WO2005058805A1

WO2005058805A1 - Process for producing optically active amine compound

Info

Publication number: WO2005058805A1
Application number: PCT/JP2004/009392
Authority: WO
Inventors: Yoshiji Takemoto
Original assignee: Sumitomo Chemical Company, Limited
Priority date: 2003-12-17
Filing date: 2004-06-25
Publication date: 2005-06-30
Also published as: JPWO2005058805A1; JP4463209B2

Abstract

A process for producing an optically active amine compound (IV), characterized in that nucleophilic addition of nucleophilic agent (III) to imine compound (II) is carried out in the presence of asymmetric urea compound (I). An advantageous process for producing an optically active amine compound is provided through the development of an asymmetric nucleophilic addition reaction to imine compound using a nonmetallic asymmetric catalyst whose burden on environment is slight. (I)-(IV) wherein X is an oxygen atom or sulfur atom; C*, etc. are each an asymmetric carbon; each of R1 and R2 is a lower alkyl, etc.; R4 and R5 may cooperate with each other to form cyclohexane, etc.; R3 is a substituted or unsubstituted aryl, etc.; each of R6 and R7 is a hydrogen atom, etc.; each of R8 and R9 is a substituted or unsubstituted aryl, etc.; R10 is -P(=O)R15R16 (wherein each of the marks is a substituted or unsubstituted aryl, etc.), etc.; and Nu is -C(NO2)R27R28 (wherein each of the marks is a hydrogen atom, etc.), etc.

Description

Specification

Method for producing optically active amine compound

Technical field

The present invention relates to a method for producing an optically active amine compound using an asymmetric urea compound as an asymmetric catalyst.

Background art

Optically active amine compounds obtained by an asymmetric nucleophilic addition reaction to imine compounds are useful synthetic intermediates for amines, amino acids, pharmaceuticals, agricultural chemicals, food additives and the like (Chemistry Letters, 2002, 31st edition). Vol. 3, No. 3, pp. 276-277).

So far, several examples of the synthesis of optically active amine compounds by an asymmetric nucleophilic addition reaction to imine compounds have been reported, but they use a metal catalyst and require the treatment of metal waste liquid. Angewandte Chemie International Edition, 1999, Vol. 38, p. 276-277; Chemistry Letters, 2002, Vol. 31, Vol. 3, No. 3, p. 3504-350 6; Synlett, 2001, p. 980—982; Journal of the American Chemical Society, 2001, Vol. 123, No. 24, p. 5843—5844; Angewandte Chemie International Edition , 2001, 40th, p. 2992-2995).

Disclosure of the invention

The problem to be solved by the present invention is to develop an asymmetric nucleophilic addition reaction to an imine compound by a non-metallic asymmetric catalyst with a small burden on the environment, thereby developing amines, amino acids, pharmaceuticals, and agricultural chemicals. Another object of the present invention is to provide an advantageous method for producing an optically active amine compound useful as a synthetic intermediate such as a food additive.

In order to solve the above problems, the present inventors have developed a compound as a nonmetallic asymmetric catalyst for a nucleophilic addition reaction, in which an acidic site and a basic site for activating a nucleophile are simultaneously bonded to an optically active scaffold. Focusing on this, we conducted intensive research. As a result, by using an asymmetric urea compound as a non-metallic asymmetric catalyst, a nucleophilic addition reaction to an imine compound can be performed at a high yield and a high yield. Heading to progress body selective. Completed the present invention

That is, the present invention is as follows.

(1) General formula (I):

[In the formula, X represents an oxygen atom or a sulfur atom; C * and C "each independently represent an asymmetric carbon; R ¹ and R ² may be the same or different and may have a substituent A lower alkyl group, an optionally substituted aralkyl group or an optionally substituted aryl group, or together with the nitrogen atom to which R ¹ and R ² bind. To form an aliphatic heterocyclic ring which may have a substituent (the aliphatic heterocyclic ring may be condensed with an aromatic hydrocarbon); and R ³ has a substituent. R ⁴ represents a lower alkyl group which may be substituted, an aralkyl group which may have a substituent, an aryl group which may have a substituent or a heteroaryl group which may have a substituent; R ⁴ And R ⁵ are the same or different and each may be a lower alkyl group which may have a substituent, Represents an aralkyl group which may have a substituent or an aryl group which may have a substituent, or is substituted with an asymmetric carbon to which R ⁴ and R ⁵ are respectively bonded; R ⁶ and R ⁷ may be the same or different and have a hydrogen atom or a substituent, and may form a homocyclic ring which may have a group or a heterocyclic ring which may have a substituent. In the presence of a compound represented by the following formula (hereinafter also referred to as an asymmetric urea compound (I)) or a salt thereof:

[In the formula, R ⁸ and R ⁹ each independently represent a hydrogen atom, a lower alkyl group which may have a substituent, a lower alkenyl group which may have a substituent, An aralkyl group which may have a substituent, an aryl group which may have a substituent, a heteroaryl group which may have a substituent or a hetero atom which may have a substituent, A cyano group, one COaR ¹¹ —CONR ¹² R ¹³ or one COR ¹⁴ (where the lengths ¹¹ , R ¹² , R ¹³ and R ¹⁴ each independently have the same or different hydrogen atoms and substituents. A lower alkyl group, an optionally substituted aralkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, or together with the nitrogen atom to which R ¹² and R ¹³ are bonded, an aliphatic heterocyclic (the aliphatic heterocyclic ring which may have a substituent group may be condensed with an aromatic hydrocarbon. ) formed yo be the, or indicate a.), or coal R ⁸ and R ⁹ are attached Connexion such together with the atom, may form a heterocyclic ring which may have an optionally substituted homocyclic or a substituent; R ^{1 ()} one P (= 0) _{R l 5} R i 6, — s〇 ₂ R ¹⁷ , — C0 ₂ R ¹⁸ , —CONR ¹⁹ R ²⁰ , -COR ²¹ , -NR ²² R ²³ , -S i R ²⁴ R ²⁵ R ²⁶ (where R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²⁰ , R ²¹ , R ²² , R ²³ , R ²⁴ , R ²⁵ and R ²⁶ are each independently the same or different, and each represents a hydrogen atom, A lower alkyl group which may have a group, an aralkyl group which may have a substituent, an aryl group which may have a substituent or a heteroaryl group which may have a substituent. A) a lower alkyl group which may have a substituent, a lower alkoxy group which may have a substituent, an aralkyl group which may have a substituent, and a group which has a substituent. Good reel Or an Ariru group. However, R ⁸ and R ^1G may form a heterocyclic ring which may have a substituent, together with the carbon atom and the nitrogen atom to which they are bonded. A compound represented by] (. Hereinafter, also referred to as Imin compound ([pi)) or a salt thereof of the general formula (III): H-Nu ( III) wherein, Nu is _{^{- C (N0 2) R 27}} R ²⁸ , one CR ²⁹ (COR ³⁰ ) (COR ³¹ ), -OR ³² , _SR ³³ , one NR ³⁴ R ³⁵ (where R ²⁷ , R ²⁸ , R ³² , R ³³ , R ³⁴ and R ³⁵ are each independently The same or different, a hydrogen atom, a lower alkyl group which may have a substituent, an aralkyl group which may have a substituent, a aryl group which may have a substituent or Represents a heteroaryl group which may have a group, or R ³⁴ and R ³⁵ represent a nitrogen atom to be bonded. R ²⁹ may be a hydrogen atom, a halogen atom, a lower alkyl group which may have a substituent or a substituent, wherein R ²⁹ may have a substituent (s); And R ^3G and R ³¹ are the same or different and each represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, a Mono lower alkylamino group, a G-lower alkylamino group And represents an aryl group which may have a substituent or an aralkyl group which may have a substituent. ) Represents an azide group or a cyano group. A nucleophile (hereinafter, also referred to as nucleophile (III)) represented by the following general formula (IV):

(IV)

(Wherein, C *** represents an asymmetric carbon, and other symbols have the same meanings as described above.) (Hereinafter also referred to as optically active amine compound (IV)) or a salt thereof. Production method.

(2) The production method according to the above (1), wherein X is a sulfur atom.

(3) R ⁴ and R ⁵ form R ⁴ and Tsuteshi black propane such with the asymmetric carbon to which R ⁵ is attached respectively, cyclobutane, a cyclohexane-pentane or cyclopentane, (1) or (2 ).

(4) The above (3) wherein R ⁴ and R ⁵ are combined with the asymmetric carbon to which R ⁴ and R ⁵ are bonded to each other to form a cyclohexane, and R ⁶ and R ⁷ are hydrogen atoms. ).

(5) The production method according to the above (4), wherein the absolute configuration of C * and C ** is an S configuration or both are R configurations.

(6) R ¹⁰ gar ^{P (= O) R 15 R} 16 ( wherein each symbol is as defined above.) Is The method according to any one of the above (1) to (5).

(7) The production method according to any one of (1) to (5) above, wherein R ¹⁰ is one CO ₂ R ¹⁸ (where R ¹⁸ has the same meaning as described above).

(8) R ⁸ is a hydrogen atom, and R ⁹ is a lower alkyl optionally having a substituent The method according to any one of the above (1) to (7), which is an aryl group which may have a substituent or a heteroaryl group which may have a substituent.

(9) The method according to any one of the above (1) to (8), wherein the nucleophilic reagent is represented by HC (NO ₂ ) R ²⁷ R ²⁸ (where each symbol has the same meaning as described above). Production method.

(10) R ²⁷ is a hydrogen atom, and R ²⁸ has a hydrogen atom, an alkyl group which may have a substituent, an aryl group which may have a substituent or a substituent The production method according to the above (9), which is a heteroaryl group.

(11) The method according to any one of the above (1) to (10), wherein the reaction is performed in at least one solvent selected from methylene chloride, toluene, and tetrahydrofuran 1,4-dioxane. Production method.

Detailed description of the invention

Hereinafter, the present invention will be described in detail.

First, each symbol used in this specification is defined.

The alkyl in the present invention is linear unless otherwise prefixed (for example, iso, neo, sec-, tert, etc.). For example, if it is simply propyl, it means linear propyl.

The “halogen atom” represented by R ²⁹ is a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom, and is preferably a chlorine atom or a bromine atom.

The “lower alkyl group” represented by R ³⁰ and R ³¹ includes a straight-chain or branched alkyl group having 1 to 12 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert. Butynole, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, pendecyl, dodecyl and the like, and preferably methyl, ethyl or propyl.

As the "lower alkoxy group" for R ³⁰ and R ³¹ , an alkoxy group in which the alkyl moiety is the "lower alkyl group" defined above, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, isopentoxy, neopentoxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy, Pendyl siloxy, dodecyloxy and the like are preferable, and methoxy or ethoxy is preferable.

As the “mono-lower alkylamino group” represented by R ³⁰ and R ³¹ , a mono-alkylamino group in which the alkyl moiety is the “lower alkyl group” defined above, for example, N-methylamino, N-ethylamino, N-propylamino, N-isopropyl pyramino, N-butylamino, N-isobutylamino, N-sec-butylamino, N-tert-butylamino, N-pentylamino, N-isopentylamino, N-neopentylamino, Examples include N-hexylamino, N-heptylamino, N-octylamino, N-nonylamino, N-decylamino, N-indecylamino, N-dodecylamino and the like.

As the “di-lower alkylamino group” represented by R ³⁰ and R ³¹ , a dialkylamino group in which the alkyl moiety is the same or different “lower alkyl group” as defined above, for example, N, N-dimethylamino, N, N-diethylamino, N, N-dipropylamino, N, N-diisopropylamino, N, N-dibutylamino, N, N-diisobutylamino, N, N-disec-butylamino, N, N-diamino I-tert-butylamino, N, N-dipentylamino, N, N-diisopentylamino, N, N-dineopentylamino, N, N-dihexylamino, N, N-diheptylamino, N-methyl-N_ Ethyl ^^ amino, N-methyl-N-propylamino, N-methyl-1-N-isopropylamino, N-methyl-1-N-butylamino, N-methyl-1-N-isobutylamino, N-methyl-N-sec Butylamino, N-methynole _N_tert-butynoleamino, N-methyl-1-N-pentynoleamino, N-methyl-1-N-isopentylamino, N-methyl-1-N-neopentylamino, N-methyl-1-N-hexylamino, N —Methyl-1-N-heptylamino, N—methyl-1-N-octylamino, N-methyl-1-N-noeramino, N-methyl-1-N-decylamino, N-methyl-1-N-indecylamino, N-methyl-N-dodecylamino, and the like. Can be

^{^{^{RR 2, R 3, R 4}}} , R 5, R 6, R 7, R 8, R 9, R 10, R 1 1, R 12, R 1 3, R 14, R 15, R 16, R 1 7 ^{^{, R 1 8, R 19,}} R 20, R 21, R 22, R 23, R 24, R 25, R ₂₆ , R ₂₇ , R ₂₈ , R ₂₉ , R 32, R ₃₃ , R 34 and R ₃₅ as the “lower alkyl group” of the “lower alkyl group optionally having a substituent” Is the same alkyl group as the “lower alkyl group” defined above.

The lower alkyl group may have a substituent at a substitutable position. Examples of such a substituent include a lower alkoxy group (the same as defined above) and a mono-lower alkylamino Group (exemplified as defined above), di-lower alkylamino group (exemplified as defined above), halogen atom (exemplified as defined above) ), An aralkyloxy group (for example, benzyloxy, α- or 1-naphthylmethoxy, etc.), an aryloxy group, a propargyloxy group, a nitro group, a cyano group, a COOR ³⁶ (where R ³⁶ is as defined above) And represents the same lower alkyl group as described above). The number of the substituents is not particularly limited, and is preferably 1 to 3. When the number is 2 or more, they may be the same or different.

The “lower alkoxy group” of the “lower alkoxy group optionally having substituent (s)” for R ^1G includes the same alkoxy group as the “lower alkoxy group” defined above.

The alkoxy group may have a substituent at a substitutable position, and such a substituent is the same as the substituent exemplified in the above “optionally substituted lower alkyl group”. And substituents. The number of the substituents is not particularly limited, and is preferably 1 to 3, and when 2 or more, they may be the same or different.

R ¹ R ² , R ³ , R ⁴ , R ⁵ , R ⁸ , R ⁹ , R ¹⁰ , R ", R ¹² , R ¹³ , R ¹⁴ , R

15 R l 6 R l 7 R l 8 R l 9 R ²⁰ 21 22 23 24 R ²⁵ R ²⁶

R ²⁷ , R ²⁸ , R ²⁹ , R ³⁰ , R ³¹ , R ³² , R ³³ , R ³⁴ and R ³⁵ represented by the `` aryl group '' of the `` aryl group optionally having substituents '' An aryl group having 6 to 20 carbon atoms, for example, phenyl, 1_ or 2-naphthyl, biphenyl, binaphthyl and the like can be mentioned.

The aryl group may have a substituent at a substitutable position, and examples of such a substituent include a lower alkyl group (the same as defined above), A lower alkoxy group (the same as defined above), a mono-lower alkylamino group (the same as defined above), a di-lower alkylamino group (as defined above) A halogen atom (the same as defined above), a haloalkyl group (a lower alkyl group in which one or more halogen atoms are substituted, for example, trifluoromethyl, etc.) ), An aralkyloxy group (for example, benzyloxy, α_ or / 3-naphthyl methoxy, etc.), an aryloxy group, a propargyloxy group, a nitro group, a cyano group, -COOR ³⁶ (where R ³⁶ is as defined above) ) And the like. The number of the substituents is not particularly limited, and is preferably 1 to 3. When the number is 2 or more, they may be the same or different.

As the “substituent” of the “aryl group optionally having substituent (s)” for R ³ , an alkyl group, a haloalkyl group, a nitro group, a cyano group, a COOR ³⁶ (where R ³⁶ is as defined above) And the like) are preferable, and a haloalkyl group and the like are more preferable.

R \ R ² , R ³ , R ⁴ , R ⁵ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ R ¹⁶ R ¹⁷ R ¹⁸ R ¹⁹ R ^2Q R ²¹ R ²² R ²³ R ²⁴ R ²⁵ R ²⁶ R ²⁷ , R ²⁸ , R ³⁰ , R ³¹ , R ³² , R ³³ , R ³⁴ and R ³⁵ `` optionally substituted aralkyl group '' The “aralkyl group” is an aralkyl group formed by substituting the “aryl group” defined above at any position of the “lower alkyl group” defined above, for example, benzyl, 1- or 2-phenethyl , 1-, 2_ or 3-phenylpropyl, 1- or 2-naphthylmethyl, benzohydryl, trityl and the like.

The aralkyl group may have a substituent at a substitutable position. Examples of such a substituent are the same as the substituents exemplified in the above-mentioned “aryl group optionally having substituent (s)”. And substituents. The number of the substituents is not particularly limited, and is preferably 1 to 3. When the number is 2 or more, they may be the same or different.

^{^{^{R 3, R 8, R 9}}} , R 11, R 12, R 13, R 14, R 15, R 16, R 17, R 18, R 19,

R20 R21 R22 R 23 24 25 26 27 28 32 33 R

“Hetero” of “Heteroaryl group optionally having substituent (s)” shown in ³⁴ and R ³⁵ Examples of the "teroaryl group" include a 5- to 10-membered aromatic heterocyclic group containing 1 to 3 heteroatoms selected from an oxygen atom, a sulfur atom, and a nitrogen atom in addition to a carbon atom, and a fused heteroatom thereof. And a ring group. For example, 2- or 3-Chenyl, 2- or 3-furyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 2-, 4- or 5-oxazolyl, 2 —, 4— or 5—thiazolyl, 1—, 3—, 4— or 5—pyrazolyl, 3—, 4 mono or 5—isoxazolyl, 3 —, 4— or 5—isothiazolyl, 1, 2, 4 triazole-1 , 3,4 or 5-yl, 1,2,3-triazole-1,2 or 4-yl, 1H-tetrazol_1 or 5-yl, 2H-tetrazole-2 or 5 , 2 _, 3 _ or 4-pyridyl, 2-, 4-or 5-pyrimigel, 1-, 2-, 3-, 4-, 5-, 6-or 7-^ T drill, 2-, 3—, 4—, 5—, 6— or 7—benzofuryl, 2 _, 3—, 4—, 5—, 6— or 7—benzothenyl, 1—, 2 _, 4—, 5—, 6— Or 7—Benzimi Zolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-1, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl .

The heteroaryl group may have a substituent at a substitutable position, and such a substituent is the same as the substituent exemplified in the above “optionally substituted aryl group”. And substituents. The number of the substituents is not particularly limited, and is preferably 1 to 3. When the number is 2 or more, they may be the same or different.

As "substituent" of the "heteroaryl group which may have a substituent" represented in R ^3, an alkyl group, a haloalkyl group, a nitro group, Shiano group, one COOR ^{3 6} (wherein, R ^{3 6} Represents the same meaning as described above.

Examples of the `` lower alkenyl group '' of the `` lower alkenyl group optionally having substituent (s) '' for R ⁸ and R ⁹ include a linear or branched alkenyl group having 2 to 10 carbon atoms, for example, 1 1-Propenyl, aryl, 1-methyl-2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentyl, 2-pentenyl, 1-hexenyl, 2-hexenyl, etc. And preferably Etul.

The lower alkenyl group may have a substituent at a substitutable position. Examples of such a substituent include a lower alkoxy group (the same as defined above), a mono-lower alkylamino group (the same as defined above), a di-lower alkylamino group ( The same as defined above are exemplified), a halogen atom (the same as defined above) is exemplified, an aralkyl oxy group (for example, benzyloxy, α- or —naphthyl methoxy, etc.), an aryloxy group , Propargyloxy, nitro, cyano, —COOR ³⁶ (where R ³⁶ represents the same lower alkyl group as defined above), aryl group which may have a substituent (as described above) The same ones as defined are exemplified). The number of the substituents is not particularly limited, and is preferably 1 to 3, and when 2 or more, they may be the same or different.

Preferred embodiments of the “optionally substituted lower alkenyl group” represented by R ⁸ and R ⁹ include, for example, 2-phenylenyl and the like.

The “hetero atom” of the “hetero atom optionally having substituent (s)” represented by R ⁸ and R ⁹ includes, for example, a nitrogen atom, an oxygen atom, a sulfur atom and the like.

Examples of the substituent which the hetero atom may have include, for example, "a lower alkyl group which may have a substituent" and "an aralkyl group which may have a substituent" as defined above. "," Aryl group optionally having substituent (s) "," heteroaryl group optionally having substituent (s) "and the like.

The “hetero atom” of the “hetero atom having a substituent” represented by R ²⁹ includes, for example, a nitrogen atom, an oxygen atom, a sulfur atom and the like.

Examples of the substituent of the hetero atom include a “lower alkyl group optionally having a substituent”, an “aralkyl group optionally having a substituent”, and a “ have good Ariru group optionally "," optionally substituted Heteroariru group ^{_{", - COOR 37, -SO 2 R}} 38, -COR 39, -CONR 40 R 41 ( wherein, R ^37, R ³⁸ , R ³⁹ , R ⁴⁰ and R ^{41 each} represent a lower alkyl group (the same as defined above), or together with a nitrogen atom connecting R ^4G and R ^41. An aliphatic heterocyclic ring which may have a substituent (the aliphatic heterocyclic ring may be condensed with an aromatic hydrocarbon) (as defined below) The same is exemplified. ) May be formed. ) And the like.

The “aliphatic heterocycle” of the “aliphatic heterocycle optionally having substituent (s)” which may be formed together with the nitrogen atom to which R ¹ and R ² are bonded, includes a carbon atom and at least one 5- to 10-membered aliphatic heterocyclic ring, for example, pyridine, pyridine, etc., which may contain 1 to 3 heteroatoms selected from oxygen, sulfur, and nitrogen. Lysine, morpholine, thiomorpholine, piperazine and the like can be mentioned.

The aliphatic heterocycle may be condensed with an aromatic hydrocarbon, and examples of such an aromatic hydrocarbon include benzene, naphthalene, biphenyl, binaphthyl, and the like.

The aliphatic heterocyclic ring may have a substituent at a substitutable position, and examples of such a substituent include the substituents exemplified in the above “aryl group optionally having substituent (s)”. And the same substituents as mentioned above. The number of the substituents is not particularly limited, and is preferably 1 to 3. When the number is 2 or more, they may be the same or different.

As R ^{1 2} and R ^{1 3} or R ^{3 4} and R ^{3 5} is a nitrogen atom and connexion formed "aliphatic heterocyclic ring which may have a substituent" which may be a combined binding includes the Similar things are listed.

R ⁴ and R ⁵ may be formed together with the asymmetric carbon to which they are respectively bonded. As the “homocycle” of the “homocycle optionally having a substituent”, for example, an asymmetric urea compound A cycloalkane having 3 to 7 carbon atoms (eg, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, etc.) or a carbon atom, including the asymmetric carbon represented by C * and C ** in (I). 4 to 7 cycloalkenes (e.g., cyclobutene, cyclopentene, cyclohexene, cycloheptene, etc.) and the like, preferably cyclopropane, cyclobutane, cyclopentane, cyclohexane and the like, more preferably cyclohexane And the like.

Examples of the “heterocycle” of the “heterocycle optionally having substituent (s)” which may be formed together with the asymmetric carbon to which R ⁴ and R ⁵ are bonded include, for example, an asymmetric urea compound (I ) Contains asymmetric carbons represented by C * and C ** and oxygen atoms other than carbon atoms. And a 5- to 10-membered heterocyclic ring containing 1 to 3 heteroatoms selected from sulfur, nitrogen and nitrogen atoms, for example, tetrahydropyran, tetrahydrofuran, pyrrolidine, piperidine and the like.

The “homocycle” and “heterocycle” may be further condensed with an aromatic hydrocarbon (eg, benzene, naphthalene, biphenyl, binaphthyl, etc.).

The “homocycle” or “heterocycle” may have a substituent at a substitutable position, and examples of such a substituent include the aforementioned “aryl group optionally having a substituent”. And the same substituents as those exemplified above. The number of the substituents is not particularly limited, and is preferably 1 to 3, and when 2 or more, they may be the same or different.

The “homocycle” of the “homocycle optionally having substituent (s)” which may be formed together with the carbon atom to which R ⁸ and R ⁹ are bonded includes, for example, a carbon atom having 3 to 7 carbon atoms. Cycloalkanes (eg, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, etc.) or cycloalkenes having 4 to 7 carbon atoms (eg, cyclobutene, cyclopentene, cyclohexene, cycloheptene, etc.). And preferably cyclopropane, cyclobutane, cyclopentane, cyclohexane and the like, and more preferably cyclohexane and the like.

As the "heterocycle" may be connexion formed such together with the carbon atom of the "optionally substituted heterocycle" R ⁸ and R ⁹ are attached, for example, an oxygen atom in addition to carbon atoms, Examples thereof include a 5- to 10-membered complex ring containing 1 to 3 heteroatoms selected from a sulfur atom and a nitrogen atom, for example, tetrahydropyran, tetrahydrofuran, pyrrolidine, piberidine and the like.

The "homocycle" and "heterocycle" may be further condensed with an aromatic hydrocarbon (eg, benzene, naphthalene, biphenyl, binaphthyl, etc.).

R ⁸ and R ^{1 Q} are formed together with the carbon and nitrogen atoms to which they are attached, respectively. The "heterocycle" of the "heterocycle optionally having substituent (s)" may be, for example, a heteroatom selected from an oxygen atom, a sulfur atom, a phosphorus atom and a nitrogen atom in addition to a carbon atom and a nitrogen atom And a 5- to 10-membered heterocyclic ring containing 1 to 3 such as tetrahydro-1,2-phosphazine, tetrahydro-1,2,3-thiazine and the like. The “heterocycle” may have a substituent at a substitutable position, and examples of such a substituent include the substituents exemplified for the “aryl group optionally having a substituent” above. The same substituent as the group can be mentioned. The number of the substituents is not particularly limited, and is preferably 1 to 3. When the number is 2 or more, they may be the same or different.

The “asymmetric carbons” represented by C C ** and C *** each have an independent absolute configuration and are not particularly limited. The absolute configuration of C * and C ** in the asymmetric urea compound (I) may be appropriately selected in order to obtain an optically active amine compound (IV) having a desired configuration.

The asymmetric urea compound (I), the imine compound (Π) and the optically active amine compound (IV) may be in the form of a salt. Such salts include, for example, inorganic acid salts (eg, hydrochloride, sulfate, nitrate, phosphate, etc.); organic acid salts (eg, acetate, propionate, methanesulfonate, 4-toluenesulfonic acid) Salts, oxalates, maleates, etc.); alkali metal salts (eg, sodium salts, potassium salts, etc.); alkaline earth metal salts (eg, calcium salts, magnesium salts, etc.); organic base salts (eg, trimethylamine) Salts, triethylamine salts, pyridine salts, picoline salts, dicyclohexylamine salts, etc.).

X in the asymmetric urea compound (I) is preferably a sulfur atom.

R ⁴ and R ⁵ of the asymmetric urea compound (I) are preferably an homocyclic ring or a substituent which may have a substituent formed together with the asymmetric carbon to which R ⁴ and R ⁵ are bonded. A heterocyclic ring which may have a substituent; more preferably an homocyclic ring which may have a substituent formed by forming an asymmetric carbon to which R ⁴ and R ⁵ are bonded. More preferably cyclopropane, cyclobutane, cyclopentane or cyclohexane formed together with the asymmetric carbon to which R ⁴ and R ⁵ are each bonded, and more preferably R ⁴ and R ⁵ are each A bond formed with the asymmetric carbon to be bonded The mouth is hexane.

When R ⁴ and R ⁵ are cyclohexane formed together with the asymmetric carbon to which R ⁴ and R ⁵ are respectively bonded, R ⁶ and R ⁷ are preferably a hydrogen atom. It is preferred that the absolute configurations of * and C ** are both S configurations or both are R configurations.

R ¹ and R ² of the asymmetric urea compound (I) are preferably a lower alkyl group which may have a substituent or a nitrogen atom to which R ¹ and R ² are bonded, and An aliphatic heterocyclic ring which may have a group and which may be condensed with an aromatic hydrocarbon, more preferably methyl, ethyl, isopropyl or together with a nitrogen atom to which R ¹ and R ² are bonded Isoindolin formed as such, more preferably methyl or isopropyl.

R ³ of the asymmetric urea compound (I) is preferably an optionally substituted aryl group, more preferably an optionally substituted phenyl group, more preferably a haloalkyl A phenyl substituted with a nitro group, a nitro group, a cyano group or one COOR ³⁶ (where R ³⁶ has the same meaning as described above), more preferably a phenyl substituted with a haloalkyl group, and further preferably a triphenyl It is phenyl substituted with orthomethyl.

R ⁸ and R ⁹ of the imine compound (II) may not represent the same group because C *** of the optically active amine compound (IV) is an asymmetric carbon.

R ⁸ and R ⁹ of the imine compound (II) preferably have a hydrogen atom, a lower alkyl group which may have a substituent, an aryl group which may have a substituent or a substituent. And more preferably a hydrogen atom, an aryl group which may have a substituent or a heteroaryl group which may have a substituent.

R ^1G of the imine compound (Π) is preferably an electron-withdrawing group, preferably one CO ₂ R ¹⁸ , one P (= 0) R ¹⁵ R ¹⁶ , one S 0 ₂ R ¹⁷ (where each symbol is and showing the same meaning.), and is more preferably one C0 ₂ R ¹⁸ or a ^{P (= 0) R 15 R} 16 ( in here, each symbol is as defined above.). In the nucleophilic reagent (ΠΙ), preferably, HC (NO ₂ ) R ²⁷ R ²⁸ (where each symbol has the same meaning as described above).

When the nucleophile (III) is HC (NO ₂ ) R ²⁷ R ²⁸ (where each symbol has the same meaning as described above), R ²⁷ and R ²⁸ preferably have a hydrogen atom or a substituent. And more preferably both are hydrogen atoms, or one is a hydrogen atom and the other is methyl or ethyl.

Hereinafter, a method for producing the optically active amine compound (IV) of the present invention (hereinafter, also simply referred to as the production method of the present invention) will be described.

The production method of the present invention is shown in the following reaction scheme.

, 9

(ID (HI) (IV)

(In the formula, each symbol has the same meaning as described above.)

That is, the production method of the present invention comprises, for example, nucleophilic addition of a nucleophile (III) to an imine compound (II) in the presence of an asymmetric urea compound (I) in a solvent or in the absence of a solvent. This is a method for producing compound (IV).

Although the optical purity of the optically active amine compound (IV) produced by the production method of the present invention is not particularly limited, it is usually 63% e.e. or more as an enantiomer excess ratio measured by HP LC chiral analysis. , Preferably 76% e.e. or more.

The nucleophilic addition in the production method of the present invention refers to a reaction in which a nucleophile (III) is added to a carbon atom of an imino group in an imine compound (II).

In the production method of the present invention, the order of addition of the reagents is not particularly limited, and the asymmetric urea compound (I), the imine compound (II) and the nucleophile (III) may be added simultaneously or sequentially. . The amount of the asymmetric urea compound (I) used in the production method of the present invention may be a catalytic amount relative to 1 mol of the imine compound (II), and is, for example, from 0.01 to 1.0 mol. More preferably, the amount is from 0.05 mol to 0.20 mol. If the amount of the asymmetric urea compound (I) is less than this range, the reaction tends to be slow. If the amount exceeds this range, the effect corresponding to the amount used is reduced, and there is a tendency to be economically disadvantageous. .

The amount of the nucleophilic reagent (III) used in the production method of the present invention is preferably from 1 mol to 20 mol, more preferably from 1.2 mol to 10 mol, per 1 mol of the imine compound (II). preferable. If the amount of the nucleophile (ΠΙ) used is less than this range, the reaction tends to be incomplete. If the amount exceeds this range, the effect corresponding to the amount used is reduced and the economical disadvantage tends to occur. is there.

The production method of the present invention can be carried out in a solvent, but can also be carried out without a solvent. When the reaction is carried out without a solvent, no solvent is required, which is economically advantageous, and the volume efficiency can be increased, which is industrially advantageous.

When a solvent is used in the production method of the present invention, any solvent may be used as long as it does not inhibit the reaction. For example, a halogen-based solvent such as methylene chloride, chloroform, benzene, and a, a, α-trifluorotoluene , Methyl-tert-butyl ether, 1,2-dimethoxetane, tetrahydrofuran, 1,4-dioxane, ethyl acetate, isopropyl acetate, tert-butyl acetate, toluene, xylene, acetate nitrile, etc., alone or in combination However, it is preferable to use methylene chloride, toluene, tetrahydrofuran or 1,4-dioxane because of good yield and good stereoselectivity.

When a mixed solvent is used, it may be mixed at any ratio.

The amount of the solvent to be used is generally 1 L to 100 L, more preferably 10 L to 30 L, per 1 kg of the imine compound (Π).

The reaction temperature of the production method of the present invention is usually −78 ° C. to 100 ° C., preferably 0 ° C. to 40 ° C.

The reaction time depends on the reagents used and the reaction temperature, but is usually 0.1 hours to 100 hours. The optically active amine compound (IV) produced by the production method of the present invention can be isolated and purified by a conventional method. For example, the optically active amine compound (IV) can be isolated by pouring the reaction solution into water, separating the solution, washing the organic layer, concentrating under reduced pressure, or concentrating the reaction solution. After the isolation, the product may be purified by, for example, silica gel column chromatography, but is not limited thereto. When isolating and purifying the optically active amine compound (IV), the asymmetric urea compound (I) can be easily separated and recovered. For example, since the asymmetric urea compound (I) has a basic amine, it is transferred to the aqueous layer as a salt by treating it with an acidic aqueous solution (eg, hydrochloric acid, nitric acid, sulfuric acid, etc.) in the extraction operation. Thereby, it can be separated from the optically active amine compound (IV). After neutralizing the aqueous solution, extraction with an organic solvent (eg, ethyl acetate, toluene, chloroform, methylene chloride, etc.) allows separation and recovery of the asymmetric urea compound (I). Alternatively, they may be separated and recovered by silica gel column chromatography.

The asymmetric urea compound (I) thus separated and recovered can be reused in the production method of the present invention. That is, since the asymmetric urea compound (I) of the present invention is a nonmetal, the catalytic activity of a metal catalyst or the like hardly deteriorates, and it can be reused any number of times by recovering it. It is advantageous.

The optically active amine compound (IV) produced by the production method of the present invention is a useful synthetic intermediate such as amines, amino acids, drugs, agricultural chemicals, and food additives. For example, (S) -N- (1-funylu-2-2-2troetinole) 1 p, P-dipheninolephosphine amide, which is an example of the optically active amine compound (IV), is available from Chemistry Letters, 2000. Year, Vol. 31, Vol. 3, No. 3, it can be induced to ICI-1991, a κ-opioid receptor agonist.

The asymmetric urea compound (I) used in the present invention can be produced by Production Method 1 shown by the following reaction scheme. Manufacturing method 1

R

C:

, R '

\ R ²

(V) (I)

(In the formula, each symbol has the same meaning as described above.)

That is, the asymmetric urea compound (I) is, for example, a compound represented by the general formula (V) in a solvent [hereinafter, also referred to as compound (V). ] And an isocyanate compound or an isothiosinate compound represented by the general formula (VI) [hereinafter, also referred to as isocyanates (VI). ] Can be synthesized by reacting

In Production Method 1, the order of adding the compound (V) and the isocyanates (VI) is not particularly limited, and they may be added simultaneously or sequentially to the solvent.

The amount of the isocyanate (VI) used in Production Method 1 is preferably 0.5 mol to 5 mol, more preferably 0.9 mol to 1.5 mol, per 1 mol of compound (V). .

The solvent used in the production method 1 may be any solvent that does not inhibit the reaction, and examples thereof include a halogen-based solvent such as methylene chloride, chlorophonolem, benzene, α-a, α-trifluoro-toluene, and methyl-tert-butyl ether. , 1,2-Dimethoxetane, tetrahydrofuran, 1,4-dioxane, ethyl acetate, isopropyl acetate, tert-butyl acetate, toluene, xylene, acetonitrile and the like can be used alone or in combination. When a mixed solvent is used, they may be mixed at an arbitrary ratio.

The amount of the solvent to be used is generally 1 L to 100 L, more preferably 10 L to 30 L, per 1 kg of compound (V).

The reaction temperature of production method 1 is usually -78 ° C to 100 ° C, but is preferably 0 ° C to 40 ° C. The reaction time depends on the reagent used and the reaction temperature, but is usually 1 hour to 10 hours.

The asymmetric urea compound (I) produced by the production method 1 can be isolated and purified by a conventional method. For example, the asymmetric urea compound (I) can be isolated by pouring the reaction solution into water, separating the solution, washing the organic layer, and concentrating the solution under reduced pressure, or concentrating the reaction solution. After the isolation, the product may be purified by, for example, silica gel column chromatography, but is not limited thereto.

Compound (V), which is a raw material of Production Method 1, can be produced by a known method (for example, the method described in Tetrahedron, 57, 1765-1769 (2001)). For example, in a preferred embodiment of the present invention, a compound represented by the general formula (V a):

Λ (V a)

Hku N ,,,, '· C

C · ',

(Wherein each symbol has the same meaning as described above.) Can be produced by the method described in Tetrahedron Letters, 41, 8431-8434 (2000).

The isocyanates (VI), which are other raw materials in Production Method 1, can be synthesized by a known method (for example, the method described in Eur. J. Org. Chem., 3004-3014 (2002)) to obtain R ³ — Ν ₂ ( Here, R ³ has the same meaning as described above), and a commercially available product can also be used.

The imine compound (II), which is a raw material of the production method of the present invention, is a carbonyl compound represented by the following general formula (VII) according to a known method, for example, the method described in Tetrahedron, 1991, 47, 5561-5568. (Hereinafter, also referred to as carbonyl compound (VII)) and a compound represented by the following general formula (VIII) (hereinafter, also referred to as compound (VIII)) by condensation in the presence of titanium tetrachloride and triethylamine. Can be manufactured.

(VII) (VIII) (n)

(In the formula, each symbol has the same meaning as described above.)

Further, the imine compound (II) can be synthesized with the carbonyl compound (VII) according to the method described in J. Org. Chem., 1994, 59, 1238-1240 or Chem. Eur. J., 1997, 3, 1691-1709. The compound (VIII) is reacted with sodium benzenesulfinate in the presence of formic acid to obtain a compound represented by the following general formula (ΙΓ), which is reacted with a base such as lithium carbonate to form benzene. It can also be produced by removing a sulfonyl group.

(In the formula, each symbol has the same meaning as described above.)

The carbonyl compound (VII) and the compound (VIII) are commercially available. The nucleophile (ΠΙ) as a raw material of the present invention can be prepared by known methods, for example, Tetrahedron Letters, 39, 8013-8016 (1998), Bull. Chem. So Jpn., 61, 4029-4035 (1988), and the like. It can be produced by the method described. Commercially available products such as nitromethane, which is a preferable example of the nucleophile (II), may be used.

Example

Hereinafter, the present invention will be described more specifically with reference to examples. The present invention They are in no way limiting.

Production example 1 A

(R, R) -trans-1-[3,5-bis (trifluoromethyl) phenyl] 1-3- [2- (N, N-dimethylamino) cyclohexyl] thiourea

Under an argon atmosphere, a solution of 3,5-bis (trifluoromethyl) phenylisothiocyanate (605 mg, 2.23 mmol) in dry tetrahydrofuran (1. Oml) was added to (R, R) -trans-N, N -Dimethyl-1,2-diaminocycline hexane (317 mg, 2.23 mmol 1) was added. The reaction mixture was stirred at room temperature for 3 hours, and then the mixture was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: chloroform / methanolnotriethylamine = 100 51) to give the title compound as a white amorphous solid (597 mg, yield 65%) Obtained.

_{^{. [a] D 16 -32 7}} (c 0. 99, CHC 1 3);

! H-NMR (500MHz, DMSO- d ₆ ) δ: 10.0 (s, 1H), 8.21 (s, 1H), 8.17 (s, 2H), 7.66 (s, 1H), 4.09 (brs, 1H), 2.54 (brs, 1H), 2.21 (s, 7H), 1.82 (brs, 1H), 1.74 (brs, 1H), 1.63 (brd, J = ll.0Hz, 1H), 1.31-1.01 (m, 4H) ppm;

¹³ C-NMR (126 MHz, DMS0-d ₆ ) 6: 178.6, 142.0, 130.8, 130.5, 130.3, 130.0, 126.5, 124.3, 122.2, 120.9, 120.0, 115.3, 65.0, 55.3, 45.7, 31.6, 24.6, 24.5, 21.0 ppm;

_{IR (CHC1 3) v: 3402} , 3200, 2942, 2865, 1528, 1469, 1383, 1278 cm- 1;

MS (FAB ⁺ ): 414 (MH ⁺ , 100);

. Analysis Calculated _{_{_{(for C 17 H 21 F 6}}} N 3 S):. C, 49.39; H, 5.12; N, 10.16; F, 27.57 analysis: C, 49.36; H, 5.28 ; N, 10.11; F , 27.71.

Production example 1 B (R, R)-trans-1-[3,5-bis (trifluoromethyl) phenyl] _ 3-[2- (N, N-dimethylamino) cyclohexyl] urea

Under an argon atmosphere, a solution of 3,5-bis (trifluoromethyl) phenyl isocyanate (0.26 ml, 1.5 mmol 1) in dry benzene (0.60 ml) was added to (R, R ) —Trans—N, N-dimethyl-1,2-diaminocyclohexane (213 mg, 1.5 rnrno 1) was added. The reaction mixture was stirred at room temperature for 1 hour, and then the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel force ram chromatography Dara Fi one - was purified by _{(CHC 1 3 / Me OH =} 2 0/1 7/1), to give the title compound as a solid white amorphous.

_{^{[a] D 25 -3 5. 3}} (c 0. 9 3, CHC 1 3);

JH-NMR (500 MHz, DMSO-d ₆ ) δ: 9.39 (s, 1H), 8.02 (s, 2H), 7.51 (s, 1H), 6.21 (d, J = 5.5 Hz, 1H), 3.35 (ddd, J = 15.2, 10.5, 4.3Hz, 1H), 2.28 (dt, J = 3.1, 10.2Hz, 1H), 2.18 (brs, 1H), 2.15 (s, 6H), 1.85-1.66 (m, 2H), 1.63 -1.52 (m, 1H), 1.31-0.96 (ra, 4H) ppm;

¹³ C-NMR (126 MHz, DMSO-d ₆ ) 6: 154.9, 142.9, 131.3, 131.1, 130.8, 130.5, 126.9, 124.7, 122.5, 120.4, 117.12, 117.09, 113.4, 113.3, 65.6, 50.9, 39.9, 33.2, 24.9, 24.5, 21.4 ppm;

_{IR (CHC1 3) v: 3424} , 3332, 2939, 2864, 2792, 1695, 1549, 1473 cm -1;

MS (FAB +): 398 (H ⁺ , 100);

. Analysis Calculated _{_{_{(for C 17 H 21 F 6}}} N 3 0):. C, 51.38; H, 5.33; N, 10.57; F, 28.69 analysis: C, 51.30; H, 5.22 ; N, 10.58; F , 28.46.

Production Example 2

N-benzylidene P, P-diphenylphosphinamide

Heat P, P-diphenylphosphine amide (0.22 g, 1. Ommol) It was placed in a dry 25 ml test tube and dissolved with methylene chloride (4.4 ml). To this solution were added benzaldehyde (0.20 ml, 2. Ommo 1) and triethylamine (0.42 ml, 3. Ommo 1), and the mixture was cooled in an ice-water bath. A solution of titanium tetrachloride in methylene chloride (1.0 M, 0.55 ml) was added dropwise to the cooled solution over about 5 minutes. After removing the ice-water bath, the mixture was stirred at room temperature for 2 hours, and then diluted with toluene (about 2 Oml). The mixture was transferred to a 20 Oml flask and further diluted with toluene (about 7 Oml). The suspension was filtered through celite and the celite was washed with toluene. The solvent was distilled off to obtain a brown oil mainly containing the title compound and benzaldehyde. Excess benzaldehyde was removed under high vacuum, and the obtained solid was recrystallized from benzene to give the title compound (0.26 g, yield 85%). Melting point: 141-142 ° C (benzene).

_{! H- NMR (CDC1 3) δ} : 7.41-7.54 (8Η, m), 7.59 (1H, t, J = 7.2Hz), 7.95 (4H, dd, J = 8.2, 11.9Hz), 8.02 (2H, d , J = 7.6Hz), 9.33 (1H, d, J = 32.4Hz) ppm;

IR (film) v: 3060, 1640, 1600, 1500, 1220 cm "¹;

MS (m / z): 297 (M ⁺ , 69), 201 (100), 154 (7), 125 (18), 96 (76), 77 (58).

Production Examples 3 to 9

The following compounds were synthesized as in Production Example 2.

Production Example 3: N- (4-methylbenzylidene) -1-P, P-diphenylphosphine amide,

Production Example 4: N- (4-chlorobenzylidene) -P, P-diphenylphosphine amide,

Production Example 5: N- (2-naphthylmethylene) -1-P, P-diphenylphosphine amide,

Production Example 6: N- (2-furfuridene) -P, P-diphenylphosphineamide Production Example 7: N- (2-pyridylmethylene) -P, P-diphenylphosphineamide Production Example 8: N_ (2- Chenylmethylene) 1 P, P-diphenylphosphinamide, Production Example 9: N-cinnamylidene P, P-diphenylphosphinamide

Production Example 10

t e rt-butynole N-benzylidene carbamate

Benzaldehyde (1/2, 250 mL) of tert-butyl carbamate (10.0 g, 85.5 mmo 1) and sodium benzenesulfinate (28 g, 17 Ommo 1) 1 3. OmL, 128mmo 1) and formic acid (98%, 6.4mL) were added at a stretch, respectively, and the mixture was stirred at room temperature for 48 hours. The precipitated crystals were collected by filtration, washed with water and ethyl ether, and dried under reduced pressure to obtain colorless crystals (23.6 g, 80%).

The above crystals (5.2 g, 15 mmo 1) and anhydrous tetrahydrofuran were added to a mixture of anhydrous potassium carbonate (12.4 g, 90. Ommo 1) and anhydrous sodium sulfate (15 g) that had been dried by heating under reduced pressure. (14 OmL), and the mixture was heated to reflux under a nitrogen atmosphere. After 15 hours, the reaction solution was cooled and filtered, and the obtained filtrate was evaporated under reduced pressure to give the title compound as a colorless oil (3.07 g, yield 100%).

_{Ή-NMR (400MHz, CDC1 3} ) δ: 8.88 (1H, s), 7.93- 7.90 (2H, m, ArH), 7.57- 7.54 (1H, m, ArH), 7.49- 7.43 (2H, m, ArH) , 1.59 (9H, s, C (CH ₃ ) ₃ ) ppm;

^{1 3 C- NMR (100MHz, CDC1} 3) 169.7, 162.6, 134.0, 133.5, 130.2, 128.8, 82.3, 27. 9 ppm;

IR (thin film) v: 2980, 1717, 1633, 1270, 1152 cm ¹ ;

MS (AP, m / z): 206 (M ⁺ ).

Example 1

(S) — N— (1—Feninole 2-2-2 Troetinole)-P, P—Diphenylphosphinamide

N-benzylidene-P, P-diphenylphosphinamide (61.1 mg, 0.2 Ommo 1) and (R, R) — trans— 1 _ [3,5-bis (trifluoromethyl) phenyl] —3— [2— (N, N-Dimethylamino) cyclohexyl] thiourea (8.3 mg, 0.02 mmo 1) in methylene chloride (0.40 ml) was stirred with nitromethane (0.4%). 1 Add 1 ml, 2.0 Ommo 1) And stirred for 24 hours. Then, the reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution solvent: chloroform formosetone = 10/1) to obtain the title compound as crystals (63.7 mg, yield). 87%). Table 1 shows the yield and optical purity. Melting point 1 97-1 98 ° C (form-form Zn-Hexane).

HP LC analysis conditions:

Column: Chiral Cell OD-H (manufactured by Daicel Chemical), mobile phase: n-hexane 2-propanol = 90/10, flow rate: 1.0 m 1 minute, detection: λ = 254 nm, retention time: (S ) Isomer (main peak); 13.9 min, (R) isomer; 21.9 min.

_{^{[a] D 28 + 33. 2}} (c 0. 90, CHC 1 3);

] H-NMR (500MHz, CDC1 3) 8 7.93-7.67 (m, 4H), 7.59- 7.10 (m, 11H), 4.97- 4.77 (m, 3H), 4.36 (dd, J = 8.2, 7.3 Hz, 1H ) ppm;

^{13 C-NMR (126MHz, CDC1} 3) δ: 138.04, 137.99, 132.44, 132.36, 132.3, 131.8, 131.7, 131.3, 130.8, 129.1, 128.7, 128.6, 128.5, 126.4, 80.8, 80.7, 53.3, 53.2 ppm;

_{IR (CHC1 3) v: 3371} , 3063, 3034, 2991, 1555cm- 1;

MS (FAB ⁺ ): 367 (MH ⁺ , 76), 154 (100);

111 ¾ 13 (? 8 ⁺ ) Calculated value [(: _2. 112 ₍ ^ ₂₀ ) ⁺ : 367.1211; Analytical value: 367.1210.

Example 2

(S) — N— [1— (4-Methylphenyl) 1-2-nitroethyl] -P, P—Dipheninolephosphine amide

Performed in the same manner as in Example 1 except that N- (4-methylbenzylidene) -1-Ρ, Ρ-diphenylphosphineamide was used instead of N-benzylidene-P, P-diphenylphosphineamide. The compound was obtained. Table 1 shows the yield and optical purity. With a melting point of 142-143 (cloth form Ζη-hexane).

HP LC analysis conditions:

Column: Chiral Cell OD—H (manufactured by Daicel Chemical Industries), mobile phase: n 2 _ propanol = 90/10, flow rate: 1.0 ml min, detection: λ = 254 nm, retention time: (S) isomer (main peak); 14.2 min, (R) isomer; 19 0 minutes.

_{^{[a] D 30 + 87. 3}} (c 1. 1 3, CHC 1 3);

Ή-NMR (500 MHz, DMSO-d ₆ ) δ: 7.81-7.59 (m, 4H), 7.59-7.35 (m, 6H), 7.21 (d, J = 7.9 Hz, 2H), 7.11 (d, J = 7.9 Hz, 2H), 6.26 (t, J = 10.0Hz, 1H), 4.87 (dd, J = 8.9, 12.2Hz, 1H), 4.79 (dd, J = 6.1, 12.2Hz, 1H), 4.64 (dt, J = 17.4, 8.7Hz, 1H), 2.26 (s, 3H) ppm;

¹³ C-NMR (126 MHz, DMSO-d ₆ ) δ: 137.1, 136.60, 136.57, 133.8, 133.6, 132.8, 132.6, 131.81, 131.78, 131.74, 131,71, 131.67, 131.6, 129.0, 128.52, 128.45, 128.43, 128.35, 126.8, 80.9, 80.8, 53.2, 20.6 ppm;

_{IR (CHC1 3) v: 3371} , 2992, 1555 cm "1;

MS (FAB ⁺ ): 381 (MH ⁺ , 100);

HRMS (FAB ⁺⁾ calc _{_{_{[C 21 H 22 N 2 0}}} 3 P] +: 381.1368; ANALYSIS: 381.1374.

Example 3

(S) — N— [1— (4-chlorophenyl) 1-2-nitroethyl] — P, P—diphenolenophosphinamide

The procedure was performed in the same manner as in Example 1, except that N- (4-cyclobenzylidene) -P, P-diphenylphosphineamide was used instead of N-benzylidene-P, P-diphenylphosphineamide. The title compound was obtained. Table 1 shows the yield and optical purity. Melting point 169-171 ° C (chloroform Zn-hexane).

HP LC analysis conditions:

Column: Chiral Cell OD-H (manufactured by Daicel Chemical), mobile phase: n-hexane Z ethanol = 97/3, flow rate: 1.0 m1 min, detection: λ = 254 nm, retention time: (S ) isomer (major peak); 23.9 min, (R) isomer;. 26.3 minutes _{^{[a] D 29 + 46. 6}} (c 1. 01, CHC 1 3);

_{Ή-NMR (500MHz, CDC1 3} ) 6: 7.89-7.71 (m, 4H), 7.56-7.49 (m, 2H), 7 · 48 - 7.38 (m, 4H), 7.31 (d, J = 8.6Hz, 2H ), 7.24 (d, J = 8.6Hz, 2H), 4.93-4.76 (m, 3H), 4.32-4.16 (m, 1H) ppm;

^{13 C-NMR (126MHz, CDC1} 3) 8: 136.5, 136.4, 134.5, 132.44, 132.35, 132.3, 132.1, 131.8, 131.7, 131.6, 131.0, 130.6, 129.3, 128.8, 128.7, 127.8, 80.58, 80.56, 52.7 ppm ;

_{IR (CHC1 3) v: 3370} , 2992, 1556 cm "1;

MS (FAB ⁺ ): 401 (MH ⁺ , 44);

. Analysis Calculated _{_{_{(for C 20 H 18 C1N 2}}} 0 3 P):. C, 59.93; H, 4.53; N, 6.99; CI, 8.85; P, 7.73 Analysis values: C, 59.64; H, 4.63 ; N , 6.97; CI, 8.78; P, 7.47.

Example 4

(S) -N- [1- (2-naphthyl) -1-2-nitroethyl] — P, P—diphenylphosphine amide

N- (2) instead of N-benzylidene P, P-diphenylphosphinamide

—Naphthylmethylene) — The title compound was obtained in the same manner as in Example 1 except that _P, P-diphenylphosphineamide was used. Table 1 shows the yield and optical purity. Melting point 19 9 _ 19 3. C (cloth mouth Holm).

HP LC analysis conditions:

Column: Chiral cell OD-H (manufactured by Daicel Chemical), mobile phase: n-hexane Z 2-propanol = 90/10, flow rate: 1.0 ml Z min, detection: λ = 254 nm, retention Time: (S) isomer (main peak); 26.0 minutes; (R) isomer; 32.3 minutes.

[a] _D ^3. + 56.6 (c 0.47, Me OH);

! H-NMR (500MHz, CDC1 3) δ 7.96-7.76 (m, 7H), 7.73 (s, 1H), 7.59-7.32 (m, 9H), 5.13-4.88 (m, 3H), 4.22-4.14 (m , 1H) ppm;

^{13 C-NMR (126MHz, CDC1} 3) S: 137.04, 137.02, 133.9, 133.5, 132.8, 132.7, 132.5, 131.9, 131.84, 131, 77, 131.7, 131.6, 128.6, 128.5, 128.4, 128.34, 128.25, 127.9, 127.6, 126.4, 126.3, 125.8, 124.8, 80.8, 80.7, 53.7 ppm; IR (CHC1 3) v: 3360, 3060, 1555 cm- 1;

MS (FAB ⁺ ): 417 (MH ⁺ , 47); HRMS (FAB +) calc _{_{_{[C 24 H 22 N 2 0}}} 3 P] +: 417.1368; ANALYSIS: 417.1373.

Example 5

(S) -N- [1-(2-furyl) 1 2 _nitroethyl] — P, P—diphenyl phosphine amide

The title compound was obtained in the same manner as in Example 1 except that N- (2-furfuridene) _P, P-diphenylphosphineamide was used instead of N-benzylidene-P, P-diphenylphosphineamide. Got. Table 1 shows the yield and optical purity. Melting point 1337-1338 ° C (form-form Zn-hexane).

HP LC analysis conditions:

Column: Chiral Cell OD-H (manufactured by Daicel Chemical), mobile phase: n-hexane Z 2-propanol = 90/10, flow rate: 1.0 ml Z min, detection: λ = 254 nm, retention Time: (S) isomer (main peak); 12.5 minutes, (R) isomer; 18.1 minutes.

_{^{[a] D 29 + 4 1.}} 8 (c 0. 9 8, CHC 1 3);

_{Ή-NMR (500MHz, CDC1 3} ) δ: 7.91 (dd, J = 8.2, 12.2Hz, 2H), 7.84 (dd, J = 8.4, 12.4Hz, 2H), 7.59-7.51 (m, 2H), 7.51- 7.43 (m, 4H), 7.40—7.31 (m, 1H), 6.41-6.29 (m, 2H), 5.05—4.82 (m, 3H), 3.87 (dd, J = 7.9, 1.6Hz, 1H) ppm;

^{1 3 C-NMR (126MHz,} CDC1 3) δ 150.7, 150.6, 142.8, 132.41, 132.38, 132.3, 132.1, 131.8, 131.7, 131.6, 131.1, 130.6, 128.82, 128.75, 128.71, 128.65, 110.7, 108.2, 78.4, 78.3, 47.7 ppm;

_{IR (CHC1 3) v: 3376} , 2992, 1557 cm "1;

MS (FAB ⁺ ): 357 (MH ⁺ , 83), 154 (100);

. Analysis Calculated _{_{_{(for C 18 H 17 C1N 2}}} 0 4 P):. C, 60.68; H, 4.81; N, 7.86; P, 8.69 Analysis values: C, 60.84; H, 4.85 ; N, 7.70; P , 8.96.

Example 6

(S) — N— [1-(2-pyridyl) -1-2-nitroethyl] — P, P—diphenolenophosphine amide

N—benzylidene P, P—diphenylphosphinamide (Pyridylmethylene) The title compound was obtained in the same manner as in Example 1 except that 1P, P-diphenylphosphineamide was used. Table 1 shows the yield and optical purity. Melting point 164-166 ° C (chloroform / n-hexane).

HP LC analysis conditions:

Column: Chiral Cell OD-H (manufactured by Daicel Chemical), mobile phase: n-hexaneethanol = 95/5, flow rate: 1.0 ml, detection: λ = 254 nm, retention time: (S) Isomer (main peak); 37.8 min, (R) isomer; 46.9 min.

_{^{[a] D 27 + 33. 5}} (c 0. 82, CHC 1 3);

_{Ή-NMR (500MHz, CDC1 3} ) δ: 8.54 (d, J = 4.0Hz, 1H), 7.96- 7.75 (m, 4H), 7.69 (dt, J = l.7, 7.7Hz, 1H), 7.61- 7.34 (m, 7H), 7.24 (dd, J = 4.9, 6.7Hz, 1H), 5.10 (dd, J = 4.9, 12.5Hz, 1H), 4.98-4.82 (m, 2H), 4.43 (t, J = 8.5Hz, 1H) ppm;

^{1 3 C-NMR (126MHz,} CDC1 3) δ: 156.8, 156.7, 149.4, 137.2, 132.3, 132.23, 132.20, 132.15, 132.1, 132.0, 131.8, 131.7, 131.2, 130.9, 128.7, 128.58, 128.57, 23.3, 122.3 , 79.41, 79.38, 53.3 ppm;

_{IR (CHC1 3) v: 3363} , 3061, 2991, 1592, 1554 cm- 1;

MS (FAB ⁺ ): 368 (MH ⁺ , 100);

. Analysis Calculated _{_{_{(for C 19 H 18 N 3}}} 0 3 P):. C, 62.12; H, 4.94; N, 11.44; P, 8.43 Analysis values: C, 61.82; H, 4.95 ; N, 11.29; P , 8.17.

Example 7

(S) -N- [1- (4-Chenyl) 1-2-nitroethyl] P, P-diphenylphosphinamide

The procedure was performed in the same manner as in Example 1 except that N- (4-phenylphenyl) phosphine amide was used instead of N-benzylidene-P, P-diphenylphosphine amide. The compound was obtained. Table 1 shows the yield and optical purity. Melting point 171-1 72 ° C (cloth form / n-hexane).

HP LC analysis conditions:

Column: Chiral Cell OD-H (manufactured by Daicel Chemical), mobile phase: n-hexanexan-2-propanol = 90/10, flow rate: 1.0 ml min, detection: λ = 254 n m, retention time: (S) isomer (main peak); 12.8 minutes, (R) isomer; 25.0 minutes.

_{^{. [a] D 25 +21 1}} (c 1. 16, CHC 1 3);

_{Ή-NR (500MHz, CDC1 3} ) δ: 7.91 (dd, J = 7.2, 12.1Hz, 2H), 7.85 (dd, J = 7.6, 11.6Hz, 2H), 7.52 (t, J = 7.5Hz, 2H) , 7.48-7.39 (m, 4H), 7.32-- 7.21 (m, 1H), 7.02-6.89 (m, 2H), 5.15-4.88 (m, 3H), 4.39 (dd, J = 6.4, 10.7Hz, 1H) ppm;

^{, 3 C-NMR (126MHz,} CDC1 3) 6: 142.0, 141.9, 132.5, 132.4, 132.3, 132.2, 131.7, 131.6, 131.4, 131.2, 130.4, 128.8, 128.72, 128.67, 128.6, 127.4, 125.5, 125.0, 80.29 , 80.28, 49.3 ppm;

_{IR (CHC1 3) v: 3359} , 3061, 2992, 1556 cm "1;

MS (FAB ⁺ ): 373 (MH ⁺ , 100);

. Analysis Calculated _{_{_{(for C 18 H 17 N 2}}} 0 3 PS):. C, 58.06; H, 4.60; N, 7.5; P, 8.32 minutes析値: C, 57.78; H, 4.58 ; N, 7.46; P , 8.19.

Example 8

(S) — N— (4-phenyl-1-1-nitro-3-butene-2-yl) -P, P—dipheninolephosphine amide

The title compound was obtained in the same manner as in Example 1 except that N-cinnamylidene-P, P-diphenylphosphineamide was used instead of N-benzylidene-P, P-diphenylphosphineamide. Table 1 shows the yield and optical purity. Melting point 145-148 ° C (form-form Zn-hexane).

HP LC analysis conditions:

Column: Chiral cell OD-H (manufactured by Daicel Chemical), mobile phase: n-hexane Z 2-propanol = 90/10, flow rate: 1.0 ml min, detection: λ = 254 nm, retention time: (S ) Isomer (main peak); 17.5 min, (R) isomer; 25.1 min.

_{^{[a] D 30 + 39. 1}} (c 1. 04, CHC 1 3);

! H-NMR (500MHz, CDC1 3) 6: 7.93- 7.82 (m, 4H), 7.53-7.45 (m, 6H), 7.30-7.26 (m, 5H), 6.59 (d, J = 15.9Hz, 1H) , 6.18 (dd, J = 15.9, 6.1Hz, 1H), 4.80-4.71 (m, 2H), 4.41-4.40 (m, IH), 3.94- 3.91 (m, IH) ppm;

^{13 C-NMR (126MHz, CDC1} 3) 6: 135.6, 133.4, 132.5, 132.44, 132.35, 132.0, 131.8, 131.7, 131.5, 130.9, 128.84, 128.79, 128.73, 128.68, 128.65, 128.4, 126.8, 125.44, 125.39, 80.3, 51.6 ppm;

IR (CHC1 ₃ ) v: 3371, 3031, 2993, 1554 cnf ¹ ;

MS (FAB ⁺ ): 393 (MH ⁺ , 25), 154 (100);

HRMS (FAB +) calc _{_{_{[C 22 H 22 N 2 0}}} 3 P] +: 393.1368; ANALYSIS: 393.1374.

Example 9

N— [1—Feninole 1 _Nitropropinole] — P, P—Dipheninolephosphine amide

Except that nitroethane was used in place of nitromethane, the same procedure as in Example 1 was carried out to obtain a diastereomer mixture (73/27) of the title compound. Yield 83%. Purification was performed by silica gel column chromatography (elution solvent: black form Zaceton = 10/1). Table 1 shows the optical purity of the main diastereomer. Mp 2 1 2 — 215 ° C (chloroform).

HP LC analysis conditions:

Column: Chiral Cell AD (manufactured by Daicel Chemical), mobile phase: n-hexane Z2-propanol = 90/10, flow rate: 1.0 m1 min, detection: λ = 254 nm, retention time: (S) Isomer (main peak); 39.8 min, (R) isomer; 43.4 min.

_{Ή-NMR (500MHz, CDC1 3} ) δ: 7.81 (dd, J = 7.5, 12.1Hz, 2H), 7.70 (dd, J = 7.6, 12.2Hz, 2H), 7.55 (t, J = 7.2 Hz, 1H) , 7.51-7.40 (m, 3H), 7.36-7.28 (m, 5H), 7.15 (d, J = 6.4 Hz, 2H), 4.89 (dt, J = 6.7, 13.4 Hz, 1H), 4.49 (dt, J = 6.9, 10.3Hz, 1H), 4.04 (dd, J = 7.3, 10.4Hz, IH), 1.55 (d, J = 6.7 Hz, 3H) ppm;

^{1 3 CN R (126MHz, CDC1} 3) δ: 139.2, 134.0, 133.8, 133.0, 132.8, 131.72, 131,70, 131.62, 131.57, 131.5, 128.4, 128.3, 128.2, 128.1, 127.9, 127.5, 87.7, 87.6, 58.6, 16.4 ppm;

_{IR (CHC1 3) v: 3381} , 2991, 1554 cnf 1; MS (FAB ⁺ ): 381 (MH ⁺ , 100);

HRMS (FAB +) calc _{_{_{[C 21 H 22 N 2 0}}} 3 P] +: 381.1368; ANALYSIS: 381.1365.

Example 1 0

tert-Butyl [(R) —2-nitro-1-1-furethyl] carbamate Under argon atmosphere, tert-butyl N-benzylidene carbamate (41.1 mg, 0.20 mm o 1) and (R, R) -trans — 1— [3,5-bis (trifluoromethyl) phenyl] — 3— [2— (N, N-dimethylamino) cyclohexyl] urea (7.9 mg, 0.02 mm o 1) To a solution of the above in methylene chloride (0.4 mL) was added, with stirring, utromethane (0.1 mL, 2.00 mmol) at room temperature. After 24 hours, the reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 5Zl) to give the title compound as colorless needle crystals. Obtained (45.8 mg, yield 86%, optical purity 87% ee). Table 1 shows the yield and optical purity. Melting point 99-100 ° C (n-hexane Z ethyl acetate).

HP LC analysis conditions:

Column: Chiral Cell AD (manufactured by Daicel Chemical), mobile phase: n-hexane Z ethanol = 85/15, flow rate: 1.0 ml, detection: f = 210 nm, retention time : (R) isomer (main peak); 9.8 min, (R) isomer; 12.1 min.

_{^{[a] D 30 - 2 5.}} 3 (c 1. 2, CHC 1 3);

_{! H- NMR (500Hz, CDC1 3} ) 6: 7.30-7.42 (m, 5H), 5.39 (brs, 1H), 5.29 (brs, 1H), 4.69-4.87 (m, 2H), 1.44 (s, 9H) ppra;

^{13 C-NMR (500Hz, CDC1} 3) δ: 154.9, 137.0, 129.3, 128.9, 126.4, 80.8, 79.0, 52.9, 28.3 ppm;

_{IR (CHC1 3) v: 3442} , 3027, 2981, 1713, 1557, 1164, 862, 758, 699 cm "1;

MS (FAB ⁺ ): 267 (MH +, 100);

HRMS (FAB ^+): Calculated _{_{_{(C 13 H 19 N 2 0}}} 4), [M + H] +: 267.1345; ANALYSIS: 267.1352.

(ID (III) (IV)

1) diastereomeric mixture, 2) primary diastereomer, industrial applicability

According to the present invention, a non-metallic asymmetric urea compound (I) is used as an asymmetric catalyst for an asymmetric nucleophilic addition reaction to an imine compound (Π), so that an optically active amine compound (IV) can be produced in high yield. It can be manufactured with high efficiency and high stereoselectivity.

In addition, since the asymmetric urea compound (I) of the present invention is non-metallic, there is no need to treat a metal waste liquid and the like, and it is an environmentally friendly catalyst. Furthermore, since it is non-metallic, it can be easily collected and reused. This application is based on a patent application No. 2003-420201 filed in Japan, the contents of which are incorporated in full herein.

Claims

The scope of the claims

General formula (I)

[In the formula, X represents an oxygen atom or a sulfur atom; C * and C ** each independently represent an asymmetric carbon; R ¹ and R ² are the same or different and may have a substituent A lower alkyl group, an optionally substituted aralkyl group or an optionally substituted aryl group, or together with the nitrogen atom to which R ¹ and R ² bind. To form an aliphatic heterocyclic ring which may have a substituent (the aliphatic heterocyclic ring may be condensed with an aromatic hydrocarbon); R ³ represents a substituent A lower alkyl group which may be substituted, an aralkyl group which may be substituted, an aryl group which may be substituted, or a heteroaryl group which may be substituted; R ⁴ and R ⁵ are the same or different, optionally substituted lower § alkyl group Or it represents an § Li Ichiru group optionally having also good Ararukiru group or substituent have a substituent, or taken together with the asymmetric carbon to which R ⁴ and R ⁵ are bonded respectively, substituted R ⁶ and R ⁷ may be the same or different and have a hydrogen atom or a substituent, and may form a homocyclic ring which may have a group or a heterocyclic ring which may have a substituent. And a lower alkyl group which may be substituted. In the presence of a compound represented by the formula or a salt thereof, a compound represented by the general formula (II):

(I I)

[Wherein, R ⁸ and R ⁹ are each independently a different hydrogen atom, a lower alkyl group optionally having substituent (s), a lower alkenyl group optionally having substituent (s), An aralkyl group which may have a aralkyl group which may have a substituent, A heteroaryl group which may have a substituent or a heteroatom which may have a substituent, a cyano group, one COzR ¹¹ —CONR ¹² R ¹³ or one COR ¹⁴ (where Rn, R ¹² , R ¹³ and R ¹⁴ are independently the same or different and each have a hydrogen atom, a lower alkyl group which may have a substituent, an aralkyl group which may have a substituent, and a substituent Represents an aryl group which may be substituted, a heteroaryl group which may have a substituent, or may have a substituent together with the nitrogen atom to which R ¹² and R ¹³ bind. May form a good aliphatic heterocycle (the aliphatic heterocycle may be condensed with an aromatic hydrocarbon.) Or a carbon atom to which R ⁸ and R ⁹ are bonded. Taken together, an optionally substituted homocyclic ring or an optionally substituted May form good heterocycles; R ^1Q is one P (= 0) R ¹⁵ R ¹⁶ , — S0 ₂ R ¹⁷ , _CO ₂ R ¹⁸ , —CONR ¹⁹ R ²⁰ , -COR ²¹ ,-NR ²² R ²³ , -S i R ² R ²⁵ R ²⁶ (where R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²⁰ , R ²¹ , R ²² , R ²³ , R ²⁴ , R ²⁵ and R ²⁶ are A hydrogen atom, a lower alkyl group which may have a substituent, an aralkyl group which may have a substituent, and an aryl which may have a substituent And a heteroaryl group which may have a substituent or a substituent.), A lower alkyl group which may have a substituent, a lower alkoxy group which may have a substituent, and a substituent It represents an aralkyl group which may have, an aryl group or an aryl group which may have a substituent. However, R ⁸ and R ^1Q may form a heterocyclic ring which may have a substituent, together with the carbon atom and the nitrogen atom to be bonded to each other. And a salt thereof represented by the general formula (III): H-Nu (III) wherein Nu is one of C (NO ₂ ) R ²⁷ R ²⁸ , -CR ²⁹ (COR ³⁰ ) (COR ³¹ ^{^{), -OR 32, - SR 3}} 3, one NR ³⁴ R ³⁵ (wherein ^{^{^{R 27, R 28, R 32}}} , R 33, R 34 and R ³⁵ their respective independently the same or different, hydrogen Atom, lower alkyl group optionally having substituent (s), aralkyl group optionally having substituent (s), aryl group optionally having substituent (s) or optionally having substituent (s) R ²⁹ represents hydrogen or may represent a teloaryl group, or R ³⁴ and R ³⁵ may form an optionally substituted aliphatic heterocycle together with the nitrogen atom to which they are attached; Atom, halogen atom, substituent Represents an optionally substituted lower alkyl group or an optionally substituted aryl group or a substituted heteroatom; R ^3Q and R ³¹ are the same or different and are a hydrogen atom, a lower alkyl group, a lower alkoxy group, A monoalkyl lower alkylamino group, a di-lower alkylamino group, an aryl group which may have a substituent or an aralkyl group which may have a substituent. ) Represents an azide group or a cyano group. Wherein a nucleophile represented by the general formula (IV) is reacted:

(IV)

(In the formula, C *** represents an asymmetric carbon, and other symbols have the same meanings as described above.)

2. The method according to claim 1, wherein X is a sulfur atom.

3. R ⁴ and R ^5, Tsuteshi black propane such with the asymmetric carbon to which R ⁴ and R ⁵ are bonded respectively, to form a hexane cyclobutane, the cyclopentane or cyclopentane, prepared according to claim 1 or 2, wherein Method.

4. R ⁴ and R ^5, R ⁴ and R ⁵ hexane was formed into Tsuteshi black such with the asymmetric carbon bonded to each other and R ⁶ and R ⁷ are hydrogen atom, according to claim 3, wherein Manufacturing method.

5. The production method according to claim 4, wherein the absolute configurations of C * and C "are both S configuration or both R configuration.

6. (wherein each symbol is as defined above.) R ¹⁰ is one ^{P (= 0) R 15 R} 16 is The method according to any one of claims 1 to 5.

7. R ¹⁰ gar C0 ₂ R ¹⁸ (wherein, R ¹⁸ is. Indicating the same meaning) is The method according to any one of claims 1-5.

8. R ⁸ is a hydrogen atom, and R ⁹ is a lower alkyl group which may have a substituent, an aryl group which may have a substituent, or a group which has a substituent. The production method according to any one of claims 1 to 7, which is a good heteroaryl group.

9. If the nucleophile is HC (NO ₂ ) R ²⁷ R ²⁸ (where each symbol is as defined above) You. The method according to any one of claims 1 to 8, which is represented by:

10. Even if R ²⁷ is a hydrogen atom, and R ²⁸ has a hydrogen atom, an alkyl group which may have a substituent, an aryl group which may have a substituent or a substituent 10. The production method according to claim 9, which is a good heteroaryl group.

11. The production method according to any one of claims 1 to 10, wherein the production is performed in at least one solvent selected from ethylene chloride, toluene, tetrahydrofuran, and 1,4-dioxane.