭素原子を示し、Ｒ１ＨＮ－及びＲ２ＨＮ－は不斉炭素原子上で同一の立体配置を有する。）
で表される光学活性ジアミノシクロヘキサンカルボン酸類又はそのブレンステッド酸塩からなる付加反応又は縮合反応用不斉有機触媒を提供するものである。 (In the formula, one of R 1 and R 2 represents a hydrogen atom and the other represents an acyl group, and R 3 represents an alkoxy group, an aryloxy group, an aralkyloxy group, an amino group, an alkylamino group, or a dialkylamino group. * Represents an asymmetric carbon atom, and R 1 HN— and R 2 HN— have the same configuration on the asymmetric carbon atom.)
An asymmetric organic catalyst for addition reaction or condensation reaction comprising an optically active diaminocyclohexanecarboxylic acid represented by the formula (1) or a Bronsted acid salt thereof is provided.
　また、本発明は、式（２） Also, the present invention provides the formula (2)
Figure JPOXMLDOC01-appb-C000002
Figure JPOXMLDOC01-appb-C000002
（式中、Ｒ４及びＲ５は水素原子又は有機基を示す）
で表されるケトン類と式（３） (Wherein R 4 and R 5 represent a hydrogen atom or an organic group)
And ketones represented by formula (3)
Figure JPOXMLDOC01-appb-C000003
Figure JPOXMLDOC01-appb-C000003
（式中、Ｒ６は有機基を示す）
で表されるアルデヒド類とを、上記式（１）の不斉有機触媒の存在下に反応させることを特徴とする式（４） (Wherein R 6 represents an organic group)
In the presence of the asymmetric organic catalyst of the above formula (1).
Figure JPOXMLDOC01-appb-C000004
Figure JPOXMLDOC01-appb-C000004
（＊は不斉炭素原子を示し、特定の立体配置を有し、Ｒ４、Ｒ５及びＲ６は前記と同じ）
で表される光学活性ケトアルコールの製造法を提供するものである。 (* Represents an asymmetric carbon atom, has a specific configuration, and R 4 , R 5 and R 6 are the same as above)
The manufacturing method of optically active keto alcohol represented by these is provided.
　本発明の不斉有機触媒を用いれば、少ない触媒量で、光学純度の高いエナンチオマーが選択的に得られる。特にアルドール反応に適用した場合、得られるケトアルコールのエナンチオ選択性は高く、用いる不斉有機触媒の選択により、目的とするケトアルコールのエナンチオマーを選択的に得ることができる。 If the asymmetric organic catalyst of the present invention is used, an enantiomer having high optical purity can be selectively obtained with a small amount of catalyst. In particular, when applied to the aldol reaction, the enantioselectivity of the resulting keto alcohol is high, and the desired keto alcohol enantiomer can be selectively obtained by selecting the asymmetric organic catalyst to be used.
　本発明の不斉有機触媒は、式（１）で表される光学活性ジアミノシクロヘキサンカルボン酸エステル及びアミド類からなる。式（１）中、Ｒ１及びＲ２のうち、一方は水素原子、他方はアシル基である。ここでアシル基は、オキソ酸の一個以上のヒドロキシ基の除去により生成される基であり、その例としてはカルボン酸又はスルホン酸からヒドロキシ基の除去により生成される基が挙げられる。アシル基の例としては、アルカノイル基、アロイル基、アルカンスルホニル基、ハロゲノアルカンスルホニル基、アリールスルホニル基等が挙げられる。 The asymmetric organic catalyst of the present invention comprises an optically active diaminocyclohexanecarboxylic acid ester and an amide represented by the formula (1). In formula (1), one of R 1 and R 2 is a hydrogen atom and the other is an acyl group. Here, the acyl group is a group generated by removing one or more hydroxy groups of oxo acid, and examples thereof include a group generated by removing a hydroxy group from carboxylic acid or sulfonic acid. Examples of the acyl group include an alkanoyl group, an aroyl group, an alkanesulfonyl group, a halogenoalkanesulfonyl group, and an arylsulfonyl group.
　ここでアルカノイル基としては、炭素数２～１２のアルカノイル基が好ましく；アセチル基、プロピオニル基、ブチリル基がより好ましい。アロイル基としてはベンゾイル基、置換基を有するベンゾイル基等が好ましい。アルカンスルホニル基としては、炭素数１～６のアルカルスルホニル基が好ましく；メタンスルホニル基、エタンスルホニル基がより好ましい。ハロゲノアルカンスルホニル基としては、ハロゲン原子が１～１５個置換した炭素数１～６のアルカンスルホニル基が好ましく；トリフルオロメタンスルホニル基、ペンタフルオロエタンスルホニル基が好ましい。アリールスルホニル基としてはベンゼンスルホニル基、パラトルエンスルホニル基が好ましい。 Here, the alkanoyl group is preferably an alkanoyl group having 2 to 12 carbon atoms; more preferably an acetyl group, a propionyl group, or a butyryl group. As the aroyl group, a benzoyl group, a benzoyl group having a substituent, and the like are preferable. As the alkanesulfonyl group, an alkanesulfonyl group having 1 to 6 carbon atoms is preferable; a methanesulfonyl group and an ethanesulfonyl group are more preferable. The halogenoalkanesulfonyl group is preferably an alkanesulfonyl group having 1 to 6 carbon atoms substituted with 1 to 15 halogen atoms; a trifluoromethanesulfonyl group or a pentafluoroethanesulfonyl group is preferred. As the arylsulfonyl group, a benzenesulfonyl group and a paratoluenesulfonyl group are preferable.
　Ｒ１又はＲ２で示されるアシル基のうち、アルカンスルホニル基又はハロゲノアルカンスルホニル基が特に好ましい。 Of the acyl groups represented by R 1 or R 2 , an alkanesulfonyl group or a halogenoalkanesulfonyl group is particularly preferred.
　ここで、Ｒ１及びＲ２の一方は水素原子であり、他方はアシル基であることが、式（１）の化合物が不斉有機触媒としての機能を発揮するうえで重要である。これは、水素原子がブレンステッド酸として作用しているためと考えられる。 Here, it is important that one of R 1 and R 2 is a hydrogen atom and the other is an acyl group in order for the compound of the formula (1) to function as an asymmetric organic catalyst. This is considered because the hydrogen atom acts as a Bronsted acid.
　式（１）中、Ｒ３はアルコキシ基、アリールオキシ基、アラルキルオキシ基、アミノ基、アルキルアミノ基又はジアルキルアミノ基を示す。アルコキシ基としては、炭素数１～１２の直鎖、分岐鎖又は環状のアルコキシ基が挙げられ、例えばメトキシ基、エトキシ基、ｎ－プロピルオキシ基、イソプロピルオキシ基、イソブチルオキシ基、ｔｅｒｔ－ブチルオキシ基、シクロペンチルオキシ基、シクロヘキシルオキシ基等が挙げられる。このうち、炭素数１～６のアルコキシ基が特に好ましい。 In formula (1), R 3 represents an alkoxy group, an aryloxy group, an aralkyloxy group, an amino group, an alkylamino group or a dialkylamino group. Examples of the alkoxy group include linear, branched or cyclic alkoxy groups having 1 to 12 carbon atoms, such as methoxy group, ethoxy group, n-propyloxy group, isopropyloxy group, isobutyloxy group, tert-butyloxy group. , Cyclopentyloxy group, cyclohexyloxy group and the like. Of these, alkoxy groups having 1 to 6 carbon atoms are particularly preferable.
　アリールオキシ基としては、炭素数６～１４のアリールオキシ基、例えばフェノキシ基、ナフチルオキシ基、アントラセニルオキシ基等が挙げられる。アラルキルオキシ基としては、炭素数６～１４のアリール基に炭素数１～６のアルコキシ基が結合した基が挙げられ、例えばフェニルＣ１－６アルコキシ基、より具体的にはベンジルオキシ基、ジフェニルメチルオキシ基等が挙げられる。 Examples of the aryloxy group include an aryloxy group having 6 to 14 carbon atoms, such as a phenoxy group, a naphthyloxy group, and an anthracenyloxy group. Examples of the aralkyloxy group include a group in which an alkoxy group having 1 to 6 carbon atoms is bonded to an aryl group having 6 to 14 carbon atoms, such as a phenyl C 1-6 alkoxy group, more specifically, a benzyloxy group, diphenyl A methyloxy group etc. are mentioned.
　アルキルアミノ基としては、炭素数１～１２のアルキルアミノ基が挙げられ、例えばメチルアミノ基、エチルアミノ基、プロピルアミノ基、イソプロピルアミノ基等が挙げられる。このうち、炭素数１～６のアルキルアミノ基が特に好ましい。 Examples of the alkylamino group include alkylamino groups having 1 to 12 carbon atoms, such as a methylamino group, an ethylamino group, a propylamino group, and an isopropylamino group. Of these, an alkylamino group having 1 to 6 carbon atoms is particularly preferable.
　ジアルキルアミノ基としては、ジ（Ｃ１－１２アルキル）アミノ基が挙げられ、例えばジメチルアミノ基、ジエチルアミノ基、ジプロピルアミノ基、ジブチルアミノ基等が挙げられる。このうち、ジ（Ｃ１－１２アルキル）アミノ基が特に好ましい。 Examples of the dialkylamino group include a di (C 1-12 alkyl) amino group, such as a dimethylamino group, a diethylamino group, a dipropylamino group, and a dibutylamino group. Of these, a di (C 1-12 alkyl) amino group is particularly preferred.
　Ｒ３で示される基のうち、アルコキシ基、アラルキルオキシ基、アルキルアミノ基、ジアルキルアミノ基が特に好ましい。 Of the groups represented by R 3 , an alkoxy group, an aralkyloxy group, an alkylamino group, and a dialkylamino group are particularly preferable.
　これらの不斉有機触媒は、ブレンステッド酸との塩形体でも触媒として作用し、基質によってはこれらの塩の方が良好な値を与える場合もある。カウンターの酸としては、例えば塩酸、硫酸、りん酸等の無機酸、酢酸、安息香酸、酒石酸等の有機カルボン酸、又はメシル酸、パラトルエンスルホン酸等の有機スルホン酸等が挙げられる。このうち、メシル酸等の有機スルホン酸が特に好ましい。 These asymmetric organic catalysts act as catalysts even in a salt form with Bronsted acid, and depending on the substrate, these salts may give better values. Examples of the counter acid include inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid, organic carboxylic acids such as acetic acid, benzoic acid and tartaric acid, and organic sulfonic acids such as mesylic acid and paratoluenesulfonic acid. Of these, organic sulfonic acids such as mesylic acid are particularly preferred.
　式（１）の＊は不斉炭素原子を示し、Ｒ１ＨＮ－及びＲ２ＨＮ－は不斉炭素原子上で同一の立体配置を有する。－ＣＯＲ３の立体配置は制限されない。従って、式（１）の化合物の立体配置は、Ｒ１又はＲ２を水素原子として示せば、次の４種である。 * In the formula (1) represents an asymmetric carbon atom, and R 1 HN— and R 2 HN— have the same configuration on the asymmetric carbon atom. The configuration of —COR 3 is not limited. Therefore, the configuration of the compound of the formula (1) is the following four types if R 1 or R 2 is shown as a hydrogen atom.
Figure JPOXMLDOC01-appb-C000005
Figure JPOXMLDOC01-appb-C000005
（式中、Ｒ１～Ｒ３は前記と同じ） (Wherein R 1 to R 3 are the same as above)
　式（１）の化合物は、例えば次の反応式に従って製造することができる。なお、次の反応式の立体配置は式（１ａ）の場合であるが、他の立体配置の化合物も同様にして製造することができる。 The compound of the formula (1) can be produced, for example, according to the following reaction formula. In addition, although the configuration of the following reaction formula is the case of Formula (1a), the compound of another configuration can be manufactured similarly.
Figure JPOXMLDOC01-appb-C000006
Figure JPOXMLDOC01-appb-C000006
（式中、Ｒ３ａはアルキル基、アリール基又はアラルキル基を示し、Ｂｏｃはｔ－ブトキシカルボニル基を示し、Ｚはベンジルオキシカルボニル基を示し、Ｒ１は前記と同じ） (Wherein R 3a represents an alkyl group, an aryl group or an aralkyl group, Boc represents a t-butoxycarbonyl group, Z represents a benzyloxycarbonyl group, and R 1 is the same as above)
　まず、容易に入手可能なシクロヘキセンカルボン酸（Ａ）をヨウ素化を用いたヨードラクトン化反応で化合物（Ｂ）が得られる。このヨードラクトン化反応は、化合物（Ａ）に、ヨウ素及びヨウ化カリウムを炭酸水素ナトリウム等のアルカリの存在下で反応させることにより行うことができる。 First, a compound (B) is obtained by an iodolactone reaction using iodination of a readily available cyclohexene carboxylic acid (A). This iodolactonization reaction can be performed by reacting compound (A) with iodine and potassium iodide in the presence of an alkali such as sodium bicarbonate.
　化合物（Ｂ）に水酸化ナトリウム等のアルカリを反応させることにより、ラクトン環の開環と同時にエポキシ化させて化合物（Ｃ）を得る。化合物（Ｃ）をアジ化ナトリウム等を用いてアジド化することにより化合物（Ｄ）を得る。次いで化合物（Ｄ）にジ－ｔｅｒｔ－ブチルジカルボナートの存在下に還元することにより化合物（Ｅ）が得られる。ここで還元反応は、パラジウム炭素等を触媒として用いる接触還元が好ましい。化合物（Ｅ）のヒドロキシ基をアジド化することにより、化合物（Ｆ）が得られる。次いで化合物（Ｆ）を還元、好ましくは接触還元すれば化合物（Ｇ）が得られる。次に化合物（Ｇ）の一級アミノ基にＢｏｃとは異なる保護基で保護すれば化合物（Ｈ）が得られる。 Compound (C) is obtained by reacting compound (B) with an alkali such as sodium hydroxide to cause lactone ring opening and epoxidation. Compound (D) is obtained by azidating compound (C) with sodium azide or the like. Compound (E) is then obtained by reducing compound (D) in the presence of di-tert-butyl dicarbonate. Here, the reduction reaction is preferably catalytic reduction using palladium carbon or the like as a catalyst. Compound (F) is obtained by azidating the hydroxy group of compound (E). The compound (F) is then reduced, preferably catalytically reduced, to give the compound (G). Next, if the primary amino group of compound (G) is protected with a protecting group different from Boc, compound (H) is obtained.
　化合物（Ｈ）の保護基のうち、Ｂｏｃを加水分解により脱離させて化合物（Ｉ）を得、これにアシル化剤（Ｒ１）を反応させて化合物（Ｊ）を得、次いで保護基（Ｚ）を水素添加により脱離すれば、化合物（１ａ）が得られる。 Of the protecting groups of compound (H), Boc is eliminated by hydrolysis to obtain compound (I), which is reacted with acylating agent (R 1 ) to obtain compound (J), and then protecting group ( If Z) is eliminated by hydrogenation, compound (1a) is obtained.
　一方、化合物（１ａ）とは、相違するアミノ基がアシル化された化合物（１ｂ）を得るには、次の反応式のようにすればよい。 On the other hand, in order to obtain a compound (1b) in which an amino group different from the compound (1a) is acylated, the following reaction formula may be used.
Figure JPOXMLDOC01-appb-C000007
Figure JPOXMLDOC01-appb-C000007
（式中、Ｒ２、Ｒ３ａ、Ｂｏｃ及びＺは前記と同じ） (Wherein R 2 , R 3a , Boc and Z are the same as above)
　すなわち、化合物（Ｈ）に水素添加して保護基（Ｚ）を脱離させて化合物（Ｋ）を得、これにアシル化剤（Ｒ２）を反応させて化合物（Ｌ）を得、次いで保護基（Ｂｏｃ）を加水分解により脱離すれば化合物（１ｂ）が得られる。 That is, the compound (H) is hydrogenated to remove the protecting group (Z) to obtain a compound (K), which is reacted with an acylating agent (R 2 ) to obtain a compound (L), and then protected. If the group (Boc) is eliminated by hydrolysis, the compound (1b) is obtained.
　なお、上記の反応式において、アミノ基の保護基であるＢｏｃやＺは、２つのアミノ基からそれぞれ相違する反応条件で脱離させることができる保護基であれば、他の保護基に代えることもできる。当該保護基としては、ベンゾイル基、３，４，５－トリメトキシフェニルメチル基等の加水分解脱離性基と、ベンジル基、フェニルエチル基等の水素添加脱離性基との組み合せが挙げられる。 In the above reaction formula, Boc and Z, which are protecting groups for amino groups, can be replaced with other protecting groups as long as they can be removed from the two amino groups under different reaction conditions. You can also. Examples of the protective group include a combination of a hydrolytic leaving group such as a benzoyl group or 3,4,5-trimethoxyphenylmethyl group and a hydrogenation leaving group such as a benzyl group or a phenylethyl group. .
　式（１）の化合物のうち、Ｒ３がアミノ基、アルキルアミノ基又はジアルキルアミノ基である化合物は、上記反応工程の任意の段階で、エステル（－ＣＯＯＲ３ａ）をアミド化することにより得られる。アミド化反応は、例えばアンモニア、アンモニウム塩、アルキルアミン、ジアルキルアミンを用いて行うことができる。 Among the compounds of formula (1), a compound in which R 3 is an amino group, an alkylamino group or a dialkylamino group can be obtained by amidating an ester (—COOR 3a ) at any stage of the above reaction step. . The amidation reaction can be performed using, for example, ammonia, ammonium salt, alkylamine, or dialkylamine.
　このようにして得られる化合物（１）は、付加反応又は縮合反応用の不斉有機触媒として有用である。すなわち、化合物（１）の存在下に付加反応又は縮合反応を行えば、高収率かつ高光学純度でエナンチオマーが得られ、エナンチオ選択的不斉合成が可能である。 The compound (1) thus obtained is useful as an asymmetric organic catalyst for addition reaction or condensation reaction. That is, if an addition reaction or a condensation reaction is performed in the presence of the compound (1), an enantiomer can be obtained with high yield and high optical purity, and enantioselective asymmetric synthesis is possible.
　ここで付加反応又は縮合反応としては、アルドール反応、マンニッヒ反応、マイケル反応、アミノ化反応、ハロゲン化反応等が挙げられる。このうち、本発明の触媒はアルドール反応に適用するのが特に好ましい。 Here, examples of the addition reaction or condensation reaction include aldol reaction, Mannich reaction, Michael reaction, amination reaction, halogenation reaction and the like. Of these, the catalyst of the present invention is particularly preferably applied to the aldol reaction.
　本発明の不斉有機触媒を用いたアルドール反応は次の反応式で表される。 The aldol reaction using the asymmetric organic catalyst of the present invention is represented by the following reaction formula.
Figure JPOXMLDOC01-appb-C000008
Figure JPOXMLDOC01-appb-C000008
（式中、Ｒ４及びＲ５は水素原子又は有機基を示し、Ｒ６は有機基を示す。＊は不斉炭素原子を示し、特定の立体配置を有する） (In the formula, R 4 and R 5 represent a hydrogen atom or an organic group, R 6 represents an organic group, * represents an asymmetric carbon atom, and has a specific configuration)
　すなわち、ケトン類（２）とアルデヒド類（３）とを式（１）の不斉有機触媒の存在下に反応させれば、式（４）の光学活性ケトアルコールが得られる。 That is, when the ketones (2) and the aldehydes (3) are reacted in the presence of the asymmetric organic catalyst of the formula (1), the optically active keto alcohol of the formula (4) is obtained.
　Ｒ４、Ｒ５及びＲ６で示される有機基としては、特に限定されないが、炭化水素基、複素環式基、アルコール、エーテル等が挙げられる。炭化水素基としては、芳香族炭化水素基及び脂肪族炭化水素基のいずれも含まれる。またこれらの炭化水素基及び複素環式基、アルコール、エーテル等は、ハロゲン原子、ニトロ基、アミノ基、シアノ基、カルボキシル基、アルコキシカルボニル基、シリル基等の置換基を有していてもよい。またＲ４とＲ５は一緒になってシクロアルカン構造を成形していてもよい。 The organic group represented by R 4, R 5 and R 6, but are not limited to, hydrocarbon group, heterocyclic group, an alcohol, ether and the like. As the hydrocarbon group, both an aromatic hydrocarbon group and an aliphatic hydrocarbon group are included. These hydrocarbon groups and heterocyclic groups, alcohols, ethers and the like may have a substituent such as a halogen atom, a nitro group, an amino group, a cyano group, a carboxyl group, an alkoxycarbonyl group, or a silyl group. . R 4 and R 5 may be combined to form a cycloalkane structure.
　用いる式（１）の触媒は、式（２）又は式（３）の原料化合物に対して０．５～１０モル％、さらに１～１０モル％用いればよい。この触媒使用量は従来の不斉有機触媒の使用量に比べて少ないものである。 The catalyst of the formula (1) to be used may be used in an amount of 0.5 to 10 mol%, more preferably 1 to 10 mol%, relative to the raw material compound of the formula (2) or the formula (3). The amount of catalyst used is small compared to the amount of conventional asymmetric organic catalysts used.
　反応は通常のアルドール反応に従い、例えば溶媒の存在下又は不存在下、０～２０℃で０．５～７２時間程度行えばよい。 The reaction may be carried out in accordance with a normal aldol reaction, for example, at 0 to 20 ° C. for about 0.5 to 72 hours in the presence or absence of a solvent.
　本発明においては、用いる式（１）の不斉有機触媒の立体配置を変更することにより、目的とするケトアルコールのエナンチオマーの立体配置をコントロールすることができる。すなわち、式（１ａ）の触媒を用いる場合と式（１ｂ）の触媒を用いる場合とで、得られるケトアルコールのエナンチオマーの立体配置が決定されるため、共通の不斉源から２つの触媒を合成することにより、目的とするエナンチオマーを選択的に得ることができる。 In the present invention, the configuration of the enantiomer of the target keto alcohol can be controlled by changing the configuration of the asymmetric organic catalyst of the formula (1) used. That is, the configuration of the enantiomer of the keto alcohol obtained is determined depending on whether the catalyst of the formula (1a) or the catalyst of the formula (1b) is used, so that two catalysts are synthesized from a common asymmetric source. By doing so, the target enantiomer can be selectively obtained.
　また、本発明の触媒は、反応混合物から回収し、再利用することができる。 Also, the catalyst of the present invention can be recovered from the reaction mixture and reused.
　次に実施例を挙げて本発明を詳細に説明する。 Next, the present invention will be described in detail with reference to examples.
［参考例１］（１Ｒ＊，３Ｒ＊，４Ｓ＊）－３，４－エポキシシクロヘキサン－１－カルボン酸　エチルエステル [Reference Example 1] (1R * , 3R * , 4S * )-3,4-epoxycyclohexane-1-carboxylic acid ethyl ester
Figure JPOXMLDOC01-appb-C000009
Figure JPOXMLDOC01-appb-C000009
　（１Ｒ＊，４Ｒ＊，５Ｒ＊）－４－ヨード－６－オキサビシクロ［３．２．１］オクタン－７－オン（Ｊ．Ｏｒｇ．Ｃｈｅｍ．，１９９６年，６１巻，８６８７頁）（１４．３ｇ）をエタノール（１３０ｍＬ）に溶解し、氷冷下２規定水酸化ナトリウム水溶液（３４．５ｍＬ）を加えたのち、室温で７時間攪拌した。溶媒を減圧下留去し、残さに水を加えてジクロロメタンで抽出したのち、無水硫酸ナトリウムで乾燥した。溶媒を減圧下留去し、残さをシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝８３：１７）で精製し、標題化合物（６．５４ｇ）を無色油状物として得た。
１Ｈ－ＮＭＲ（ＣＤＣｌ３）δ：１．２５（３Ｈ，ｔ，Ｊ＝７．１Ｈｚ），１．５０－１．７０（２Ｈ，ｍ），１．７１－１．８２（１Ｈ，ｍ），２．０８－２．２８（４Ｈ，ｍ），３．１６（２Ｈ，ｓ），４．１２（２Ｈ，ｑ，Ｊ＝７．１Ｈｚ）． (1R * , 4R * , 5R * )-4-iodo-6-oxabicyclo [3.2.1] octane-7-one (J. Org. Chem., 1996, 61, 8687) (14 3 g) was dissolved in ethanol (130 mL), and 2N aqueous sodium hydroxide solution (34.5 mL) was added under ice cooling, followed by stirring at room temperature for 7 hours. The solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with dichloromethane, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 83: 17) to give the title compound (6.54 g) as a colorless oil.
1 H-NMR (CDCl 3 ) δ: 1.25 (3H, t, J = 7.1 Hz), 1.50-1.70 (2H, m), 1.71-1.82 (1H, m) 2.08-2.28 (4H, m), 3.16 (2H, s), 4.12 (2H, q, J = 7.1 Hz).
［参考例２］（１Ｒ＊，３Ｓ＊，４Ｓ＊）－３－アジド－４－ヒドロキシシクロヘキサン－１－カルボン酸　エチルエステル [Reference Example 2] (1R * , 3S * , 4S * )-3-azido-4-hydroxycyclohexane-1-carboxylic acid ethyl ester
Figure JPOXMLDOC01-appb-C000010
Figure JPOXMLDOC01-appb-C000010
　（１Ｒ＊，３Ｒ＊，４Ｓ＊）－３，４－エポキシシクロヘキサン－１－カルボン酸　エチルエステル（１３．６ｇ）をＮ，Ｎ－ジメチルホルムアミド（１００ｍＬ）に溶かし、室温にて塩化アンモニウム（６．４５ｇ）、アジ化ナトリウム（７．８ｇ）を順次加えたのち、７５℃で１２時間攪拌した。溶媒を３分の１程度まで濃縮し、水及び酢酸エチルで希釈し、３分間攪拌した。有機層を水及び飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、残さをシリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝１：４）で精製し、標題化合物（１５．８ｇ）を無色油状物として得た。
１Ｈ－ＮＭＲ（ＣＤＣｌ３）δ：１．２８（３Ｈ，ｔ，Ｊ＝７．１Ｈｚ），１．３７－１．６７（２Ｈ，ｍ），１．８６－１．９５（１Ｈ，ｍ），２．０４－２．１８（２Ｈ，ｍ），２．３２－２．４３（１Ｈ，ｍ），２．６８－２．７８（１Ｈ，ｍ），３．４０－３．６０（２Ｈ，ｍ），４．１７（２Ｈ，ｑ，Ｊ＝７．１Ｈｚ）． (1R * , 3R * , 4S * )-3,4-epoxycyclohexane-1-carboxylic acid ethyl ester (13.6 g) was dissolved in N, N-dimethylformamide (100 mL), and ammonium chloride (6. 45 g) and sodium azide (7.8 g) were sequentially added, followed by stirring at 75 ° C. for 12 hours. The solvent was concentrated to about one third, diluted with water and ethyl acetate, and stirred for 3 minutes. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 4) to obtain the title compound (15.8 g) as a colorless oil.
1 H-NMR (CDCl 3 ) δ: 1.28 (3H, t, J = 7.1 Hz), 1.37-1.67 (2H, m), 1.86-1.95 (1H, m) , 2.04-2.18 (2H, m), 2.32-2.43 (1H, m), 2.68-2.78 (1H, m), 3.40-3.60 (2H, m), 4.17 (2H, q, J = 7.1 Hz).
［参考例３］（１Ｒ＊，３Ｓ＊，４Ｓ＊）－３－ｔｅｒｔ－ブトキシカルボニルアミノ－４－ヒドロキシシクロヘキサン－１－カルボン酸　エチルエステル [Reference Example 3] (1R * , 3S * , 4S * )-3-tert-butoxycarbonylamino-4-hydroxycyclohexane-1-carboxylic acid ethyl ester
Figure JPOXMLDOC01-appb-C000011
Figure JPOXMLDOC01-appb-C000011
　（１Ｒ＊，３Ｓ＊，４Ｓ＊）－３－アジド－４－ヒドロキシシクロヘキサン－１－カルボン酸　エチルエステル（１００ｍｇ）及びジ－ｔｅｒｔ－ブチルジカルボナート（１３３ｍｇ）を酢酸エチル（１２ｍＬ）に溶解し、触媒量の１０％パラジウム炭素を加え、水素気流下室温で１２時間攪拌した。不溶物をろ過したのち、溶媒を減圧下留去し、残さをシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝３：１）で精製し、標題化合物（１４５ｍｇ）を無色固体として得た。
１Ｈ－ＮＭＲ（ＣＤＣｌ３）δ：１．２８（３Ｈ，ｔ，Ｊ＝７．１Ｈｚ），１．４５（９Ｈ，ｓ），１．３８－１．５７（２Ｈ，ｍ），１．８６－１．９５（１Ｈ，ｍ），２．０５－２．１７（１Ｈ，ｍ），２．２９－２．３９（２Ｈ，ｍ），２．６１－２．６８（１Ｈ，ｍ），３．２５－３．６６（３Ｈ，ｍ），４．１７（２Ｈ，ｑ，Ｊ＝７．１Ｈｚ），４．５３（１Ｈ，ｂｒ．ｓ）． (1R * , 3S * , 4S * )-3-Azido-4-hydroxycyclohexane-1-carboxylic acid ethyl ester (100 mg) and di-tert-butyl dicarbonate (133 mg) were dissolved in ethyl acetate (12 mL). Then, a catalytic amount of 10% palladium carbon was added, and the mixture was stirred at room temperature for 12 hours under a hydrogen stream. The insoluble material was filtered off, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to give the title compound (145 mg) as a colorless solid.
1 H-NMR (CDCl 3 ) δ: 1.28 (3H, t, J = 7.1 Hz), 1.45 (9H, s), 1.38-1.57 (2H, m), 1.86 -1.95 (1H, m), 2.05-2.17 (1H, m), 2.29-2.39 (2H, m), 2.61-2.68 (1H, m), 3 .25-3.66 (3H, m), 4.17 (2H, q, J = 7.1 Hz), 4.53 (1H, br.s).
［参考例４］（１Ｒ＊，３Ｓ＊，４Ｒ＊）－４－アジド－３－（ｔｅｒｔ－ブトキシカルボニルアミノ）シクロヘキサン－１－カルボン酸　エチルエステル及び（１Ｒ＊，３Ｓ＊，４Ｓ＊）－４－アジド－３－（ｔｅｒｔ－ブトキシカルボニルアミノ）シクロヘキサン－１－カルボン酸　エチルエステル [Reference Example 4] (1R * , 3S * , 4R * )-4-azido-3- (tert-butoxycarbonylamino) cyclohexane-1-carboxylic acid ethyl ester and (1R * , 3S * , 4S * )-4 -Azido-3- (tert-butoxycarbonylamino) cyclohexane-1-carboxylic acid ethyl ester
Figure JPOXMLDOC01-appb-C000012
Figure JPOXMLDOC01-appb-C000012
　（１Ｒ＊，３Ｓ＊，４Ｓ＊）－３－ｔｅｒｔ－ブトキシカルボニルアミノ－４－ヒドロキシシクロヘキサン－１－カルボン酸　エチルエステル（１６ｇ）及びトリエチルアミン（３８ｍＬ）をジクロロメタン（１５０ｍＬ）に溶解し、－７８℃に冷却後、同温にてメタンスルホニルクロリド（１３ｍＬ）を滴下した。同温にて１５分間攪拌したのち、０℃まで昇温し３０分、さらに室温で２時間攪拌した。０．１規定塩酸を加えジクロロメタンで希釈したのち、有機層を分離し、飽和炭酸水素ナトリウム水溶液及び飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、粗製の（１Ｒ＊，３Ｓ＊，４Ｓ＊）－３－ｔｅｒｔ－ブトキシカルボニルアミノ－４－メタンスルホニルオキシシクロヘキサン－１－カルボン酸　エチルエステルを得た。
　上記生成物をＮ，Ｎ－ジメチルホルムアミド（１００ｍＬ）に溶解し、室温にてアジ化ナトリウム（１８ｇ）を加え、７５℃まで昇温して１２時間攪拌した。溶媒を３分の１程度まで濃縮し、水及びＡｃＯＥｔで希釈し３分間攪拌した。有機層を分離し、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、残さをシリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝１：４）で精製し、標題化合物［（１Ｒ＊，３Ｓ＊，４Ｒ＊）－体、６．７４ｇ］及び［（１Ｒ＊，３Ｓ＊，４Ｓ＊）－体、１．３２ｇ］をそれぞれ無色固体として得た。
（１Ｒ＊，３Ｓ＊，４Ｒ＊）－体：
１Ｈ－ＮＭＲ（ＣＤＣｌ３）δ：１．２６（３Ｈ，ｔ，Ｊ＝７．１Ｈｚ），１．４５（９Ｈ，ｓ），１．３８－２．３３（６Ｈ，ｍ），２．５７－２．６８（１Ｈ，ｍ），３．７７－４．２０（４Ｈ，ｍ），４．６３（１Ｈ，ｂｒ．ｓ）．
（１Ｒ＊，３Ｓ＊，４Ｓ＊）－体：
１Ｈ－ＮＭＲ（ＣＤＣｌ３）δ：１．２７（３Ｈ，ｔ，Ｊ＝７．１Ｈｚ），１．４６（９Ｈ，ｓ），１．５３－２．３０（６Ｈ，ｍ），２．５０－２．６５（１Ｈ，ｍ），３．４２－３．７２（２Ｈ，ｍ），４．１５（２Ｈ，ｑ．Ｊ＝７．１Ｈｚ），４．６７（１Ｈ，ｂｒ．ｓ）． (1R * , 3S * , 4S * )-3-tert-butoxycarbonylamino-4-hydroxycyclohexane-1-carboxylic acid ethyl ester (16 g) and triethylamine (38 mL) were dissolved in dichloromethane (150 mL) and dissolved at −78 ° C. After cooling, methanesulfonyl chloride (13 mL) was added dropwise at the same temperature. After stirring at the same temperature for 15 minutes, the temperature was raised to 0 ° C., followed by stirring for 30 minutes and further at room temperature for 2 hours. After adding 0.1N hydrochloric acid and diluting with dichloromethane, the organic layer was separated, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain crude (1R * , 3S * , 4S * )-3-tert-butoxycarbonylamino-4-methanesulfonyloxycyclohexane-1-carboxylic acid ethyl ester.
The above product was dissolved in N, N-dimethylformamide (100 mL), sodium azide (18 g) was added at room temperature, and the mixture was heated to 75 ° C. and stirred for 12 hours. The solvent was concentrated to about one third, diluted with water and AcOEt, and stirred for 3 minutes. The organic layer was separated, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 4) to give the title compound [(1R * , 3S * , 4R * )-isomer, 6.74 g] and [ (1R * , 3S * , 4S * )-isomer, 1.32 g] were obtained as colorless solids.
(1R * , 3S * , 4R * )-body:
1 H-NMR (CDCl 3 ) δ: 1.26 (3H, t, J = 7.1 Hz), 1.45 (9H, s), 1.38-2.33 (6H, m), 2.57 -2.68 (1H, m), 3.77-4.20 (4H, m), 4.63 (1H, br.s).
(1R * , 3S * , 4S * )-body:
1 H-NMR (CDCl 3 ) δ: 1.27 (3H, t, J = 7.1 Hz), 1.46 (9H, s), 1.53-2.30 (6H, m), 2.50 -2.65 (1H, m), 3.42-3.72 (2H, m), 4.15 (2H, q.J = 7.1 Hz), 4.67 (1H, br.s).
［参考例５］（１Ｒ＊，２Ｓ＊，４Ｒ＊）－Ｎ２－ｔｅｒｔ－ブトキシカルボニル－４－エトキシカルボニル－１，２－シクロヘキサンジアミン [Reference Example 5] (1R * , 2S * , 4R * )-N 2 -tert-butoxycarbonyl-4-ethoxycarbonyl-1,2-cyclohexanediamine
Figure JPOXMLDOC01-appb-C000013
Figure JPOXMLDOC01-appb-C000013
　（１Ｒ＊，３Ｓ＊，４Ｒ＊）－４－アジド－３－（ｔｅｒｔ－ブトキシカルボニルアミノ）シクロヘキサン－１－カルボン酸　エチルエステル（５．４ｇ）をエタノール（１０ｍＬ）及び酢酸エチル（１０ｍＬ）の混合溶媒に溶解し、触媒量の１０％パラジウム炭素を加え、水素気流下室温にて２０時間攪拌した。不溶物をろ過したのち、減圧下溶媒を留去し、標題化合物（４．７ｇ）を淡黄色油状物として得た。 (1R * , 3S * , 4R * )-4-azido-3- (tert-butoxycarbonylamino) cyclohexane-1-carboxylic acid ethyl ester (5.4 g) mixed with ethanol (10 mL) and ethyl acetate (10 mL) It melt | dissolved in the solvent, the catalyst amount of 10% palladium carbon was added, and it stirred at room temperature under hydrogen stream for 20 hours. The insoluble material was filtered off, and the solvent was evaporated under reduced pressure to give the title compound (4.7 g) as a pale yellow oil.
［参考例６］（１Ｓ，３Ｓ，４Ｒ）－３，４－エポキシシクロヘキサン－１－カルボン酸　エチルエステル
　（１Ｓ，４Ｓ，５Ｓ）－４－ヨード－６－オキサビシクロ［３．２．１］オクタン－７－オン（Ｊ．Ｏｒｇ．Ｃｈｅｍ．，１９９６年，６１巻，８６８７頁）（８９．３ｇ）をエタノール（８１０ｍＬ）に溶解し、２規定水酸化ナトリウム水溶液（２１３ｍＬ）を加えたのち、室温で３時間攪拌した。溶媒を減圧下留去し、残さに水を加え、ジクロロメタンで抽出したのち、無水硫酸マグネシウムで乾燥した。溶媒を減圧下留去し、残さをシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１７：３）で精製し、標題化合物（４１．２ｇ）を淡黄褐色油状物として得た。
〔α〕Ｄ－５８°（Ｃ＝１．０，クロロホルム）． [Reference Example 6] (1S, 3S, 4R) -3,4-epoxycyclohexane-1-carboxylic acid ethyl ester (1S, 4S, 5S) -4-iodo-6-oxabicyclo [3.2.1] octane -7-one (J. Org. Chem., 1996, 61, 8687) (89.3 g) was dissolved in ethanol (810 mL), and 2N aqueous sodium hydroxide solution (213 mL) was added. For 3 hours. The solvent was distilled off under reduced pressure, water was added to the residue, extracted with dichloromethane, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 17: 3) to obtain the title compound (41.2 g) as a pale tan oil.
[Α] D −58 ° (C = 1.0, chloroform).
［参考例７］（１Ｓ，３Ｒ，４Ｒ）－３－アジド－４－ヒドロキシシクロヘキサン－１－カルボン酸　エチルエステル
　（１Ｓ，３Ｓ，４Ｒ）－３，４－エポキシシクロヘキサン－１－カルボン酸　エチルエステル（４１ｇ）をＮ，Ｎ－ジメチルホルムアミド（３００ｍＬ）に溶かし、室温にて塩化アンモニウム（１９．３ｇ）、アジ化ナトリウム（２３．５ｇ）を順次加えたのち、７５℃で１３時間攪拌した。反応液をろ過し、ろ液を濃縮して４００ｍＬの溶媒を留去し、残さに先のろ取物を入れ、水を加え溶解させた。酢酸エチルで抽出し、有機層を水及び飽和食塩水で洗浄したのち、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、標題化合物（５１．５ｇ）を油状物として得た。
〔α〕Ｄ＋８°（Ｃ＝１．０，クロロホルム） [Reference Example 7] (1S, 3R, 4R) -3-Azido-4-hydroxycyclohexane-1-carboxylic acid ethyl ester (1S, 3S, 4R) -3,4-epoxycyclohexane-1-carboxylic acid ethyl ester ( 41 g) was dissolved in N, N-dimethylformamide (300 mL), ammonium chloride (19.3 g) and sodium azide (23.5 g) were successively added at room temperature, and the mixture was stirred at 75 ° C. for 13 hours. The reaction solution was filtered, the filtrate was concentrated, 400 mL of the solvent was distilled off, the previous filtrate was put into the residue, and water was added to dissolve it. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (51.5 g) as an oil.
[Α] D + 8 ° (C = 1.0, chloroform)
［参考例８］（１Ｓ，３Ｒ，４Ｒ）－３－（ｔｅｒｔ－ブトキシカルボニルアミノ）－４－ヒドロキシシクロヘキサン－１－カルボン酸　エチルエステル
　（１Ｓ，３Ｒ，４Ｒ）－３－アジド－４－ヒドロキシシクロヘキサン－１－カルボン酸　エチルエステル（５１．２ｇ）及びジ－ｔｅｒｔ－ブチルジカルボナート（６８．１ｇ）を酢酸エチル（１０００ｍＬ）に溶解し、５％パラジウム炭素を加え、室温下水素圧５ｋｇ／ｃｍ２で１６時間攪拌した。不溶物をろ過したのち、溶媒を減圧下濃縮し、残さをシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝４：１）で精製し、ヘキサンを加え固化し、標題化合物（５３．６ｇ）を無色結晶として得た。
〔α〕Ｄ＋２５°（Ｃ＝１．０，クロロホルム）． [Reference Example 8] (1S, 3R, 4R) -3- (tert-butoxycarbonylamino) -4-hydroxycyclohexane-1-carboxylic acid ethyl ester (1S, 3R, 4R) -3-azido-4-hydroxycyclohexane 1-carboxylic acid ethyl ester (51.2 g) and di-tert-butyl dicarbonate (68.1 g) were dissolved in ethyl acetate (1000 mL), 5% palladium carbon was added, and hydrogen pressure at room temperature was 5 kg / cm. For 16 hours. The insoluble material was filtered off, and the solvent was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) and solidified by adding hexane to give the title compound (53.6 g) as colorless crystals. Got as.
[Α] D + 25 ° (C = 1.0, chloroform).
［参考例９］（±）－３－シクロヘキセン－１－カルボン酸　ベンジルエステル [Reference Example 9] (±) -3-Cyclohexene-1-carboxylic acid benzyl ester
Figure JPOXMLDOC01-appb-C000014
Figure JPOXMLDOC01-appb-C000014
　（±）－３－シクロヘキセン－１－カルボン酸（５０ｇ）をＮ，Ｎ－ジメチルホルムアミド（５５０ｍＬ）に溶解し、氷冷下トリエチルアミン（１７０ｍＬ）、ベンジルブロミド（６１ｍＬ）を加え室温で１２時間攪拌した。水を加え、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄したのち、無水硫酸マグネシウムで乾燥した。溶媒を減圧下留去し、残さをシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル＝３：１）で精製し、標題化合物（７０．８ｇ）を赤褐色油状物として得た。
１Ｈ－ＮＭＲ（ＣＤＣｌ３）δ：１．６６－１．７６（１Ｈ，ｍ），２．００－２．１３（３Ｈ，ｍ），２．２７－２．２９（２Ｈ，ｍ），２．５８－２．６５（１Ｈ，ｍ），５．１３（２Ｈ，ｓ），５．６６（２Ｈ，ｂｒ．ｓ），７．２９－７．３８（５Ｈ，ｍ）． (±) -3-Cyclohexene-1-carboxylic acid (50 g) was dissolved in N, N-dimethylformamide (550 mL), triethylamine (170 mL) and benzyl bromide (61 mL) were added under ice cooling, and the mixture was stirred at room temperature for 12 hours. . Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (hexane: ethyl acetate = 3: 1) to obtain the title compound (70.8 g) as a reddish brown oil.
1 H-NMR (CDCl 3 ) δ: 1.66-1.76 (1H, m), 2.00-2.13 (3H, m), 2.27-2.29 (2H, m), 2 58-2.65 (1H, m), 5.13 (2H, s), 5.66 (2H, br.s), 7.29-7.38 (5H, m).
［参考例１０］（１Ｒ＊，３Ｓ＊，４Ｒ＊）－３，４－エポキシシクロヘキサン－１－カルボン酸　ベンジルエステル [Reference Example 10] (1R * , 3S * , 4R * )-3,4-epoxycyclohexane-1-carboxylic acid benzyl ester
Figure JPOXMLDOC01-appb-C000015
Figure JPOXMLDOC01-appb-C000015
　（±）－３－シクロヘキセン－１－カルボン酸　ベンジルエステル（４０ｇ）をジクロロメタン（５００ｍＬ）に溶解し、氷冷下４－クロロ過安息香酸（８６ｇ）を加え２時間攪拌した。１０％チオ硫酸ナトリウム水溶液を加え２０分攪拌したのち、有機層を分離し、飽和炭酸水素ナトリウム溶液及び飽和食塩水で洗浄したのち、無水硫酸マグネシウムで乾燥した。溶媒を減圧下留去し、残さをシリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝１：９）にて精製し、標題化合物（２３．４ｇ）と（１Ｒ＊，３Ｒ＊，４Ｓ＊）－３，４－エポキシシクロヘキサン－１－カルボン酸　ベンジルエステル（１２．１ｇ）を無色油状物として得た。
１Ｈ－ＮＭＲ（ＣＤＣｌ３）δ：１．３９－１．４９（１Ｈ，ｍ），１．７５－１．８２（１Ｈ，ｍ），１．９０－２．０４（３Ｈ，ｍ），２．３０（１Ｈ，ｄｄ，Ｊ＝１４．９，４．９Ｈｚ），２．５４－２．６１（１Ｈ，ｍ），３．１２－３．１４（１Ｈ，ｍ），３．２２－３．２４（１Ｈ，ｍ），５．１２（２Ｈ，ｓ），７．３０－７．３９（５Ｈ，ｍ）．
ＭＳ（ＦＡＢ）ｍ／ｚ：２３３（Ｍ＋Ｈ）＋． (±) -3-Cyclohexene-1-carboxylic acid benzyl ester (40 g) was dissolved in dichloromethane (500 mL), and 4-chloroperbenzoic acid (86 g) was added under ice cooling, followed by stirring for 2 hours. After adding 10% aqueous sodium thiosulfate solution and stirring for 20 minutes, the organic layer was separated, washed with saturated sodium bicarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 9) to give the title compound (23.4 g) and (1R * , 3R * , 4S * )-3, 4-Epoxycyclohexane-1-carboxylic acid benzyl ester (12.1 g) was obtained as a colorless oil.
1 H-NMR (CDCl 3 ) δ: 1.39-1.49 (1H, m), 1.75-1.82 (1H, m), 1.90-2.04 (3H, m), 2 .30 (1H, dd, J = 14.9, 4.9 Hz), 2.54-2.61 (1H, m), 3.12-3.14 (1H, m), 3.22-3. 24 (1H, m), 5.12 (2H, s), 7.30-7.39 (5H, m).
MS (FAB) m / z: 233 (M + H) <+> .
［参考例１１］（１Ｒ＊，３Ｓ＊，４Ｓ＊）－４－アジド－３－ヒドロキシシクロヘキサン－１－カルボン酸　ベンジルエステル [Reference Example 11] (1R * , 3S * , 4S * )-4-azido-3-hydroxycyclohexane-1-carboxylic acid benzyl ester
Figure JPOXMLDOC01-appb-C000016
Figure JPOXMLDOC01-appb-C000016
　（１Ｒ＊，３Ｓ＊，４Ｒ＊）－３，４－エポキシシクロヘキサン－１－カルボン酸　ベンジルエステル（５２．３ｇ）をＮ，Ｎ－ジメチルホルムアミド（１０００ｍＬ）に溶解し、塩化アンモニウム（２１．９ｇ）、アジ化ナトリウム（１８．１ｇ）を加え７０℃に加熱して２４時間攪拌した。溶媒を減圧下留去し、残さに水を加え、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄したのち、無水硫酸マグネシウムで乾燥した。溶媒を減圧下留去し、標題化合物（６１．８ｇ）を無色油状物として得た。
１Ｈ－ＮＭＲ（ＣＤＣｌ３）δ：１．５１－１．６６（２Ｈ，ｍ），１．９１－１．９８（１Ｈ，ｍ），２．０７－２．１０（１Ｈ，ｍ），２．２７－２．３２（１Ｈ，ｍ），２．５１－２．５２（１Ｈ，ｍ），２．８１－２．８６（１Ｈ，ｍ），３．３０－３．３６（１Ｈ，ｍ），３．７０－３．７５（１Ｈ，ｍ），５．１３（２Ｈ，ｓ），７．３０－７．３９（５Ｈ，ｍ）． (1R * , 3S * , 4R * )-3,4-epoxycyclohexane-1-carboxylic acid benzyl ester (52.3 g) was dissolved in N, N-dimethylformamide (1000 mL) and ammonium chloride (21.9 g) Sodium azide (18.1 g) was added and heated to 70 ° C. and stirred for 24 hours. The solvent was evaporated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (61.8 g) as a colorless oil.
1 H-NMR (CDCl 3 ) δ: 1.51-1.66 (2H, m), 1.91-1.98 (1H, m), 2.07-2.10 (1H, m), 2 .27-2.32 (1H, m), 2.51-2.52 (1H, m), 2.81-2.86 (1H, m), 3.30-3.36 (1H, m) 3.70-3.75 (1H, m), 5.13 (2H, s), 7.30-7.39 (5H, m).
［参考例１２］（１Ｒ＊，３Ｓ＊，４Ｓ＊）－４－（Ｎ－ｔｅｒｔ－ブトキシカルボニルアミノ）－３－ヒドロキシシクロヘキサン－１－カルボン酸　ベンジルエステル [Reference Example 12] (1R * , 3S * , 4S * )-4- (N-tert-butoxycarbonylamino) -3-hydroxycyclohexane-1-carboxylic acid benzyl ester
Figure JPOXMLDOC01-appb-C000017
Figure JPOXMLDOC01-appb-C000017
　（１Ｒ＊，３Ｓ＊，４Ｓ＊）－４－アジド－３－ヒドロキシシクロヘキサン－１－カルボン酸　ベンジルエステル（５．２７ｇ）をテトラヒドロフラン（２５ｍＬ）に溶解し、トリフェニルホスフィン（５．５３ｇ）及び水（０．５５ｍＬ）を加え室温で２０時間攪拌した。反応液に、ジ－ｔｅｒｔ－ブチルジカーボナート（４．８２ｇ）を加え、さらに２時間攪拌を続けた。溶媒を減圧下留去し、シリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝２：１）で精製し、標題化合物（６．２２ｇ）を無色油状物として得た。
１Ｈ－ＮＭＲ（ＣＤＣｌ３）δ：１．４４（９Ｈ，ｓ），１．５９－１．６６（２Ｈ，ｍ），１．８８－２．００（２Ｈ，ｍ），２．２９－２．３２（１Ｈ，ｍ），２．８０－２．８５（１Ｈ，ｍ），３．０２（１Ｈ，ｂｒ．ｓ），３．４２（１Ｈ，ｂｒ．ｓ），３．５９－３．６５（１Ｈ，ｍ），４．５６（１Ｈ，ｂｒ．ｓ），５．１２（２Ｈ，ｑ，Ｊ＝１２．５Ｈｚ），７．３０－７．３８（５Ｈ，ｍ）．
ＭＳ（ＦＡＢ）ｍ／ｚ：３５０（Ｍ＋Ｈ）＋． (1R * , 3S * , 4S * )-4-azido-3-hydroxycyclohexane-1-carboxylic acid benzyl ester (5.27 g) was dissolved in tetrahydrofuran (25 mL), triphenylphosphine (5.53 g) and water. (0.55 mL) was added and stirred at room temperature for 20 hours. Di-tert-butyl dicarbonate (4.82 g) was added to the reaction solution, and stirring was continued for another 2 hours. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give the title compound (6.22 g) as a colorless oil.
1 H-NMR (CDCl 3 ) δ: 1.44 (9H, s), 1.59-1.66 (2H, m), 1.88-2.00 (2H, m), 2.29-2 .32 (1H, m), 2.80-2.85 (1H, m), 3.02 (1H, br.s), 3.42 (1H, br.s), 3.59-3.65 (1H, m), 4.56 (1H, br.s), 5.12 (2H, q, J = 12.5 Hz), 7.30-7.38 (5H, m).
MS (FAB) m / z: 350 (M + H) <+> .
［参考例１３］（１Ｒ＊，３Ｓ＊，４Ｓ＊）－４－Ｎ－（ｔｅｒｔ－ブトキシカルボニルアミノ）－３－ヒドロキシシクロヘキサン－１－カルボン酸　メチルエステル [Reference Example 13] (1R * , 3S * , 4S * )-4-N- (tert-butoxycarbonylamino) -3-hydroxycyclohexane-1-carboxylic acid methyl ester
Figure JPOXMLDOC01-appb-C000018
Figure JPOXMLDOC01-appb-C000018
　（１Ｒ＊，３Ｓ＊，４Ｓ＊）－４－Ｎ－（ｔｅｒｔ－ブトキシカルボニルアミノ）－３－ヒドロキシシクロヘキサン－１－カルボン酸　ベンジルエステル（２．５４ｇ）を酢酸エチル（１５ｍＬ）に溶解し、触媒量の１０％パラジウム炭素を加え水素気流下室温で２０時間攪拌した。触媒をろ去し、ろ液を減圧下濃縮し、（１Ｒ＊，３Ｓ＊，４Ｓ＊）－４－Ｎ－（ｔｅｒｔ－ブトキシカルボニルアミノ）－３－ヒドロキシシクロヘキサン－１－カルボン酸を無色油状物として得た。これをメタノール（８ｍＬ）とトルエン（１５ｍＬ）の混合溶液に溶解し、氷冷下トリメチルシリルジアゾメタン２規定溶液（１０ｍＬ）を加え室温にて３０分攪拌した。溶媒を減圧下留去し、シリカゲルカラムクロマトフラフィー（ヘキサン：酢酸エチル＝１：１）で精製し、標題化合物（１．８２ｇ）を無色油状物として得た。
１Ｈ－ＮＭＲ（ＣＤＣｌ３）δ：１．４４（９Ｈ，ｓ），１．３６－２．３２（７Ｈ，ｍ），２．７４－２．８２（１Ｈ，ｍ），３．０４（１Ｈ，ｂｒ．ｓ），３．３３－３．４７（１Ｈ，ｍ），３．５５－３．６５（１Ｈ，ｍ），３．６８（３Ｈ，ｓ），４．５６（１Ｈ，ｂｒ．ｓ）．
ＭＳ（ＦＡＢ）ｍ／ｚ：２７４（Ｍ＋Ｈ）＋． (1R * , 3S * , 4S * )-4-N- (tert-butoxycarbonylamino) -3-hydroxycyclohexane-1-carboxylic acid benzyl ester (2.54 g) was dissolved in ethyl acetate (15 mL) to prepare a catalyst. An amount of 10% palladium carbon was added and stirred at room temperature for 20 hours under a hydrogen stream. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to give (1R * , 3S * , 4S * )-4-N- (tert-butoxycarbonylamino) -3-hydroxycyclohexane-1-carboxylic acid as a colorless oil. Got as. This was dissolved in a mixed solution of methanol (8 mL) and toluene (15 mL), trimethylsilyldiazomethane 2N solution (10 mL) was added under ice cooling, and the mixture was stirred at room temperature for 30 min. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to obtain the title compound (1.82 g) as a colorless oil.
1 H-NMR (CDCl 3 ) δ: 1.44 (9H, s), 1.36-2.32 (7H, m), 2.74-2.82 (1H, m), 3.04 (1H , Br.s), 3.33-3.47 (1H, m), 3.55-3.65 (1H, m), 3.68 (3H, s), 4.56 (1H, br. S). ).
MS (FAB) m / z: 274 (M + H) <+> .
［参考例１４］（１Ｒ＊，３Ｒ＊，４Ｓ＊）－３－アジド－４－Ｎ－（ｔｅｒｔ－ブトキシカルボニルアミノ）シクロヘキサン－１－カルボン酸　メチルエステル及び（１Ｒ＊，３Ｒ＊，４Ｒ＊）－３－アジド－４－Ｎ－（ｔｅｒｔ－ブトキシカルボニルアミノ）シクロヘキサン－１－カルボン酸　メチルエステル [Reference Example 14] (1R * , 3R * , 4S * )-3-azido-4-N- (tert-butoxycarbonylamino) cyclohexane-1-carboxylic acid methyl ester and (1R * , 3R * , 4R * ) -3-Azido-4-N- (tert-butoxycarbonylamino) cyclohexane-1-carboxylic acid methyl ester
Figure JPOXMLDOC01-appb-C000019
Figure JPOXMLDOC01-appb-C000019
　（１Ｒ＊，３Ｓ＊，４Ｓ＊）－４－Ｎ－（ｔｅｒｔ－ブトキシカルボニルアミノ）－３－ヒドロキシシクロヘキサン－１－カルボン酸　メチルエステル（１．８１ｇ）をジクロロメタン（３６ｍＬ）に溶解し、－７８℃にてトリエチルアミン（４．６ｍＬ）、メタンスルホニルクロリド（１．６３ｍＬ）を加え、３０分後０℃まで昇温し、さらに３０分攪拌した。１規定塩酸を加え、ジクロロメタンで抽出し、有機層を飽和食塩水で洗浄したのち、無水硫酸マグネシウムで乾燥した。溶媒を減圧下留去し、粗製の（１Ｒ＊，３Ｓ＊，４Ｓ＊）－４－Ｎ－（ｔｅｒｔ－ブトキシカルボニルアミノ）－３－（メタンスルホニルオキシ）シクロヘキサン－１－カルボン酸メチルエステルを得た。
　粗製の（１Ｒ＊，３Ｓ＊，４Ｓ＊）－４－Ｎ－（ｔｅｒｔ－ブトキシカルボニルアミノ）－３－（メタンスルホニルオキシ）シクロヘキサン－１－カルボン酸　メチルエステルをＮ，Ｎ－ジメチルホルムアミド（２３ｍＬ）に溶解し、アジ化ナトリウム（１．２９ｇ）を加え、７０℃に加熱して１２時間攪拌した。反応液に水を加え、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄したのち、無水硫酸マグネシウムで乾燥した。溶媒を減圧下留去し、残さをフラシュカラムクロマトグラフィー（酢酸エチル：ヘキサン＝３：１７）で精製し、（１Ｒ＊，３Ｒ＊，４Ｒ＊）－３－アジド－４－（Ｎ－ｔｅｒｔ－ブトキシカルボニルアミノ）シクロヘキサン－１－カルボン酸　メチルエステル（８５ｍｇ）と（１Ｒ＊，３Ｒ＊，４Ｓ＊）－３－アジド－４－（Ｎ－ｔｅｒｔ－ブトキシカルボニルアミノ）シクロヘキサン－１－カルボン酸　メチルエステル（５９０ｍｇ）を無色油状物として得た。
（１Ｒ＊，３Ｒ＊，４Ｓ＊）－体：１Ｈ－ＮＭＲ（ＣＤＣｌ３）δ：１．４５（９Ｈ，ｓ），１．３５－２．３５（７Ｈ，ｍ），２．４５－２．５５（１Ｈ，ｍ），３．７３（３Ｈ，ｓ），３．６７－３．８４（２Ｈ，ｍ），４．７０（１Ｈ，ｂｒ．ｓ）．
ＭＳ（ＦＡＢ）ｍ／ｚ：２９９（Ｍ＋Ｈ）＋．
（１Ｒ＊，３Ｒ＊，４Ｒ＊）－体：１Ｈ－ＮＭＲ（ＣＤＣｌ３）δ：１．４５（９Ｈ，ｓ），１．５６－２．２５（７Ｈ，ｍ），２．６８－２．８０（１Ｈ，ｍ），３．７０（３Ｈ，ｓ），３．４８－３．６８（２Ｈ，ｍ），４．５６（１Ｈ，ｂｒ．ｓ）．
ＭＳ（ＦＡＢ）ｍ／ｚ：２９９（Ｍ＋Ｈ）＋． (1R * , 3S * , 4S * )-4-N- (tert-butoxycarbonylamino) -3-hydroxycyclohexane-1-carboxylic acid methyl ester (1.81 g) was dissolved in dichloromethane (36 mL) and -78 Triethylamine (4.6 mL) and methanesulfonyl chloride (1.63 mL) were added at 0 ° C., 30 minutes later, the temperature was raised to 0 ° C., and the mixture was further stirred for 30 minutes. 1N Hydrochloric acid was added, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain crude (1R * , 3S * , 4S * )-4-N- (tert-butoxycarbonylamino) -3- (methanesulfonyloxy) cyclohexane-1-carboxylic acid methyl ester. It was.
Crude (1R * , 3S * , 4S * )-4-N- (tert-butoxycarbonylamino) -3- (methanesulfonyloxy) cyclohexane-1-carboxylic acid methyl ester was converted to N, N-dimethylformamide (23 mL). The mixture was dissolved in sodium azide (1.29 g), heated to 70 ° C. and stirred for 12 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by flash column chromatography (ethyl acetate: hexane = 3: 17), and (1R * , 3R * , 4R * )-3-azido-4- (N-tert- Butoxycarbonylamino) cyclohexane-1-carboxylic acid methyl ester (85 mg) and (1R * , 3R * , 4S * )-3-azido-4- (N-tert-butoxycarbonylamino) cyclohexane-1-carboxylic acid methyl ester (590 mg) was obtained as a colorless oil.
(1R * , 3R * , 4S * )-isomer: 1 H-NMR (CDCl 3 ) δ: 1.45 (9H, s), 1.35-2.35 (7H, m), 2.45-2 .55 (1H, m), 3.73 (3H, s), 3.67-3.84 (2H, m), 4.70 (1H, br.s).
MS (FAB) m / z: 299 (M + H) <+> .
(1R * , 3R * , 4R * )-isomer: 1 H-NMR (CDCl 3 ) δ: 1.45 (9H, s), 1.56-2.25 (7H, m), 2.68-2 .80 (1H, m), 3.70 (3H, s), 3.48-3.68 (2H, m), 4.56 (1H, br.s).
MS (FAB) m / z: 299 (M + H) <+> .
［参考例１５］（１Ｒ＊，２Ｓ＊，４Ｓ＊）－Ｎ１－（ｔｅｒｔ－ブトキシカルボニル）－４－メトキシカルボニル－１，２－シクロヘキサンジアミン [Reference Example 15] (1R * , 2S * , 4S * )-N 1- (tert-butoxycarbonyl) -4-methoxycarbonyl-1,2-cyclohexanediamine
Figure JPOXMLDOC01-appb-C000020
Figure JPOXMLDOC01-appb-C000020
（１Ｒ＊，３Ｒ＊，４Ｓ＊）－３－アジド－４－（Ｎ－ｔｅｒｔ－ブトキシカルボニルアミノ）シクロヘキサン－１－カルボン酸　メチルエステル（２３０ｍｇ）を酢酸エチル（８ｍＬ）に溶解し、触媒量の１０％パラジウム炭素を加え、水素気流下２０時間攪拌した。不溶物をろ去し、ろ液を減圧下濃縮し、標題化合物（２２０ｍｇ）を淡黄色油状物として得た。 (1R * , 3R * , 4S * )-3-azido-4- (N-tert-butoxycarbonylamino) cyclohexane-1-carboxylic acid methyl ester (230 mg) was dissolved in ethyl acetate (8 mL) 10% palladium carbon was added and stirred for 20 hours under a hydrogen stream. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (220 mg) as a pale yellow oil.
［参考例１６］（１Ｒ，３Ｓ，４Ｒ）－３，４－エポキシシクロヘキサン－１－カルボン酸　ベンジルエステル
１）参考例９と同様の方法で、（１Ｒ）－３－シクロヘキセン－１－カルボン酸（Ｊ．Ａｍ．Ｃｈｅｍ．Ｓｏｃ，１９７８年，１００巻，５１９９頁）から、（１Ｒ）－３－シクロヘキセン－１－カルボン酸　ベンジルエステルを得た。
２）参考例１０と同様の方法で、上記の生成物から標題化合物を得た。
ＭＳ（ＦＡＢ）ｍ／ｚ：２３３（Ｍ＋Ｈ）＋． [Reference Example 16] (1R, 3S, 4R) -3,4-epoxycyclohexane-1-carboxylic acid benzyl ester 1) In the same manner as in Reference Example 9, (1R) -3-cyclohexene-1-carboxylic acid ( J. Am. Chem. Soc, 1978, 100, 5199), (1R) -3-cyclohexene-1-carboxylic acid benzyl ester was obtained.
2) In the same manner as in Reference Example 10, the title compound was obtained from the above product.
MS (FAB) m / z: 233 (M + H) <+> .
［参考例１７］（１Ｒ，３Ｓ，４Ｓ）－４－（Ｎ－ｔｅｒｔ－ブトキシカルボニルアミノ）－３－ヒドロキシシクロヘキサン－１－カルボン酸　ベンジルエステル
１）参考例１３と同様の方法で、（１Ｒ，３Ｓ，４Ｒ）－３，４－エポキシシクロヘキサン－１－カルボン酸　ベンジルエステルから、（１Ｒ，３Ｓ，４Ｓ）－４－アジド－３－ヒドロキシシクロヘキサン－１－カルボン酸　ベンジルエステルを得た。
２）参考例１２と同様の方法で、上記の生成物から標題化合物を得た。
ＭＳ（ＦＡＢ）ｍ／ｚ：３５０（Ｍ＋Ｈ）＋． [Reference Example 17] (1R, 3S, 4S) -4- (N-tert-butoxycarbonylamino) -3-hydroxycyclohexane-1-carboxylic acid benzyl ester 1) In the same manner as in Reference Example 13, (1R, (1R, 3S, 4S) -4-azido-3-hydroxycyclohexane-1-carboxylic acid benzyl ester was obtained from 3S, 4R) -3,4-epoxycyclohexane-1-carboxylic acid benzyl ester.
2) In the same manner as in Reference Example 12, the title compound was obtained from the above product.
MS (FAB) m / z: 350 (M + H) <+> .
［参考例１８］（１Ｒ，３Ｒ，４Ｓ）－３－アジド－４－（Ｎ－ｔｅｒｔ－ブトキシカルボニルアミノ）シクロヘキサン－１－カルボン酸　ベンジルエステル [Reference Example 18] (1R, 3R, 4S) -3-Azido-4- (N-tert-butoxycarbonylamino) cyclohexane-1-carboxylic acid benzyl ester
Figure JPOXMLDOC01-appb-C000021
Figure JPOXMLDOC01-appb-C000021
　参考例１４と同様の方法で、（１Ｒ，３Ｓ，４Ｓ）－４－（Ｎ－ｔｅｒｔ－ブトキシカルボニルアミノ）－３－ヒドロキシシクロヘキサン－１－カルボン酸　ベンジルエステルから標題化合物を得た。
１Ｈ－ＮＭＲ（ＣＤＣｌ３）δ：１．４５（９Ｈ，ｓ），１．５２－１．６６（２Ｈ，ｍ），１．８３－２．０１（３Ｈ，ｍ），２．２０－２．２８（１Ｈ，ｍ），２．５１－２．５４（１Ｈ，ｍ），３．７７（２Ｈ，ｂｒ．ｓ），４．７０（１Ｈ，ｂｒ．ｓ），５．１５（２Ｈ，ＡＢｑ，Ｊ＝１２．２Ｈｚ），７．３３－７．３８（５Ｈ，ｍ）．
ＭＳ（ＦＡＢ）ｍ／ｚ：３７５（Ｍ＋Ｈ）＋． In the same manner as in Reference Example 14, the title compound was obtained from (1R, 3S, 4S) -4- (N-tert-butoxycarbonylamino) -3-hydroxycyclohexane-1-carboxylic acid benzyl ester.
1 H-NMR (CDCl 3 ) δ: 1.45 (9H, s), 1.52-1.66 (2H, m), 1.83 to 2.01 (3H, m), 2.20-2 .28 (1H, m), 2.51-2.54 (1H, m), 3.77 (2H, br.s), 4.70 (1H, br.s), 5.15 (2H, ABq) , J = 12.2 Hz), 7.33-7.38 (5H, m).
MS (FAB) m / z: 375 (M + H) <+> .
［参考例１９］（１Ｒ，３Ｒ，４Ｓ）－３－アジド－４－（Ｎ－ｔｅｒｔ－ブトキシカルボニルアミノ）シクロヘキサン－１－カルボン酸　メチルエステル [Reference Example 19] (1R, 3R, 4S) -3-Azido-4- (N-tert-butoxycarbonylamino) cyclohexane-1-carboxylic acid methyl ester
Figure JPOXMLDOC01-appb-C000022
Figure JPOXMLDOC01-appb-C000022
　（１Ｒ，３Ｒ，４Ｓ）－３－アジド－４－（Ｎ－ｔｅｒｔ－ブトキシカルボニルアミノ）シクロヘキサン－１－カルボン酸　ベンジルエステル（３．５ｇ）をテトラヒドロフラン（１３０ｍＬ）、水（１６ｍＬ）に溶解し、氷冷下水酸化リチウム（２９１ｍｇ）を加え、１０分後室温に戻し攪拌を続けた。２０時間後反応を停止し、溶媒を減圧下留去後得られた残渣をシリカゲルを用いるカラムクロマトグラフィー（メタノール：ジクロロメタン＝１：２０）に付し、（１Ｒ，３Ｒ，４Ｓ）－３－アジド－４－（Ｎ－ｔｅｒｔ－ブトキシカルボニルアミノ）シクロヘキサン－１－カルボン酸（３．３４ｇ）を淡黄色油状物として得た。これをメタノール（１８ｍＬ）、トルエン（６４ｍＬ）に溶解し、氷冷下トリメチルシリルジアゾメタン（２Ｍ溶液，６．１ｍＬ）を加え、１０分後室温に戻して攪拌した。２時間後反応を停止し、溶媒を減圧下留去したのち、残さをシリカゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン＝１：４）で精製し、標題化合物（３．３５ｇ）を無色油状物として得た。
１Ｈ－ＮＭＲ（ＣＤＣｌ３）δ：１．４５（９Ｈ，ｓ），１．５７－１．６３（２Ｈ，ｍ），１．８２－１．８５（１Ｈ，ｍ），１．９５－１．９９（２Ｈ，ｍ），２．２０－２．２８（１Ｈ，ｍ），２．４８－２．５１（１Ｈ，ｍ），３．７３（３Ｈ，ｓ），３．７８（２Ｈ，ｂｒ．ｓ），４．７０－４．７２（１Ｈ，ｍ）．
ＭＳ（ＦＡＢ）ｍ／ｚ：２９９（Ｍ＋Ｈ）＋． (1R, 3R, 4S) -3-Azido-4- (N-tert-butoxycarbonylamino) cyclohexane-1-carboxylic acid benzyl ester (3.5 g) was dissolved in tetrahydrofuran (130 mL) and water (16 mL). Under ice-cooling, lithium hydroxide (291 mg) was added, and after 10 minutes, the temperature was returned to room temperature and stirring was continued. After 20 hours, the reaction was stopped, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to column chromatography using silica gel (methanol: dichloromethane = 1: 20) to give (1R, 3R, 4S) -3-azido. -4- (N-tert-butoxycarbonylamino) cyclohexane-1-carboxylic acid (3.34 g) was obtained as a pale yellow oil. This was dissolved in methanol (18 mL) and toluene (64 mL), trimethylsilyldiazomethane (2M solution, 6.1 mL) was added under ice cooling, and after 10 minutes, the mixture was returned to room temperature and stirred. After 2 hours, the reaction was stopped, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 4) to obtain the title compound (3.35 g) as a colorless oil. It was.
1 H-NMR (CDCl 3 ) δ: 1.45 (9H, s), 1.57-1.63 (2H, m), 1.82-1.85 (1H, m), 1.95-1 .99 (2H, m), 2.20-2.28 (1H, m), 2.48-2.51 (1H, m), 3.73 (3H, s), 3.78 (2H, br S), 4.70-4.72 (1H, m).
MS (FAB) m / z: 299 (M + H) <+> .
［参考例２０］（１Ｓ，３Ｒ，４Ｓ）－３－アミノ－４－ベンジルオキシカルボニルアミノ－シクロヘキシルカルボン酸　エチルエステル [Reference Example 20] (1S, 3R, 4S) -3-Amino-4-benzyloxycarbonylamino-cyclohexylcarboxylic acid ethyl ester
Figure JPOXMLDOC01-appb-C000023
Figure JPOXMLDOC01-appb-C000023
（１Ｓ，３Ｒ，４Ｓ）－３－ｔｅｒｔ－ブトキシカルボニルアミノ－４－ベンジルオキシカルボニルアミノーシクロヘキシルカルボン酸　エチルエステル（１．２６ｇ）をアセトニトリル（２０ｍＬ）中に溶解させ、メタンスルホン酸（０．９７ｍＬ）を添加し、室温で６時間攪拌した。溶媒留去後、重曹水で中和、ジクロロメタンで抽出後、酢酸エチル１０ｍＬで３時間スラリー精製を行った。結晶をろ過後、乾燥し、標題化合物１．６４ｇを得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：７．２９－７．５２（５Ｈ，ｍ，ＡｒＨ），５．３０（１Ｈ，ｂｒｓ，ＮＨ），５．０８（１Ｈ，ｂｒｓ，ＯＣＨ２Ａｒ），４．１２（２Ｈ，ｑ，Ｊ＝７．３Ｈｚ，ＯＣＨ２ＣＨ３），３．５９（１Ｈ，ｂｒｓ），２．４８－２．５５（１Ｈ，ｍ，ＣＨ），１．８９－１．９６（２Ｈ，ｍ，ＣＨ２），１．７９－１．８１（２Ｈ，ｍ，ＣＨ２），１．４０－１．５９（２Ｈ，ｍ，ＣＨ２），１．２６（３Ｈ，ｔ，Ｊ＝７．３Ｈｚ，ＯＣＨ２ＣＨ３），１．１７－１．２９（１Ｈ，ｍ，ＣＨ）．
ＨＲＭＳ（ＥＳＩ）ｅｘａｃｔ　ｍａｓｓ　ｃａｌｃｄ．ｆｏｒ　Ｃ１７Ｈ２４Ｎ２Ｏ４　ｍ／ｚ　３２１．１８１３（［Ｍ＋Ｈ］＋），ｆｏｕｎｄ：ｍ／ｚ　３２１．１８１４（［Ｍ＋Ｈ］＋）． (1S, 3R, 4S) -3-tert-Butoxycarbonylamino-4-benzyloxycarbonylamino-cyclohexylcarboxylic acid ethyl ester (1.26 g) was dissolved in acetonitrile (20 mL) and methanesulfonic acid (0.97 mL) was dissolved. ) And stirred at room temperature for 6 hours. After the solvent was distilled off, the residue was neutralized with aqueous sodium hydrogen carbonate, extracted with dichloromethane, and then purified by slurry with 10 mL of ethyl acetate for 3 hours. The crystals were filtered and dried to give 1.64 g of the title compound.
1 H-NMR (400 MHz, CDCl 3 ) δ: 7.29-7.52 (5H, m, ArH), 5.30 (1H, brs, NH), 5.08 (1H, brs, OCH 2 Ar) , 4.12 (2H, q, J = 7.3Hz, OCH 2 CH 3), 3.59 (1H, brs), 2.48-2.55 (1H, m, CH), 1.89-1 .96 (2H, m, CH 2 ), 1.79-1.81 (2H, m, CH 2 ), 1.40-1.59 (2H, m, CH 2 ), 1.26 (3H, t , J = 7.3 Hz, OCH 2 CH 3 ), 1.17-1.29 (1H, m, CH).
HRMS (ESI) exact mass calcd. for C 17 H 24 N 2 O 4 m / z 321.1813 ([M + H] +), found: m / z 321.1814 ([M + H] +).
［参考例２１］ベンジル　ｔｅｒｔ－ブチル　｛（１Ｓ，２Ｒ，４Ｓ）－４－［（ジメチルアミノ）カルボニル］シクロヘキサン－１，２－ジイル｝ビスカルバメート [Reference Example 21] Benzyl tert-butyl {(1S, 2R, 4S) -4-[(dimethylamino) carbonyl] cyclohexane-1,2-diyl} biscarbamate
Figure JPOXMLDOC01-appb-C000024
Figure JPOXMLDOC01-appb-C000024
　エチル　（１Ｓ，３Ｒ，４Ｓ）－４－｛［（ベンジロキシ）カルボニル］アミノ｝－３－［（ｔｅｒｔ－ブトキシカルボニル）アミノ］シクロヘキサンカルボキシレート（３．２ｇ）をエタノール３２ｍＬに溶解した後、室温にて反応液に２Ｍ水酸化リチウム水溶液（１１．４ｍＬ）を加え、３時間攪拌した。反応液に６Ｎ塩酸（２．６ｍＬ）を加えｐＨ７に調整し、反応液をそのまま留去した。得られた残渣をＤＭＦ（３２ｍＬ）を加え、ジメチルアミン・塩酸塩（２．４８ｇ）及び１－ヒドロキシベンゾトリアゾール（１．５４ｇ）を加えた攪拌した。溶解後、１－エチル－３－（３－ジメチルアミノプロピル）カルボジイミド塩酸塩（２．１９ｇ）を加え、室温にて１６時間攪拌した。反応液に酢酸エチルエステル及び水を加えて抽出し、水層に酢酸エチルエステルを加え抽出した。有機層をあわせ、水にて洗浄後、無水硫酸マグネシウムにて乾燥した。溶媒を減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィーに付し、標題化合物２．９４ｇを得た。
１Ｈ－ＮＭＲ（ＣＤＣｌ３）δ：１．２０－１．５０（２Ｈ，ｍ），１．４４（９Ｈ，ｓ），１．５０－２．１０（４Ｈ，ｍ），２．６０（１Ｈ，ｂｒ．ｔ，Ｊ＝１１．６Ｈｚ），２．９３（３Ｈ，ｓ），３．０２（３Ｈ，ｓ），３．７０（１Ｈ，ｂｒ．ｓ），４．１４（１Ｈ，ｂｒ．ｓ），４．６５（１Ｈ，ｂｒ．ｓ），５．００－５．３０（３Ｈ，ｍ），７．２６－７．４０（５Ｈ，ｍ）． Ethyl (1S, 3R, 4S) -4-{[(benzyloxy) carbonyl] amino} -3-[(tert-butoxycarbonyl) amino] cyclohexanecarboxylate (3.2 g) was dissolved in 32 mL of ethanol and then brought to room temperature. Then, 2M lithium hydroxide aqueous solution (11.4 mL) was added to the reaction solution, and the mixture was stirred for 3 hours. 6N hydrochloric acid (2.6 mL) was added to the reaction solution to adjust to pH 7, and the reaction solution was distilled off as it was. DMF (32 mL) was added to the resulting residue, and dimethylamine hydrochloride (2.48 g) and 1-hydroxybenzotriazole (1.54 g) were added and stirred. After dissolution, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (2.19 g) was added and stirred at room temperature for 16 hours. The reaction mixture was extracted with ethyl acetate and water, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water, and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography to obtain 2.94 g of the title compound.
1 H-NMR (CDCl 3 ) δ: 1.20-1.50 (2H, m), 1.44 (9H, s), 1.50-2.10 (4H, m), 2.60 (1H , Br.t, J = 11.6 Hz), 2.93 (3H, s), 3.02 (3H, s), 3.70 (1H, br.s), 4.14 (1H, br.s). ), 4.65 (1H, br.s), 5.00-5.30 (3H, m), 7.26-7.40 (5H, m).
［参考例２２］ｔｅｒｔ－ブチル　｛（１Ｒ，２Ｓ，５Ｓ）－２－アミノ－５－［（ジメチルアミノ）カルボニル］シクロヘキシル｝カルバメート　シュウ酸塩 [Reference Example 22] tert-butyl {(1R, 2S, 5S) -2-amino-5-[(dimethylamino) carbonyl] cyclohexyl} carbamate oxalate
Figure JPOXMLDOC01-appb-C000025
Figure JPOXMLDOC01-appb-C000025
＜Ａ法＞
　（１Ｒ，２Ｒ，４Ｓ）－２－［（ｔｅｒｔ－ブトキシカルボニル）アミノ］－４－［（ジメチルアミノ）カルボニル］シクロヘキシル　メタンスルホネート（２０．０ｇ）のトルエン溶液（１００ｍＬ）に室温にて、アジ化ナトリウム（７．１４ｇ）及びドデシルピリジニウム　クロリド（７．８０ｇ）を加えた。６０℃にて、７２時間攪拌後、反応液に水を加え、有機層を飽和重層水、水にて洗浄後、有機層にメタノールを加え、７．５％Ｐｄ－Ｃ及びギ酸アンモニウムを加えて４０℃で１時間攪拌した。Ｐｄ－Ｃをろ過除去後、溶媒を減圧濃縮し、これに含水アセトニトリル（２００ｍＬ）及び無水シュウ酸（４．９４ｇ）を加え、室温下１７時間攪拌し、結晶をろ取した。得られた結晶をアセトニトリル（２００ｍＬ）に加えて、４０℃にて２４時間攪拌した。得られた結晶をろ取・乾燥し、標題化合物１２．７ｇを得た。
１Ｈ－ＮＭＲ（Ｄ２Ｏ）δ：１．３０（９Ｈ，ｓ），１．３７－１．４９（２Ｈ，ｍ），１．６３（１Ｈ，ｔ，Ｊ＝２．７Ｈｚ），１．７２－１．８３（３Ｈ，ｍ），２．７７（３Ｈ，ｓ），２．８０（１Ｈ，ｔ，Ｊ＝１２．４Ｈｚ），２．９６（３Ｈ，ｍ），３．３２（１Ｈ，ｄ，Ｊ＝１２．２Ｈｚ），４．１０（１Ｈ，ｂｒ）．
元素分析：Ｃａｌｃ．Ｃ；５０．７０％、Ｈ；７．７５％、Ｎ；１０．９６％
Ｏｂｓｄ．Ｃ；５１．１９％、Ｈ；７．７９％、Ｎ；１１．１９％．
＜Ｂ法＞ <Method A>
(1R, 2R, 4S) -2-[(tert-Butoxycarbonyl) amino] -4-[(dimethylamino) carbonyl] cyclohexyl Methanesulfonate (20.0 g) in toluene solution (100 mL) at room temperature Sodium (7.14 g) and dodecylpyridinium chloride (7.80 g) were added. After stirring at 60 ° C. for 72 hours, water was added to the reaction solution, the organic layer was washed with saturated multistory water and water, methanol was added to the organic layer, and 7.5% Pd—C and ammonium formate were added. Stir at 40 ° C. for 1 hour. After removing Pd—C by filtration, the solvent was concentrated under reduced pressure, water-containing acetonitrile (200 mL) and oxalic anhydride (4.94 g) were added thereto, and the mixture was stirred at room temperature for 17 hours, and the crystals were collected by filtration. The obtained crystals were added to acetonitrile (200 mL) and stirred at 40 ° C. for 24 hours. The obtained crystals were collected by filtration and dried to obtain 12.7 g of the title compound.
1 H-NMR (D 2 O) δ: 1.30 (9H, s), 1.37-1.49 (2H, m), 1.63 (1H, t, J = 2.7 Hz), 1. 72-1.83 (3H, m), 2.77 (3H, s), 2.80 (1H, t, J = 12.4 Hz), 2.96 (3H, m), 3.32 (1H, d, J = 12.2 Hz), 4.10 (1H, br).
Elemental analysis: Calc. C; 50.70%, H; 7.75%, N; 10.96%
Obsd. C; 51.19%, H; 7.79%, N; 11.19%.
<Method B>
Figure JPOXMLDOC01-appb-C000026
Figure JPOXMLDOC01-appb-C000026
　ベンジル　ｔｅｒｔ－ブチル｛（１Ｓ，２Ｒ，４Ｓ）－４－［（ジメチルアミノ）カルボニル］シクロヘキサン－１，２－ジイル｝ビスカルバメート（２．３ｇ）のエタノール溶液（３５ｍＬ）に、７．５％Ｐｄ－Ｃ（２３０ｍｇ）を加え、水素雰囲気下、１６時間攪拌した。Ｐｄ－Ｃを濾去後、得られたろ液を減圧下濃縮した。得られた残渣に酢酸エチルエステル（２０ｍＬ）及び無水シュウ酸（４９３．６ｍｇ）を加え、室温下１７時間攪拌した後、結晶をろ取し、標題化合物１．９３ｇを得た。各種スペクトルデータは上記＜Ａ法＞で得たものと完全に一致した。 7.5% Pd in ethanol solution (35 mL) of benzyl tert-butyl {(1S, 2R, 4S) -4-[(dimethylamino) carbonyl] cyclohexane-1,2-diyl} biscarbamate (2.3 g) -C (230 mg) was added, and the mixture was stirred under a hydrogen atmosphere for 16 hours. After removing Pd—C by filtration, the obtained filtrate was concentrated under reduced pressure. Acetic acid ethyl ester (20 mL) and oxalic anhydride (493.6 mg) were added to the obtained residue, and the mixture was stirred at room temperature for 17 hr. The crystals were collected by filtration to give 1.93 g of the title compound. Various spectrum data completely matched with those obtained by the above <Method A>.
実施例１（１Ｓ，３Ｒ，４Ｓ）－４－ベンジルオキシカルボニルアミノ－３－トリフルオロメタンスルホニルアミノ－シクロヘキシルカルボン酸　エチルエステル Example 1 (1S, 3R, 4S) -4-benzyloxycarbonylamino-3-trifluoromethanesulfonylamino-cyclohexylcarboxylic acid ethyl ester
Figure JPOXMLDOC01-appb-C000027
Figure JPOXMLDOC01-appb-C000027
　（１Ｓ，３Ｒ，４Ｓ）－３－アミノ－４－ベンジルオキシカルボニルアミノーシクロヘキシルカルボン酸　エチルエステル（１．８ｇ）をジクロロメタン１０ｍＬ中に入れ、さらにトリエチルアミン（０．９６ｍＬ）を連続的に入れ、－７８℃に冷却した。無水トリフルオロメタンスルホン酸（０．９３ｍＬ）を滴下し、１時間攪拌した。反応終了後、水を加え、分液操作後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１：１）で精製し、標題化合物２．２７ｇを得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：７．２９－７．３８（５Ｈ，ｍ，ＡｒＨ），６．２３（１Ｈ，ｂｒｓ，ＮＨＴｆ），５．０６－５．１３（３Ｈ，ｍ，ＮＨ，ＣＨ２Ａｒ），４．１５（２Ｈ，ｑ，Ｊ＝７．３Ｈｚ，ＯＣＨ２ＣＨ３），３．５９（１Ｈ，ｂｒｓ），２．４８－２．５５（１Ｈ，ｍ，ＣＨ），１．８９－１．９６（２Ｈ，ｍ，ＣＨ２），１．７９－１．８１（２Ｈ，ｍ，ＣＨ２），４．０５－４．１１（１Ｈ，ｍ，ＣＨ），３．８１－３．８３（１Ｈ，ｍ，ＣＨ），２．５６（１Ｈ，ｂｒｓ），２．０１－２．０８（２Ｈ，ｍ，ＣＨ２），１．８７－１．８９（２Ｈ，ｍ，ＣＨ２），１．５３－１．７１（２Ｈ，ｍ，ＣＨ２），１．２７（３Ｈ，ｔ，Ｊ＝７．３Ｈｚ，ＯＣＨ２ＣＨ３）．
ＨＲＭＳ（ＥＳＩ）ｅｘａｃｔ　ｍａｓｓ　ｃａｌｃｄ．ｆｏｒ　Ｃ１８Ｈ２３Ｎ２Ｏ６Ｆ３Ｓ　ｍ／ｚ　４７５．１１２５（［Ｍ＋Ｎａ］＋），ｆｏｕｎｄ：ｍ／ｚ　４７５．１１２６（［Ｍ＋Ｎａ］＋） (1S, 3R, 4S) -3-Amino-4-benzyloxycarbonylamino-cyclohexylcarboxylic acid ethyl ester (1.8 g) was placed in 10 mL of dichloromethane, and triethylamine (0.96 mL) was continuously added. Cooled to 78 ° C. Trifluoromethanesulfonic anhydride (0.93 mL) was added dropwise and stirred for 1 hour. After completion of the reaction, water was added, and after the liquid separation operation, the solvent was distilled off. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give 2.27 g of the title compound.
1 H-NMR (400 MHz, CDCl 3 ) δ: 7.29-7.38 (5H, m, ArH), 6.23 (1H, brs, NHTf), 5.06-5.13 (3H, m, NH, CH 2 Ar), 4.15 (2H, q, J = 7.3 Hz, OCH 2 CH 3 ), 3.59 (1H, brs), 2.48-2.55 (1H, m, CH) 1.89-1.96 (2H, m, CH 2 ), 1.79-1.81 (2H, m, CH 2 ), 4.05-4.11 (1H, m, CH), 3. 81-3.83 (1H, m, CH), 2.56 (1H, brs), 2.01-1.08 (2H, m, CH 2 ), 1.87-1.89 (2H, m, CH 2), 1.53-1.71 (2H, m, CH 2), 1.27 (3H, t, J = 7.3Hz, OCH 2 CH 3).
HRMS (ESI) exact mass calcd. for C 18 H 23 N 2 O 6 F 3 S m / z 475.1125 ([M + Na] +), found: m / z 475.1126 ([M + Na] +)
実施例２（１Ｓ，３Ｒ，４Ｓ）－４－アミノ－３－トリフルオロメタンスルホニルアミノ－シクロヘキサンカルボン酸　エチルエステル Example 2 (1S, 3R, 4S) -4-amino-3-trifluoromethanesulfonylamino-cyclohexanecarboxylic acid ethyl ester
Figure JPOXMLDOC01-appb-C000028
Figure JPOXMLDOC01-appb-C000028
　（１Ｓ，３Ｒ，４Ｓ）－４－ベンジルオキシカルボニルアミノ－３－トリフルオロメタンスルホニルアミノ－シクロヘキシルカルボン酸　エチルエステル（２．２７ｇ）をメタノール（２０ｍＬ）中に入れ、引き続きＰｄ／Ｃ（２００ｍｇ）を入れ４０℃で６時間攪拌した。反応終了後、セライトろ過をし、残渣を濃縮した。濃縮残渣に酢酸エチル２０ｍＬを入れ、３時間スラリー精製を行った、ろ過、乾燥後、標題化合物（１．３３ｇ）を得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤ３ＯＤ）δ：４．１０（２Ｈ，ｑ，Ｊ＝７．２Ｈｚ，ＣＯ２ＣＨ２ＣＨ３），３．７４（１Ｈ，ｓ，ＮＨ），３．０７－３．１１（１Ｈ，ｍ，ＣＨＮＨ），２．７８－２．８３（１Ｈ，ｍ，ＮＨＣＨ），２．０６（１Ｈ，ｄｄ，Ｊ＝１３．６，１．２Ｈｚ，ＣＨ），１．９７（１Ｈ，ｄｄ，Ｊ＝１３．６，１．２Ｈｚ，ＣＨ），１．７７－１．８５（１Ｈ，ｍ），１．６８－１．７１（１Ｈ，ｍ），１．５８－１．６４（１Ｈ，ｍ），１．４２－１．５１（１Ｈ，ｍ），１．２２（３Ｈ，ｔ，Ｊ＝７．２Ｈｚ，ＣＯ２ＣＨ２ＣＨ３）．
ＨＲＭＳ（ＦＡＢ）ｅｘａｃｔ　ｍａｓｓ　ｃａｌｃｄ．ｆｏｒ　Ｃ１０Ｈ１７Ｎ２Ｏ４Ｆ３Ｓ　ｍ／ｚ　３１９．０９３５（［Ｍ＋Ｈ］＋），ｆｏｕｎｄ：ｍ／ｚ　３１９．０９３９（［Ｍ＋Ｈ］＋）；［α］２０ Ｄ＝＋３．３（ｃ＝０．３，ＭｅＯＨ）． (1S, 3R, 4S) -4-Benzyloxycarbonylamino-3-trifluoromethanesulfonylamino-cyclohexylcarboxylic acid ethyl ester (2.27 g) was placed in methanol (20 mL), followed by Pd / C (200 mg). The mixture was stirred at 40 ° C. for 6 hours. After completion of the reaction, the mixture was filtered through celite and the residue was concentrated. 20 mL of ethyl acetate was added to the concentrated residue, and slurry purification was performed for 3 hours. After filtration and drying, the title compound (1.33 g) was obtained.
1 H-NMR (400 MHz, CD 3 OD) δ: 4.10 (2H, q, J = 7.2 Hz, CO 2 CH 2 CH 3 ), 3.74 (1H, s, NH), 3.07- 3.11 (1H, m, CHNH), 2.78-2.83 (1H, m, NHCH), 2.06 (1H, dd, J = 13.6, 1.2 Hz, CH), 1.97 (1H, dd, J = 13.6, 1.2 Hz, CH), 1.77-1.85 (1H, m), 1.68-1.71 (1H, m), 1.58-1. 64 (1H, m), 1.42-1.51 (1H, m), 1.22 (3H, t, J = 7.2 Hz, CO 2 CH 2 CH 3 ).
HRMS (FAB) exact mass calcd. for C 10 H 17 N 2 O 4 F 3 S m / z 319.0935 ([M + H] + ), found: m / z 319.0939 ([M + H] + ); [α] 20 D = + 3.3 ( c = 0.3, MeOH).
実施例３（１Ｓ，３Ｒ，４Ｒ）－３－ｔｅｒｔ－ブトキシカルボニルアミノ－４－トリフルオロメチルスルホニルアミン－シクロヘキサンカルボン酸　エチルエステル Example 3 (1S, 3R, 4R) -3-tert-butoxycarbonylamino-4-trifluoromethylsulfonylamine-cyclohexanecarboxylic acid ethyl ester
Figure JPOXMLDOC01-appb-C000029
Figure JPOXMLDOC01-appb-C000029
　（１Ｒ＊，２Ｓ＊，４Ｒ＊）－３－ｔｅｒｔ－ブトキシカルボニル－４－エトキシカルボニル－１，２－シクロヘキサンジアミン（１．６２ｇ）をジクロロメタン（１０ｍＬ）中に入れ、引き続きトリエチルアミン（０．９６ｍＬ）を入れ、－７８℃に冷却した。無水トリフルオロメタンスルホン酸（０．９３ｍＬ）を滴下し、そのままの温度で１時間攪拌した。反応終了後、０℃まで温度を上げ、水を加えて反応を停止させた。分液後、有機層を濃縮し、ショートシリカゲルカラムクロマトグラフィに付し、標題化合物（２．２７ｇ）を得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：４．１３（２Ｈ，ｑ，Ｊ＝７．３Ｈｚ，ＣＯ２ＣＨ２ＣＨ３），３．６１（２Ｈ，ｂｒｓ，ＮＨ），２．３９（１Ｈ，ｂｒｓ，ＮＨ），１．８８－２．０８（４Ｈ，ｍ，ＣＨ２），１．５５－１．６８（２Ｈ，ｍ，ＣＨ２），１．４６（９Ｈ，ｓ，ｔ－Ｂｕ），１．２５（３Ｈ，ｔ，Ｊ＝７．３Ｈｚ，ＣＯ２ＣＨ２ＣＨ３）．
ＨＲＭＳ（ＥＳＩ）ｅｘａｃｔ　ｍａｓｓ　ｃａｌｃｄ．ｆｏｒ　Ｃ１５Ｈ２５Ｎ２Ｏ６Ｆ３Ｓ　ｍ／ｚ　４４１．１２９０（［Ｍ＋Ｎａ］＋），ｆｏｕｎｄ：ｍ／ｚ　４４１．１２８３（［Ｍ＋Ｎａ］＋）． (1R * , 2S * , 4R * )-3-tert-butoxycarbonyl-4-ethoxycarbonyl-1,2-cyclohexanediamine (1.62 g) was placed in dichloromethane (10 mL), followed by triethylamine (0.96 mL). And cooled to -78 ° C. Trifluoromethanesulfonic anhydride (0.93 mL) was added dropwise and stirred at that temperature for 1 hour. After completion of the reaction, the temperature was raised to 0 ° C., and water was added to stop the reaction. After liquid separation, the organic layer was concentrated and subjected to short silica gel column chromatography to obtain the title compound (2.27 g).
1 H-NMR (400 MHz, CDCl 3 ) δ: 4.13 (2H, q, J = 7.3 Hz, CO 2 CH 2 CH 3 ), 3.61 (2H, brs, NH), 2.39 (1H , Brs, NH), 1.88-2.08 (4H, m, CH 2 ), 1.55-1.68 (2H, m, CH 2 ), 1.46 (9H, s, t-Bu) , 1.25 (3H, t, J = 7.3Hz, CO 2 CH 2 CH 3).
HRMS (ESI) exact mass calcd. for C 15 H 25 N 2 O 6 F 3 S m / z 441.1290 ([M + Na] +), found: m / z 441.1283 ([M + Na] +).
実施例４（１Ｓ，３Ｒ，４Ｒ）－３－アミノ－４－トリフルオロメタンスルホニルアミノ－シクロヘキサンカルボン酸　エチルエステル Example 4 (1S, 3R, 4R) -3-Amino-4-trifluoromethanesulfonylamino-cyclohexanecarboxylic acid ethyl ester
Figure JPOXMLDOC01-appb-C000030
Figure JPOXMLDOC01-appb-C000030
　（１Ｓ，３Ｒ，４Ｒ）－３－ｔｅｒｔ－ブトキシカルボニルアミノ－４－トリフルオロメタンスルホニルアミノ－シクロヘキサンカルボン酸　エチルエステル１．２６ｇをアセトニトリル２０ｍＬ中に入れ、メタンスルホン酸（０．９７ｍＬ）を入れて、６時間室温で攪拌した。結晶をろ取し、標題化合物のメタンスルホン酸塩を取得した。その化合物を重曹水で中和した後、ジクロロメタンで抽出し、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィ（ヘキサン：酢酸エチル＝１：１）で精製し、標題化合物８１２ｍｇを得た。
実施例５
　シクロヘキサノン０．９ｍＬ及びｐ－ニトロベンズアルデヒド４５．３ｍｇをテトラヒドロフラン０．９ｍＬ及び水０．９ｍＬの混合液に添加した。これに化合物（１ａ－１）又は化合物（１ｂ－１）をｐ－ニトロベンズアルデヒド１モルに対して５モル％添加して、室温（２５℃）で３～４日間攪拌した。反応混合液を酢酸エチル３ｍＬにて抽出、分液操作後、有機層を濃縮した。残渣をシリカゲルカラムクロマトグラフィにて精製して、アルドール付加体を７４．９ｍｇ（収率９９％、ジアステレオ比：７／９３（ｓｙｎ／ａｎｔｉ）、９７％ｅｅ）得た。 1.26 g of (1S, 3R, 4R) -3-tert-butoxycarbonylamino-4-trifluoromethanesulfonylamino-cyclohexanecarboxylic acid ethyl ester is placed in 20 mL of acetonitrile and methanesulfonic acid (0.97 mL) is added. Stir for 6 hours at room temperature. The crystals were collected by filtration to obtain the methanesulfonate salt of the title compound. The compound was neutralized with aqueous sodium bicarbonate, extracted with dichloromethane, and the solvent was distilled off. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to obtain 812 mg of the title compound.
Example 5
0.9 mL cyclohexanone and 45.3 mg p-nitrobenzaldehyde were added to a mixture of 0.9 mL tetrahydrofuran and 0.9 mL water. To this was added 5 mol% of compound (1a-1) or compound (1b-1) with respect to 1 mol of p-nitrobenzaldehyde, and the mixture was stirred at room temperature (25 ° C.) for 3 to 4 days. The reaction mixture was extracted with 3 mL of ethyl acetate, and after liquid separation, the organic layer was concentrated. The residue was purified by silica gel column chromatography to obtain 74.9 mg (yield 99%, diastereo ratio: 7/93 (syn / anti), 97% ee) of an aldol adduct.
Figure JPOXMLDOC01-appb-C000031
Figure JPOXMLDOC01-appb-C000031
　実施例５と同様にしてアルドール反応を行った結果を表１に示す。 Table 1 shows the results of the aldol reaction as in Example 5.
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000001
　表１から明らかに、本発明の触媒を用いれば、１つの不斉源から合成された２つの触媒により、互いに異なる高純度のエナンチオマーが選択的に得られる。 As is apparent from Table 1, when the catalyst of the present invention is used, high-purity enantiomers different from each other can be selectively obtained by two catalysts synthesized from one asymmetric source.
実施例６
　シクロペンタノン０．９ｍＬ及びｐ－ニトロベンズアルデヒド４５．３ｍｇをテトラヒドロフラン０．９ｍＬ及び水０．９ｍＬの混合液に添加した。これに化合物（１ａ－１）又は化合物（１ｂ－１）をｐ－ニトロベンズアルデヒド１モルに対して５モル％添加して、室温（２５℃）で１６～２２時間撹拌した。以下、実施例５と同様に処理して、アルドール付加体を６９．９ｍｇ（収率９９％、ジアステレオ比９２／８（ｓｙｎ／ａｎｔｉ）、９３％ｅｅ）得た。 Example 6
0.9 mL of cyclopentanone and 45.3 mg of p-nitrobenzaldehyde were added to a mixture of 0.9 mL of tetrahydrofuran and 0.9 mL of water. To this was added 5 mol% of compound (1a-1) or compound (1b-1) with respect to 1 mol of p-nitrobenzaldehyde, and the mixture was stirred at room temperature (25 ° C.) for 16 to 22 hours. Thereafter, the same treatment as in Example 5 was performed to obtain 69.9 mg (yield 99%, diastereo ratio 92/8 (syn / anti), 93% ee) of an aldol adduct.
Figure JPOXMLDOC01-appb-C000032
Figure JPOXMLDOC01-appb-C000032
　実施例６と同様にしてアルドール反応を行った結果を表２に示す。 Table 2 shows the results of the aldol reaction performed in the same manner as in Example 6.
Figure JPOXMLDOC01-appb-T000002
Figure JPOXMLDOC01-appb-T000002
実施例７
　シクロヘキサノンに代えて２，２－ジメチル－１，３－ジオキサ－５－オンを用いる以外は、実施例５とほぼ同様にして、反応を行った。その結果を表３に示す。 Example 7
The reaction was performed in substantially the same manner as in Example 5 except that 2,2-dimethyl-1,3-dioxa-5-one was used instead of cyclohexanone. The results are shown in Table 3.
Figure JPOXMLDOC01-appb-C000033
Figure JPOXMLDOC01-appb-C000033
Figure JPOXMLDOC01-appb-T000003
Figure JPOXMLDOC01-appb-T000003

Claims (4)

  1. 　式（１）
    Figure JPOXMLDOC01-appb-C000034
     （式中、Ｒ１及びＲ２は、一方が水素原子、他方がアシル基を示し、Ｒ３はアルコキシ基、アリールオキシ基、アラルキルオキシ基、アミノ基、アルキルアミノ基又はジアルキルアミノ基を示す。＊は不斉炭素原子を示し、Ｒ１ＨＮ－及びＲ２ＨＮ－は不斉炭素原子上で同一の立体配置を有する。）
    で表される光学活性ジアミノシクロヘキサンカルボン酸類又はそのブレンステッド酸塩からなる付加反応又は縮合反応用不斉有機触媒。     Formula (1)
    Figure JPOXMLDOC01-appb-C000034
     (In the formula, one of R 1 and R 2 represents a hydrogen atom and the other represents an acyl group, and R 3 represents an alkoxy group, an aryloxy group, an aralkyloxy group, an amino group, an alkylamino group, or a dialkylamino group. * Represents an asymmetric carbon atom, and R 1 HN— and R 2 HN— have the same configuration on the asymmetric carbon atom.)
    An asymmetric organic catalyst for addition reaction or condensation reaction comprising an optically active diaminocyclohexanecarboxylic acid represented by the formula (1) or a Bronsted acid salt thereof.
  2. 　Ｒ１及びＲ２の一方が水素原子であり、他方がアルカンスルホニル基又はハロゲノアルカンスルホニル基である請求項１記載の不斉有機触媒。 The asymmetric organic catalyst according to claim 1, wherein one of R 1 and R 2 is a hydrogen atom, and the other is an alkanesulfonyl group or a halogenoalkanesulfonyl group.
  3. 　Ｒ３がアルコキシ基、アラルキルオキシ基、アルキルアミノ基又はジアルキルアミノ基である請求項１又は２記載の不斉有機触媒。 The asymmetric organic catalyst according to claim 1 or 2, wherein R 3 is an alkoxy group, an aralkyloxy group, an alkylamino group or a dialkylamino group.
  4. 　式（２）
    Figure JPOXMLDOC01-appb-C000035
     （式中、Ｒ４及びＲ５は水素原子又は有機基を示す）
    で表されるケトン類と式（３）
    Figure JPOXMLDOC01-appb-C000036
     （式中、Ｒ６は有機基を示す）
    で表されるアルデヒド類とを、請求項１～３のいずれか１項記載の不斉有機触媒の存在下に反応させることを特徴とする式（４）
    Figure JPOXMLDOC01-appb-C000037
     （＊は不斉炭素原子を示し、特定の立体配置を有し、Ｒ４、Ｒ５及びＲ６は前記と同じ）
    で表される光学活性ケトアルコールの製造法。     Formula (2)
    Figure JPOXMLDOC01-appb-C000035
     (Wherein R 4 and R 5 represent a hydrogen atom or an organic group)
    And ketones represented by formula (3)
    Figure JPOXMLDOC01-appb-C000036
     (Wherein R 6 represents an organic group)
    The aldehydes represented by formula (4) are reacted in the presence of the asymmetric organic catalyst according to any one of claims 1 to 3.
    Figure JPOXMLDOC01-appb-C000037
     (* Represents an asymmetric carbon atom, has a specific configuration, and R 4 , R 5 and R 6 are the same as above)
    The manufacturing method of optically active keto alcohol represented by these.
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WO2012002538A1 (en) * 2010-07-02 2012-01-05 第一三共株式会社 Process for preparation of optically active diamine derivative salt
CN103080078A (en) * 2010-07-02 2013-05-01 第一三共株式会社 Process for preparation of optically active diamine derivative salt
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CN105017121A (en) * 2015-06-09 2015-11-04 哈尔滨工程大学 Optically active phenylacetylene derivative with Fmoc-L-hydroxyproline and preparation and application methods

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