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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carboxylic acid
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中山 敬司
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第一三共株式会社
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    • C07C311/00Amides 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
    • C07C311/01Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
    • C07C311/02Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C311/09Sulfonamides 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
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01JCHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/02Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
    • B01J31/04Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides containing carboxylic acids or their salts
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    • C07BGENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B53/00Asymmetric syntheses
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    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C205/00Compounds containing nitro groups bound to a carbon skeleton
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    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00Carboxylic acid nitriles
    • C07C255/49Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/56Carboxylic 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
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    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61Preparation 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
    • C07C45/67Preparation 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
    • C07C45/68Preparation 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
    • C07C45/72Preparation 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
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    • C07DHETEROCYCLIC COMPOUNDS
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    • C07D319/041,3-Dioxanes; Hydrogenated 1,3-dioxanes
    • C07D319/061,3-Dioxanes; Hydrogenated 1,3-dioxanes not condensed with other rings
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    • B01J2231/00Catalytic reactions performed with catalysts classified in B01J31/00
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    • C07C2601/08Systems containing only non-condensed rings with a five-membered ring the ring being saturated
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    • C07C2601/14The ring being saturated

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

Asymmetric organic catalysts

The present invention relates to a method for producing optically active keto alcohols using asymmetric organic catalysts and this for addition reactions or condensation reactions.

The compounds having an asymmetric carbon atom, different optically active forms of configuration are present. Among such optically active substance, the other optically active substance may compound bioactive like are largely different, it is very important to selectively produce the useful optically active substance. The selective preparation of optically active substances, there is also an optical splitting means, the reaction was carried out for compounds that do not have an element of asymmetry, a method for selectively synthesizing one enantiomer (enantioselective asymmetric synthetic) are useful there is no waste of raw materials.

In the enantioselective asymmetric synthesis, requires highly selective asymmetric catalysts, it is widely known metal complex as such asymmetric catalyst. But the metal complex may be not generated as metal waste, is often metal serving as the center is a rare metal (rare metals), there is a problem when considering earth's resources etc., there is environmental problems.

From this point of view, the asymmetric organic catalysts have attracted attention recovered and can be reused. Examples of such asymmetric organic catalysts, amino acids and primary amino groups such as proline, secondary amino group, and diamines having tertiary amino groups have been reported (Non-Patent Documents 1-5). However, these asymmetric organic catalysts, the amount is large, optically active yield is not sufficient, there is a substrate specificity such problems. Further, these catalysts in the synthesis of different enantiomers is derived from the opposite optically active forms, it has required that the opposite as asymmetric sources, the induction was troublesome.

J. Am. Chem. Soc. 2000,122,7386-7387 J. Am. Chem. Soc. 2000,122,2395-2396 J. Am. Chem. Soc. 2001,123,5260-5267 J. Am. Chem. Soc. 2007,129,3074-3075 Chem. Rev. 2007,107,5471-5569

An object of the present invention is less in amount to provide an enantioselective asymmetric synthesis using a new asymmetric organic catalysts and their can achieve high optical activity yields.

The present inventor has were studied asymmetric organic catalysts in aldol reactions, by performing an aldol reaction using cyclohexane carboxylic acids having the following primary amino groups and secondary amino groups, a small amount, enantioselectivity at a high yield it is capable of selective asymmetric synthesis, further by the selection of the optically active substance of the catalyst, it found that it is possible to obtain the enantiomers of keto-alcohol compound obtained selectively, and have completed the present invention.

That is, the present invention has the formula (1)

Figure JPOXMLDOC01-appb-C000001

(Wherein, R 1 and R 2, one is a hydrogen atom and the other acyl group, 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, R 1 HN- and R 2 HN- have the same configuration on the asymmetric carbon atoms.)
There is provided an optically active diaminocyclohexane acids or addition reaction or condensation reaction organocatalysis made from the Bronsted acid salt represented in.

Further, the present invention provides a compound of formula (2)

Figure JPOXMLDOC01-appb-C000002

(Wherein, R 4 and R 5 represents a hydrogen atom or an organic group)
In represented by ketones of the formula (3)

Figure JPOXMLDOC01-appb-C000003

(Wherein, R 6 represents an organic group)
In the represented aldehydes, which comprises reacting in the presence of an asymmetric organic catalysts of the above formula (1) Equation (4)

Figure JPOXMLDOC01-appb-C000004

(* Indicates an asymmetric carbon atom, have a specific configuration, R 4, R 5 and R 6 are the same as defined above)
There is provided a process for producing an optically active keto alcohol represented in.

The use of asymmetric organic catalysts of the present invention, a small amount of catalyst, enantiomers high optical purity is selectively obtained. Particularly when applied to aldol reaction, the enantioselectivity of the keto alcohol obtained high, by selection of an asymmetric organic catalyst used, it is possible to obtain the enantiomers of keto alcohol of interest selectively.

Asymmetric organic catalysts of the present invention consists of an optically active diaminocyclohexane carboxylic acid esters and amides of the formula (1). In the formula (1), of R 1 and R 2, one is a hydrogen atom and the other is an acyl group. Wherein acyl is a group produced by removing one or more hydroxy groups of the oxo acids, examples of which include groups created by removal of the hydroxy group from a carboxylic acid or sulfonic acid. Examples of the acyl group include alkanoyl group, aroyl group, alkanesulfonyl group, halogeno-alkanesulfonyl group, an aryl sulfonyl group.

Here, as the alkanoyl group is preferably an alkanoyl group having 2 to 12 carbon atoms; an acetyl group, a propionyl group, a butyryl group are more preferable. Aroyl The group benzoyl group, a benzoyl group preferably has a substituent. The alkanesulfonyl group is preferably an Al Cal sulfonyl group having 1 to 6 carbon atoms; methanesulfonyl group, ethanesulfonyl group is more preferable. Halogenoalkyl The Roh alkanesulfonyl group, alkanesulfonyl group having 1 to 6 carbon atoms a halogen atom and 1-15 substituents are preferred; trifluoromethanesulfonyl group, pentafluoro ethane sulfonyl group are preferable. The arylsulfonyl group benzenesulfonyl group, p-toluenesulfonyl group.

Among the acyl groups represented by R 1 or R 2, alkanesulfonyl group or halogenoalkyl alkanesulfonyl group it is particularly preferred.

Here, one of R 1 and R 2 is a hydrogen atom and the other be an acyl group, is important in the compound of formula (1) can exhibit the function as the asymmetric organic catalysts. This is considered because the hydrogen atoms acting as a Bronsted acid.

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. The alkoxy group, a straight-chain having 1 to 12 carbon atoms and an alkoxy group having branched or cyclic, such as methoxy group, ethoxy group, n- propyl group, an isopropyl group, isobutyl group, tert- butyloxy , cyclopentyloxy group, cyclohexyloxy group and the like. Of these, particularly preferably an alkoxy group having 1 to 6 carbon atoms.

The aryloxy group is an aryloxy group having 6 to 14 carbon atoms, such as phenoxy group, naphthyloxy group, anthracenyloxy group, and the like. The aralkyloxy group include a group alkoxy group is bonded having 1 to 6 carbon atoms in the aryl group having 6 to 14 carbon atoms, such as phenyl C 1-6 alkoxy group, more particularly a benzyl group, diphenyl such as a methyl group and the like.

The alkylamino groups include alkylamino groups having 1 to 12 carbon atoms, for example methylamino group, ethylamino group, propylamino group, isopropylamino group and the like. Of these, particularly preferred is an alkylamino group having 1 to 6 carbon atoms.

The dialkylamino group include di (C 1-12 alkyl) amino group is, for example, dimethylamino group, diethylamino group, dipropylamino group, dibutylamino group and the like. Of these, di (C 1-12 alkyl) amino groups are particularly preferred.

Among the groups represented by R 3, an alkoxy group, an aralkyloxy group, an alkylamino group, a dialkylamino group it is particularly preferred.

These asymmetric organic catalyst acts as a catalyst in salt form with a Bronsted acid, by the substrates is sometimes better of these salts provide good value. As the acid counter, for example hydrochloric, sulfuric, inorganic acids such as phosphoric acid, acetic acid, benzoic acid, an organic carboxylic acid or tartaric acid, or mesylate, and organic sulfonic acids such as p-toluenesulfonic acid. Of these, organic sulfonic acids such as mesylate are particularly preferred.

Formula (1) * represents an asymmetric carbon atom, R 1 HN- and R 2 HN- have the same configuration on the asymmetric carbon atom. Configuration of -COR 3 is not limited. Therefore, the configuration of the compound of formula (1), if Shimese R 1 or R 2 as hydrogen, which is the next four.

Figure JPOXMLDOC01-appb-C000005

(Wherein, R 1 ~ R 3 are as defined above)

Compounds of formula (1) can be prepared, for example according to the following reaction scheme. Although the configuration of the following reaction scheme is the case of the formula (1a), it can be prepared in the same manner other compounds of configurations.

Figure JPOXMLDOC01-appb-C000006

(Wherein, R 3a represents an alkyl group, an aryl group or an aralkyl group, Boc represents a t- butoxycarbonyl group, Z is shown a benzyloxycarbonyl group, R 1 is as defined above)

First, compound (B) is obtained with readily available cyclohexene carboxylic acid (A) in iodolactonization reaction using iodinated. The iodolactonization reaction, compound (A), can be carried out by reacting iodine and potassium iodide in the presence of an alkali such as sodium hydrogen carbonate.

The compound (B) reacting an alkali such as sodium hydroxide, to obtain a ring-opening simultaneously with epoxidized allowed to compounds of the lactone ring with (C). Obtain the compound (D) Compound (C) by azide using sodium azide or the like. Then compound by reducing the presence of di -tert- butyl dicarbonate (E) is obtained compound (D). Here reduction reaction, catalytic reduction using palladium carbon or the like as a catalyst. By azide the hydroxy group of the compound (E), compound (F) is obtained. Followed by reduction the compound (F), preferably compound (G) can be obtained by catalytic reduction. Then Compound Compound if protected with a protecting group different from Boc to primary amino groups of the (G) (H) is obtained.

Of the protective group of the compound (H), the Boc and desorbed by hydrolysis to give compound (I), to give it the acylating agent (R 1) compound is reacted with a (J), followed by protecting group ( if elimination by hydrogenation of Z), the compound (1a) is obtained.

On the other hand, the compound (1a), to obtain compounds in which the amino group which differs is acylated (1b), may be obtained in the following reaction scheme.

Figure JPOXMLDOC01-appb-C000007

(Wherein, R 2, R 3a, Boc and Z are as defined above)

That is, the compound (H) desorbed by hydrogenating a protective group (Z) to give compound (K), obtained this acylating agent (R 2) compound is reacted with an (L), followed by protection if elimination compound (1b) can be obtained based on (Boc) by hydrolysis.

In the above reaction scheme, Boc or Z is a protecting group of the amino group, if a protecting group can be eliminated by reaction conditions that differ from each of two amino groups, be replaced by other protecting groups It can also be. As the protecting groups include combinations of benzoyl group, a hydrolyzed partial liberation dissociable group such as 3,4,5-trimethoxyphenyl methyl group, a benzyl group, a hydrogenated leaving group such as a phenyl ethyl group .

Among the compounds of formula (1), R 3 is an amino group, an alkylamino group or a dialkylamino group, at any stage of the reaction process, can be obtained by amidating the ester (-COOR 3a) . Amidation reaction, for example, ammonia, ammonium salts, alkylamine, can be carried out using a dialkylamine.

Compounds thus obtained (1) is useful as an asymmetric organic catalysts for the addition reaction or condensation reaction. That is, by performing an addition reaction or condensation reaction in the presence of the compound (1), the enantiomers are obtained in high yield and high optical purity, it is possible enantioselective asymmetric synthesis.

The addition reaction or condensation reaction wherein the aldol reaction, a Mannich reaction, Michael reaction, amination reaction, and the halogenation reaction and the like. Of these, the catalyst of the present invention is particularly preferably applied to aldol reaction.

Aldol reaction using asymmetric organic catalysts of the present invention is represented by the following reaction formula.

Figure JPOXMLDOC01-appb-C000008

(Wherein, R 4 and R 5 represents a hydrogen atom or an organic group, R 6 represents an organic group. * Indicates an asymmetric carbon atom, having a specific configuration)

That, is reacted ketone (2) with an aldehyde and (3) in the presence of an asymmetric organic catalysts of the formula (1), optically active keto alcohols of formula (4) is obtained.

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. The hydrocarbon group includes any of the aromatic hydrocarbon group and aliphatic hydrocarbon group. Also these hydrocarbon groups and heterocyclic groups, alcohols, ethers, etc., a halogen atom, a nitro group, an amino group, a cyano group, a carboxyl group, an alkoxycarbonyl group, which may have a substituent such as a silyl group . The R 4 and R 5 may be molded cycloalkane structure together.

The catalyst of formula (1) used is 0.5 to 10 mol% relative to the starting compound of formula (2) or Formula (3) may be used more preferably 1 to 10 mol%. The amount of catalyst used is one less than the amount of conventional asymmetric organic catalysts.

The reaction follows the usual aldol reaction, for example, the presence or absence of a solvent, may be performed about 0.5 to 72 hours at 0 ~ 20 ° C..

In the present invention, by changing the configuration of the asymmetric organic catalysts of the formula (1) used, it is possible to control the configuration of the enantiomers of the keto alcohol of interest. That is, synthesized in the case of using a catalyst in the case of formula (1b) using a catalyst of formula (1a), since the configuration of the enantiomers of the resulting keto alcohol is determined, the two catalysts from a common asymmetric source by, it is possible to obtain the enantiomer of interest selectively.

The catalysts of the present invention recovered from the reaction mixture, can be reused.

Then examples illustrate the present invention in detail.

[Reference Example 1] (1R *, 3R * , 4S *) -3,4- epoxycyclohexane-1-carboxylic acid ethyl ester

Figure JPOXMLDOC01-appb-C000009

(1R *, 4R *, 5R *) -4- iodo-6-oxabicyclo [3.2.1] octane-7-one (J.Org.Chem., 1996 years, Vol. 61, p. 8687) (14 was dissolved .3G) in ethanol (130 mL), then it was added under ice-cooling 2 N aqueous sodium hydroxide (34.5 mL), and stirred at room temperature for 7 hours. The solvent was evaporated under reduced pressure, then extracted with dichloromethane by adding water to the residue, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 83: 17) to afford the title compound (6.54 g) as a colorless oil.
1 H-NMR (CDCl 3) 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).

[Reference Example 2] (1R *, 3S * , 4S *) -3- azido-4-hydroxy-cyclohexane-1-carboxylic acid ethyl ester

Figure JPOXMLDOC01-appb-C000010

(1R *, 3R *, 4S *) -3,4- dissolved epoxycyclohexane-1-carboxylic acid ethyl ester (13.6 g) N, N- dimethylformamide (100 mL), ammonium chloride at room temperature (6. 45 g), then were successively added sodium azide (7.8 g), and stirred for 12 hours at 75 ° C.. The solvent was concentrated to about 1/3, 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, the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 4) to give the title compound (15.8 g) as a colorless oil.
1 H-NMR (CDCl 3) 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).

[Reference Example 3] (1R *, 3S * , 4S *) -3-tert- butoxycarbonylamino-4-hydroxy-cyclohexane-1-carboxylic acid ethyl ester

Figure JPOXMLDOC01-appb-C000011

(1R *, 3S *, 4S *) -3- azido-4-hydroxy-cyclohexane-1-carboxylic acid ethyl ester (100 mg) and di -tert- butyl dicarbonate (133 mg) was dissolved in ethyl acetate (12 mL) , added 10% palladium-carbon catalyst amount, and the mixture was stirred for 12 hours in a hydrogen stream at room temperature. After the insoluble matter was filtered, and the solvent was distilled off under reduced pressure, 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 = 7.1Hz), 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).

[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

(1R *, 3S *, 4S *) -3-tert- butoxycarbonylamino-4-hydroxy-cyclohexane-1-carboxylic acid ethyl ester (16g) and triethylamine (38 mL) was dissolved in dichloromethane (150mL), -78 ℃ after cooling to it was added dropwise methanesulfonyl chloride (13 mL) at the same temperature. After stirring at the same temperature for 15 minutes, the temperature was raised 30 minutes 0 ° C., further stirred for 2 hours at room temperature. After diluting with dichloromethane with 0.1 N hydrochloric acid, 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, the crude (1R *, 3S *, 4S *) was obtained -3-tert-butoxycarbonylamino-4-methanesulfonyloxy-cyclohexane-1-carboxylic acid ethyl ester.
Dissolving the product in N, N- dimethylformamide (100 mL), added sodium azide (18 g) at room temperature and stirred for 12 hours then heated to 75 ° C.. The solvent was concentrated to about 1/3, and the mixture was stirred and diluted with water and AcOEt 3 minutes. The organic layer was separated, washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 4) to give the title compound [(1R *, 3S *, 4R *) - Body, 6.74 g] and [ (1R *, 3S *, 4S *) - body, give 1.32 g] as each colorless solid.
(1R *, 3S *, 4R *) - the body:
1 H-NMR (CDCl 3) 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 *) - the body:
1 H-NMR (CDCl 3) 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).

[Reference Example 5] (1R *, 2S * , 4R *) -N 2 -tert- butoxycarbonyl-4-ethoxycarbonyl-1,2-cyclohexanediamine

Figure JPOXMLDOC01-appb-C000013

(1R *, 3S *, 4R *) Mixing of -4-azido-3-(tert-butoxycarbonylamino) cyclohexane-1-carboxylic acid ethyl ester (5.4 g) in ethanol (10 mL) and ethyl acetate (10 mL) dissolved in a solvent, adding 10% palladium-carbon catalytic amount, and stirred for 20 hours under a hydrogen stream at room temperature. After the insoluble matter was filtered, and the solvent was evaporated under reduced pressure to give the title compound (4.7 g) as a pale yellow oil.

[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 After dissolving the (J.Org.Chem., 1996 year, Vol. 61, 8687 pp.) and (89.3 g) ethanol (810 mL), was added 2 N aqueous sodium hydroxide solution (213 mL), at room temperature and the mixture was stirred in 3 hours. The solvent was evaporated under reduced pressure, water added to the residue, after extraction with dichloromethane, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 17: 3) to afford the title compound (41.2 g) as a light brown oil.
[Α] D -58 ° (C = 1.0, chloroform).

[Reference Example 7] (1S, 3R, 4R) -3- azido-4-hydroxy-cyclohexane-1-carboxylic acid ethyl ester (1S, 3S, 4R) -3,4- epoxycyclohexane-1-carboxylic acid ethyl ester ( dissolve 41 g) in N, N- dimethylformamide (300 mL), then it was successively added ammonium chloride at room temperature (19.3 g), sodium azide (23.5 g), and stirred for 13 hours at 75 ° C.. The reaction solution was filtered and evaporated to 400mL The filtrate was concentrated, placed ahead of the filter Tobutsu to the residue was added water solubility. And extracted with ethyl acetate, The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (51.5 g) as an oil.
[Α] D + 8 ° (C = 1.0 , chloroform)

[Reference Example 8] (1S, 3R, 4R) -3- (tert- butoxycarbonylamino) -4-hydroxy-cyclohexane-1-carboxylic acid ethyl ester (1S, 3R, 4R) -3- azido-4-hydroxy-cyclohexane 1-carboxylic acid ethyl ester (51.2 g) and di -tert- butyl dicarbonate (68.1 g) was dissolved in ethyl acetate (1000 mL), was added 5% palladium-carbon at room temperature under a hydrogen pressure of 5 kg / cm 2 in the mixture was stirred for 16 hours. After the insoluble matter was filtered, the solvent was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give solidified added hexane to give the title compound (53.6 g) as colorless crystals It was obtained as a.
[Α] D + 25 ° (C = 1.0 , chloroform).

[Reference Example 9] (±) -3- cyclohexene-1-carboxylic acid benzyl ester

Figure JPOXMLDOC01-appb-C000014

(±)-3-cyclohexene-1-carboxylic acid (50 g) was dissolved in N, N- dimethylformamide (550 mL), under ice-cooling triethylamine (170 mL), and stirred for 12 hours at room temperature was added benzyl bromide (61 mL) . Water was added, extracted with ethyl acetate, then the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, the residue is purified by silica gel chromatography (hexane: ethyl acetate = 3: 1) to give the title compound (70.8 g) as a red-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).

[Reference Example 10] (1R *, 3S * , 4R *) -3,4- epoxy cyclohexane-1-carboxylic acid benzyl ester

Figure JPOXMLDOC01-appb-C000015

(±)-3-cyclohexene-1-carboxylic acid benzyl ester (40 g) was dissolved in dichloromethane (500 mL), stirred for 2 hours was added under ice-cooling 4-chloro-perbenzoic acid (86 g). After stirring for 20 minutes was added 10% aqueous sodium thiosulfate solution, the organic layer was separated, then washed with saturated sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, silica gel column chromatography (ethyl acetate: hexane = 1: 9). The residue was purified by the title compound (23.4g) (1R *, 3R *, 4S *) -3, 4-epoxy-cyclohexane-1-carboxylic acid benzyl ester (12.1 g) 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 = 14.9,4.9Hz), 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) +.

[Reference Example 11] (1R *, 3S * , 4S *) -4- azido-3-hydroxy-cyclohexane-1-carboxylic acid benzyl ester

Figure JPOXMLDOC01-appb-C000016

(1R *, 3S *, 4R *) was dissolved 3,4-epoxycyclohexane-1-carboxylic acid benzyl ester (52.3 g) N, N- dimethylformamide (1000 mL), ammonium chloride (21.9 g) and stirred for 24 hours and heated to 70 ° C. was added sodium azide (18.1 g). The solvent was evaporated under reduced pressure, water was added to the residue, followed by extraction with ethyl acetate, then 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).

[Reference Example 12] (1R *, 3S * , 4S *) -4- (N-tert- butoxycarbonylamino) -3-hydroxy-cyclohexane-1-carboxylic acid benzyl ester

Figure JPOXMLDOC01-appb-C000017

(1R *, 3S *, 4S *) -4- azido-3-hydroxy-cyclohexane-1-carboxylic acid benzyl ester (5.27 g) was dissolved in tetrahydrofuran (25 mL), triphenylphosphine (5.53 g) and water (0.55 mL) and the mixture was stirred at room temperature for 20 hours. To the reaction solution was added di -tert- butyl dicarbonate (4.82 g), it was further stirred for 2 hours. The solvent was evaporated under reduced pressure, 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 = 12.5Hz), 7.30-7.38 (5H, m).
MS (FAB) m / z: 350 (M + H) +.

[Reference Example 13] (1R *, 3S * , 4S *) -4-N- (tert- butoxycarbonylamino) -3-hydroxy-cyclohexane-1-carboxylic acid methyl ester

Figure JPOXMLDOC01-appb-C000018

(1R *, 3S *, 4S *) -4-N- (tert- butoxycarbonylamino) -3-hydroxy-cyclohexane-1-carboxylic acid benzyl ester (2.54 g) was dissolved in ethyl acetate (15 mL), catalyst adding 10% palladium-carbon in an amount and stirred for 20 hours in a hydrogen stream at room temperature. The catalyst is removed by filtration, the filtrate was concentrated under reduced pressure, (1R *, 3S *, 4S *) -4-N- (tert- butoxycarbonylamino) -3-hydroxy-cyclohexane-1-carboxylic acid as a colorless oil It was obtained as a. This was dissolved in a mixed solution of methanol (8 mL) and toluene (15 mL), and stirred at room temperature for 30 minutes under cooling with ice trimethylsilyldiazomethane 2N solution (10 mL) was added. The solvent was evaporated under reduced pressure, silica gel column chromatography Hula fee (hexane: ethyl acetate = 1: 1) to give 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) +.

[Reference Example 14] (1R *, 3R * , 4S *) -3- azido -4-N- (tert- butoxycarbonylamino) cyclohexane-1-carboxylic acid methyl ester and (1R *, 3R *, 4R *) azido -4-N- (tert- butoxycarbonylamino) cyclohexane-1-carboxylic acid methyl ester

Figure JPOXMLDOC01-appb-C000019

(1R *, 3S *, 4S *) -4-N- (tert- butoxycarbonylamino) -3-hydroxy-cyclohexane-1-carboxylic acid methyl ester (1.81 g) was dissolved in dichloromethane (36 mL), -78 ° C. at triethylamine (4.6 mL), methanesulfonyl chloride (1.63 mL) was added, the temperature was raised to 0 ℃ after 30 minutes, followed by stirring for 30 minutes. 1 N hydrochloric acid was added, and the mixture was extracted with dichloromethane, then the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. Give the solvent was distilled off under reduced pressure, the crude (1R *, 3S *, 4S *) -4-N- and (tert- butoxycarbonyl) -3- (methanesulfonyloxy) cyclohexane-1-carboxylic acid methyl ester It was.
Of crude (1R *, 3S *, 4S *) -4-N- (tert- butoxycarbonylamino) -3- (methanesulfonyloxy) cyclohexane-1-carboxylic acid methyl ester N, N- dimethylformamide (23 mL) dissolved in, added sodium azide (1.29 g), and stirred for 12 hours and heated to 70 ° C.. Water was added to the reaction solution, and extracted with ethyl acetate, then the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, flash column chromatography (ethyl acetate: hexane = 3: 17) The residue was purified by, (1R *, 3R *, 4R *) -3- azido-4-(N-tert butoxycarbonylamino) cyclohexane-1-carboxylic acid methyl ester (85mg) (1R *, 3R *, 4S *) -3- azido-4-(N-tert-butoxycarbonylamino) cyclohexane-1-carboxylic acid methyl ester the (590 mg) as a colorless oil.
(1R *, 3R *, 4S *) - Body: 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 *) - Body: 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) +.

[Reference Example 15] (1R *, 2S * , 4S *) -N 1 - (tert- butoxycarbonyl) -4-methoxycarbonyl-1,2-cyclohexanediamine

Figure JPOXMLDOC01-appb-C000020

(1R *, 3R *, 4S *) -3- azido-4- (N-tert-butoxycarbonylamino) cyclohexane-1-carboxylic acid methyl ester (230 mg) was dissolved in ethyl acetate (8 mL), a catalytic amount of 10% palladium-carbon was added, followed by stirring under a hydrogen stream for 20 hours. The insoluble material was removed by filtration, the filtrate was concentrated under reduced pressure to give the title compound (220 mg) as a pale yellow oil.

[Reference Example 16] (1R, 3S, 4R) -3,4- epoxy cyclohexane-1-carboxylic acid benzyl ester 1) obtained in Reference Example 9, (1R)-3-cyclohexene-1-carboxylic acid ( J.Am.Chem.Soc, 1978 years, 100 vol, pp 5199), was obtained (1R)-3-cyclohexene-1-carboxylic acid benzyl ester.
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) +.

In Reference Example 17] (1R, 3S, 4S) -4- (N-tert- butoxycarbonylamino) -3-hydroxy-cyclohexane-1-carboxylic acid benzyl ester 1) In a similar manner as in Reference Example 13, (1R, 3S, 4R)-3,4-epoxy cyclohexane-1-carboxylic acid benzyl ester to give (1R, 3S, the 4S) -4- azido-3-hydroxy-cyclohexane-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) +.

[Reference Example 18] (1R, 3R, 4S) -3- azido-4-(N-tert-butoxycarbonylamino) cyclohexane-1-carboxylic acid benzyl ester

Figure JPOXMLDOC01-appb-C000021

In the same manner as in Reference Example 14 to give (1R, 3S, 4S) -4- an (N-tert-butoxycarbonylamino) -3-title compound from hydroxy cyclohexane-1-carboxylic acid benzyl ester.
1 H-NMR (CDCl 3) 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) +.

[Reference Example 19] (1R, 3R, 4S) -3- azido-4-(N-tert-butoxycarbonylamino) cyclohexane-1-carboxylic acid methyl ester

Figure JPOXMLDOC01-appb-C000022

(1R, 3R, 4S) -3- azido-4-(N-tert-butoxycarbonylamino) cyclohexane-1-carboxylic acid benzyl ester (3.5 g) in tetrahydrofuran (130 mL), was dissolved in water (16 mL), under ice cooling lithium hydroxide (291 mg) was added and stirring was continued returning to room temperature after 10 minutes. 20 hours after the reaction was stopped, column chromatography the solvent obtained was distilled off under reduced pressure the residue on silica gel subjected to (methanol: dichloromethane = 1 20), (1R, 3R, 4S) -3- azido -4- (N-tert-butoxycarbonylamino) cyclohexane-1-carboxylic acid (3.34 g) as a pale yellow oil. Which was dissolved in methanol (18 mL), was dissolved in toluene (64 mL), under ice-cooling trimethylsilyldiazomethane (2M solution, 6.1 mL) was added and stirred to warm to room temperature after 10 minutes. After 2 hours the reaction was stopped, after the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 4) to give give 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) +.

[Reference Example 20] (1S, 3R, 4S) -3- amino-4-benzyloxycarbonylamino - cyclohexyl carboxylic acid ethyl ester

Figure JPOXMLDOC01-appb-C000023

(1S, 3R, 4S) -3-tert- butoxycarbonylamino-4-benzyloxycarbonylamino-over-cyclohexyl-carboxylic acid ethyl ester (1.26 g) was dissolved in acetonitrile (20 mL), methanesulfonic acid (0.97 mL ) was added and stirred at room temperature for 6 hours. After the solvent was distilled off, neutralized with sodium bicarbonate solution, then extracted with dichloromethane and subjected to 3 hours slurry purified in ethyl acetate 10 mL. After filtering the crystals and dried to give the title compound 1.64 g.
1 H-NMR (400MHz, 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 = 7.3Hz, 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] +).

[Reference Example 21] benzyl tert- butyl {(1S, 2R, 4S) -4 - [(dimethylamino) carbonyl] cyclohexane-1,2-diyl} bis carbamate

Figure JPOXMLDOC01-appb-C000024

Ethyl (1S, 3R, 4S) -4 - {[(benzyloxy) carbonyl] amino} -3 - [(tert- butoxycarbonyl) amino] After cyclohexanecarboxylate a (3.2 g) was dissolved in ethanol 32 mL, room temperature 2M lithium hydroxide aqueous (11.4 mL) was added to the reaction mixture Te and stirred for 3 hours. The reaction solution was adjusted to pH7 was added 6N hydrochloric acid (2.6 mL), the reaction solution was distilled off as it is. The resulting residue in DMF (32 mL) was added and stirred was added dimethylamine hydrochloride (2.48 g) and 1-hydroxybenzotriazole (1.54 g). After dissolution, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (2.19 g) was added, followed by stirring at room temperature for 16 hours. The reaction solution was extracted by adding ethyl acetate and water and extracted with ethyl acetate was added to the aqueous layer. The organic layers were combined, washed with water and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure, the resulting residue was subjected to silica gel column chromatography to give the title compound 2.94 g.
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 = 11.6Hz), 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).

[Reference Example 22] tert-butyl {(1R, 2S, 5S) -2- amino-5 - [(dimethylamino) carbonyl] cyclohexyl} carbamate oxalate

Figure JPOXMLDOC01-appb-C000025

<A method>
(1R, 2R, 4S) -2 - [(tert- butoxycarbonyl) amino] -4 - at room temperature [(dimethylamino) carbonyl] toluene solution of cyclohexyl methanesulfonate (20.0 g) (100 mL), azide It was added sodium (7.14 g) and dodecyl pyridinium chloride (7.80 g). At 60 ° C. After stirring for 72 hours, water was added to the reaction mixture, saturated organic layer layered water, washed with water, methanol was added to the organic layer, the addition of 7.5% Pd-C and ammonium formate and the mixture was stirred for 1 hour at 40 ℃. After filtering off the pd-C, the solvent was concentrated under reduced pressure, to which water-containing acetonitrile (200 mL) and anhydrous oxalic acid (4.94 g) was added, and stirred at room temperature for 17 hours, the resulting crystals were collected by filtration. The obtained crystals in acetonitrile (200 mL), and stirred for 24 hours at 40 ° C.. The resulting crystals were collected by filtration and dried to give the title compound 12.7 g.
1 H-NMR (D 2 O ) 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).
Elemental analysis: Calc. C; 50.70%, H; 7.75%, N; 10.96%
Obsd. C; 51.19%, H; 7.79%, N; 11.19%.
<B method>

Figure JPOXMLDOC01-appb-C000026

Benzyl tert- butyl {(1S, 2R, 4S) -4 - [(dimethylamino) carbonyl] cyclohexane-1,2-diyl} ethanol bis carbamate (2.3 g) solution (35mL), 7.5% Pd -C a (230 mg) was added, under hydrogen atmosphere and stirred for 16 hours. After filtering off Pd-C, the obtained filtrate was concentrated under reduced pressure. The resulting residue, ethyl acetate (20 mL) and anhydrous oxalic acid (493.6mg) was added, the mixture was stirred at room temperature for 17 hours, and the crystals were collected by filtration to give the title compound 1.93 g. Various spectral data were in complete agreement with those obtained in the above <A Method>.

Example 1 (1S, 3R, 4S) -4- benzyloxycarbonylamino-3- trifluoromethanesulfonyl-amino - cyclohexyl carboxylic acid ethyl ester

Figure JPOXMLDOC01-appb-C000027

(1S, 3R, 4S) -3- amino-4-benzyloxycarbonylamino-over-cyclohexyl-carboxylic acid ethyl ester (1.8 g) was placed in dichloromethane 10 mL, further continuously charged triethylamine (0.96 mL), - It was cooled to 78 ℃. It was added dropwise triflic anhydride (0.93 mL), and stirred for 1 hour. After completion of the reaction, water was added, after separation operation, the solvent was evaporated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give the title compound 2.27 g.
1 H-NMR (400MHz, 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 = 7.3Hz, 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), 4.05-4.11 (1H, m, CH), 3. 81-3.83 (1H, m, CH) , 2.56 (1H, brs), 2.01-2.08 (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] +)

Example 2 (1S, 3R, 4S) -4- amino-3-trifluoromethanesulfonyl-amino - cyclohexanecarboxylic acid ethyl ester

Figure JPOXMLDOC01-appb-C000028

(1S, 3R, 4S) -4- benzyloxycarbonylamino-3- trifluoromethanesulfonyl-amino - cyclohexyl carboxylic acid ethyl ester (2.27 g) was placed in methanol (20 mL), subsequently placed Pd / C (200mg) and the mixture was stirred for 6 hours at 40 ℃. After completion of the reaction, it was filtered through Celite and concentrated the residue. Put ethyl acetate 20mL the concentrated residue was subjected to 3 hours slurry purification, filtration, dried to give the title compound (1.33 g).
1 H-NMR (400MHz, CD 3 OD) δ: 4.10 (2H, q, J = 7.2Hz, 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 = 13.6,1.2Hz, 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, 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).

Example 3 (1S, 3R, 4R) -3-tert- butoxycarbonylamino-4-trifluoromethyl-sulfonyl amine - cyclohexanecarboxylic acid ethyl ester

Figure JPOXMLDOC01-appb-C000029

(1R *, 2S *, 4R *) -3-tert- butoxycarbonyl-4-ethoxycarbonyl-1,2-cyclohexane diamine (1.62 g) was placed in dichloromethane (10 mL), subsequently triethylamine (0.96 mL) necked flask, and the mixture was cooled to -78 ℃. It was added dropwise triflic anhydride (0.93 mL), and stirred for 1 hour at the same temperature. After completion of the reaction, raising the temperature to 0 ° C., the reaction was quenched by addition of water. After separation, the organic layer was concentrated and subjected to a short silica gel column chromatography to give the title compound (2.27 g).
1 H-NMR (400MHz, CDCl 3) δ: 4.13 (2H, q, J = 7.3Hz, 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] +).

Example 4 (1S, 3R, 4R) -3- amino-4-trifluoromethanesulfonyl-amino - cyclohexanecarboxylic acid ethyl ester

Figure JPOXMLDOC01-appb-C000030

(1S, 3R, 4R) -3-tert- butoxycarbonylamino-4-trifluoromethanesulfonyl-amino - cyclohexanecarboxylic acid ethyl ester 1.26g was placed in acetonitrile 20 mL, put methanesulfonic acid (0.97 mL), and the mixture was stirred at room temperature for 6 hours. The crystals were collected by filtration to get the methanesulfonic acid salt of the title compound. After neutralizing the compound with sodium bicarbonate water, and extracted with dichloromethane, the solvent was distilled off. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give the title compound 812 mg.
Example 5
Cyclohexanone 0.9mL and p- nitrobenzaldehyde 45.3mg was added to a mixture of tetrahydrofuran 0.9mL and water 0.9mL. This compound (1a-1) or compound (1b-1) was added 5 mol% with respect to the p- nitrobenzaldehyde 1 mol, and stirred for 3-4 days at room temperature (25 ° C.). Extracting the reaction mixture with ethyl acetate 3 mL, after liquid separation operation, the organic layer was concentrated. The residue was purified by silica gel column chromatography, the aldol adduct 74.9mg (99% yield, diastereomeric ratio: 7/93 (syn / anti), 97% ee) was obtained.

Figure JPOXMLDOC01-appb-C000031

Table 1 shows the results of to aldol reaction in the same manner as in Example 5.

Figure JPOXMLDOC01-appb-T000001

Clearly from Table 1, using the catalyst of the present invention, by one of the two catalyst synthesized from chiral source, different high purity enantiomer selectively obtain each other.

Example 6
Cyclopentanone 0.9mL and p- nitrobenzaldehyde 45.3mg was added to a mixture of tetrahydrofuran 0.9mL and water 0.9mL. This compound (1a-1) or compound (1b-1) was added 5 mol% with respect to the p- nitrobenzaldehyde 1 mol, and stirred 16-22 hours at room temperature (25 ° C.). Hereinafter, it was treated in the same manner as in Example 5, the aldol adduct 69.9 mg (99% yield, diastereomeric ratio 92/8 (syn / anti), ee 93%) was obtained.

Figure JPOXMLDOC01-appb-C000032

Table 2 shows the results of to aldol reaction in the same manner as in Example 6.

Figure JPOXMLDOC01-appb-T000002

Example 7
But using 2,2-dimethyl-1,3-dioxa-5-one in place of cyclohexanone, in much the same way as in Example 5, the reaction was carried out. The results are shown in Table 3.

Figure JPOXMLDOC01-appb-C000033

Figure JPOXMLDOC01-appb-T000003

Claims (4)

  1. Equation (1)
    Figure JPOXMLDOC01-appb-C000034
    (Wherein, R 1 and R 2, one is a hydrogen atom and the other acyl group, 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, R 1 HN- and R 2 HN- have the same configuration on the asymmetric carbon atoms.)
    In optically active diaminocyclohexane acids or addition reaction or condensation reaction organocatalysis made from the Bronsted acid salt represented.
  2. One of R 1 and R 2 is a hydrogen atom, the asymmetric organic catalysts of claim 1, wherein the other is alkanesulphonyl group or halogenoalkyl alkanesulfonyl group.
  3. R 3 is an alkoxy group, an aralkyloxy group, according to claim 1 or 2, wherein the asymmetric organic catalysts alkylamino group or a dialkylamino group.
  4. Equation (2)
    Figure JPOXMLDOC01-appb-C000035
    (Wherein, R 4 and R 5 represents a hydrogen atom or an organic group)
    In represented by ketones of the formula (3)
    Figure JPOXMLDOC01-appb-C000036
    (Wherein, R 6 represents an organic group)
    In the represented aldehydes, which comprises reacting in the presence of an asymmetric organic catalysts according to any one of claims 1 to 3, formula (4)
    Figure JPOXMLDOC01-appb-C000037
    (* Indicates an asymmetric carbon atom, have a specific configuration, R 4, R 5 and R 6 are the same as defined above)
    Process for producing an optically active keto alcohol represented in.
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US8541443B2 (en) 2010-03-19 2013-09-24 Daiichi Sankyo Company, Limited Crystal of diamine derivative and method of producing same
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
US20130165657A1 (en) * 2010-07-02 2013-06-27 Daiichi Sankyo Company, Limited Process for preparation of optically active diamine derivative salt
US8901345B2 (en) 2010-07-02 2014-12-02 Daiichi Sankyo Company, Limited Process for preparation of optically active diamine derivative salt
CN103080078B (en) * 2010-07-02 2015-02-11 第一三共株式会社 Process for preparation of optically active diamine derivative salt
JP5780657B2 (en) * 2010-07-02 2015-09-16 第一三共株式会社 Method for producing a salt of an optically active diamine derivative
CN104781244A (en) * 2012-11-23 2015-07-15 第一三共株式会社 Process for the preparation of (1S,4S,5S)-4-bromo-6-oxabicyclo[3.2.1]octan-7-one
CN104936961A (en) * 2013-03-29 2015-09-23 第一三共株式会社 Method for producing (1S,4S,5S)-4-bromo-6- oxabicyclo[3.2.1]octane-7-one
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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