JP2006143627A - Optically active amino acid derivative having axial asymmetry, and method for producing optically active compound using the amino acid derivative as asymmetric catalyst - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an advantageous method for producing an optically active compound useful as a synthetic intermediate of a medicine or the like by developing a new nonmetallic asymmetric catalyst capable of achieving high-yield and highly stereoselective asymmetric reaction. <P>SOLUTION: The amino acid derivative is represented by general formula (I) [wherein, R<SP>1</SP>is an aryl group which may have a substituent, a group represented by the formula: -CO<SB>2</SB>R<SP>4</SP>(wherein, R<SP>4</SP>is a hydrogen atom or the like) or the like; and R<SP>2</SP>and R<SP>3</SP>are the same or different and each a hydrogen atom or the like]. The method for producing the optically active compound uses the optically active substance as an asymmetric catalyst. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

The present invention relates to a novel optically active amino acid derivative having axial asymmetry. The amino acid derivative of the present invention is useful as a catalyst for asymmetric synthesis.
Furthermore, this invention relates to the manufacturing method of the optically active compound characterized by using the said amino acid derivative as an asymmetric catalyst.

  Most recently developed drugs have become non-racemic drugs in order to further improve drug efficacy and safety. Conventionally, the optical resolution method has been the mainstream in the synthesis of these optically active pharmaceuticals, but the atom economy is shifting to asymmetric catalyst synthesis, and development of asymmetric catalysts that can achieve high yield and high optical purity. Is attracting attention as the underlying technology. Asymmetric catalyst synthesis is expected to be applied not only to pharmaceuticals but also to various fields such as agricultural chemicals and highly functional materials (for example, liquid crystals and nonlinear optical materials).

Aldol reactions such as direct aldol reaction and O-nitrosoaldol reaction are used for the synthesis of various pharmaceuticals (see, for example, Non-Patent Document 1), and their application to asymmetric catalyst synthesis can be a very useful technique. . Therefore, asymmetric catalysts for various asymmetric aldol reactions have been reported so far, most of which have used transition metal catalysts having an asymmetric ligand (for example, Non-Patent Document 2). reference).
However, many transition metal catalysts are highly toxic or unstable in catalytic activity, and there are many cases that require careful handling. Further, the catalytic activity often deteriorates when used in the reaction, and its recovery and reuse are generally difficult. Furthermore, since it is necessary to treat the metal waste liquid, the cost is increased and there is also an environmental problem.

As a catalytic asymmetric aldol reaction without using a transition metal, a method using an amino acid derivative such as L-proline as an asymmetric catalyst has been reported (see Non-Patent Document 3 or 4). However, the yield and stereoselectivity were low and were not satisfactory for practical use.
“Helvetica Chemica Acta”, 1987, 70, p. 1412-1418 “Journal of the American Chemical Society”, 1999, Vol. 121, p. 669-685 “Journal of the American Chemical Society”, 2001, Vol. 123, p. 5260-5267 “Journal of the American Chemical Society”, 2003, vol. 125, p. 10808-10809

  That is, the present invention has been made to solve the above-mentioned problems found in conventional asymmetric aldol reactions, and its purpose is to achieve a high yield and high stereoselective asymmetric aldol reaction. Advantages of optically active compounds useful as synthetic intermediates for pharmaceuticals, agricultural chemicals, highly functional materials, etc. by developing new asymmetric catalysts for metals and providing new asymmetric aldol reactions using such asymmetric catalysts Providing a simple manufacturing method.

In order to solve the above-mentioned problems, the present inventor has intensively studied focusing on an amino acid derivative having axial asymmetry as a nonmetallic asymmetric catalyst for an asymmetric aldol reaction. As a result, the inventors have found that a novel amino acid derivative having a binaphthyl structure as an axial asymmetry source can be a non-metallic asymmetric catalyst excellent in an asymmetric aldol reaction, and has completed the present invention.
That is, the present invention is as follows.
[1] General formula (I):

(In the formula, R ¹ represents a hydrogen atom, an aryl group which may have a substituent, a heteroaryl group which may have a substituent, or a group represented by —CO ₂ R ⁴ (where R 1 is ⁴ represents a hydrogen atom, a lower alkyl group which may have a substituent, a cycloalkyl group which may have a substituent, or an aryl group which may have a substituent. ² and R ³ are the same or different and each represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group), or a salt thereof (hereinafter also referred to as compound (I)).
[2] The compound or a salt thereof according to the above [1], wherein R ¹ is a hydrogen atom, an optionally substituted phenyl group or a carboxyl group.
[3] The compound or salt thereof according to [1] or [2], which is optically active.
[4] An asymmetric catalyst comprising the compound according to the above [3] or a salt thereof.
[5] The asymmetric catalyst according to the above [4], which is an asymmetric catalyst for an asymmetric aldol reaction, asymmetric Mannich type reaction, asymmetric halogenation reaction or asymmetric Michael reaction.
[6] The asymmetric catalyst according to the above [5], which is an asymmetric catalyst for the asymmetric aldol reaction.
[7] The asymmetric catalyst according to the above [6], wherein the asymmetric aldol reaction is an asymmetric direct aldol reaction or an asymmetric O-nitrosoaldol reaction.
[8] General formula (II) in the presence of the compound or salt thereof according to [3] above:

(Wherein R ⁵ and R ⁶ are the same or different and have a hydrogen atom, a lower alkyl group which may have a substituent, a lower alkenyl group which may have a substituent, or a substituent. A cycloalkyl group which may have a substituent, an aryl group which may have a substituent, an aralkyl group which may have a substituent, a heteroaryl group which may have a substituent or a substituent. Or a heteroarylalkyl group which may be substituted, or R ⁵ and R ⁶ may be connected to form a ring optionally having a substituent together with the carbon atom to which each is bonded. ) (Hereinafter also referred to as compound (II)) and general formula (III):

(In the formula, R ⁷ has a lower alkyl group which may have a substituent, a lower alkenyl group which may have a substituent, a cycloalkyl group which may have a substituent, and a substituent. An aryl group that may be substituted, an aralkyl group that may have a substituent, a heteroaryl group that may have a substituent, or a heteroarylalkyl group that may have a substituent. A compound represented by the general formula (IV): wherein the compound represented by formula (hereinafter also referred to as compound (III)) is reacted.

(Wherein * represents an asymmetric carbon, and other symbols have the same meanings as defined above). A method for producing a compound represented by the following (hereinafter also referred to as compound (IV)).
[9] The production method of the above-mentioned [8], wherein R ⁵ is a lower alkyl group, R ⁶ is a hydrogen atom, and R ⁷ is an aryl group which may have a substituent.
[10] In the presence of the compound of the above-mentioned [3] or a salt thereof, general formula (V):

(Wherein R ⁸ represents a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted lower alkenyl group, an optionally substituted cycloalkyl group, substituted An aryl group which may have a group, an aralkyl group which may have a substituent, a heteroaryl group which may have a substituent or a heteroarylalkyl group which may have a substituent; R ⁹ represents a lower alkyl group which may have a substituent, a lower alkenyl group which may have a substituent, a cycloalkyl group which may have a substituent, or a substituent. An aryl group which may have a substituent, an aralkyl group which may have a substituent, a heteroaryl group which may have a substituent or a heteroarylalkyl group which may have a substituent, or R ⁸ and R ⁹ are connected, And a compound represented by the general formula (hereinafter also referred to as compound (V)), which may form a ring which may have a substituent together with the carbon atoms to which they are bonded. (VI):

(Wherein R ¹⁰ represents an aryl group which may have a substituent or a heteroaryl group which may have a substituent) (hereinafter also referred to as nitroso compound (VI)). In general formula (VII):

(Wherein * represents an asymmetric carbon, and other symbols have the same meanings as defined above). A method for producing a compound represented by the following (hereinafter also referred to as compound (VII)).
[11] General formula (VIII) including a step of reducing compound (VII) obtained by the production method of [10] above:

(In the formula, each symbol has the same meaning as described above.) A method for producing a compound represented by the following (hereinafter also referred to as compound (VIII)).
[12] The production method of the above-mentioned [10] or [11], wherein R ⁸ is a hydrogen atom, R ⁹ is a lower alkyl group, and R ¹⁰ is an aryl group which may have a substituent.
[13] General formula (Ia) characterized by including the following steps (ia) to (vi-a):

(In the formula, Ra ¹ represents an aryl group which may have a substituent or a heteroaryl group which may have a substituent, and R ² and R ³ are as defined above). A method for producing a compound (hereinafter also referred to as compound (Ia)) or a salt thereof;
(I-a) General formula (IX):

(Wherein R ² and R ³ are as defined above, and OTf represents a trifluoromethanesulfonyloxy group) (hereinafter also referred to as compound (IX)), a transition metal catalyst and a base In the presence of a compound represented by the general formula (X): Ra ¹ -B (OH) ₂ (X) (wherein Ra ¹ is as defined above) (hereinafter also referred to as compound (X)). And general formula (XI):

(Wherein each symbol has the same meaning as described above) (hereinafter, also referred to as compound (XI));
The presence of (ii-a) obtained compound (XI) to transition metal catalyst and a base, carbon monoxide and the general formula ^{(XII): R 4 'OH} (XII) ( wherein, R ^4' and the substituents An alcohol represented by a lower alkyl group which may have, a cycloalkyl group which may have a substituent, or an aryl group which may have a substituent (hereinafter referred to as alcohol (XII)). And the general formula (XIII):

(Wherein each symbol has the same meaning as described above) (hereinafter also referred to as compound (XIII));
(Iii-a) The obtained compound (XIII) is reacted with a halogenating agent in the presence of a radical initiator to give a general formula (XIV):

(Wherein, X ¹ represents a halogen atom, and other symbols are as defined above) (hereinafter also referred to as compound (XIV));
(Iv-a) The obtained compound (XIV) is reacted with allylamine to give a general formula (XV):

(Wherein each symbol has the same meaning as described above) (hereinafter also referred to as compound (XV));
(V-a) The resulting compound (XV) is deprotected in the presence of a transition metal catalyst to give a general formula (XVI):

Wherein each symbol is as defined above (hereinafter also referred to as compound (XVI));
(Vi-a) The obtained compound (XVI) is hydrolyzed to obtain compound (Ia).
[14] The production method of the above-mentioned [13], wherein Ra ¹ is a phenyl group which may have a substituent.
[15] General formula (Ib) comprising the following steps (ib) to (vb):

(Wherein each symbol has the same meaning as described above) (hereinafter also referred to as compound (Ib)) or a salt production method thereof;
(Ib) Compound (IX) is reacted with carbon monoxide and alcohol (XII) in the presence of a transition metal catalyst and a base to give a compound of the general formula (XVII):

(Wherein each symbol is as defined above) (hereinafter also referred to as compound (XVII));
(Ii-b) The obtained compound (XVII) is reacted with a halogenating agent in the presence of a radical initiator to give a general formula (XVIII):

(Wherein each symbol is as defined above) (hereinafter also referred to as compound (XVIII));
(Iii-b) The obtained compound (XVIII) is reacted with allylamine to give a general formula (XIX):

(Wherein each symbol is as defined above) (hereinafter also referred to as compound (XIX));
(Iv-b) The obtained compound (XIX) is deprotected in the presence of a transition metal catalyst to give a general formula (XX):

Wherein each symbol is as defined above (hereinafter also referred to as compound (XX));
(Vb) The obtained compound (XX) is hydrolyzed to obtain compound (Ib).
[16] The production method according to any one of [13] to [15], wherein the optically active compound (IX) is used.
[17] General formula (Ic) characterized in that it includes the following steps (ic) to (vii-c):

(Wherein each symbol has the same meaning as described above) (hereinafter also referred to as compound (Ic)) or a salt thereof;
(I-c) General formula (XXI):

(Wherein R ² and R ³ have the same meanings as described above, and R ¹¹ represents a lower alkyl group) (hereinafter also referred to as compound (XXI)) in the presence of a base, By reacting with a halogenating agent, general formula (XXII):

(Wherein R ² , R ³ and R ¹¹ are as defined above, and X ² represents a halogen atom) (hereinafter also referred to as compound (XXII));
(Ii-c) The obtained compound (XXII) is reduced to give a general formula (XXIII):

(Wherein each symbol is as defined above) (hereinafter also referred to as compound (XXIII));
(Iii-c) The obtained compound (XXIII) is reacted with a halogenating agent to give a general formula (XXIV):

Wherein R ² , R ³ and X ² are as defined above, and X ³ is the same as or different from X ² and represents a halogen atom (hereinafter also referred to as compound (XXIV)). .);
(Iv-c) The obtained compound (XXIV) is reacted with allylamine to give a general formula (XXV):

(Wherein each symbol is as defined above) (hereinafter also referred to as compound (XXV));
(V-c) The obtained compound (XXV) is reacted with carbon monoxide and alcohol (XII) in the presence of a transition metal catalyst and a base to give a general formula (XXVI):

(Wherein each symbol is as defined above) (hereinafter also referred to as compound (XXVI));
(Vi-c) The resulting compound (XXVI) is deprotected in the presence of a transition metal catalyst to give a general formula (XXVII):

(Wherein each symbol is as defined above) (hereinafter also referred to as compound (XXVII));
(Vii-c) The resulting compound (XXVII) is hydrolyzed to obtain compound (Ic).
[18] The production method of the above-mentioned [17], which uses an optically active compound represented by the general formula (XXI).

According to the present invention, there is provided a novel amino acid derivative which is a nonmetallic asymmetric catalyst that enables a high yield and high stereoselective asymmetric aldol reaction, that is, compound (I), which is asymmetrical aldol reaction. By using as an asymmetric catalyst, an advantageous method for producing an optically active compound useful as a synthetic intermediate for pharmaceuticals and the like is provided.
In addition, since the asymmetric catalyst of the present invention is non-metallic, it is environmentally friendly, and it is not necessary to treat the metal waste liquid, which is advantageous in terms of cost. Furthermore, since it is non-metallic, its catalytic activity is stable and can be easily recovered and reused.

Hereinafter, the present invention will be described in detail.
1. Explanation of Symbols In the alkyl of the present invention, it is linear unless it is prefixed (for example, iso, neo, sec-, tert-, etc.). For example, if it is simply propyl, it means linear propyl. It is.

The “halogen atom” represented by R ² , R ³ , X ¹ , X ² and X ³ is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. R ² and R ³ are preferably a chlorine atom or a bromine atom. X ¹ is preferably a chlorine atom or a bromine atom. X ² is preferably a bromine atom. X ³ is preferably a chlorine atom or a bromine atom.

The “lower alkyl group” represented by R ² , R ³ and R ¹¹ is a linear or branched alkyl group having 1 to 12 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl. , Tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl and the like, preferably methyl, ethyl, isopropyl or tert-butyl.

The “lower alkoxy group” represented by R ² and R ³ is an alkoxy group in which the alkyl portion is the “lower alkyl group” defined above, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec- Examples include butoxy, tert-butoxy, pentoxy, isopentoxy, neopentoxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy, undecyloxy, dodecyloxy and the like, preferably methoxy or ethoxy.

The “lower alkyl group” of the “lower alkyl group optionally having substituent (s)” represented by R ⁴ , R ⁴ ′, R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ is defined above. And the same alkyl group as the above-mentioned “lower alkyl group”.
The lower alkyl group may have a substituent at a substitutable position. Examples of such a substituent include a lower alkoxy group as defined above, a halogen atom as defined above, a nitro group, and a cyano group. Etc. The number of the substituents is not particularly limited, preferably 1 to 3, and may be the same or different when two or more.

The “lower alkenyl group” of the “lower alkenyl group optionally having substituent (s)” represented by R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ is a linear or branched group having 2 to 12 carbon atoms. Branched alkenyl groups such as ethenyl, 1-propenyl, allyl, 1-methyl-2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 1-hexenyl, 2-hexenyl, Examples include 1-heptenyl, 2-heptenyl, 1-octenyl, 2-octenyl, 1-nonenyl, 2-nonenyl, 1-decenyl, 2-decenyl, and the like, and preferably ethenyl or allyl. The alkenyl group may have a substituent at a substitutable position. Examples of such a substituent include the substituents exemplified in the above-mentioned “lower alkyl group optionally having substituent (s)”. The same substituents; or “aryl groups optionally having substituents” defined below. The number of the substituents is not particularly limited, preferably 1 to 3, and may be the same or different when two or more.

“Aryl group” of “aryl group optionally having substituent (s)” represented by R ¹ , Ra ¹ , R ⁴ , R ⁴ ′, R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ "Includes an aryl group having 6 to 12 carbon atoms, such as phenyl, 1- or 2-naphthyl, biphenyl and the like. The aryl group may have a substituent at a substitutable position. Examples of such a substituent include a lower alkyl group and a halo lower alkyl group defined above (eg, trifluoromethyl group, etc.); An aryl group which may be substituted with a halogen atom; the same substituents as those exemplified above for the “lower alkyl group which may have a substituent” and the like. The number of the substituents is not particularly limited, preferably 1 to 3, and may be the same or different when two or more.

As the “cycloalkyl group” of the “cycloalkyl group optionally having substituent (s)” represented by R ⁴ , R ⁴ ′, R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ , ˜7 cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. The cycloalkyl group may have a substituent at a substitutable position. Examples of such a substituent include the substituents exemplified in the above-mentioned “aryl group optionally having substituent (s)”. The same substituents can be mentioned. The number of the substituents is not particularly limited, preferably 1 to 3, and may be the same or different when two or more.

The “aralkyl group” of the “aralkyl group optionally having substituent (s)” represented by R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ is any of the “lower alkyl groups” defined above An aralkyl group formed by substituting the above-defined “aryl group” at the position of, for example, benzyl, 1- or 2-phenylethyl, 1-, 2- or 3-phenylpropyl, 1- or 2-naphthyl Examples include methyl, benzohydryl, trityl and the like. The aralkyl group may have a substituent at a substitutable position, and as such a substituent, the same substituent as the substituent exemplified in the above-mentioned “aryl group optionally having substituent (s)” is used. Groups. The number of the substituent is not particularly limited and is preferably 1 to 3, and may be the same or different in the case of 2 or more.

As the “heteroaryl group” of the “heteroaryl group optionally having substituent (s)” represented by R ¹ , Ra ¹ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ , for example Examples thereof include 5- to 6-membered aromatic heterocyclic groups containing 1 to 2 heteroatoms selected from oxygen atoms, sulfur atoms and nitrogen atoms in addition to carbon atoms, and condensed heterocyclic groups thereof. For example 2- or 3-thienyl, 2- or 3-furyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 2-, 4- or 5-oxazolyl, 2- 4-, 5-thiazolyl, 1-, 3-, 4- or 5-pyrazolyl, 3-, 4- or 5-isoxazolyl, 3-, 4- or 5-isothiazolyl, 1,2,4-triazole-1 3, 4, or 5-yl, 1,2,3-triazol-1, 2, or 4-yl, 1H-tetrazol-1 or 5-yl, 2H-tetrazol-2 or 5-yl, 2-, 3- Or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 2-, 3-, 4-, 5-, 6 -Or 7-benzofuryl, 2-, 3-, 4-, 5-, 6- or 7-benzothienyl, -, 2-, 4-, 5-, 6- or 7-benzimidazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl and the like can be mentioned. 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 “aryl group optionally having substituent”. A substituent is mentioned. The number of the substituents is not particularly limited, preferably 1 to 3, and may be the same or different when two or more.

The “heteroarylalkyl group” of the “heteroarylalkyl group optionally having substituent (s)” represented by R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ is the “lower alkyl” defined above. A group formed by substituting the “heteroaryl group” defined above at any position of the “group”, for example, 3-indolylmethyl, 2-pyridylmethyl, 2-thienylmethyl and the like. The aralkyl group may have a substituent at a substitutable position, and as such a substituent, the same substituent as the substituent exemplified in the above-mentioned “aryl group optionally having substituent (s)” is used. Groups. The number of the substituents is not particularly limited, preferably 1 to 3, and may be the same or different when two or more.

Examples of the ring that R ⁵ and R ⁶ and R ⁸ and R ⁹ may form together with the carbon atoms to which R ⁵ and R ⁶ are bonded, respectively, include a 5- to 6-membered allocyclic ring or a condensed ring thereof (for example, cyclopentane, Cyclohexane, cycloheptane, 1,2,3,4-tetrahydronaphthalene, indane, etc.) or a 5- to 6-membered heterocyclic ring containing 1 to 2 heteroatoms such as nitrogen, oxygen or sulfur atoms in addition to carbon atoms Or a condensed ring thereof (for example, tetrahydrofuran, tetrahydropyran, tetrahydrothiophene, tetrahydrothiopyran, pyrrolidine, piperidine, 1,4-dioxane, morpholine, thiomorpholine, piperazine, dihydrobenzofuran, chroman, isochroman, thiochroman, etc.). The ring may have a substituent at a substitutable position, and examples of such a substituent include the same substituents as those exemplified above for the “aryl group optionally having substituents”. Is mentioned. The number of the substituents is not particularly limited, preferably 1 to 3, and may be the same or different when two or more.

  * In the compounds (IV), (VII) and (VIII) indicates that the attached carbon atom is an asymmetric carbon, and that each compound is an optically active compound.

  Compounds (I), (Ia), (Ib), (Ic), (IX), (XI), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), ( XIX), (XX), (XXI), (XXII), (XXIII), (XXIV), (XXV), (XXVI), and (XXVII) are axial asymmetry based on rotation failure of a single bond connecting naphthalene rings. And atropisomerism that is optically resolvable at room temperature, including optically active compounds and racemates.

  Optical activity means that it is not an equimolar mixture (for example, racemate) of isomers having different configurations in asymmetric carbon or axial asymmetry, and when one stereoisomer is present in excess (for example, 6: 4 mixture) is defined as optical activity.

  When the compounds described herein have two or more asymmetric carbon or axial asymmetry, all stereoisomers or mixtures thereof (for example, diastereomers or mixtures thereof, etc.) are included.

Compounds (I), (Ia), (Ib) and (Ic) are amino acid derivatives having an amino group and a carboxyl group, and may be in the form of a salt. Examples of such salts include inorganic acid salts (for example, hydrochloride, sulfate, nitrate, phosphate, etc.); organic acid salts (for example, acetate, propionate, methanesulfonate, 4-toluenesulfonate) , Oxalate, maleate, 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 salt, picoline salt, dicyclohexylamine salt, etc.).
Moreover, the aspect which forms the same salt may also be sufficient as the other compound defined by this specification.

R ¹ of the compound (I) is preferably a hydrogen atom, a phenyl group or a carboxyl group which may have a substituent, and more preferably a phenyl group or a carboxyl group which may have a substituent.

R ⁵ of the compound (II) is preferably a lower alkyl group or an aryl group having a substituent, more preferably a methyl group or a phenyl group, and R ⁶ is preferably a hydrogen atom. R ⁷ of compound (III) is preferably an aryl group which may have a substituent, and more preferably a nitro group, a cyano group or a phenyl group substituted with a chlorine atom.

As R ⁸ of the compound (V), a hydrogen atom is preferable. R ⁹ is preferably a lower alkyl group which may have a substituent, and more preferably a methyl group. R ¹⁰ of the nitroso compound (VI) is preferably an aryl group which may have a substituent, and more preferably a phenyl group.

2. Production method of compound (I) Among compounds (I) of the present invention, a compound in which R ¹ is an optionally substituted aryl group or an optionally substituted heteroaryl group, ie, compound ( Ia) can be produced by the production method 1 including the following steps (ia) to (vi-a).

(In the formula, each symbol is as defined above.)
(I-a) Compound (IX) is reacted with Compound (X) in the presence of a transition metal catalyst and a base to give Compound (XI);
(Ii-a) reacting compound (XI) with carbon monoxide and alcohol (XII) in the presence of a transition metal catalyst and a base to obtain compound (XIII);
(Iii-a) compound (XIII) is reacted with a halogenating agent in the presence of a radical initiator to obtain compound (XIV);
(Iv-a) reacting compound (XIV) with allylamine to obtain compound (XV);
(V-a) Compound (XV) is deprotected in the presence of a transition metal catalyst to give compound (XVI);
(Vi-a) Compound (XVI) is hydrolyzed to give compound (Ia).

In the compound (I) of the present invention, a compound in which R ¹ is a group represented by —CO ₂ R ⁴ (R ⁴ has the same meaning as described above), that is, the compound (Ib) is prepared by the following step (i -b) to (v-b).

(In the formula, each symbol is as defined above.)
(Ib) Compound (IX) is reacted with carbon monoxide and alcohol (XII) in the presence of a transition metal catalyst and a base to give compound (XVII);
(Ii-b) Compound (XVII) is reacted with a halogenating agent in the presence of a radical initiator to give compound (XVIII);
(Iii-b) reacting compound (XVIII) with allylamine to obtain compound (XIX);
(Iv-b) Compound (XIX) is deprotected in the presence of a transition metal catalyst to give compound (XX);
(Vb) The obtained compound (XX) is hydrolyzed to obtain compound (Ib).

  Compound (IX), which is a raw material of production methods 1 and 2, can be prepared, for example, by the method described in J. Am. Chem. Soc., 2003, 125, p.5139-5151. By using the optically active compound (IX), the optically active compound (Ia) or (Ib) can be produced.

Among compounds (I), a compound in which R ¹ is a hydrogen atom, that is, compound (Ic) can be produced by production method 3 including the following steps (ic) to (vii-c).

(Ic) Compound (XXI) is reacted with a halogenating agent in the presence of a base to give compound (XXII);
(Ii-c) reducing compound (XXII) to obtain compound (XXIII);
(Iii-c) reacting compound (XXIII) with a halogenating agent to obtain compound (XXIV);
(Iv-c) reacting compound (XXIV) with allylamine to give compound (XXV);
(V-c) reacting compound (XXV) with carbon monoxide and alcohol (XII) in the presence of a transition metal catalyst and a base to obtain compound (XXVI);
(Vi-c) Compound (XXVI) is deprotected in the presence of a transition metal catalyst to give compound (XXVII);
(Vii-c) The compound (XXVII) is hydrolyzed to obtain the compound (Ic).

  Compound (XXI), which is a raw material of production method 3, can be easily obtained by esterifying 1,1′-naphthyl-2,2′-dicarboxylic acid or a derivative thereof, which is commercially available, by a method known per se. Can be prepared. By using the optically active compound (XXI), the optically active compound (Ic) can be produced.

Hereinafter, steps (ia) to (vi-a), steps (ib) to (vb), and steps (ic) to (viic) will be described.
The compound obtained in each step should be isolated and purified by ordinary isolation operations (eg, concentration, extraction, neutralization, washing, filtration, etc.) or purification operations (eg, recrystallization, silica gel column chromatography, etc.). Can do.
2-1. Step (i-a)
Step (ia) is a step of obtaining compound (XI) by substituting ^one OTf of compound (IX) with a group represented by Ra1. Step (ia) may be carried out according to the Suzuki coupling reaction (see Synlett, 221 (1990)). For example, compound (IX), compound (X), transition metal catalyst and base are mixed in a solvent. This can be done. The order of addition of each reagent is not particularly limited, and may be added sequentially or simultaneously.

The transition metal catalyst used in the step (ia) is formed by coordination of a monovalent or divalent phosphine ligand to a transition metal selected from zero-valent or divalent palladium and nickel. Transition metal complexes such as Ni (PPh ₃ ) ₄ , NiCl ₂ (PPh ₃ ) ₂ , NiCl ₂ (dppe), NiCl ₂ (dppp), NiCl ₂ (dppb), Pd (PPh ₃ ) ₄ , PdCl ₂ (PPh ₃ ) ₂ , PdCl ₂ (dppe), PdCl ₂ (dppp), PdCl ₂ (dppb), Pd (OAc) ₂ (PPh ₃ ) ₂ , Pd (OAc) ₂ (dppe), Pd (OAc) ₂ (dppp), Pd (OAc) ₂ (dppb) (where dpppe represents 1,2-bis (diphenylphosphino) ethane and dppp represents 1,3-bis (diphenyl) Phenyphosphino) propane, dppb represents 1,4-bis (diphenylphosphino) butane.) And the like, and Pd (OAc) ₂ (dppp) and Pd (OAc) ₂ (PPh ₃ ) ₂ are preferable. These transition metal complexes are formed in a reaction system from a transition metal salt (eg, NiCl ₂ , PdCl ₂ , Pd (OAc) _2, etc.) and a phosphine ligand (eg, PPh ₃ , dppe, dppp, dppb etc.). In this case, the ratio of the phosphine ligand to the transition metal salt may be in the range of 1 to 3 equivalents.

  The amount of the transition metal catalyst to be used is generally 0.001 to 0.2 equivalent, preferably 0.005 to 0.1 equivalent, relative to compound (IX). The transition metal catalyst can be used even when the amount of the transition metal catalyst is outside this range, but if the amount is less than this range, the reaction will be slow, and even if it is used in a large amount, an effect commensurate with it will not be obtained and the cost will increase.

  Although it does not specifically limit as a base used for process (ia), For example, organic bases, such as inorganic bases, such as potassium phosphate and sodium phosphate, N-ethyldiisopropylamine, a triethylamine, N, N-dimethylaniline And potassium phosphate is preferred. The amount of the base to be used is generally 1 to 10 equivalents, preferably 1.2 to 3.5 equivalents, relative to compound (IX). The reaction can be carried out even when the amount of the base used is outside this range, but if the amount is less than this range, the reaction rate is deteriorated.

  The amount of compound (X) to be used is generally 0.9 to 2 equivalents, preferably 1 to 1.5 equivalents, relative to compound (IX). The compound (X) can be used even when the amount used is outside this range, but if the amount is less than this range, the reaction rate deteriorates, and if it is used in a large amount, it reacts with the other OTf of the compound (IX). May generate.

  The solvent used in the step (i-a) may be any solvent that does not inhibit the reaction. For example, 1,4-dioxane, tetrahydrofuran (THF), 1,2-dimethoxyethane, diglyme, methyl tert-butyl ether, toluene, A single or mixed solvent such as xylene may be mentioned, and 1,4-dioxane or THF is preferable. The amount of the solvent to be used is generally in the range of 3 to 50 L with respect to 1 kg of compound (IX).

  The reaction temperature in the step (ia) is usually 40 ° C to 120 ° C, but preferably 60 ° C to 100 ° C. The reaction time is usually 1 hour to 24 hours, although it depends on the reagent used and the reaction temperature.

2-2. Process (ii-a)
Step (ii-a) is compound (XI) _-CO 2 ^{R 4} a OTf of ^{'(R 4'} is. Which are of the same meaning) is replaced with a group represented by to obtain a compound (XIII) Step For example, it can be carried out by reacting a mixture of compound (XI), alcohol (XII), transition metal catalyst and base in a solvent in a carbon monoxide atmosphere. The order of addition of the reagents is not particularly limited, and may be added sequentially or simultaneously.

Examples of the transition metal catalyst used in the step (ii-a) include the same ones as in the step (ia), and Pd (OAc) ₂ (dppp) and Pd (OAc) ₂ (PPh ₃ ) ₂ are preferable. . The amount of the transition metal catalyst to be used is generally 0.001 to 0.5 equivalent, preferably 0.01 to 0.3 equivalent, relative to compound (XI). The transition metal catalyst can be used even when the amount of the transition metal catalyst is outside this range, but if the amount is less than this range, the reaction will be slow, and even if it is used in a large amount, an effect commensurate with it will not be obtained and the cost will increase.

  Examples of the base used in the step (ii-a) include the same as those in the step (i-a), and N-ethyldiisopropylamine is preferable. The amount of the base to be used is generally 1 to 10 equivalents, preferably 2 to 6 equivalents, relative to compound (XI). The reaction can be carried out even when the amount of the base used is outside this range, but if the amount is less than this range, the reaction rate is deteriorated.

  The amount of alcohol (XII) to be used is generally 2-100 equivalents, preferably 5-80 equivalents, relative to compound (XI). Alcohol (XVII) can be used even when the amount used is outside this range, but if the amount is less than this range, the reaction rate will be slow, and even if it is used in a large amount, an effect commensurate with it will not be obtained and the cost will increase.

  Step (ii-a) is usually carried out under pressurized conditions of carbon monoxide. The pressure of carbon monoxide is usually 2 to 30 atmospheres, preferably 5 to 20 atmospheres. The reaction can be carried out even if the pressure of carbon monoxide is outside this range, but if it is lower than this range, the reaction is slow, and if it is high, expensive pressure-resistant equipment is required and the cost is increased.

  The solvent used in step (ii-a) may be any solvent that does not inhibit the reaction. For example, dimethyl sulfoxide (DMSO), sulfolane, N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMAc) Or a mixed solvent such as DMSO is preferred. The amount of the solvent to be used is generally in the range of 3 to 100 L with respect to 1 kg of compound (XI).

  The reaction temperature in step (ii-a) is usually 40 ° C to 130 ° C, but preferably 60 ° C to 100 ° C. The reaction time is usually 3 hours to 48 hours, although it depends on the reagent used and the reaction temperature.

2-3. Step (iii-a)
Step (iii-a) is a step of halogenating two methyl groups of compound (XIII) to obtain compound (XIV). For example, compound (XIII), a radical initiator and a halogenating agent are combined in a solvent. This can be done by mixing. The order of addition of each reagent is not particularly limited, and may be added sequentially or simultaneously.

  As the halogenating agent, conventionally known halogenating agents can be used without particular limitation, and examples thereof include N-bromosuccinimide (NBS) and N-chlorosuccinimide (NCS), and NBS is preferable. The amount of the halogenating agent to be used is generally 2-3 equivalents, preferably 2-2.5 equivalents, relative to compound (XIII). The reaction can be performed even when the amount of the halogenating agent used is outside this range, but if the amount is less than this range, the reaction is difficult to complete, and if it is large, excessive halogenation may proceed.

  As the radical initiator, conventionally known ones can be used without particular limitation, and examples thereof include 2,2′-azobisisobutyronitrile (AIBN) and 2,2′-azobis (2,4-dimethylvaleronitrile). ) (AMVN), azobis compounds such as 2,2′-azobis (4-methoxy-2,4-dimethylvaleronitrile) (MeO-AMVN), peroxides such as dibenzoyl peroxide and di-t-butyl peroxide AIBN is preferable. The usage-amount of a radical initiator is 0.001-0.2 equivalent normally with respect to compound (XIII), Preferably it is 0.01-0.15 equivalent. The radical initiator can be used even when the amount used is outside this range, but if the amount is less than this range, the reaction is difficult to complete, and even if it is used in a large amount, an effect commensurate with it cannot be obtained and the cost increases.

  The solvent used in the step (iii-a) is not particularly limited as long as it does not inhibit the reaction, and examples thereof include benzene, chlorobenzene, ethyl acetate, butyl acetate and the like, and benzene, chlorobenzene, or ethyl acetate is preferable. . The amount of the solvent to be used is generally in the range of 5 to 50 L with respect to 1 kg of compound (XIII).

  The reaction temperature in the step (iii-a) is usually from 40 ° C to 150 ° C, but preferably from 50 ° C to 110 ° C. The reaction time is usually 1 hour to 24 hours, although it depends on the reagent used and the reaction temperature.

2-4. Process (iv-a)
Step (iv-a) is a step of cyclizing compound (XIV) with allylamine to obtain compound (XV). For example, step (iv-a) can be performed by mixing compound (XIV) and allylamine in a solvent. The order of addition of each reagent is not particularly limited, and may be added sequentially or simultaneously.

  The amount of allylamine to be used is generally 1 to 5 equivalents, preferably 1.5 to 3.5 equivalents, relative to compound (XIV). The reaction can be carried out even when the amount of allylamine used is outside this range, but if the amount is less than this range, the reaction is difficult to complete, and even if it is used in a large amount, an effect commensurate with it cannot be obtained and the cost increases.

  The solvent used in the step (iv-a) is not particularly limited as long as it does not inhibit the reaction. Examples thereof include acetonitrile, DMSO, THF, 1,4-dioxane and the like, and acetonitrile is preferable. The usage-amount of a solvent is the range of 5-50L with respect to 1 kg of compounds (XIV).

  The reaction temperature in the step (iv-a) is usually 20 ° C to 100 ° C, but preferably 40 ° C to 70 ° C. The reaction time is usually 1 hour to 24 hours, although it depends on the reagent used and the reaction temperature.

2-5. Step (v-a)
The step (v-a) is a step of deprotecting the allyl group of the compound (XV). The deprotection described in “Protective Groups in Organic Synthesis”, John Wiley: USA, 1999, 3rd Edithion p.574-575. Just like the protection law. For example, it can be carried out by mixing the compound (XIV) and the transition metal catalyst in a solvent, preferably in the presence of an acid. The order of addition of each reagent is not particularly limited, and may be added sequentially or simultaneously.

Examples of the transition metal catalyst used in the step (va) include the same transition metal catalyst as in the step (ia), and Pd (OAc) ₂ (dppp) and Pd (OAc) ₂ (PPh ₃ ) ₂ are preferable. . The amount of the transition metal catalyst to be used is generally 0.001 to 0.2 equivalent, preferably 0.01 to 0.1 equivalent, relative to compound (XV). The transition metal catalyst can be used even when the amount of the transition metal catalyst is outside this range, but if the amount is less than this range, the reaction will be slow, and even if it is used in a large amount, an effect commensurate with it will not be obtained and the cost will increase.

  The step (va) is preferably performed in the presence of an acid in order to accelerate the reaction. A conventionally well-known thing can be used as said base without a restriction | limiting especially, For example, N, N- dimethyl barbituric acid (NDMBA), formic acid, an acetic acid etc. are mentioned, NDMBA is preferable. The amount of the acid to be used is generally 0.005-0.5 equivalent, preferably 0.02-0.2 equivalent, relative to compound (XV). The reaction can be carried out even if the amount of acid used is outside this range, but if the amount is less than this range, the reaction will be slow, and even if it is used in a large amount, an effect commensurate with it will not be obtained and the cost will increase.

  The solvent used in the step (v-a) may be any solvent as long as it does not inhibit the reaction. Examples thereof include dichloromethane, DMSO, THF, toluene and the like, and dichloromethane is preferable. The usage-amount of a solvent is the range of 2-30L with respect to 1 kg of compounds (XV).

  The reaction temperature in the step (va) is usually from 0 ° C to 80 ° C, but preferably from 10 ° C to 50 ° C. The reaction time is usually 2 to 24 hours, although it depends on the reagents used and the reaction temperature.

2-6. Process (vi-a)
Step (vi-a) is a step in which compound (XVI) is hydrolyzed to obtain compound (Ia), and can be performed, for example, by treating compound (XVI) with a base in a solvent. The order of addition of each reagent is not particularly limited, and may be added sequentially or simultaneously.

  As the base used in the step (vi-a), a conventionally known base can be used without particular limitation, and examples thereof include sodium hydroxide, potassium hydroxide, lithium hydroxide and the like. Potassium is preferred. The base may be added to the reaction system as an aqueous solution, and water in that case becomes a part of the solvent described later. The amount of the base to be used is generally 0.5 to 5 equivalents, preferably 1 to 3 equivalents, relative to compound (XVI). The reaction can be carried out even when the amount of the base used is outside this range, but if it is less than this range, the reaction is difficult to complete, and even if it is used in a large amount, an effect commensurate with it cannot be obtained and the cost increases.

  The solvent used in the step (vi-a) may be any solvent as long as it does not inhibit the reaction, and examples thereof include alcohols such as ethanol, methanol and isopropyl alcohol, THF, water and the like alone or in a mixed solvent such as methanol, THF and A mixed solvent of water is preferred. The usage-amount of a solvent is the range of 3-30L with respect to 1 kg of compounds (XIV).

  The reaction temperature in the step (vi-a) is usually 20 ° C to 130 ° C, preferably 40 ° C to 100 ° C. The reaction time is usually 0.5 hours to 10 hours, although it depends on the reagents used and the reaction temperature.

2-7. Step (i-b)
In step (ib), both OTf of compound (IX) are substituted with a group represented by —CO ₂ R ⁴ ′ (wherein R ⁴ ′ has the same meaning as described above), to thereby convert compound (XVII). For example, it can be carried out by reacting a mixture of compound (IX), alcohol (XII), transition metal catalyst and base in a solvent in a carbon monoxide atmosphere.
Step (i-b) can be performed under the same conditions as in step (ii-a) above, so description thereof will be omitted.

2-8. Process (ii-b)
Step (ii-b) is a step of halogenating two methyl groups of compound (XVII) to obtain compound (XVIII). For example, compound (XVII), a radical initiator and a halogenating agent are combined in a solvent. This can be done by mixing.
Step (ii-b) can be performed under the same conditions as in step (iii-a) above, and thus the description thereof is omitted.

2-9. Step (iii-b)
Step (iii-b) is a step of cyclizing compound (XVIII) with allylamine to obtain compound (XIX), and can be performed, for example, by mixing compound (XVIII) and allylamine in a solvent.
Step (iii-b) can be performed under the same conditions as in the above step (iv-a), and thus the description thereof is omitted.

2-10. Process (iv-b)
Step (iv-b) is a step of deprotecting the allyl group of compound (XIX). For example, compound (XIX) and the transition metal catalyst are mixed in a solvent, preferably in the presence of an acid such as NDMBA. Can be performed.
Step (iv-b) can be performed under the same conditions as in step (v-a) above, and thus description thereof is omitted.

2-10. Process (v-b)
Step (v-b) is a step of hydrolyzing both or one ester of compound (XX) to obtain compound (Ib), for example, by treating compound (XX) with a base in a solvent. Can be done.
In the step (vb), in an embodiment where R ⁴ of the obtained compound (Ib) is a hydrogen atom (hereinafter also referred to as compound (Ib ′)), both esters of compound (XX) are hydrolyzed. In that case, the same conditions as in the above step (vi-a) except that the amount of the base used is 0.8 to 2 equivalents, preferably 1 to 1.5 equivalents, relative to compound (XX). Can be done.
On the other hand, R ^{4 of} the resulting compound (Ib) is a lower alkyl group that may have a substituent, a cycloalkyl group that may have a substituent, or an aryl group that may have a substituent. For some embodiments (hereinafter also referred to as compound (Ib ″)), one ester of compound (XX) may be hydrolyzed, and in that case, the amount of base used may be 0.8 with respect to compound (XX). The reaction can be carried out under the same conditions as in the above step (vi-a) except that the amount is -1.3 equivalents, preferably 0.9-1.2 equivalents.
Furthermore, compound (Ib ″) can also be obtained by partially esterifying compound (Ib ′) according to a conventional method.

2-11. Process (i-c)
Step (i-c) is a step in which compound (XXI) is halogenated to obtain compound (XXII), and can be performed, for example, by mixing compound (XXI), a base and a halogenating agent in a solvent. it can. The order of addition of each reagent is not particularly limited and may be added sequentially or simultaneously. To selectively halogenate the 3-position of the naphthalene ring of compound (XXI), after treating compound (XXI) with a base, It is preferable to add a halogenating agent.

The lower alkyl group represented by R ¹¹ of the compound (XXI) is not particularly limited, but is preferably a relatively sterically bulky alkyl group, for example, neopentyl or the like, for increasing optical purity.

  As the base used in the step (ic), for example, tetramethylpiperidinemagnesium salt and the like are preferable. The amount of the base to be used is generally 2 to 6 equivalents, preferably 3 to 4 equivalents, relative to compound (XXI). The reaction can be carried out even when the amount of the base used is outside this range, but if the amount is less than this range, the reaction rate will deteriorate, and if it is used more than this range, the reaction will not be adversely affected, but there will also be a positive effect such as improved yield. Since it does not reach, cost increases.

The halogenating agent used in the step (ic) is not particularly limited, and examples thereof include bromine, chlorine, iodine, chlorofluorocarbon (for example, BrCF ₂ CF ₂ Br and the like), and bromine is preferable. The amount of the halogenating agent to be used is generally 4 to 12 equivalents, preferably 6 to 8 equivalents, relative to compound (XXI). Although the amount of the halogenating agent can be used outside this range, if the amount is less than this range, the reaction rate deteriorates, and if it is used more than this range, the reaction is not adversely affected, but the yield is improved. The cost is high because it has no effect.

  The solvent used in the step (i-c) may be any solvent that does not inhibit the reaction. For example, 1,4-dioxane, tetrahydrofuran (THF), 1,2-dimethoxyethane, diglyme, methyl tert-butyl ether, toluene, Examples thereof include single or mixed solvents such as xylene, and THF is preferable. The amount of the solvent to be used is generally in the range of 6 to 10 L with respect to 1 kg of compound (XXI).

  The reaction temperature in the step (ic) is usually from -100 ° C to 60 ° C, but preferably from -78 ° C to 40 ° C. The reaction time is usually 1 hour to 12 hours, although it depends on the reagent used and the reaction temperature.

2-11. Process (ii-c)
Step (ii-c) is a step of obtaining compound (XXIII) by reducing compound (XXII), and can be performed, for example, by reacting compound (XXII) with a reducing agent in a solvent. The order of adding each reagent is not particularly limited, and may be added sequentially or simultaneously.

  The reducing agent used in step (ii-c) is not particularly limited as long as it can reduce an ester group to an alcohol, and examples thereof include lithium aluminum hydride and diisobutylaluminum hydride. Aluminum lithium or diisobutylaluminum hydride is preferred. The usage-amount of the said reducing agent is 8-16 equivalent normally as a hydrogen equivalent with respect to compound (XXII), Preferably it is 8-12 equivalent. Although the amount of the reducing agent can be used outside this range, if the amount is less than this range, the reaction rate is deteriorated.

  The solvent used in the step (ii-c) may be any solvent that does not inhibit the reaction. For example, 1,4-dioxane, tetrahydrofuran (THF), 1,2-dimethoxyethane, diglyme, methyl tert-butyl ether, toluene, Examples thereof include single or mixed solvents such as xylene, and THF is preferable. The usage-amount of a solvent is the range of 20-100L normally with respect to 1 kg of compounds (XXII).

  The reaction temperature in step (ii-c) is usually −20 ° C. to 80 ° C., but preferably 0 ° C. to 40 ° C. The reaction time is usually 2 to 6 hours, although it depends on the reagents used and the reaction temperature.

2-12. Step (iii-c)
Step (iii-c) is a step of halogenating compound (XXIII) to obtain compound (XXIV), and can be performed, for example, by mixing compound (XXIII) and a halogenating agent in a solvent. The order of adding each reagent is not particularly limited, and may be added sequentially or simultaneously.

  The halogenating agent used in the step (iii-c) is not particularly limited as long as it can substitute a hydroxyl group with a halogen atom, and examples thereof include boron tribromide. The amount of the halogenating agent to be used is generally 2-50 equivalents, preferably 2-30 equivalents, relative to compound (XXIII). Although the amount of the halogenating agent can be used outside this range, if the amount is less than this range, the reaction rate deteriorates, and even if it is used in a large amount, an effect commensurate with it cannot be obtained and the cost increases.

  The solvent used in step (iii-c) may be any solvent that does not inhibit the reaction. For example, methylene chloride, chloroform, 1,4-dioxane, tetrahydrofuran (THF), 1,2-dimethoxyethane, diglyme, methyl tert -Single or mixed solvents, such as butyl ether, toluene, xylene, etc. are mentioned, A methylene chloride is preferable. The amount of the solvent to be used is generally in the range of 30 to 90 L with respect to 1 kg of compound (XXIII).

  The reaction temperature in step (iii-c) is usually −20 ° C. to 40 ° C., preferably 0 ° C. to 10 ° C. The reaction time is usually 1 hour to 6 hours, although it depends on the reagents used and the reaction temperature.

2-13. Process (iv-c)
Step (iv-c) is a step of cyclizing compound (XXIV) with allylamine to obtain compound (XXV). For example, step (iv-c) can be performed by mixing compound (XXIV) and allylamine in a solvent.
Step (iv-c) can be performed under the same conditions as in the above step (iv-a), and thus the description thereof is omitted.

2-14. Process (v-c)
In the step (v-c), the halogen atom represented by X ² of the compound (XXV) is substituted with a group represented by —CO ₂ R ⁴ ′ (R ⁴ ′ has the same meaning as described above). This is a step of obtaining compound (XXVI), and can be carried out, for example, by reacting a mixture of compound (XXV), alcohol (XII), transition metal catalyst and base in a carbon monoxide atmosphere in a solvent.
The step (v-c) can be performed under the same conditions as the above step (ii-a), and thus description thereof is omitted.

2-15. Process (vi-c)
Step (vi-c) is a step of deprotecting the allyl group of compound (XXVI). For example, compound (XXVI) and a transition metal catalyst are mixed in a solvent, preferably in the presence of an acid such as NDMBA. Can be performed.
The step (vi-c) can be performed under the same conditions as the above step (va), and thus description thereof is omitted.

2-16. Process (vii-c)
Step (iv-b) is a step of hydrolyzing compound (XXVII) to obtain compound (Ic), and can be performed, for example, by treating compound (XXVII) with a base in a solvent.
Step (vii-c) can be performed under the same conditions as in the above step (vi-a), and thus the description thereof is omitted.

3. Asymmetric Catalyst When the compound (I) of the present invention is optically active (hereinafter referred to as optically active compound (I)), it can be used as a catalyst for an asymmetric reaction, that is, an asymmetric catalyst.

  Since the optically active compound (I) is non-metallic, it exhibits a stable catalytic activity unless it is decomposed, and it is also possible to carry out asymmetric reactions continuously by adding a reaction substrate. In addition, since it is an amino acid derivative, it can be easily separated and recovered from the reaction substrate and product by separation operation under acidic or basic conditions, etc., and can be reused any number of times, which is economically advantageous. is there.

  The asymmetric reaction catalyzed by the optically active compound (I) is not particularly limited, and examples thereof include an asymmetric aldol reaction, asymmetric Mannich type reaction, asymmetric halogenation reaction, asymmetric Michael reaction, etc. The asymmetric aldol reaction is preferable because of its high versatility in synthetic intermediates such as pharmaceuticals and agricultural chemicals.

  Examples of the asymmetric aldol reaction include an asymmetric direct aldol reaction and an asymmetric O-nitrosoaldol reaction.

4). Asymmetric reaction (production of optically active compound using optically active compound (I) as an asymmetric catalyst)
In the asymmetric reaction catalyzed by the optically active compound (I), the optically active compound can be obtained, for example, by bringing a substrate into contact with the optically active compound (I) in a solvent.
Here, the substrate means a compound which is a raw material for the asymmetric reaction, and an achiral or prochiral compound is preferable, but also includes an optically active compound having an asymmetric center or a racemate. The substrate may be a single compound or a combination of two or more compounds.
Hereinafter, the asymmetric direct aldol reaction and the asymmetric O-nitrosoaldol reaction which are preferred embodiments of the asymmetric reaction will be described, but the asymmetric reaction by the asymmetric catalyst of the present invention is not limited thereto.

4-1. Asymmetric direct aldol reaction In the asymmetric direct aldol reaction of the present invention, for example, compound (II) and compound (III) are used as substrates, and the reaction is carried out in the presence of optically active compound (III). This is a method for obtaining (IV).

(In the formula, each symbol is as defined above.)
As a specific operation, for example, optically active compound (I), compound (II) and compound (III) can be mixed in a solvent. The order of addition of each reagent is not particularly limited, and may be added sequentially or simultaneously.

The amount of compound (II) to be used is generally 1 to 10 ⁵ equivalents, preferably 10 to ³ × 10 ⁴ equivalents, relative to compound (III). It can be carried out even if the amount of compound (II) used is outside this range. , The cost will be higher.

  The amount of optically active compound (I) to be used is generally 0.001 to 0.5 equivalent, preferably 0.01 to 0.2 equivalent, relative to compound (III). Although the amount of the optically active compound (I) can be used even outside this range, if it is less than this range, the reaction rate tends to be slow. Become.

  The solvent used in the asymmetric direct aldol reaction is not particularly limited as long as it does not inhibit the reaction, and examples thereof include DMF, DMSO, DMAc, N, N′-dimethylimidazolidinone (DMI) and the like alone or in combination. DMF or DMSO is preferred. The usage-amount of a solvent is the range of 3-100L with respect to 1 kg of compound (III).

  The reaction temperature of the asymmetric direct aldol reaction is usually 0 ° C to 60 ° C, but preferably 10 ° C to 50 ° C. The reaction time is usually 1 hour to 24 hours, although it depends on the reagent used and the reaction temperature.

  The resulting compound (IV) can be isolated and purified by a conventional method. For example, it can be purified by silica gel column chromatography after extraction, drying and concentration operations, but is not limited thereto.

4-2. Asymmetric O-nitrosoaldol reaction In the asymmetric O-nitrosoaldol reaction of the present invention, for example, compound (V) and nitroso compound (VI) are used as a substrate and reacted in the presence of optically active compound (I). This is a method for obtaining an optically active compound (VII).
Since compound (VII) is unstable, it is usually isolated as compound (VIII) by reduction without isolation and purification.

  A specific operation can be performed, for example, by mixing the optically active compound (I), the compound (V) and the compound (VI) in a solvent, and adding a reducing agent after completion of the reaction.

  The amount of compound (V) to be used is generally 1-10 equivalents, preferably 1.5-5 equivalents, relative to nitroso compound (VI). The compound (V) can be used even when the amount used is outside this range, but if the amount is less than this range, the reaction tends to be slow and the amount of by-products tends to increase. Cost increases.

  The usage-amount of optically active compound (I) is 0.001-0.5 equivalent normally with respect to nitroso compound (VI). Although the amount of the optically active compound (I) can be used even outside this range, if it is less than this range, the reaction rate tends to be slow. Become.

  The solvent used in the asymmetric O-nitrosoaldol reaction is not particularly limited as long as it does not inhibit the reaction. Examples thereof include mesitylene, toluene, xylene and the like alone, and mesitylene or toluene is preferable. The usage-amount of a solvent is the range of 5-200L with respect to 1 kg of nitroso compounds (VI).

  The reaction temperature of the asymmetric O-nitrosoaldol reaction is usually -50 ° C to 50 ° C, preferably -30 ° C to 30 ° C. The reaction time is usually 0.5 hours to 10 hours, although it depends on the reagents used and the reaction temperature.

After completion of the reaction, compound (VIII) can be derived by adding a reducing agent to the mixture.
As the reducing agent, conventionally known reducing agents can be used without limitation, and examples thereof include sodium borohydride, lithium borohydride, lithium aluminum hydride and the like, and sodium borohydride is preferable. The usage-amount of the said reducing agent is 1-20 equivalent normally with respect to nitroso compound (VI), Preferably it is 2-10 equivalent. Although the amount of the reducing agent can be used outside this range, if the amount is less than this range, the reaction may not be completed, and even if it is used in a large amount, an effect commensurate with it cannot be obtained and the cost increases.

When sodium borohydride or the like is used as the reducing agent, alcohols (for example, methanol, ethanol, etc.) or water is added as a proton source. The addition amount of the alcohol is usually 1 to 10 ⁵ equivalents relative to the reducing agent, preferably 10 to 10 ⁴ equivalents.

  The reaction temperature after adding the reducing agent is usually -20 ° C to 80 ° C, but preferably 0 ° C to 50 ° C. The reaction time is usually 5 minutes to 6 hours, although it depends on the reagent used and the reaction temperature.

  The resulting compound (VIII) can be isolated and purified by a conventional method. For example, it can be purified by silica gel column chromatography after extraction, drying and concentration operations, but is not limited thereto.

  In the post-treatment of the asymmetric reaction of the present invention, the optically active compound (I) can be recovered from the reaction mixture by performing a liquid separation operation under acidic or basic conditions. For example, when the aqueous layer is made basic with sodium bicarbonate or the like in the extraction operation, the optically active compound (I) moves to the aqueous layer and can be easily separated from the substrate and the product. After neutralizing or acidifying the aqueous layer with hydrochloric acid or the like, the optically active compound (I) can be recovered by filtration or extraction.

  Hereinafter, the present invention will be described more specifically with reference to examples. The present invention is not limited by these.

Example 1: (S) -2,2'-dimethyl-1,1'-binaphthyl-3,3'-dicarboxylic acid dimethyl ester (compound 2)

(S) -3,3′-bis (trifluoromethylsulfonyloxy) -2,2′-dimethyl-1,1′-binaphthyl (Compound 1) (231 mg, 0.40 mmol), palladium acetate (4.5 mg, 0.02 mmol), 1,3-bis (diphenylphosphino) propane (8.2 mg, 0.02 mmol) and N-ethyldiisopropylamine (307 μL, 1.76 mmol) in DMSO (10 mL) and methanol (5 mL) And heated at 80 ° C. for 12 hours in an autoclave under a carbon monoxide atmosphere of 10 atm. Then, water was added and extracted three times with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated by an evaporator. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 10) to give the title compound (149 mg, 0.37 mmol) in a yield of 93%. Got in.
¹ H-NMR (400 MHz, CDCl ₃ , Me ₄ Si): δ 2.21 (s, 6H), 4.00 (s, 6H), 6.95 (d, J = 8.4 Hz, 2H), 7 .28 (app t, J = 7.2 Hz, 2H), 7.45 (app t, J = 7.0 Hz, 2H), 7.96 (d, J = 8.0 Hz, 2H), 8.54 ( s, 2H).

Example 2: (S) -2,2'-bis (bromomethyl) -1,1'-binaphthyl-3,3'-dicarboxylic acid dimethyl ester (compound 3)

(S) -2,2′-dimethyl-1,1′-binaphthyl-3,3′-dicarboxylic acid dimethyl ester (compound 2) (149 mg, 0.37 mmol), NBS (146 mg, 0.82 mmol) and AIBN ( 6 mg, 0.037 mmol) was dissolved in 3 mL of benzene, deaerated and replaced with an argon atmosphere, and then refluxed for 4 hours. Water was added to the resulting reaction solution, followed by extraction three times with ethyl acetate, and the organic layer was washed with saturated brine and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated by an evaporator. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 10) to give the title compound (187 mg, 0.33 mmol) in a yield of 90%. Got in.
¹ H-NMR (400 MHz, CDCl ₃ , Me ₄ Si): δ 4.00 (s, 6H), 4.66 (d, J = 10 Hz, 2H), 4.78 (d, J = 10 Hz, 2H) 7.01 (d, J = 8.8 Hz, 2H), 7.36 (app t, J = 7.4 Hz, 2H), 7.54 (app t, J = 7.4 Hz, 2H), 8. 01 (d, J = 8.0 Hz, 2H), 8.68 (s, 2H).

Example 3: (S) -4-allyl-4,5-dihydro-3H-4-aza-cyclohepta [2,1-a: 3,4-a ′] dinaphthalene-2,6-dicarboxylic acid dimethyl ester (Compound 4)

(S) -2,2′-bis (bromomethyl) -1,1′-binaphthyl-3,3′-dicarboxylic acid dimethyl ester (compound 3) (187 mg, 0.33 mmol) and allylamine (76 μL, 1.0 mmol) Was stirred in 1.5 mL of acetonitrile at 50 ° C. for 5 hours. Water was added to the resulting reaction solution, followed by extraction three times with ethyl acetate, and the organic layer was washed with saturated brine and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated by an evaporator. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 3) to give the title compound (138 mg, 0.31 mmol) in a yield of 91%. Got in.
¹ H-NMR (400 MHz, CDCl ₃ , Me ₄ Si): δ 2.91-2.98 (m, 3H), 3.31 (dd, J = 13, 6.0 Hz, 1H), 4.00 ( s, 6H), 4.79 (d, J = 13 Hz, 2H), 5.10-5.14 (m, 2H), 5.92-6.01 (m, 1H), 7.22-7. 34 (m, 4H), 7.50 (app t, J = 7.4 Hz, 2H), 8.01 (d, J = 8.0 Hz, 2H), 8.60 (s, 2H).

Example 4: (S) -4,5-dihydro-3H-4-aza-cyclohepta [2,1-a: 3,4-a '] dinaphthalene-2,6-dicarboxylic acid dimethyl ester (compound 5)

(S) -4-Allyl-4,5-dihydro-3H-4-aza-cyclohepta [2,1-a: 3,4-a ′] dinaphthalene-2,6-dicarboxylic acid dimethyl ester (Compound 4) (138 mg, 0.31 mmol), NDMBA (143 mg, 0.92 mmol), palladium acetate (1.4 mg, 0.0062 mmol) and triphenylphosphine (6.6 mg, 0.025 mmol) were dissolved in 2 mL of dichloromethane and dissolved in argon. After replacing the atmosphere, the mixture was stirred at 35 ° C. for 12 hours. The solvent was removed from the reaction solution by an evaporator, and the obtained solid was dissolved again in benzene. Next, an aqueous sodium hydrogen carbonate solution was added, followed by extraction three times with ethyl acetate, and the organic layer was washed with saturated brine and dried over sodium sulfate. After sodium sulfate was removed by filtration and the filtrate was concentrated by an evaporator, the residue was purified by silica gel column chromatography (methanol: dichloromethane = 1: 50) to give the title compound (111 mg, 0.27 mmol) in 89% yield. Obtained.
¹ H-NMR (400 MHz, CDCl ₃ , Me ₄ Si): δ 3.21 (d, J = 12 Hz, 2H), 4.02 (s, 6H), 4.78 (d, J = 12 Hz, 2H) 7.24-7.35 (m, 4H), 7.50 (app t, J = 7.4 Hz, 2H), 8.01 (d, J = 8.4 Hz, 2H), 8.59 (s) , 2H).

Example 5: (S) -4,5-dihydro-3H-4-aza-cyclohepta [2,1-a: 3,4-a '] dinaphthalene-2,6-dicarboxylic acid (Compound 6)

(S) -4,5-dihydro-3H-4-aza-cyclohepta [2,1-a: 3,4-a ′] dinaphthalene-2,6-dicarboxylic acid dimethyl ester (compound 5) (111 mg, 0 .27 mmol) was dissolved in methanol (1 mL) and THF (0.6 mL), aqueous sodium hydroxide (1N, 1 mL) was added, and the mixture was refluxed for 1 hr. Dichloromethane (1 mL) was added to the obtained reaction solution, and hydrochloric acid (1N) was added until the solution became acidic. The precipitated solid was filtered through a Kiriyama funnel and washed with hexane to obtain the title compound (64 mg, 0.17 mmol) in a yield of 62%.
¹ H-NMR (400 MHz, CD ₃ OD, Me ₄ Si): δ 3.52 (d, J = 12.8 Hz, 2H), 5.40 (d, J = 13.2 Hz, 2H), 7.24 (D, J = 9.2 Hz, 2H), 7.39 (app t, J = 8.4 Hz, 2H), 7.62 (app t, J = 7.2 Hz, 2H), 8.14 (d, J = 8.0 Hz, 2H), 8.69 (s, 2H).

Example 6: (S) -2,2'-dimethyl-3-phenyl-3'-trifluoromethanesulfonyloxy-1,1'-binaphthyl (compound 7)

  (S) -3,3′-bis (trifluoromethylsulfonyloxy) -2,2′-dimethyl-1,1′-binaphthyl (compound 1) (3.8 g, 6.6 mmol), phenylboronic acid (805 mg) , 6.6 mmol), potassium phosphate n-hydrate (4.19 g, 19.8 mmol), palladium acetate (74 mg, 0.33 mmol) and triphenylphosphine (346 mg, 1.32 mmol) in 1,4-dioxane ( 65 mL), and after replacing with an argon atmosphere, the mixture was stirred at 80 ° C. for 12 hours. Aqueous ammonium chloride solution was added to the reaction solution, and the mixture was filtered through celite and extracted three times with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated by an evaporator. The residue was purified by silica gel column chromatography (dichloromethane: hexane = 1: 10) to give the title compound and the dicoupled product (S) -2, A mixture of 2′-dimethyl-3,3′-diphenyl-1,1′-binaphthyl (2.58 g) was obtained.

Example 7: (S) -2,2'-Dimethyl-3'-phenyl-1,1'-binaphthyl-3-carboxylic acid methyl ester (Compound 8)

  (S) -2,2′-dimethyl-3-phenyl-3′-trifluoromethanesulfonyloxy-1,1′-binaphthyl (compound 7) and a dicoupled mixture (2.58 g), palladium acetate (336 mg) , 1.5 mmol), 1,3-bis (diphenylphosphino) propane (619 mg, 1.5 mmol) and N-ethyldiisopropylamine (5.2 mL, 30 mmol) were dissolved in DMSO (20 mL) and methanol (20 mL). The mixture was heated in an autoclave at 80 ° C. for 36 hours under a carbon monoxide atmosphere of 10 atm. Then, water was added and extracted three times with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated by an evaporator. The residue was purified by silica gel column chromatography (ether: hexane = 1: 30) to give the title compound (927 mg, 2.2 mmol) in a yield of 33% ( 2 steps).

Example 8: (S) -2,2'-bis (bromomethyl) -3'-phenyl-1,1'-binaphthyl-3-carboxylic acid methyl ester (Compound 9)

  (S) -2,2′-dimethyl-3′-phenyl-1,1′-binaphthyl-3-carboxylic acid methyl ester (compound 8) (927 mg, 2.2 mmol), NBS (872 mg, 4.9 mmol) and AIBN (36 mg, 0.22 mmol) was dissolved in 12 mL of benzene, deaerated and replaced with an argon atmosphere, and then refluxed for 4 hours. Water was added to the resulting reaction solution, followed by extraction three times with ethyl acetate, and the organic layer was washed with saturated brine and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated by an evaporator. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 5) to give the title compound (1.26 g, 2.2 mmol) in yield. Obtained at> 99%.

Example 9: (S) -4-allyl-4,5-dihydro-6-phenyl-3H-4-aza-cyclohepta [2,1-a: 3,4-a ′] dinaphthalene-2-carboxylic acid Methyl ester (compound 10)

  (S) -2,2′-bis (bromomethyl) -3′-phenyl-1,1′-binaphthyl-3-carboxylic acid methyl ester (compound 9) (1.26 g, 2.2 mmol) and allylamine (495 μL, (6.6 mmol) was stirred in 10 mL of acetonitrile at 50 ° C. for 12 hours. Water was added to the resulting reaction solution, followed by extraction three times with ethyl acetate, and the organic layer was washed with saturated brine and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated by an evaporator. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 10) to give the title compound (888 mg, 1.9 mmol) in a yield of 86%. Got in.

Example 10: (S) -4,5-dihydro-6-phenyl-3H-4-aza-cyclohepta [2,1-a: 3,4-a ′] dinaphthalene-2-carboxylic acid methyl ester (compound 11)

  (S) -4-allyl-4,5-dihydro-6-phenyl-3H-4-aza-cyclohepta [2,1-a: 3,4-a ′] dinaphthalene-2-carboxylic acid methyl ester (compound 10) (888 mg, 1.9 mmol), NDMBA (890 mg, 5.7 mmol), palladium acetate (21 mg, 0.095 mmol), and triphenylphosphine (100 mg, 0.38 mmol) were dissolved in 10 mL of dichloromethane under an argon atmosphere. The mixture was stirred at 35 ° C. for 2 hours. The solvent was removed from the reaction solution by an evaporator, and the obtained solid was dissolved again in benzene. Next, an aqueous sodium hydrogen carbonate solution was added, followed by extraction three times with ethyl acetate, and the organic layer was washed with saturated brine and dried over sodium sulfate. After sodium sulfate was removed by filtration and the filtrate was concentrated by an evaporator, the residue was purified by silica gel column chromatography (methanol: dichloromethane = 1: 50) to obtain the title compound (816 mg, 1.9 mmol) in a yield> 99%. Got in.

Example 11: (S) -4,5-dihydro-6-phenyl-3H-4-aza-cyclohepta [2,1-a: 3,4-a '] dinaphthalene-2-carboxylic acid (compound 12)

(S) -4,5-dihydro-6-phenyl-3H-4-aza-cyclohepta [2,1-a: 3,4-a ′] dinaphthalene-2-carboxylic acid methyl ester (compound 11) (215 mg , 0.5 mmol) was dissolved in methanol (1.5 mL) and THF (1.0 mL), an aqueous sodium hydroxide solution (1N, 1 mL) was added, and the mixture was refluxed for 1 hour. Dichloromethane (1 mL) was added to the resulting reaction solution, hydrochloric acid (1N) was added until acidic, and the mixture was extracted 3 times with dichloromethane. Thereafter, the organic layer was washed with saturated brine and dried over sodium sulfate. After sodium sulfate was removed by filtration and the filtrate was concentrated by an evaporator, the residue was purified by silica gel column chromatography (methanol: dichloromethane = 1: 15) to give the title compound (207 mg, 0.5 mmol) in a yield> 99%. Got in.
¹ H-NMR (400 MHz, CD ₃ OD, Me ₄ Si): δ 3.54 (d, J = 12.8 Hz, 1H), 3.64 (d, J = 13.2 Hz, 1H), 4.44 (D, J = 13.2 Hz, 1H), 5.14 (d, J = 13.2 Hz, 1H), 7.24-7.61 (m, 11H), 8.06-8.08 (m, 3H), 8.42 (s, 1H).

Example 12: (S) -2,2'-dimethyl-3- (3,4,5-trifluorophenyl) -3'-trifluoromethanesulfonyloxy-1,1'-binaphthyl (Compound 13)

  (S) -3,3′-bis (trifluoromethylsulfonyloxy) -2,2′-dimethyl-1,1′-binaphthyl (compound 1) (2.16 g, 3.7 mmol), 3,4,5 -Trifluorophenylboronic acid (651 mg, 3.7 mmol), potassium phosphate n-hydrate (2.3 g, 11.1 mmol), palladium acetate (42 mg, 0.185 mmol) and triphenylphosphine (194 mg, 0.74 mmol) ) Was dissolved in THF (35 mL) and replaced with an argon atmosphere, followed by stirring at 80 ° C. for 12 hours. Aqueous ammonium chloride solution was added to the reaction solution, and the mixture was filtered through celite and extracted three times with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated by an evaporator. The residue was purified by silica gel column chromatography (dichloromethane: hexane = 1: 10) to give the title compound and dicoupled product (S) -3, A mixture (1.76 g) of 3′-bis (3,4,5-trifluorophenyl) -2,2′-dimethyl-1,1′-binaphthyl was obtained.

Example 13: (S) -2,2'-dimethyl-3 '-(3,4,5-trifluorophenyl) -1,1'-binaphthyl-3-carboxylic acid methyl ester (compound 14)

  Mixture of (S) -2,2′-dimethyl-3- (3,4,5-trifluorophenyl) -3′-trifluoromethanesulfonyloxy-1,1′-binaphthyl (compound 13) and dicoupled product (1.76 g), palladium acetate (162 mg, 0.72 mmol), 1,3-bis (diphenylphosphino) propane (297 mg, 0.72 mmol) and N-ethyldiisopropylamine (2.5 mL, 14.4 mmol), Was dissolved in DMSO (10 mL) and methanol (10 mL), and heated in an autoclave at 80 ° C. for 36 hours under a carbon monoxide atmosphere of 10 atm. Then, water was added and extracted three times with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated by an evaporator. The residue was purified by silica gel column chromatography (ether: hexane = 1: 30) to give the title compound (723 mg, 1.5 mmol) in a yield of 42% ( 2 steps).

Example 14: (S) -2,2'-bis (bromomethyl) -3 '-(3,4,5-trifluorophenyl) -1,1'-binaphthyl-3-carboxylic acid methyl ester (Compound 15)

  (S) -2,2'-dimethyl-3 '-(3,4,5-trifluorophenyl) -1,1'-binaphthyl-3-carboxylic acid methyl ester (compound 14) (723 mg, 1.5 mmol) , NBS (587 mg, 3.3 mmol) and AIBN (25 mg, 0.15 mmol) were dissolved in 8 mL of benzene, deaerated and replaced with an argon atmosphere, and then refluxed for 4 hours. Water was added to the resulting reaction solution, followed by extraction three times with ethyl acetate, and the organic layer was washed with saturated brine and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated by an evaporator. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 10) to obtain the title compound (936 mg, 1.5 mmol) in a yield> 99. %.

Example 15: (S) -4-allyl-4,5-dihydro-6- (3,4,5-trifluorophenyl) -3H-4-aza-cyclohepta [2,1-a: 3,4 a ′] Dinaphthalene-2-carboxylic acid methyl ester (Compound 16)

  (S) -2,2′-bis (bromomethyl) -3 ′-(3,4,5-trifluorophenyl) -1,1′-binaphthyl-3-carboxylic acid methyl ester (Compound 15) (936 mg, 1 0.5 mmol) and allylamine (338 μL, 4.5 mmol) were stirred in 7 mL of acetonitrile at 50 ° C. for 12 hours. Water was added to the resulting reaction solution, followed by extraction three times with ethyl acetate, and the organic layer was washed with saturated brine and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated by an evaporator. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 10) to obtain the title compound (724 mg, 1.4 mmol) in a yield of 92%. Got in.

Example 16: (S) -4,5-dihydro-6- (3,4,5-trifluorophenyl) -3H-4-aza-cyclohepta [2,1-a: 3,4-a ′] di Naphthalene-2-carboxylic acid methyl ester (Compound 17)

  (S) -4-allyl-4,5-dihydro-6- (3,4,5-trifluorophenyl) -3H-4-aza-cyclohepta [2,1-a: 3,4-a ′] di Naphthalene-2-carboxylic acid methyl ester (Compound 16) (724 mg, 1.4 mmol), NDMBA (656 mg, 4.2 mmol), palladium acetate (16 mg, 0.07 mmol) and triphenylphosphine (73 mg, 0.28 mmol) After dissolving in 8 mL of dichloromethane and replacing with an argon atmosphere, the mixture was stirred at 35 ° C. for 2 hours. The solvent was removed from the reaction solution by an evaporator, and the obtained solid was dissolved again in benzene. Next, an aqueous sodium hydrogen carbonate solution was added, followed by extraction three times with ethyl acetate, and the organic layer was washed with saturated brine and dried over sodium sulfate. After sodium sulfate was removed by filtration and the filtrate was concentrated by an evaporator, the residue was purified by silica gel column chromatography (methanol: dichloromethane = 1: 50) to obtain the title compound (675 mg, 1.4 mmol) in a yield> 99%. Got in.

Example 17: (S) -4,5-dihydro-6- (3,4,5-trifluorophenyl) -3H-4-aza-cyclohepta [2,1-a: 3,4-a ′] di Naphthalene-2-carboxylic acid (Compound 18)

(S) -4,5-dihydro-6- (3,4,5-trifluorophenyl) -3H-4-aza-cyclohepta [2,1-a: 3,4-a ′] dinaphthalene-2- Carboxylic acid methyl ester (Compound 17) (241 mg, 0.5 mmol) was dissolved in methanol (1.5 mL) and THF (1.0 mL), aqueous sodium hydroxide (1N, 1 mL) was added, and the mixture was refluxed for 1 hr. Dichloromethane (1 mL) was added to the resulting reaction solution, hydrochloric acid (1N) was added until acidic, and the mixture was extracted 3 times with dichloromethane. Thereafter, the organic layer was washed with saturated brine and dried over sodium sulfate. After sodium sulfate was removed by filtration and the filtrate was concentrated by an evaporator, the residue was purified by silica gel column chromatography (methanol: dichloromethane = 1: 15) to obtain the title compound (234 mg, 0.5 mmol) in a yield> 99%. I got it.
¹ H-NMR (400 MHz, CD ₃ OD, Me ₄ Si): δ 3.51 d, J = 13.2 Hz, 1H), 3.68 (d, J = 13.6 Hz, 1H), 4. 38 (d, J = 13.2 Hz, 1H), 5.24 (d, J = 111.2 Hz, 1H), 7.21-7.63 (m, 8H), 8.05-8.09 (m , 3H), 8.43 (s, 1H).

Reference Example 1: (S) -1,1'-naphthyl-2,2'-dicarboxylic acid dineopentyl ester (compound 20)

Thionyl chloride (5 mL) was added to (S) -1,1′-naphthyl-2,2′-dicarboxylic acid (Compound 19) (1.71 g, 5.0 mmol), and the mixture was stirred for 2 hours under reflux. After completion of the reaction, excess thionyl chloride was distilled off under reduced pressure, diethyl ether was added to the residue, further concentrated, and the resulting residue was dried under reduced pressure to obtain acid chloride. The obtained acid chloride was dissolved in tetrahydrofuran, neopentanol (1.3 g) and pyridine (1.1 mL) were added, and the mixture was stirred for 3 hours under reflux. 1N hydrochloric acid was added to the reaction mixture after completion | finish of reaction, and ethyl acetate extracted twice. The organic layer was washed with saturated brine and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated by an evaporator. The residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1: 30) to obtain the title compound (2.2 g, 4.6 mmol). Obtained at a rate of 91%.
¹ H-NMR (400 MHz, CDCl ₃ , Me ₄ Si): δ 0.65 (s, 18H), 3.60 (d, J = 10.4 Hz, 2H), 3.64 (d, J = 10. 4 Hz, 2H), 7.06 (d, J = 8.4 Hz, 2H), 7.22 (appt, J = 8.0 Hz, 2H), 7.49 (appt t, J = 7.6 Hz, 2H), 7.92 (d, J = 8.4 Hz, 2H), 7.99 (d, J = 8.4 Hz, 2H), 8.21 (d, J = 8.8 Hz, 2H).

Example 18: (S) -3-Bromo-1,1'-naphthyl-2,2'-dicarboxylic acid dineopentyl ester (Compound 21)

  Tetramethylpiperidinemagnesium salt prepared in accordance with J. Org. Chem. 2003, 68, 4576-4578. In tetrahydrofuran-hexane solution (14.7 mL, 4.0 mmol), (S) -1,1′-naphthyl-2, A solution of 2′-dicarboxylic acid dineopentyl ester (Compound 20) (482 mg, 1 mmol) in tetrahydrofuran (3.8 mL) was added dropwise at 0 ° C. After stirring at room temperature for 3 hours, the mixture was cooled to −78 ° C., and bromine (411 μL, 8.0 mmol) was added dropwise. After stirring at room temperature for 1 hour, the reaction solution was added to cooled 1N hydrochloric acid and extracted with ethyl acetate. The obtained organic layer was washed with saturated aqueous sodium sulfite and saturated brine, and dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated by an evaporator. The residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1: 10) to obtain a mixture of the title compound, unsubstituted compound and dibromide. (548 mg). Since further separation was difficult, it was directly used in the next step without further purification.

Example 19: (S) -3-Bromo-1,1'-naphthyl-2,2'-dimethanol (Compound 22)

A solution obtained by dissolving the mixture obtained in Example 18 in tetrahydrofuran (20 mL) was added dropwise at 0 ° C. to a previously prepared tetrahydrofuran solution of lithium aluminum hydride (114 mg, 3.0 mmol). After completion of the dropwise addition, the reaction was carried out at room temperature for 2 hours, the reaction solution was cooled to 0 ° C., decomposed with careful addition to 1N aqueous hydrochloric acid, and extracted with diethyl ether. The obtained organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated by an evaporator. The residue was purified by silica gel column chromatography (ethyl acetate / hexane = 2: 8) to give the title compound (166 mg, 0.42 mmol) in a yield of 42%. Got in.
¹ H-NMR (400 MHz, CDCl ₃ , Me ₄ Si): δ 3.31 (bs, 1H), 3.60 (bs, 1H), 4.06 (d, J = 11.6 Hz, 1H), 4 .07 (d, J = 11.6 Hz, 1H), 4.38 (d, J = 11.6 Hz, 1H), 4.76 (d, J = 12.4 Hz, 1H), 6.95-6. 99 (m, 2H), 7.22-7.27 (m, 2H), 7.45-7.50 (m, 2H), 7.74 (d, J = 8.8 Hz, 2H), 7. 83 (d, J = 8.4 Hz, 2H), 7.92 (d, J = 8.4 Hz, 2H), 7.99 (d, J = 8.8 Hz, 2H), 8.26 (s, 1H ).

Example 20: (S) -3-Bromo-2,2'-bis (bromomethyl) -1,1'-naphthyl (Compound 23)

(S) -3-Bromo-1,1′-naphthyl-2,2′-dimethanol (Compound 22) (86 mg, 0.22 mmol) and boron tribromide (500 μL, 5.3 mmol) in 5 mL of methylene chloride The mixture was stirred at 0 ° C. for 1 hour. Water was carefully added to the resulting reaction solution, and the mixture was extracted 3 times with methylene chloride. The organic layer was washed with saturated brine and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated by an evaporator. The residue was purified by silica gel column chromatography (hexane) to obtain the title compound (98 mg, 0.19 mmol) in a yield of 86%.
¹ H-NMR (400 MHz, CDCl ₃ , Me ₄ Si): δ 4.18 (d, J = 10.8 Hz, 1H), 4.25 (d, J = 10.0 Hz, 1H), 4.33 ( d, J = 10.8 Hz, 1H), 4.48 (d, J = 10.4 Hz, 1H), 7.03 (appt t, J = 7.2 Hz, 2H), 7.26-7.30 ( m, 2H), 7.48-7.53 (m, 2H), 7.76 (d, J = 8.8 Hz, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7. 92 (d, J = 8.4 Hz, 1H), 8.04 (d, J = 8.4 Hz, 1H), 8.32 (s, 1H).

Example 21: (S) -4-allyl-2-bromo-4,5-dihydro-3H-4-aza-cyclohepta [2,1-a: 3,4-a ′] dinaphthalene (Compound 24)

(S) -3-Bromo-2,2′-bis (bromomethyl) -1,1′-naphthyl (Compound 23) (77 mg, 0.15 mmol) and allylamine (56 μL, 0.74 mmol) in 3 mL of THF And stirred at 50 ° C. for 5 hours. Water was added to the resulting reaction solution, followed by extraction three times with ethyl acetate, and the organic layer was washed with saturated brine and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated by an evaporator. The residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1: 20-2: 8) to give the title compound (54.5 mg, 0.13 mmol). ) Was obtained in 89% yield.
¹ H-NMR (400 MHz, CDCl ₃ , Me ₄ Si): δ 3.03-3.13 (m, 3H), 3.42 (dd, J = 13.6, 6.4 Hz, 1H), 77 (d, J = 12.6 Hz, 1H), 4.35 (d, J = 12.6 Hz, 1H), 5.19 (dd, J = 10.4, 1.6 Hz, 1H), 5.25. (Dd, J = 17.2, 1.6 Hz, 1H), 5.95-6.05 (m, 1H), 7.21-7.27 (m, 2H), 7.35 (dd, J = 8.8, 1.2 Hz, 2H), 7.43-7.48 (m, 2H), 7.54 (d, J = 8.0 Hz, 1H), 7.83 (d, J = 8.4). Hz, 2H), 7.95 (t, J = 8.4 Hz, 1H), 8.26 (s, 1H).

Example 22: (S) -4-allyl-4,5-dihydro-3H-4-aza-cyclohepta [2,1-a: 3,4-a ′] dinaphthalene-2-carboxylic acid methyl ester (compound 25)

(S) -4-allyl-2-bromo-4,5-dihydro-3H-4-aza-cyclohepta [2,1-a: 3,4-a ′] dinaphthalene (compound 24) (238 mg, 0. 57 mmol), palladium acetate (13 mg, 0.057 mmol), 1,3-bis (diphenylphosphino) propane (24 mg, 0.057 mmol) and N-ethyldiisopropylamine (427 μL, 2.5 mmol) in dimethyl sulfoxide (10 mL). ) And methanol (5 mL) and heated in an autoclave at 80 ° C. for 24 hours under a carbon monoxide atmosphere of 10 atm. Then, water was added and extracted three times with methylene chloride. The organic layer was washed with saturated brine and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated by an evaporator. The residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1: 9 to 2: 8) to give the title compound (150 mg, 0.38 mmol). Obtained in 67% yield.
¹ H-NMR (400 MHz, CDCl ₃ , Me ₄ Si): δ 2.98-3.04 (m, 2H), 3.14 (d, J = 12.4 Hz, 1H), 3.23 (dd, J = 13.2, 6.4 Hz, 1H), 3.75 (d, J = 12.4 Hz, 2H), 4.00 (s, 3H), 4.75 (d, J = 13.2 Hz, 2H), 5.16-5.21 (m, 2H), 5.95-6.02 (m, 1H), 7.23-7.37 (m, 4H), 7.39-7.55 ( m, 3H), 7.95-8.01 (m, 3H), 8.57 (s, 1H).

Example 23: (S) -4,5-dihydro-3H-4-aza-cyclohepta [2,1-a: 3,4-a '] dinaphthalene-2-carboxylic acid methyl ester (Compound 26)

(S) -4-Allyl-4,5-dihydro-3H-4-aza-cyclohepta [2,1-a: 3,4-a ′] dinaphthalene-2-carboxylic acid methyl ester (compound 25) (1 0.06 g, 2.7 mmol), NDMBA (1.26 g, 8.1 mmol), palladium acetate (30 mg, 0.135 mmol) and triphenylphosphine (142 mg, 0.50 mmol) were dissolved in 15 mL of dichloromethane, The mixture was stirred at 35 ° C. for 2 hours. The solvent was removed from the reaction solution by an evaporator, and the obtained solid was dissolved again in benzene. Next, an aqueous sodium hydrogen carbonate solution was added, followed by extraction three times with ethyl acetate, and the organic layer was washed with saturated brine and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated by an evaporator. The residue was purified by silica gel column chromatography (methanol / dichloromethane = 1: 50) to yield the title compound (0.95 g, 2.7 mmol)> 99%.
¹ H-NMR (400 MHz, CDCl ₃ , Me ₄ Si): δ 3.25 (d, J = 13.2 Hz, 1H), 3.48 (d, J = 11.6 Hz, 1H), 3.89 ( d, J = 11.2 Hz, 1H), 4.01 (s, 3H), 4.65 (d, J = 12.8 Hz, 1H), 7.31-7.52 (m, 6H), 7. 62 (d, J = 8.4 Hz, 1H), 7.94-8.03 (m, 3H), 8.54 (s, 1H).

Example 24: (S) -4,5-dihydro-3H-4-aza-cyclohepta [2,1-a: 3,4-a '] dinaphthalene-2-carboxylic acid (Compound 27)

(S) -4,5-dihydro-3H-4-aza-cyclohepta [2,1-a: 3,4-a ′] dinaphthalene-2-carboxylic acid methyl ester (compound 26) (177 mg, 0.5 mmol ) Was dissolved in methanol (1.5 mL) and THF (1.0 mL), aqueous sodium hydroxide solution (1N, 1 mL) was added, and the mixture was refluxed for 1 hr. Dichloromethane (1 mL) was added to the obtained reaction solution, hydrochloric acid (1N) was added until acidic, and the mixture was concentrated under reduced pressure to obtain a residue. The obtained residue was extracted with dichloromethane three times, and then the organic layer was washed with saturated brine and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The concentrated residue was adsorbed on a cation exchange resin column (Dowex 50W-X, manufactured by Dow Chemical Co.), and the cation exchange resin column was washed with an appropriate amount of purified water. Then, the target product was eluted with 5% aqueous ammonia. The obtained aqueous ammonia solution was concentrated under reduced pressure to obtain the title compound (153 mg, 0.45 mmol) in a yield of 90%.
¹ H-NMR (400 MHz, CD ₃ OD, Me ₄ Si): δ 3.49 (d, J = 13.2 Hz, 1H), 3.77 (d, J = 12.8 Hz, 1H), 4.36 (D, J = 13.2 Hz, 1H), 5.15 (d, J = 12.8 Hz, 1H), 7.23-7.36 (m, 4H), 7.57 (t, J = 8 0.0 Hz, 2H), 7.74 (d, J = 8.8 Hz, 1H), 8.05-8.09 (m, 2H), 8.16 (d, J = 8.8 Hz, 1H), 8 .42 (s, 1H).

Example 25: (R) -1-hydroxy-1- (4-nitrophenyl) -butan-3-one (asymmetric direct aldol reaction)
(S) -4,5-dihydro-3H-4-aza-cyclohepta [2,1-a: 3,4-a ′] dinaphthalene-2 obtained in Example 5 at room temperature in a 5 mL reaction vessel, 6-dicarboxylic acid (9.6 mg, 0.025 mmol) was added to DMSO (2.5 mL), followed by acetone (500 mL) and p-nitroaldehyde (37.8 mg, 0.25 mmol). Thereafter, argon gas was blown into the reaction vessel to replace with an inert gas atmosphere. After stirring at room temperature for 10 hours, a saturated aqueous ammonium chloride solution was added, and the mixture was extracted three times with ethyl acetate. The obtained ethyl acetate solution was dried over sodium sulfate and concentrated by an evaporator. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 1) to obtain the title compound (39.2 mg). It was. The results (yield, optical purity) are shown in Table 1.
HPLC measurement conditions:
Column: Daicel Chiral Column AS
Mobile phase: n-hexane / isopropanol = 2/1
Flow rate: 1 mL / min.
Detection: 254 nm
Holding time: 9 min. (Major), 12 min. (Minor)

Example 26: (R) -1-hydroxy-1- (4-nitrophenyl) -butan-3-one (asymmetric direct aldol reaction)
(S) -4,5-dihydro-3H-4-aza-cyclohepta [2,1-a: 3,4-a ′] dinaphthalene-2,6-dicarboxylic acid was used in an amount of 19.2 mg; The title compound was obtained in the same manner as in Example 25 except that DMF was used instead of DMSO. The results (yield, optical purity) are shown in Table 1.

Example 27: (R) -1-hydroxy-1- (4-nitrophenyl) -butan-3-one (asymmetric direct aldol reaction)
(S) -4,5-dihydro-3H-4-aza-cyclohepta [2,1-a: 3,4-a ′] obtained in Example 11 instead of dinaphthalene-2,6-dicarboxylic acid Implemented except that (S) -4,5-dihydro-6-phenyl-3H-4-aza-cyclohepta [2,1-a: 3,4-a ′] dinaphthalene-2-carboxylic acid was used. In the same manner as in Example 25, the title compound was obtained. The results (yield, optical purity) are shown in Table 1.

Example 28: (R) -2- (N-phenylaminooxy) -propanol (asymmetric O-nitrosoaldol reaction)
(S) -4,5-dihydro-6- (3,4,5-trifluorophenyl) -3H-4-aza-cyclohepta [2,1-] obtained in Example 17 at room temperature in a 5 mL reaction vessel. a: 3,4-a ′] dinaphthalene-2-carboxylic acid (11.7 mg, 0.025 mmol) was added to mesitylene (2.5 mL), and then the reaction solution was cooled to 0 ° C. and nitrosobenzene (53 .6 mg, 0.5 mmol) was added. After stirring for 3 minutes, propionaldehyde (108 μL, 1.5 mmol) was added to the reaction solution. Thereafter, argon gas was blown into the reaction vessel to replace with an inert gas atmosphere. After stirring at 0 ° C. for 1.5 hours, ethyl alcohol (1 mL) and sodium borohydride (100 mg) were added and stirred for 10 minutes. To the resulting reaction solution was added a saturated aqueous solution of sodium bicarbonate and extracted three times with dichloromethane. The organic layer was dried over sodium sulfate and concentrated by an evaporator, and then the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 5 to 1: 3) to obtain the title compound (55.0 mg). . The results (yield, optical purity) are shown in Table 2.
HPLC measurement conditions:
Column: Daicel Chiral Column AS
Mobile phase: n-hexane / ethanol = 10/1
Flow rate: 1 mL / min.
Detection: 254 nm
Holding time: 18 min. (Major), 21 min. (Minor)

Example 29: (R) -2- (N-phenylaminooxy) -propanol (asymmetric O-nitrosoaldol reaction)
The same procedure as in Example 28 was performed except that the amount of mesitylene used was 5 mL. The results (yield, optical purity) are shown in Table 2.

Example 30: (R) -2- (N-phenylaminooxy) -propanol (asymmetric O-nitrosoaldol reaction)
The same procedure as in Example 29 was performed except that toluene was used instead of mesitylene and the reaction time was 1 hour. The results (yield, optical purity) are shown in Table 2.

Claims (18)

Formula (I):

(In the formula, R ¹ represents a hydrogen atom, an aryl group which may have a substituent, a heteroaryl group which may have a substituent, or a group represented by —CO ₂ R ⁴ (where R 1 is ⁴ represents a hydrogen atom, a lower alkyl group which may have a substituent, a cycloalkyl group which may have a substituent, or an aryl group which may have a substituent. ² and R ³ are the same or different and each represents a hydrogen atom, a halogen atom, a lower alkyl group, or a lower alkoxy group) or a salt thereof. The compound or a salt thereof according to claim ¹ , wherein R ¹ is a hydrogen atom, a phenyl group or a carboxyl group which may have a substituent.   The compound or a salt thereof according to claim 1 or 2, which is optically active.   An asymmetric catalyst comprising the compound according to claim 3 or a salt thereof.   The asymmetric catalyst according to claim 4, which is an asymmetric catalyst for an asymmetric aldol reaction, asymmetric Mannich type reaction, asymmetric halogenation reaction or asymmetric Michael reaction.   The asymmetric catalyst according to claim 5, which is an asymmetric catalyst for an asymmetric aldol reaction.   The asymmetric catalyst according to claim 6, wherein the asymmetric aldol reaction is an asymmetric direct aldol reaction or an asymmetric O-nitrosoaldol reaction. In the presence of the compound according to claim 3 or a salt thereof, the general formula (II):

(Wherein R ⁵ and R ⁶ are the same or different and have a hydrogen atom, a lower alkyl group which may have a substituent, a lower alkenyl group which may have a substituent, or a substituent. A cycloalkyl group which may have a substituent, an aryl group which may have a substituent, an aralkyl group which may have a substituent, a heteroaryl group which may have a substituent or a substituent. Or a heteroarylalkyl group which may be substituted, or R ⁵ and R ⁶ may be connected to form a ring optionally having a substituent together with the carbon atom to which each is bonded. And a compound represented by the general formula (III):

(In the formula, R ⁷ has a lower alkyl group which may have a substituent, a lower alkenyl group which may have a substituent, a cycloalkyl group which may have a substituent, and a substituent. An aryl group that may be substituted, an aralkyl group that may have a substituent, a heteroaryl group that may have a substituent, or a heteroarylalkyl group that may have a substituent. A compound represented by the general formula (IV):

(Wherein * represents an asymmetric carbon, and other symbols have the same meanings as described above). The production method according to claim 8, wherein R ⁵ is a lower alkyl group, R ⁶ is a hydrogen atom, and R ⁷ is an aryl group which may have a substituent. In the presence of a compound according to claim 3 or a salt thereof, the general formula (V):

(Wherein R ⁸ represents a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted lower alkenyl group, an optionally substituted cycloalkyl group, substituted An aryl group which may have a group, an aralkyl group which may have a substituent, a heteroaryl group which may have a substituent or a heteroarylalkyl group which may have a substituent; R ⁹ represents a lower alkyl group which may have a substituent, a lower alkenyl group which may have a substituent, a cycloalkyl group which may have a substituent, or a substituent. An aryl group which may have a substituent, an aralkyl group which may have a substituent, a heteroaryl group which may have a substituent or a heteroarylalkyl group which may have a substituent, or R ⁸ and R ⁹ are connected, And a compound represented by the general formula (VI): together with the carbon atom to which each is bonded, a ring which may have a substituent may be formed.

(Wherein R ¹⁰ represents an aryl group which may have a substituent or a heteroaryl group which may have a substituent), and a compound represented by the following reaction: General formula (VII):

(Wherein * represents an asymmetric carbon, and other symbols have the same meanings as described above). A step of reducing a compound represented by the general formula (VII) obtained by the production method according to claim 10, wherein the general formula (VIII):

(Wherein each symbol has the same meaning as in claim 10). The production method according to claim 10 or 11, wherein R ⁸ is a hydrogen atom, R ⁹ is a lower alkyl group, and R ¹⁰ is an aryl group which may have a substituent. General formula (Ia), characterized in that it comprises the following steps (ia) to (vi-a):

(In the formula, Ra ¹ represents an aryl group which may have a substituent or a heteroaryl group which may have a substituent, and R ² and R ³ may be the same or different and represent a hydrogen atom or a halogen atom. And represents a lower alkyl group or a lower alkoxy group.)
(I-a) General formula (IX):

(Wherein R ² and R ³ are as defined above, and OTf represents a trifluoromethanesulfonyloxy group) in the presence of a transition metal catalyst and a base, the compound represented by the general formula (X): By reacting with a compound represented by Ra ¹ -B (OH) ₂ (X) (wherein Ra ¹ is as defined above), general formula (XI):

(Wherein each symbol is as defined above) to obtain a compound represented by:
(Ii-a) the presence of the obtained formula (XI) transition compound represented by the metal catalyst and a base, carbon monoxide and the general formula ^{(XII): R 4 'OH} (XII) ( wherein, R ⁴ ′ represents an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group or an optionally substituted aryl group.) The reaction is general formula (XIII):

(Wherein each symbol is as defined above) to obtain a compound represented by:
(Iii-a) The compound represented by the general formula (XIII) thus obtained is reacted with a halogenating agent in the presence of a radical initiator to give a general formula (XIV):

(Wherein X ¹ represents a halogen atom, and other symbols are as defined above);
(Iv-a) The compound represented by the general formula (XIV) obtained is reacted with allylamine to give a general formula (XV):

(Wherein each symbol is as defined above) to obtain a compound represented by:
(V-a) The obtained compound represented by the general formula (XV) is deprotected in the presence of a transition metal catalyst to give a general formula (XVI):

(Wherein each symbol is as defined above) to obtain a compound represented by:
(Vi-a) The compound represented by the general formula (XVI) thus obtained is hydrolyzed to obtain the compound represented by the above general formula (Ia). The method according to claim 13, wherein Ra ¹ is a phenyl group which may have a substituent. General formula (Ib), characterized in that it comprises the following steps (ib) to (vb):

(In the formula, R ⁴ represents a hydrogen atom, a lower alkyl group which may have a substituent, a cycloalkyl group which may have a substituent, or an aryl group which may have a substituent; R ² and R ³ are the same or different and each represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group.)
(I-b) General formula (IX):

(Wherein R ² and R ³ are as defined above, and OTf represents a trifluoromethanesulfonyloxy group.) In the presence of a transition metal catalyst and a base, carbon monoxide and a general formula ^{(XII): R 4 'OH} (XII) ( wherein, R ^4' has an optionally substituted lower alkyl group, which may have a substituent cycloalkyl group or a substituted group An aryl group that may be present) is reacted with an alcohol represented by the general formula (XVII):

(Wherein each symbol is as defined above) to obtain a compound represented by:
(Ii-b) The resulting compound represented by the general formula (XVII) is reacted with a halogenating agent in the presence of a radical initiator to give a general formula (XVIII):

(Wherein X ¹ represents a halogen atom, and other symbols are as defined above);
(Iii-b) The compound represented by the general formula (XVIII) obtained is reacted with allylamine to give a general formula (XIX):

(Wherein each symbol is as defined above) to obtain a compound represented by:
(Iv-b) The obtained compound represented by the general formula (XIX) is deprotected in the presence of a transition metal catalyst, and the general formula (XX):

(Wherein each symbol is as defined above) to obtain a compound represented by:
(Vb) The obtained compound represented by the general formula (XX) is hydrolyzed to obtain the compound represented by the general formula (Ib).   The manufacturing method as described in any one of Claims 13-15 using the compound represented by optically active general formula (IX). General formula (Ic), characterized in that it comprises the following steps (i-c) to (vii-c):

(Wherein R ² and R ³ are the same or different and each represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group), or a method for producing a salt thereof;
(I-c) General formula (XXI):

(Wherein R ² and R ³ are as defined above, and R ¹¹ is a lower alkyl group.) In the presence of a base, a compound represented by the general formula ( XXII):

(Wherein R ² , R ³ and R ¹¹ have the same meanings as described above, and X ² represents a halogen atom);
(Ii-c) The obtained compound represented by the general formula (XXII) is reduced to give a general formula (XXIII):

(Wherein each symbol is as defined above) to obtain a compound represented by:
(Iii-c) The obtained compound represented by the general formula (XXIII) is reacted with a halogenating agent to give a general formula (XXIV):

(Wherein R ² , R ³ and X ² are as defined above, and X ³ is the same as or different from X ² and represents a halogen atom).
(Iv-c) The compound represented by the general formula (XXIV) obtained is reacted with allylamine to give a general formula (XXV):

(Wherein each symbol is as defined above) to obtain a compound represented by:
(V-c) presence of the obtained formula (XXV) transition compound represented by the metal catalyst and a base, carbon monoxide and the general formula ^{(XII): R 4 'OH} (XII) ( wherein, R ⁴ ′ represents an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group or an optionally substituted aryl group.) Reaction is general formula (XXVI):

(Wherein each symbol is as defined above) to obtain a compound represented by:
(Vi-c) The resulting compound represented by the general formula (XXVI) is deprotected in the presence of a transition metal catalyst to obtain the general formula (XXVII):

(Wherein each symbol is as defined above) to obtain a compound represented by:
(Vii-c) The compound represented by the general formula (XXVII) obtained is hydrolyzed to obtain the compound represented by the general formula (Ic).   The manufacturing method of Claim 17 using the compound represented by optically active general formula (XXI).