JPH08109179A - Condensed phenol derivative - Google Patents

Abstract

PURPOSE: To obtain the subject derivative having thromboxane A2 enzyme inhibition and 5-lipoxygenase inhibition and/or activated oxygen-extinguishing action and useful for prevention and/or cure of thrombosis, arterial sclerosis, bronchial asthma or rheumatism, etc. CONSTITUTION: This derivative is a condensed phenol derivative expressed by formula I R<1> and R<2> are each a sub-1 group or a sub-2 group, the sub-1 group is H, a halogen, cyano or an 1-10C alkyl, etc., the sub-2 group is -D<1> -E<1> [D<1> is a single bond or an 1-8C alkylene, etc.; E<1> is -NR<71> R<81> (R<71> and R<81> are each H, an 1-4C alkyl or phenyl), etc.], etc.; A is an 1-8C alkylene or a 2-8C alkenylene, etc.; B is an 1-2N-containing monocyclic heterocyclic group having 5-7 members; G is -OR<31> (R<31> is H or an 1-4C alkyl, etc.), etc.; R<4> and R<5> are each H or an 1-8C alkyl, etc.; (n) is an integer of 1-3, etc.}, such as a compound expressed by formula II. The compound of the formula I is obtained from a compound formula III (R<1-1> , R<2-1> , R<4-1> and R<5-1> are each same as R<1> , R<2> , R<4> and R<5> , etc.; R<31-1> is an 1-4C alkyl, etc.; A<a> is an 1-8C alkylene, etc.; X<a> is an eliminating group) and a compound expressed by the formula, H-B<a> (B<a> is same as B).

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to condensed phenol derivatives. More specifically, 1) General formula (I)

[0002]

Embedded image

(In the formula, all symbols have the same meanings as described below.), Condensed phenol derivatives, their non-toxic salts, their acid addition salts and their hydrate salts, 2) their production. Method, and 3) a drug containing them as an active ingredient.

[0004]

BACKGROUND OF THE INVENTION Animal tissues have a metabolic system called the arachidonic acid cascade. Arachidonic acid stored in the form of phospholipids is excised by the action of an ester hydrolase called phospholipase. Arachidonic acid is prepared by adding a molecule of oxygen by an enzyme called 5-lipoxygenase to give 5-hydroxyperoxy-6,8,1.
It is converted to 1,14-eicosatetraenoic acid (5-HPETE). 5-HPETE includes 5-hydroxy-6,8,11,14-eicosatetraenoic acid (5-HETE) and leukotriene A ₄ (L
TA ₄ ) and leukotriene B ₄ (LTB ₄ ). This LTA ₄ changes further, leukotriene C ₄
(LTC ₄ ), leukotriene D ₄ (LTD ₄ ), leukotriene E ₄ (LTE ₄ ). In addition, arachidonic acid produces prostaglandin G ₂ (PGG ₂ ) by an enzyme called cyclooxygenase. PGG ₂ produces prostaglandin H ₂ (PGH ₂ ) by PG hydroperoxidase. PGH ₂ is produced by thromboxane (TX) synthase by thromboxane A ₂ (TX
A ₂ ) is produced. This TXA ₂ is a very unstable compound and is known to be immediately converted to thromboxane B ₂ (TXB ₂ ).

[0005]

[Chemical 17]

[0006] LTB ₄ has a leukocyte migration action and an adhesion action, and further has a leukocyte degranulation action. LT
C ₄ , LTD ₄ and LTE ₄ have a pulmonary / bronchial muscle contracting action and an arterial contracting action. TXA ₂ is known to have a platelet aggregation action, a vascular smooth muscle contraction action, and a bronchial smooth muscle contraction action.

[0007]

2. Description of the Related Art Recently, studies on lipoxynase, TX and reactive oxygen species have been extensively conducted, and it has become clear that they are involved in various diseases. Therefore, research on these production inhibitors is considered to be important for the treatment of diseases, and in particular, many reports on 5-lipoxygenase and TXA ₂ synthase inhibition and active oxygen scavengers have been reported. For example, the general formula (X)

[0008]

Embedded image (In the formula, nx represents an integer of 1 to 3, and R ^x is

[Chemical 19]

Represents a nitrogen-containing heterocyclic group selected from the group consisting of: R ^1X and R ^2X are each a hydrogen atom or an alkyl group which may have a substituent, an aralkyl group, an arylalkenyl group, an aryl group or an acyl group; R ^3X represents a hydrogen atom or an alkyl group. ), 3,4-dihydro-2H-benzopyran derivative has at least one action of 5-lipoxygenase inhibitory action, antiallergic action, antihistamine action, lipid peroxidation inhibitory action, and platelet aggregation inhibitory action Is disclosed (Japanese Patent Laid-Open No. 63-264476).

The general formula (Y)

Embedded image

(In the formula, R ^Y represents lower alkyl;
^6Y represents hydrogen or acyl, R ^1Y and R ^2Y are the same or different, and are lower alkyl which may have a substituent, or R ^1Y and R ^2Y may have a substituent. represents butadienylene or R ^3Y and R ^4Y are each hydrogen or a substituent alkyl group which may have a represents a polymethylene between R ^3Y and R ^4Y, be R ^5Y is substituted Represents a lower alkyl, aromatic ring or heterocyclic group. It is disclosed that the 2,3-dihydrobenzofuran derivative represented by the formula (4) has a scavenging action of reactive oxygen species, a TXA ₂ biosynthesis inhibition, a 5-lipoxygenase inhibition or an anti-allergic action (JP-A 1-2).
72578).

Further, the general formula (Z)

[Chemical 21]

(Wherein R ^1Z is hydrogen or lower alkyl, R ^2Z is a methyl group substituted with carboxy, alkoxycarbonyl, cyano, halogen, aryl or heterocyclic group, or carboxy, alkoxycarbonyl, cyano, halogen, aryl. Alternatively, it has 2 carbon atoms and does not have a lower alkyl group at the α-position which may be substituted with a heterocyclic group.
Or R 15 is a chain hydrocarbon residue, R ^3Z is lower alkyl, R ^4Z is hydrogen or acyl, R ^5Z and R ^6Z are lower alkyl or lower alkoxy, or R ^5Z
And R ^6Z represent butadienylene. ) 2,
It is disclosed that a 3-dihydrobenzofuran derivative has a 5-lipoxygenase inhibitory action and a 12-lipoxygenase inhibitory action (JP-A-2-76869).

Further, the general formula (W)

[Chemical formula 22]

[0015] (wherein, R ^1W, R ^2W, the R ^3W and R ^4W or each same or different lower alkyl group, Ring A ^W
Represents a benzene ring substituted with at least one of a lower alkyl group, a lower alkoxy group or a halogen atom. ) 2,3-dihydrobenzofuran derivative has an action of suppressing lipid peroxide production reaction, a 5-lipoxygenase production inhibitory action, a TXA ₂ synthase inhibitory action, a prostaglandin I ₂ synthase retention promoting action, an LTD ₄ receptor It has been disclosed that it has a body antagonism and a scavenging action of reactive oxygen species (Japanese Patent Laid-Open No. 6-41123).

[0016]

OBJECTS OF THE INVENTION The present inventors have conducted research to find new compounds having TXA ₂ enzyme inhibition and 5-lipoxygenase inhibition and / or active oxygen scavenging activity,
It has been found that the condensed phenol derivative represented by the general formula (I) in which B representing a monocyclic heterocyclic group is bonded to the benzene ring via A achieves the object.

[0017]

Comparison with Prior Art The condensed phenol derivative of the present invention is a novel compound which has never been known. More specifically, the R ^X group in the compound represented by the general formula (X) represents various nitrogen-containing heterocyclic groups, but the bonding mode is such that the position of the 2-position of the benzopyran ring must be through the alkylene side chain. It takes the form combined with. That is, various nitrogen-containing heterocyclic groups are not bonded to the benzene ring. In addition, R in the compound represented by the general formula (Y) is
^{The 5Y} group represents a lower alkyl which may have a substituent, an aromatic ring group or a heterocyclic group, and its bonding mode is always a structure bonded to the 3-position of the 2,3-dihydrofuran ring. I am taking it. That is, no heterocyclic group is bonded to the benzene ring.

Further, the R ^2Z group in the compound represented by the general formula (Z) is a methyl group substituted with an aryl or heterocyclic group or a lower alkyl group at the α-position which may be substituted with an aryl or heterocyclic group. It represents a chain hydrocarbon residue having 2 to 15 carbon atoms which does not have a group, but its bonding mode is always in the form of bonding to the 2-position of the 2,3-dihydrofuran ring. Further, in the detailed description of this specification, it is disclosed that R ^5Z and R ^6Z may represent lower alkyl substituted with 3-pyridyl, 1-imidazolyl, 5-thiazolyl and the like. However, as specific compounds, only those in which R ^5Z and R ^6Z are methyl groups are disclosed. That is, a lower alkyl group in which R ^5Z and R ^6Z are substituted with 3-pyridyl, 1-imidazolyl, 5-thiazolyl, etc. is not disclosed.

Further, the compound represented by the general formula (W) is

[Chemical formula 23] Is always bonded to the 2-position of the 2,3-dihydrobenzofuran ring via a methyl group. That is,
No nitrogen-containing heterocycle is bonded to the benzene ring.

That is, what can be said in common with these four prior arts is that a compound having a substituent containing an aromatic ring group or a nitrogen-containing heterocyclic group in the oxygen-containing ring portion of the condensed benzene ring is 5 It has a lipoxygenase inhibitory action and / or a TXA ₂ synthase inhibitory action and / or an active oxygen scavenging action. On the other hand, B in the compound of the present invention
The group represents various nitrogen-containing heterocycles, the bonding mode of which is
In either case, the form is such that it is bonded to the benzene ring via the side chain represented by A. From the above points, it can be said that the compound of the present invention is a compound having a chemical structure remarkably different from the compounds of the prior art represented by the general formulas (X), (Y), (Z) and (W).

[0021]

DISCLOSURE OF THE INVENTION The present invention includes 1) general formula (I)

[Chemical formula 24] [In the formula, R ¹ and R ² are the same or different and each represents a sub 1 group or a sub 2 group. Sub 1 group is 1) hydrogen atom, 2) halogen atom, 3) trifluoromethyl group, 4) cyano group, 5) C1-10 alkyl group, 6) C1-4 alkoxy group, 7) C3-7 cycloalkyl group. 8) C7-10 phenylalkyl group, 9) C1-10 alkyl group substituted by C1-4 alkoxy group, 10) C1-4 alkyl group substituted by C3-7 cycloalkyl group, 11) Substituted by phenylthio group Cl to 6 alkyl group, 12) Cl to 6 alkyl group in which the phenyl group is substituted, 13) in -COOH group, 14) -COOR ⁶ group (group, R ⁶ represents a Cl to 6 alkyl group.), 15 ) C2～10 alkenyl or 16) when present in an ortho position to each other, taken together R ¹ and R ² represents a -CH = CH-CH = CH- group, sub-2 group, -D ¹ E ¹ group (wherein, D ¹ represents a single bond, C1-8 alkylene or C2~8 alkenylene group,

E ¹ is 1) —NR ⁷¹ R ⁸¹ group (wherein R ⁷¹ and R ⁸¹ are the same or different and each represents a hydrogen atom, a C1-4 alkyl group or a phenyl group), 2). -OR ⁹¹ group (wherein R ⁹¹ is a hydrogen atom, a C1-4 alkyl group, a C1-4 hydroxyalkyl group, a C2-5 acyl group, a phenylcarbonyl group, a C7-10 phenylalkyl group, a C7-10 phenylalkyl group .. but which shall not represent substituted carbonyl group or represent C2~4 alkoxyalkyl group, however, D ¹ when E ¹ is -OR ⁹¹ group is a single bond and C1~8 alkylene group), 3) - NR ¹⁰¹ —SO ₂ —R ¹¹¹ group (wherein R ¹⁰¹ is a hydrogen atom, a C1-6 alkyl group, a C2-6 alkenyl group,
C1~4 alkoxy group, a -SO ₂ -R ¹¹¹ group or a hydroxyl group, R ¹¹¹ is C1~6 alkyl group, -NR ⁷¹ R
^{It represents an 81} group (in which R ⁷¹ and R ⁸¹ have the same meanings as described above), a phenyl group, a pyridyl group or a trifluoromethyl group. ), 4) -NR ¹²¹ -COR ¹³¹ group (in which R ¹²¹ represents a hydrogen atom, a C1-4 alkyl group, a hydroxyl group or a C1-4 alkoxy group, and R ¹³¹ represents a C1-6 alkyl group, C1
~ 4 alkoxy group, phenyl group or -NR ⁷¹ R ⁸¹ group (in the group, R ⁷¹ and R ⁸¹ have the same meanings as described above).
Represents ), 5) -COOR ¹⁴¹ group (in the group, R ¹⁴¹ represents a hydrogen atom or a C1-6 alkyl group, provided that E ¹ is -COO.
In the case of the R ¹⁴¹ group, D ¹ does not represent a single bond. ),

6) -CONR ¹⁵¹ R ¹⁶¹ group (in the group, R
¹⁵¹ and R ¹⁶¹ are each or different and independently represent the hydrogen atom, C1 -4 alkyl group, a phenyl group, R ¹⁵¹ and R
¹⁶¹ is ^a- (CH ₂ ) _l -group (wherein l represents an integer of 4 to 7) or a nitrogen atom to which R ¹⁵¹ and R ¹⁶¹ are bonded.

[Chemical 25] Represents ), 7) -COR ¹⁷¹ group (in which R ¹⁷¹ represents a C1-4 alkyl group or a phenyl group), 8) a cyano group (however, when E ¹ is a cyano group, D ¹ is a single bond). Is not represented.), 9)

[Chemical formula 26] (In the group, R ¹⁸¹ represents a hydrogen atom or a C1-4 hydroxyalkyl group.), 10)

[Chemical 27] (In the group, R ¹⁹¹ , R ²¹¹ and R ²²¹ are the same or different and each represents a hydrogen atom, a C1-4 alkyl group or a phenyl group, and R ²⁰¹ is a hydrogen atom, a C1-4 alkyl group, a phenyl group or a cyano group. Represents a group),

11)

[Chemical 28] (In the group, R ¹⁹¹ , R ²¹¹ and R ²²¹ have the same meanings as described above.), 12)

[Chemical 29] (In the group, R ²³¹ is a hydrogen atom, C1-4 alkyl group, C1
~ 4 represents an alkoxy group or a hydroxyl group. ) 13)

Embedded image Or 14) when R ¹ and R ² and —OR ³¹ in the G group are in the ortho position to each other, R ¹ and R ² and the —OR ³¹ group are taken together.

[Chemical 31] (In the group, R ²⁴¹ and R ²⁵¹ are a hydrogen atom or C1-4.
Represents an alkyl group. ),),

A is 1) a C1-8 alkylene group, 2) a C2-8 alkenylene group, 3) a C1-6 oxyalkylene group (provided that an oxygen atom is bonded to B), or 4).

Embedded image (In the group, m represents an integer of 1 to 6 and B is bonded to the phenylene group), and B represents a nitrogen atom 1
Or, it represents a 5- to 7-membered monocyclic heterocyclic group containing two, and G is —OR ³¹ or —NR ³² R ³³ (wherein R ³¹ ,
R ³² and R ³³ are the same or different and each is a hydrogen atom, a C1-4 alkyl group, a C7-10 phenylalkyl group, a C2-5 acyl group, a phenylcarbonyl group, C
7-10 represents a carbonyl group substituted with a phenylalkyl group or a C2-4 alkoxyalkyl group. ), And R ⁴ and R ⁵ are the same or different, 1) a hydrogen atom, 2) a C1-8 alkyl group, 3) a C7-10 phenylalkyl group, and 4) a -D ² -E ² group (group). Where D ² has the same meaning as D ¹ ,

E ² is a (1) -NR ⁷² R ⁸² group (in which R
⁷² and R ⁸² are the same or different and each represents a hydrogen atom, a C1-4 alkyl group or a phenyl group. ), (2) -OR ⁹² group (wherein R ⁹² is a hydrogen atom, C
1-4 alkyl group, C1-4 hydroxyalkyl group, C
2-5 acyl group, phenylcarbonyl group, C7-10 phenylalkyl group, carbonyl group substituted by C7-10 phenylalkyl group or C2-4 alkoxyalkyl group. ), (3) —NR ¹⁰² —SO ₂ —R ¹¹² group (in the group, R ¹⁰² is a hydrogen atom, C1-6 alkyl group, C2
6 alkenyl, C1 -4 alkoxy group, -SO ₂ -
R ¹¹² represents a group or a hydroxyl group, R ¹¹² represents a C1-6 alkyl group, —NR ⁷² R ⁸² group (in the group, R ⁷² and R ⁸² have the same meanings as described above), phenyl group, pyridyl group or trifluoro group. Represents a methyl group. ), (4) -NR
^122- COR ¹³² group (wherein R ¹²² is a hydrogen atom, C1 to
4 alkyl group, a hydroxyl group or C1 -4 alkoxy group, R ¹³² is, Cl to 6 alkyl, C1 -4 alkoxy group, a phenyl group, or -NR ⁷² R ⁸² group (wherein, R ⁷²
And R ⁸² has the same meaning as described above. ) Is represented. ), (5) -COOR ¹⁴² group (in the group, R ¹⁴² represents a hydrogen atom or a C1-6 alkyl group),

(6) -CONR ¹⁵² R ¹⁶² group (in the group, R
¹⁵² and R ¹⁶² are each the same or different, a hydrogen atom, C1 -4 alkyl group, a phenyl group, R ¹⁵² and R
¹⁶² is combined with a-(CH ₂ ) _l -group (wherein l represents an integer of 4 to 7) or a nitrogen atom to which R ¹⁵² and R ¹⁶² are bonded.

[Chemical 33] Represents ), (7) -COR ¹⁷² group (in the group, R ¹⁷² represents a C1-4 alkyl group or a phenyl group),
(8) Cyano group, (9)

Embedded image (In the group, R ¹⁸² represents a hydrogen atom or a C1-4 hydroxyalkyl group.), (10)

Embedded image (In the group, R ¹⁹² , R ²¹² and R ²²² are the same or different and each represents a hydrogen atom, a C1-4 alkyl group or a phenyl group, and R ²⁰² is a hydrogen atom, a C1-4 alkyl group, a phenyl group or a cyano group. Represents a group), or (11)

Embedded image (In the group, R ¹⁹² , R ²¹² and R ²²² have the same meanings as described above.) (12)

Embedded image (In the group, R ²³² is a hydrogen atom, C1-4 alkyl group, C1
~ 4 represents an alkoxy group or a hydroxyl group. ), Or (13)

[Chemical 38]

Or 5) R ⁴ and R ⁵ together with the carbon atom to which they are attached represent a C4-7 cycloalkyl group, or n represents an integer from 1 to 3. Provided that R ⁴ and R ⁵ are the same or different and each represents a hydrogen atom, a C 1-8 alkyl group, a C 7-10 phenylalkyl group, or R ⁴ and R 5.
⁵ is C4-7 together with the carbon atom to which they are attached
When representing a cycloalkyl group, R ¹ and R ² shall not represent a sub 1 group. ] The condensed phenol derivative shown by these, their non-toxic salts, their acid addition salts, and their hydrate salts, 2) their manufacturing method, and 3) the pharmaceutical agent containing them as an active ingredient.

The present invention includes all isomers unless otherwise specified. For example, the alkyl group, the alkoxy group, the alkylene group, the alkenyl group and the alkenylene group include straight-chain and branched-chain ones, and the double bond in the alkenylene group is E, Z and a mixture of EZ. Including. Also included are isomers formed by the presence of asymmetric carbon atoms, such as when a branched chain alkyl group is present. As used herein, the wavy line represents a mixture of EZs at the double bond in the alkenylene group.

In the general formula (I), the C1-10 alkyl group represented by R ¹ and R ² means methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl groups and their isomers. It is a base. The C3-7 cycloalkyl group is a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl group. A C1-10 alkyl group substituted by a C1-4 alkoxy group means a methoxy, ethoxy, propoxy, butoxy group and methyl, ethyl substituted by any one of these isomer groups,
Propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl groups and isomer groups thereof. A C1-4 alkyl group substituted with a C3-7 cycloalkyl group means a methyl, ethyl, propyl, butyl group substituted by any one of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl groups and these Is an isomeric group. The C1-6 alkyl group substituted by a phenylthio group is a methyl, ethyl, propyl, butyl, pentyl, hexyl group substituted by one phenylthio group or an isomer group thereof. The C1-6 alkyl group substituted by a phenyloxy group is a methyl, ethyl, propyl, butyl, pentyl, hexyl group substituted by one phenyloxy group or an isomer group thereof. Halogen atoms are fluorine, chlorine, bromine and iodine atoms. C2
-10 alkenyl groups include ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, butadienyl, pentadienyl, hexadienyl, heptadienyl, octadienyl, nonadienyl, decadienyl, hexatrienyl,
Includes heptatrienyl, octatrienyl, nonatrienyl, decatrienyl groups and their isomeric groups.

[0031] In the general formula ^{(I), R 1, R} 2, R 1 and R R ¹⁰¹ in ^{2, R 121, R 131,} R 231, R 4 and R ¹⁰² of R in ^5, R ^122, R ¹³² and the C1~4 alkoxy group represented by R ²³² is methoxy, ethoxy, propoxy, butoxy and isomeric groups thereof. R ⁷¹ in R ¹ and R ² in the general formula (I),
R ⁸¹ , R ⁹¹ , R ¹²¹ , R ¹⁵¹ , R ¹⁶¹ , R ¹⁷¹ ,
R ¹⁹¹ , R ²⁰¹ , R ²¹¹ , R ²²¹ , R ²³¹ , R ²⁴¹ , R
^251, R ³¹ in the group ^{G, R 32, R 33, R} 72 in R ⁴ and ^{R 5, R 82, R 92} , R 122, R 152, R 162, R 172,
R ^192, is a C1~4 alkyl represented by R ^202, R ^212, R ²²² and R ²³² are methyl, ethyl, propyl, butyl and isomeric groups thereof. In the general formula (I), R ⁹¹ in R ¹ , R ² , R ¹ and R ² , R ³¹ in the G group, R ³² , R ³³ , R ⁴ , R ⁵ , R ⁴ and R in R ^{5. The} C7-10 phenylalkyl group represented by ⁹² is a methyl, ethyl, propyl, butyl group substituted by one phenyl group and isomer groups thereof.

In the general formula (I), a C2-5 acyl group represented by R ⁹¹ in R ¹ and R ² , R ³¹ in the G group, R ³² , R ³³ , R ⁴ and R ^{92 in} R ^5. Is an acetyl, propionyl, butyryl, valeryl group and their isomeric groups. In the general formula (I), a C2-4 alkoxyalkyl group represented by R ⁹¹ in R ¹ and R ² and R ³¹ in a G group, R ³² , R ³³ , R ⁴ and R ^{92 in} R ⁵ is , Methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl, methoxypropyl groups and isomers thereof. General formula (I)
Among, the C1~8 alkyl group represented by R ⁴ and R ⁵ are methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl and isomeric groups thereof. In the formula (I), the R ^4, R ⁵ and C4~7 cycloalkyl which they are represented by the carbon atom bonded, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

In formula (I), the C1-4 hydroxyalkyl group represented by R ⁹¹ , R ¹⁸¹ , R ⁴ and R ⁵ in R ¹ and R ² is represented by R ⁹² and R ¹⁸² .
Methyl, ethyl substituted by one hydroxy group,
Propyl, butyl and isomers thereof. In the general formula (I), R ⁶ , R ¹⁰¹ and R in R ¹ and R ² are
R ¹⁰² and R in ¹¹¹ , R ¹³¹ , R ¹⁴¹ , R ⁴ and R ^5
112, Cl to 6 represented by R ¹³² and R ¹⁴²
Alkyl groups are methyl, ethyl, propyl, butyl,
Pentyl, hexyl and isomers thereof.
In the general formula (I), R ¹⁰¹ and R ^{4 in} R ¹ and R ²
And C2-6 alkenyl group represented by R ^{102 in} R ⁵ includes ethenyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl,
Hexadienyl, hexatrienyl groups and their isomer groups. In the general formula (I), the C1-6 oxyalkylene group represented by A is an oxymethylene, oxyethylene, oxytrimethylene, oxytetramethylene, oxypentamethylene, oxyhexamethylene group or an isomer group thereof. .

[0034] In the general formula (I), C1 represented A, the D ^1, R ⁴ and D ² of R ⁵ in R ¹ and R ²
The ~ 8 alkylene group is a methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene group or an isomer group thereof. In the general formula (I), A, R ¹ and R ²
The D ^1, C2-8 alkenylene groups represented by D ² in R ⁴ and R ⁵ in, vinylene, propenylene, butenylene, pentenylene, hexenylene, heptenylene, octenylene, butadienylene, pentadienylene, hexadienylene, Heputajieniren, Okutajieniren, hexa Trienylene, heptatrienylene,
Octatrienylene groups and their isomeric groups are included. In the general formula (I), a nitrogen atom represented by B 1
Or the two-containing 5- to 7-membered monocyclic heterocyclic group means pyrrole, pyrroline, pyrrolidine, imidazole, imidazoline, imidazolidine, pyrazole, pyrazoline, pyrazolidine, pyridine, piperidine, pyridazine, pyrimidine, pyrazine, piperazine, azepine. A ring group and the like are included.

R ¹ is preferably a C1-10 alkyl group or a C3-7 cycloalkyl group. R ² is preferably a C 1-10 alkyl group or a C 3-7 cycloalkyl group, D ¹ in the R ² group is preferably a C 1-8 alkylene group, and E ¹ in the R ² group is —O.
R ⁹¹ group, -NR ¹⁰¹ -SO ₂ -R ¹¹¹ group, -NR ^121-
The COR ¹³¹ group and the -CONR ¹⁵¹ R ¹⁶¹ group are preferred. As R ³¹ in the G group, a hydrogen atom and a C2-5 acyl group are preferable. R ³² in the G group is preferably a hydrogen atom. R ³³ in the G group is a hydrogen atom or C 2
-5 acyl groups are preferred. The R ^4, C1 -4 alkyl group are preferred. As D ² in the R ⁵ group, C 1-8
Alkylene groups are preferred. As E ² in the R ⁵ group,
OR ⁹² group, -NR ¹⁰² -SO ₂ -R ¹¹² group, -NR ¹²² group
A -COR ¹³² group and a -CONR ¹⁵² R ¹⁶² group are preferred. As A, a C1-8 alkylene group is preferable. B is preferably an imidazole or pyridine ring group.

[Acid Addition Salt] The compound of the present invention represented by the general formula (I) can be converted into the corresponding acid addition salt by a known method. The salt is preferably non-toxic and water-soluble. Suitable acid addition salts include inorganic acid salts such as hydrochlorides, hydrobromides, sulfates, phosphates, nitrates, or acetates, trifluoroacetates, lactates, tartrates, oxalates. Such as, fumarate, maleate, citrate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, isethionate, glucuronate, gluconate. Organic acid salts.

[Salt] Among the compounds of the present invention represented by the general formula (I), the compounds in which at least one of R ¹ , R ² , R ⁴ and R ⁵ contains a COOH group are prepared by a known method. Converted to salt. The salt is preferably non-toxic and water-soluble. Suitable salts include salts of alkali metals (potassium, sodium, etc.), salts of alkaline earth metals (calcium, magnesium, etc.), ammonium salts, and pharmaceutically acceptable organic amines (tetramethylammonium, triethylamine, methylamine) Dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, tris (hydroxymethyl) aminomethane, lysine, arginine, N-methyl-D-glucamine and the like. The compound of the present invention represented by the general formula (I) or a salt thereof can be prepared by a known method.
It can also be converted into a hydrate.

Preferred compounds of the present invention include those of general formula I (1)

[Chemical Formula 39] (In the formula, R ¹ and R ² have the same meanings as described above.), General formula I (2)

[Chemical 40] (In the formula, R ¹ and R ² have the same meanings as described above.), General formula I (3)

Embedded image (In the formula, R ¹ and R ² have the same meanings as described above.),

General formula I (4)

Embedded image (In the formula, R ¹ and R ² have the same meanings as described above.), General formula I (5)

[Chemical 43] (Wherein R ¹ and R ² have the same meanings as described above), and the general formula I (6)

[Chemical 44] (In the formula, R ¹ and R ² have the same meanings as described above.),

General formula I (7)

Embedded image (In the formula, R ¹ and R ² have the same meanings as described above.), General formula I (8)

Embedded image (Wherein R ¹ and R ² have the same meanings as described above), and the general formula I (9)

[Chemical 47] (In the formula, R ¹ and R ² have the same meanings as described above.),

General formula I (10)

Embedded image (In the formula, R ¹ and R ² have the same meanings as described above.), General formula I (11)

[Chemical 49] (In the formula, A and B have the same meanings as described above.), And the general formula I (12).

Embedded image (In the formula, A and B have the same meanings as described above.),

General formula I (13)

[Chemical 51] (In the formula, A and B have the same meanings as described above.), General formula I (14)

Embedded image (Wherein R ⁴ and R ⁵ have the same meanings as described above), and the general formula I (15)

Embedded image (In the formula, R ⁴ and R ⁵ have the same meanings as described above.),

General formula I (16)

[Chemical 54] (In the formula, R ⁴ and R ⁵ have the same meanings as described above.) General formula I (17)

[Chemical 55] (In the formula, R ¹ has the same meaning as described above.)
(18)

[Chemical 56] (In the formula, R ¹ has the same meaning as described above.),

Formula I (19)

[Chemical 57] (In the formula, R ¹ has the same meaning as described above.)
(20)

Embedded image (In the formula, R ¹ has the same meaning as described above.)
(21)

Embedded image (In the formula, R ¹ has the same meaning as described above.),

General formula I (22)

Embedded image (In the formula, R ¹ has the same meaning as described above.)
(23)

[Chemical formula 61] (In the formula, R ¹ has the same meaning as described above.)
(24)

Embedded image (In the formula, R ¹ has the same meaning as described above.),

General formula I (25)

[Chemical formula 63] (In the formula, R ¹ has the same meaning as described above.)
(26)

[Chemical 64] (In the formula, R ¹ has the same meaning as described above.)
(27)

Embedded image (In the formula, R ¹ has the same meaning as described above.),

General formula I (28)

[Chemical formula 66] (In the formula, R ¹ has the same meaning as described above.)
(29)

Embedded image (In the formula, R ¹ has the same meaning as described above.)
(30)

[Chemical 68] (In the formula, R ¹ has the same meaning as described above.),

General formula I (31)

[Chemical 69] (In the formula, R ¹ has the same meaning as described above.)
(32)

Embedded image (In the formula, R ¹ has the same meaning as described above.)
(33)

Embedded image (In the formula, R ¹ has the same meaning as described above.),

General formula I (34)

Embedded image (In the formula, R ¹ has the same meaning as described above.)
(35)

Embedded image (In the formula, R ¹ has the same meaning as described above.)
(36)

[Chemical 74] (In the formula, R ¹ has the same meaning as described above.),

General formula I (37)

[Chemical 75] (In the formula, R ¹ has the same meaning as described above.)
(38)

[Chemical 76] (In the formula, R ¹ has the same meaning as described above.)
(39)

Embedded image (In the formula, R ¹ has the same meaning as described above.),

General formula I (40)

Embedded image (In the formula, R ¹ has the same meaning as described above.)
(41)

Embedded image (Wherein R ⁴ and R ⁵ have the same meanings as described above), and the general formula I (42)

Embedded image (In the formula, R ⁴ and R ⁵ have the same meanings as described above.),

General formula I (43)

[Chemical 81] (Wherein R ⁴ and R ⁵ have the same meanings as described above), and the general formula I (44)

[Chemical formula 82] (Wherein R ⁴ and R ⁵ have the same meanings as described above), and the general formula I (45)

[Chemical 83] (In the formula, R ⁴ and R ⁵ have the same meanings as described above.),

General formula I (46)

[Chemical 84] (In the formula, R ⁴ and R ⁵ have the same meanings as described above.), General formula I (47)

Embedded image (Wherein R ⁴ and R ⁵ have the same meanings as described above), and the general formula I (48)

[Chemical 86] (In the formula, R ⁴ and R ⁵ have the same meanings as described above.),

General formula I (49)

[Chemical 87] (Wherein R ⁴ and R ⁵ have the same meanings as described above), and the general formula I (50)

Embedded image (Wherein R ⁴ and R ⁵ have the same meanings as described above), and the general formula I (51)

[Chemical 89] (In the formula, R ⁴ and R ⁵ have the same meanings as described above.),

General formula I (52)

[Chemical 90] (Wherein R ⁴ and R ⁵ have the same meanings as described above), and the general formula I (53)

Embedded image (In the formula, R ⁴ and R ⁵ have the same meanings as described above.), General formula I (54)

Embedded image (In the formula, R ⁴ and R ⁵ have the same meanings as described above.),

General formula I (55)

Embedded image (Wherein R ⁴ and R ⁵ have the same meanings as described above), and the general formula I (56)

Embedded image (Wherein R ⁴ and R ⁵ have the same meanings as described above), and the general formula I (57)

Embedded image (In the formula, R ⁴ and R ⁵ have the same meanings as described above.),

General formula I (58)

[Chemical 96] (Wherein R ⁴ and R ⁵ have the same meanings as described above), and the general formula I (59)

Embedded image (In the formula, R ⁴ and R ⁵ have the same meanings as described above.), General formula I (60)

Embedded image (In the formula, R ⁴ and R ⁵ have the same meanings as described above.),

General formula I (61)

Embedded image (Wherein R ⁴ and R ⁵ have the same meanings as described above), and the general formula I (62)

[Chemical 100] (Wherein R ⁴ and R ⁵ have the same meanings as described above), and the general formula I (63)

[Chemical 101] (In the formula, R ⁴ and R ⁵ have the same meanings as described above.),

General formula I (64)

Embedded image (In the formula, R ⁴ and R ⁵ have the same meanings as described above.), General formula I (65)

Embedded image (In the formula, D ² , E ² , A and B have the same meanings as described above.), General formula I (66)

[Chemical 104] (In the formula, D ² , E ² , A and B have the same meanings as described above.),

General formula I (67)

Embedded image (In the formula, D ² , E ² , A and B have the same meanings as described above.), General formula I (68)

[Chemical formula 106] (In the formula, D ² , E ² , A and B have the same meanings as described above.), General formula I (69)

[Chemical formula 107] (In the formula, D ¹ , E ¹ , A and B have the same meanings as described above.),

General formula I (70)

[Chemical 108] (Wherein D ¹ , E ¹ , A and B have the same meanings as described above), and the general formula I (71)

[Chemical 109] (In the formula, D ¹ , E ¹ , A and B have the same meanings as described above.), General formula I (72)

[Chemical 110] (In the formula, D ¹ , E ¹ , A and B have the same meanings as described above.),

General formula I (73)

[Chemical 111] (Wherein R ¹ and R ² have the same meanings as described above), and the general formula I (74)

[Chemical 112] (In the formula, R ¹ and R ² have the same meanings as described above.), General formula I (75)

[Chemical 113] (In the formula, R ¹ and R ² have the same meanings as described above.),

General formula I (76)

[Chemical 114] (Wherein R ¹ and R ² have the same meanings as described above), and the general formula I (77)

[Chemical 115] (In the formula, R ¹ and R ² have the same meanings as described above.), General formula I (78)

[Chemical formula 116] (In the formula, R ¹ and R ² have the same meanings as described above.),

General formula I (79)

[Chemical 117] (Wherein R ⁴ and R ⁵ have the same meanings as described above), and the general formula I (80)

[Chemical 118] (Wherein R ⁴ and R ⁵ have the same meanings as described above), and the general formula I (81)

[Chemical formula 119] (In the formula, R ⁴ and R ⁵ have the same meanings as described above.),

General formula I (82)

[Chemical 120] (Wherein R ⁴ and R ⁵ have the same meanings as described above), and the general formula I (83)

[Chemical 121] (In the formula, R ⁴ and R ⁵ have the same meanings as described above.), General formula I (84)

[Chemical formula 122] (In the formula, R ⁴ and R ⁵ have the same meanings as described above.),

General formula I (85)

[Chemical 123] (Wherein R ⁴ and R ⁵ have the same meanings as described above), and the general formula I (86)

[Chemical formula 124] (Wherein R ⁴ and R ⁵ have the same meanings as described above), and the general formula I (87)

Embedded image (In the formula, R ⁴ and R ⁵ have the same meanings as described above.),

General formula I (88)

[Chemical formula 126] (Wherein R ⁴ and R ⁵ have the same meanings as described above), and the general formula I (89)

Embedded image (Wherein R ⁴ and R ⁵ have the same meanings as described above), and the general formula I (90).

[Chemical 128] (In the formula, R ⁴ and R ⁵ have the same meanings as described above.), A condensed phenol derivative, a non-toxic salt thereof, an acid addition salt thereof and a hydrate salt thereof.

Specific compounds of the present invention include the compounds shown in Tables 1 to 26 below, their acid addition salt and the compounds shown in Examples.

[Table 1]

[0069]

[Table 2]

[0070]

[Table 3]

[0071]

[Table 4]

[0072]

[Table 5]

[0073]

[Table 6]

[0074]

[Table 7]

[0075]

[Table 8]

[0076]

[Table 9]

[0077]

[Table 10]

[0078]

[Table 11]

[0079]

[Table 12]

[0080]

[Table 13]

[0081]

[Table 14]

[0082]

[Table 15]

[0083]

[Table 16]

[0084]

[Table 17]

[0085]

[Table 18]

[0086]

[Table 19]

[0087]

[Table 20]

[0088]

[Table 21]

[0089]

[Table 22]

[0090]

[Table 23]

[0091]

[Table 24]

[0092]

[Table 25]

[0093]

[Table 26]

[0094]

[Method for producing the compound of the present invention] Of the compounds of the present invention represented by the general formula (I), the general formula (I-1)

[Chemical formula 129]

(In the formula, R ^1-1 , R ^2-1 , R ^4-1 and R 4
^5-1 has the same meaning as R ¹ , R ² , R ⁴ and R ⁵ , respectively, but none of these groups represents a group containing a COOH group, a hydroxyl group and an amino group, and R ^31-1 is C
It represents a 1-4 alkyl group, a C2-4 alkoxyalkyl group and a C7-10 phenylalkyl group, and other symbols have the same meanings as described above. The compound of the present invention represented by () can be produced by the following methods (a) to (d).

(A) In the compound of the present invention represented by the general formula (I-1), A is a C1-8 alkylene group or C2
A compound which represents an 8-alkenylene group and in which A is bonded to the nitrogen atom in the heterocyclic group represented by B, that is, the general formula (Ia)

[0097]

Embedded image

(In the formula, A ^a represents a C1-8 alkylene group or a C2-8 alkenylene group, B ^a has the same meaning as the above B, and other symbols have the same meaning as described above.
However, it is assumed that A ^a is bonded to the nitrogen atom in the heterocyclic group represented by B ^a . ) Is a compound represented by the general formula (II-a)

[0099]

[Chemical 131]

(In the formula, X ^a represents a generally known leaving group (eg, chlorine, bromine, iodine atom, mesyl group or tosyl group), and other symbols have the same meanings as described above. Represented by the general formula (III-a)

Embedded image It is produced by reacting a compound represented by H-B ^a (III-a) (wherein B ^a has the same meaning as described above). This reaction is carried out, for example, in an organic solvent (benzene or toluene)
The reaction is carried out at 80 to 150 ° C in the medium.

(B) In the compound of the present invention represented by the general formula (I-1), A is C2-8 alkylene or C2-8.
A compound which represents an alkenylene group and in which A binds to a carbon atom in the heterocyclic group represented by B, that is to say general formula (Ib)

[0102]

Embedded image

(In the formula, A ^b represents a C2-8 alkylene group or a C2-8 alkenylene group, B ^b has the same meaning as B, and the other symbols have the same meaning as described above, provided that A ^b represents assumed to be bonded to a carbon atom in the heterocyclic group represented by B ^b compound represented by.) has the general formula (II-b)

[0104]

Embedded image

(In the formula, A ^b-2 represents a single bond, a C1-6 alkylene group or a C2-6 alkenylene group, and other symbols have the same meanings as described above.) And a compound represented by the general formula (III -b)

Ph ₃ P ⁺ —CH ₂ —B ^b-3 Y ^— (III-b) (In the formula, Y represents a halogen atom and B ^b-3 has the same meaning as B ^b . ^When the nitrogen atom in the ^b-3 group represents a free NH group, the NH group is represented by a commonly known protecting group (eg, triphenylmethyl group). It is produced by subjecting the compound to a Wittig reaction, and if desired, a hydrogenation reaction of an alkenylene group to an alkylene group, and if necessary, a deprotection reaction of an NH protecting group.

This Wittig reaction is known, and, for example, a base (sodium hydride) is added under an inert gas (argon, etc.) atmosphere under anhydrous conditions in an inert organic solvent (eg, tetrahydrofuran, benzene, hexane, etc.). , N-butyl lithium, etc.) at a temperature of −78 ° C. to room temperature.

The hydrogenation reaction is known, and examples thereof include inert solvents [ether type (tetrahydrofuran, dioxane, diemethoxyethane, diethyl ether, etc.), alcohol type (methanol, ethanol, etc.), benzene type (benzene, toluene, etc.). ), Ketones (acetone, methyl ethyl ketone, etc.), nitriles (acetonitrile, etc.), amides (dimethylformamide, etc.), water, ethyl acetate, acetic acid, or a mixed solvent of two or more thereof, etc.],
In the presence of a hydrogenation catalyst (palladium-carbon, palladium black, palladium, palladium hydroxide, platinum dioxide, nickel, Raney nickel, etc.), an inorganic acid (hydrochloric acid, sulfuric acid, hypochlorous acid, boric acid, tetrafluoroboric acid, etc.) Alternatively, it is performed in the presence or absence of an organic acid (acetic acid, p-toluenesulfonic acid, oxalic acid, trifluoroacetic acid, formic acid, etc.) at a temperature of 0 to 200 ° C. under a hydrogen atmosphere under normal pressure or pressure. When an acid is used, its salt may be used.

The deprotection reaction of the NH group differs depending on the protecting group, but is known. For example, when the protecting group is a triphenylmethyl group, an organic solvent miscible with water (methanol, tetrahydrofuran, dioxane, acetone, etc.)
The reaction is performed in an aqueous solution of an organic acid (acetic acid, trifluoroacetic acid, etc.) or an aqueous solution of an inorganic acid (hydrochloric acid, sulfuric acid, etc.) or a mixture thereof at a temperature of 0 to 100 ° C.

(C) In the compound of the present invention represented by the general formula (I-1), the group represented by A represents a methylene group, and A is bonded to the carbon atom in the heterocyclic group represented by B. Compound, ie, general formula (Ic)

[0110]

[Chemical 136]

(In the formula, A ^c represents a methylene group, and B ^c
Has the same meaning as B, and other symbols have the same meanings as described above. However, it is assumed that A ^c is bonded to the carbon atom in the heterocyclic group represented by B ^c . ) Is a compound represented by the general formula (II-c)

[0112]

[Chemical 137]

(Wherein all symbols have the same meanings as described above) and a compound of the general formula (III-c)

Embedded image B ^c-3 Li (III-c) (In the formula, B ^c-3 has the same meaning as B ^c .
^When the nitrogen atom in the ^c-3 group represents a free NH group, N
The H group is protected by a generally known protecting group (eg, triphenylmethyl group). ), The compound represented by the formula (1) is reacted, followed by the elimination reaction of the hydroxyl group generated by the reaction with alkyllithium, and if desired, the deprotection reaction of the NH protecting group.

This reaction with alkyl lithium is known, and, for example, under an inert gas (argon, nitrogen, etc.) atmosphere,
The halide is reacted with an alkyllithium (n-butyllithium, etc.) in an inert organic solvent (diethyl ether, tetrahydrofuran, etc.) at a temperature of −78 to −20 ° C.,
Aldehyde is added to the obtained lithium compound at -78 to -20 ° C.
The reaction is carried out at the temperature of.

The dehydroxylation reaction is known, and, for example, trialkylsilane (triethylsilane, triphenylsilane) in an inert organic solvent (chloroform, methylene chloride, etc.) under an inert gas (argon, nitrogen, etc.) atmosphere. Etc.) in the presence of an acid (acetic acid, trifluoroacetic acid, trifluoroborane, etc.) at a temperature of 0 ° C. to room temperature. The elimination reaction of the NH protecting group is carried out in the same manner as the above-mentioned method.

(D) In the compound of the present invention represented by the general formula (I-1), the group represented by A is a C1-6 oxyalkylene group, or

[0117]

[Chemical 139] A compound represented by the general formula (Id)

[0118]

[Chemical 140] (In the formula, A ^d is a C1-6 oxyalkylene group, or

[0119]

[Chemical 141]

(In the group, m has the same meaning as described above.)
And B ^d has the same meaning as B, and the other symbols have the same meaning as described above. ) Is a compound represented by the general formula (II-d)

[0121]

[Chemical 142]

(In the formula, X ^d represents the above-mentioned generally known leaving group (eg, chlorine, bromine, iodine atom, mesyl group or tosyl group), and A ^d-2 represents C1-6. Represents an alkylene group and the other symbols have the same meanings as defined above) and a compound represented by the general formula (III-d-1)

HO-B ^d (III-d-1) (in the formula, B ^d has the same meaning as described above),

Or the general formula (III-d-2)

[Chemical 144] (In the formula, B ^d has the same meaning as described above.) And can be produced.

This reaction is carried out, for example, in an inert gas (argon, nitrogen, etc.) atmosphere, in an inert organic solvent (dimethylformamide, acetonitrile, acetone, etc.) in the presence of a base (potassium carbonate, sodium hydride, etc.). ~ 100
It is carried out by reacting at a temperature of ° C.

Among the compounds of the present invention represented by the general formula (I), the general formula (I-2)

[Chemical 145]

(Wherein R ^1-2 , R ^2-2 , R ^4-2 and R 2
^5-2 represents the same meaning as R ¹ , R ² , R ⁴ and R ⁵ , respectively, but neither group represents a group containing a COOH group, and further, R ^1-2 , R ^2-2 , R ^4-2 and R ^5-2 represent at least one group containing a hydroxyl group or an amino group, and the other symbols have the same meanings as described above. ) Is a compound of the general formula (I-1) produced by the above method, that is, the compound of the general formula (I-1)
-k)

[0127]

[Chemical 146]

(Wherein R ^1k , R ^2k , R ^4k and R ^5k are R
^1-2 , R ^2-2 , R ^4-2 and R ^5-2 have the same meanings, but the hydroxyl group and amino group in the group are respectively a hydroxyl group-protecting group (eg trimethylsilyl group or benzyl group) and amino. The group is protected by a protecting group (eg, trifluoroacetyl group or benzyl group), and other symbols have the same meanings as described above. Can be produced by deprotecting the compound represented by the formula (1).

For example, when the protective group for the hydroxyl group is a trimethylsilyl group, the deprotection reaction is known, and for example, it is carried out in an organic solvent (eg, tetrahydrofuran, acetonitrile, etc.) in the presence of tetrabutylammonium fluoride at 0 to 40 ° C. It is carried out by reacting at temperature. For example, when the amino-group protecting group is a trifluoroacetyl group, the deprotection reaction is known, and for example, deprotection under alkaline conditions is performed using an organic solvent (eg methanol).
In the presence of an alkali metal hydroxide or carbonate
It is carried out by reacting at a temperature of -40 ° C. For example, when the protective group for the hydroxyl group and the amino group is a benzyl group, the deprotection reaction is known, and the deprotection is carried out by the hydrogenation reaction. The hydrogenation reaction is performed by the method described above.

Among the compounds of the present invention represented by the general formula (I), the general formula (I-3)

[Chemical 147]

(In the formula, R ^31-3 represents a hydrogen atom,
^1-3 , R ^2-3 , R ^4-3 and R ^5-3 are R ¹ and R, respectively.
² , R ⁴ and R ⁵ have the same meanings, but none of them represents a group containing a COOH group, and the other symbols have the same meanings as described above. ) Is a compound of the general formula (I-1) and the general formula (I-2) produced by the above method, that is, the general formula (Ij)

[0132]

Embedded image

(Wherein R ^31-3j represents a C2-4 alkoxyalkyl group or a —CH ₂ C ₆ H ₅ group, and other symbols have the same meanings as described above) It can be produced by subjecting it to a protection reaction or a hydrogenation reaction.

The deprotection reaction with an acid is known and, for example, in an organic solvent (methanol, tetrahydrofuran, dioxane, ethyl acetate, etc.), an organic acid (acetic acid, trifluoroacetic acid, etc.) or an inorganic acid (hydrochloric acid, sulfuric acid, etc.) is used. Alternatively, it is carried out by reacting in an aqueous solution thereof or a mixture thereof at a temperature of 0 to 100 ° C. The hydrogenation reaction is
It is performed in the same manner as the above-mentioned method.

Among the compounds of the present invention represented by the general formula (I), the general formula (I-4)

[Chemical 149]

(Wherein R ^1-4 , R ^2-4 , R ^4-4 and R 4
^5-4 has the same meaning as R ¹ , R ² , R ⁴ and R ⁵ , respectively, but at least one of R ^1-4 , R ^2-4 , R ^4-4 and R ^5-4 is COOH. Represents a group containing a group, and the other groups represent groups other than a group containing a COOH group and an ester group, R ^31-4 represents a hydrogen atom, a C1-4 alkyl group, a C2-4 alkoxyalkyl group and C7. ~
10 represents a phenylalkyl group, and other symbols have the same meanings as described above. ) Are compounds represented by the general formula (I-1), the general formula (I-2) and the general formula (I-3) produced by the above method, that is, the general formula (Ie)

[0137]

[Chemical 150]

(In the formula, R ^1e , R ^2e , R ^4e and R ^5e have the same meanings as R ¹ , R ² , R ⁴ and R ⁵ , respectively, but R ^1e , R ^2e , R ^4e and R ^5e Among them, at least one group necessarily represents a group containing an ester group, and another group represents a group other than a group containing an ester group, and other symbols have the same meanings as described above.). It can be produced by subjecting it to an ester hydrolysis reaction.

The ester hydrolysis reaction is known. For example, hydrolysis under alkaline conditions is carried out at 0 to 40 ° C. with an alkali metal hydroxide or carbonate in a suitable solvent (for example, methanol). Done at temperature.

Among the compounds of the present invention represented by the general formula (I), the general formula (I-5)

Embedded image

(Wherein R ^1-5 , R ^2-5 , R ^4-5 and R 4
^5-5 has the same meaning as R ¹ , R ² , R ⁴ and R ⁵ , respectively, but at least one of R ^1-5 , R ^2-5 , R ^4-5 and R ^5-5 is COOH. Represents a group containing a group, and at least one of the other groups represents a group containing an ester group, and the other symbols have the same meanings as described above. ) Is a compound represented by the general formula (I-1), the general formula (I-2) or the general formula (I-3) produced by the above method, that is, the general formula (If)

[0142]

[Chemical 152]

(In the formula, R ^1f , R ^2f , R ^4f and R ^5f have the same meanings as R ¹ , R ² , R ⁴ and R ⁵ , respectively, but R ^1f , R ^2f , R ^4f and R ^5f At least one of them is a COOt-butyl group or COO-CH ₂ C ₆ H
₅ represents a group containing ₅ groups, and at least one of the other groups represents a group containing an ester group, and the other symbols have the same meanings as described above. ) Is represented by t
-Butyl ester It can be produced by subjecting it to a hydrolysis reaction or a hydrogenation reaction.

The t-butyl ester hydrolysis reaction is known, and, for example, in an inert organic solvent (methylene chloride, chloroform, methanol, dioxane, ethyl acetate, anisole, etc.), an organic acid (trifluoroacetic acid, etc.) or an inorganic acid is used. (Hydrochloric acid) or a mixture thereof at a temperature of 0 to 90 ° C. The hydrogenation reaction is carried out by the method described above.

Among the compounds of the present invention represented by the general formula (I), the general formula (I-6)

Embedded image (In the formula, R ^1-6 , R ^2-6 , R ^4-6 and R ^5-6 have the same meanings as R ¹ , R ² , R ⁴ and R ⁵ , respectively,
R ^1-6 , R ^2-6 , R ^4-6 and R ^5-6 are all COOH
Represents a group containing a group, and other symbols have the same meanings as described above. The compound represented by), the general formula prepared in the manner described (I-1), general formula (I-2) and formula (I-3) in R ^1-6, R ^2-6, R ^{4 -6} and R ^5-6 are all compounds containing an ester group, that is, a compound of the general formula (Ig)

[0146]

Embedded image

[0147] (wherein, R ^1g, R ^2g, although each R ^4g and R ^{5 g} represents the same meaning as R ^1, R ^2, R ⁴ and ^{R 5, R 1g, R 2g} , R 4g and R ^{5 g} All Represents an ester group-containing group, and other symbols have the same meanings as described above.), And the resulting compound is subjected to an ester hydrolysis reaction. The ester hydrolysis reaction is carried out by the method described above.

Among the compounds of the present invention represented by the general formula (I), the general formula (I-7)

[Chemical 155]

(In the formula, R ^31-7 represents a carbonyl group substituted with a C 2-5 acyl group, a phenylcarbonyl group or a C 7-10 phenylalkyl group, and R ^1-7 , R ^2-7 , R
^4-7 and R ^5-7 have the same meanings as R ¹ , R ² , R ⁴ and R ⁵ , but none of them represent a group containing a hydroxyl group and an amino group, and other symbols are as defined above. Has the same meaning as. ) Is a compound produced by the above method, that is, a compound represented by the general formula (Ih)

[0150]

[Chemical 156] (In the formula, all symbols have the same meanings as described above.) The compound is produced by subjecting it to an acylation reaction.

The acylation reaction is known, and, for example, in an inert organic solvent (methylene chloride etc.) or in the absence of a solvent, in the presence of a tertiary amine (pyridine, triethylamine etc.), the corresponding acid chloride or acid anhydride is used. It is carried out by reacting at a temperature of 0 to 40 ° C.

Among the compounds of the present invention represented by the general formula (I), the general formula (I-8)

[Chemical 157]

(In the formula, R ^1-8 , R ^2-8 , R ^4-8 and R ^4
5-8 has the same meaning as R ¹ , R ² , R ⁴ and R ⁵ , but at least one of R ^1-8 , R ^2-8 , R ^4-8 and R ^5-8 is a hydroxyl group or an amino group. Represents a group containing a group, and other symbols have the same meanings as described above. ) Is a compound produced by the above method, that is, a compound represented by the general formula (Ir)

[0154]

[Chemical 158]

(Wherein R ^1r , R ^2r , R ^4r and R ^5r are R
^1-8 , R ^2-8 , R ^4-8 and R ^5-8 have the same meanings, but the hydroxyl group and amino group in the group are respectively a hydroxyl group-protecting group (eg trimethylsilyl group) and an amino group-protecting group. It is assumed that it is protected by a group (for example, a t-butylcarbamate group etc.), and other symbols have the same meanings as described above. ) Is subjected to an acylation reaction, and further subjected to a deprotection reaction with an acid. The acylation reaction and the deprotection reaction with an acid are carried out by the method described above.

Among the compounds of the present invention represented by the general formula (I), the general formula (I-9)

[Chemical 159]

(Wherein all symbols have the same meanings as described above), the compound represented by the general formula (Is)

[0158]

[Chemical 160]

It can be produced by subjecting a compound represented by the formula (wherein all symbols have the same meaning as described above) to a reduction reaction of a nitro group. This reduction reaction of the nitro group is known, and is carried out, for example, by the above-mentioned hydrogenation reaction.

Among the compounds of the present invention represented by the general formula (I), the general formula (I-10)

[Chemical 161]

(In the formula, R ^33-10 is a C1-4 alkyl group, a C7-10 phenylalkyl group, a C2-5 acyl group, a phenylcarbonyl group, a carbonyl group substituted with a C7-10 phenylalkyl group or a C2-10 group. 4 alkoxyalkyl groups, R ^1-10 , R ^2-10 , R ^4-10 and R
^5-10 has the same meaning as R ¹ , R ² , R ⁴ and R ⁵ , but does not represent a group containing a hydroxyl group and an amino group, and the other symbols have the same meanings as described above. ) Is a compound produced by the above method, that is, a compound represented by the general formula (It)

[0162]

[Chemical 162]

It is produced by subjecting a compound represented by the formula (wherein all symbols have the same meanings as described above) to N-alkylation, N-acylation and N-alkoxyalkylation. This N-alkylation reaction is known, and examples thereof include inert organic solvents (methylene chloride, chloroform, dimethylformamide, dimethyl sulfoxide, etc.).
In the presence of 1 equivalent of a base (sodium hydride, sodium hydroxide, pyridine, triethylamine, etc.), 1 equivalent of the corresponding alkyl halide is reacted at a temperature of 0 to 100 ° C. This N-acylated acid reaction is known, and, for example, 1 equivalent of a base (sodium hydride, sodium hydroxide, pyridine, triethylamine, etc.) in an inert organic solvent (methylene chloride, chloroform, dimethylformamide, dimethylsulfoxide, etc.) It is carried out in the presence of 1 equivalent of the corresponding chloride or anhydride at a temperature of 0 to 100 ° C. This N-alkoxyalkylation reaction is known, and, for example, 1 equivalent of a base (sodium hydride, sodium hydroxide, pyridine, triethylamine, etc.) in an inert organic solvent (methylene chloride, chloroform, dimethylformamide, dimethylsulfoxide, etc.) In the presence of 0 with 1 equivalent of the corresponding alkoxyalkyl halide
It is carried out by reacting at a temperature of -100 ° C.

Among the compounds of the present invention represented by the general formula (I), the general formula (I-11)

[Chemical formula 163]

(Wherein R ^1-11 , R ^2-11 , R ^4-11 and R 1
^5-11 has the same meaning as R ¹ , R ² , R ⁴ and R ⁵ , but at least one of R ^1-11 , R ^2-11 , R ^4-11 and R ^5-11 is a hydroxyl group or an amino group. Represents a group containing a group, and other symbols have the same meanings as described above. ) Is a compound produced by the method described above, that is, a compound represented by the general formula (Iu)

[0166]

[Chemical 164]

(Wherein R ^1u , R ^2u , R ^4u and R ^5u are R
^1-11 , R ^2-11 , R ^4-11 and R ^5-11 have the same meanings, but the hydroxyl group and amino group in the group are respectively a hydroxyl group-protecting group (eg trimethylsilyl group etc.) and an amino group-protecting group. It is assumed that it is protected by a group (for example, a t-butylcarbamate group etc.), and other symbols have the same meanings as described above. ) Is subjected to N-alkylation, N-acylation, N-alkoxyalkylation reaction, and further subjected to deprotection reaction with an acid. These N-alkylation, N-acylation, N-alkoxyalkylation reaction and deprotection reaction with an acid are carried out by the method described above.

Among the compounds of the present invention represented by the general formula (I), the general formula (I-12)

[Chemical 165]

(In the formula, R ^32-12 and R ^33-12 are the same or different and each is a C1-4 alkyl group or C7-
10 phenylalkyl group, C2-5 acyl group, a phenylcarbonyl group, a carbonyl group or C2~4 alkoxyalkyl group C7~10 phenylalkyl group is ^{substituted, R 1-12, R 2-12, R} 4-12 And R ^5-12 is R ¹ ,
It has the same meaning as R ² , R ⁴ and R ⁵ , but does not represent a group containing a hydroxyl group and an amino group, and the other symbols have the same meanings as described above. The compound represented by the formula () is produced by subjecting the compound represented by the general formula (I-10) to N-alkylation, N-acylation, and N-alkoxyalkylation. These N-alkylation, N-acylation and N-alkoxyalkylation reactions are carried out by the methods shown above.

Of the compounds of the present invention represented by the general formula (I), the general formula (I-13)

[Chemical 166]

(Wherein R ^1-13 , R ^2-13 , R ^4-13 and R ^4-13
5-13 has the same meaning as R ¹ , R ² , R ⁴ and R ⁵ , but at least one of R ^1-13 , R ^2-13 , R ^4-13 and R ^5-13 is a hydroxyl group or an amino group. Represents a group containing a group, and other symbols have the same meanings as described above. ) Is a compound produced by the method described above, that is, a compound represented by the general formula (Iw)

[0172]

[Chemical 167]

(Wherein R ^1w , R ^2w , R ^4w and R ^5w are R
^1-13 , R ^2-13 , R ^4-13 and R ^5-13 have the same meanings, but the hydroxyl group and amino group in the group are respectively a hydroxyl group-protecting group (eg trimethylsilyl group etc.) and an amino group-protecting group. It is assumed that the group is protected with a group (for example, a t-butylcarbamate group etc.), and other symbols have the same meanings as described above. ) Is subjected to N-alkylation, N-acylation, N-alkoxyalkylation reaction, and further subjected to deprotection reaction with an acid. These N-alkylation, N-acylation, N-alkoxyalkylation reaction and deprotection reaction with an acid are carried out by the method described above.

General formulas (II-a), (II-b), (II-c),
The compound represented by (II-d) can be produced by using a known reaction. For example, it can be produced by the method represented by the following reaction scheme and the method described in Examples.

[0175]

[Chemical 168]

[0176]

[Chemical 169]

[0177]

[Chemical 170]

[0178]

[Chemical 171]

[0179]

[Chemical 172]

In the above reaction scheme, MOM represents a methoxymethyl group, Bn represents a benzyl group, and 9-B
BN represents 9-borabicyclo [3.3.1] nonane, LAH represents lithium aluminum hydride, THF represents tetrahydrofuran, MsCl
Represents mesyl chloride. R ^1p and R ^2p is, R ¹
And R ² have the same meanings, but do not represent a COOR ⁶ group (wherein R ⁶ has the same meaning as described above), a group containing a COOH group and a cyano group, and R ^3p
Represents a methoxymethyl group and a benzyl group, R ^4p
And R ^5p have the same meanings as R ⁴ and R ⁵ ,
COOR ¹⁴² group (wherein R ¹⁴² has the same meaning as described above) and a group containing a cyano group are not represented, and A ^p represents a C1-6 alkylene group and a C2-6 alkenylene group, A ^q represents a C1-8 alkylene group and a C2-8 alkenylene group, and X ^p represents a mesyl group.

The compound represented by the general formula (V) is a partial compound group of the compound represented by the general formula (II-c). The compound represented by the general formula (VI) is a partial compound group of the compound represented by the general formula (II-b). The compound represented by the general formula (VII) is a partial compound group of the compound represented by the general formula (II-a). The compound represented by the general formula (VIII) is a partial compound group of the compound represented by the general formula (II-d). The compound represented by the general formula (IV) used as a starting material can be produced by a known method. For example, it can be produced by the method described in the examples of the present specification.

In each reaction in the present specification, the reaction product can be purified by an ordinary purification method such as distillation under normal pressure or reduced pressure, high performance liquid chromatography using silica gel or magnesium silicate, thin layer chromatography, or It can be purified by a method such as column chromatography, washing, or recrystallization. Purification may be carried out for each reaction or after completion of some reactions. Other starting materials and respective reagents in the present invention are known per se or can be produced by known methods.

[0183]

[Pharmacological activity] The compound of the present invention represented by the general formula (I) is
It was proved by the following experiments that it has a TXA ₂ synthase inhibitory action and a 5-lipoxygenase inhibitory action and / or a reactive oxygen scavenging action. i) Inhibitory effect on human 5-lipoxygenase activity [Experimental method] Test drug 5 was added to 85 μl of potassium / phosphate buffer (pH 7.4) containing 1.18 mM calcium ion.
μl was added, and 5 μl of a soluble fraction of peripheral blood polymorphonuclear leukocytes prepared from a healthy person was further added and preincubated at 30 ° C. for 5 minutes. 5 μl of 1 mM ¹⁴ C-arachidonic acid was added thereto, and the mixture was further reacted for 1 minute. Diethyl ether / methanol / 1M citric acid (30/4
/ 1) 300 μl of the mixed solution was added and stirred to stop the reaction.
After completion of stirring, the organic layer obtained by centrifugation (1700 G, 4 ° C., 2 minutes) was separated, sodium borohydride was added, and the mixture was allowed to stand for 10 minutes or more. Thereafter, the mixture was dried under a nitrogen stream, 200 μl of a diethyl ether / methanol (30/4) mixture was added, 100 μl of 1M citric acid was added, and the mixture was stirred and centrifuged (1700G,
4 ° C., 2 minutes). Thin layer chromatography was carried out using this centrifugal supernatant as a sample (developing solvent: diethyl ether / petroleum ether / acetic acid = 85/15 / 0.01). After completion of the development, autoradiography was performed to quantify the residual group mass and arachidonic acid metabolite with a densitometer. 5-lipoxygenase activity is 15-of the total radioactivity
The conversion rate to metabolites excluding hydroxyeicosatetraenoic acid was used as an index. The action of the test drug was expressed as the inhibition rate of 5-lipoxygenase activity in the solvent (50% ethanol aqueous solution) control group.

Ii) Inhibitory effect on human TXA ₂ synthase activity [Experimental method] Citric acid blood sampling [1/9 (v /
v)] and prepare washed platelets by a conventional method, and add 1 with Krebs-Henseleit solution (pH 7.4) containing no calcium ion.
The cells were suspended at 0.8 × 10 ⁷ cells / ml. 5 μl of the test drug was added to 185 μl of the washed platelets, preincubated at 37 ° C. for 2 minutes, and then 100 μM ¹⁴ C-
10 μl of arachidonic acid was added and the reaction was continued for 2 minutes. The reaction was stopped by adding 300 μl of a mixed solution of diethyl ether / methanol / 1M citric acid (30/4/1) and stirring, and then centrifuging (1700 G, 4 ° C., 2 minutes). The obtained organic layer was separated and subjected to thin layer chromatography (developing solvent: ethyl acetate / isooctane / acetic acid / distilled water = 110/50/20/100). After completion of the development, autoradiography was performed to quantify the residual group mass and arachidonic acid metabolite with a densitometer. For the TXA ₂ synthase activity, the conversion rate of total radioactivity to thromboxane B ₂ (TXB ₂ : stable metabolite of TXA ₂ ) was used as an index. The action of the test drug was expressed as the control rate for the conversion rate to TXB ₂ in the solvent (50% ethanol aqueous solution) control group.

Iii) Leukotriene B from human whole blood
₄ (LTB ₄ ) and thromboxane B ₂ (TXB ₂ )
Inhibitory effect on production [Experimental method] Heparin blood sampling from a healthy person (final concentration 10 U
/ Ml), 1/100 volume of the test drug was added to 1 volume of the obtained whole blood, and preincubation was performed at 37 ° C for 5 minutes. Subsequently, 1/200 volume of 6 mM calcium ionophore A23187 was added, and the mixture was further reacted for 5 minutes. Immediately after completion of the reaction, centrifugation (1200 rpm, 1-2 minutes) was performed to collect plasma, which was stored at -70 ° C until measurement of LTB ₄ and TXB ₂ . LTB ₄ and TXB in plasma
_Two concentrations were measured using an EIA kit from Chyman after partial purification. The effect of the test drug is the solvent (50%
Aqueous ethanol solution) LTB ₄ and TXB _{2 in} control group
It was expressed as the control rate for the production amount. The results are shown in Table 27.

[0186]

[Table 27]

Iv) Antioxidant Effect [Experimental Method] Sprague-Dawley male rats fasted overnight were opened under ether anesthesia, and liver tissues were perfused and excised. The extracted tissue was homogenated with 1.15% potassium chloride. To 200 μl of this homogenate, 5 μl of the test drug was added, and further 10 μl of 4.4 mM ferrous chloride was added to give 3
The reaction was carried out at 7 ° C for 1 hour and the amount of lipid peroxide produced was determined by the method of OHKAWA et al. (Analitical Biochemistry, 9
5 , 351-358, 1979) and was measured as a thiobarbituric acid positive substance (TBARS). The action of the test drug was expressed as the inhibition rate against the TBARS production in the solvent (50% ethanol aqueous solution) control group. The results are shown in Table 28.

[0188]

[Table 28]

[0189]

[Toxicity] On the other hand, the toxicity of the compound of the present invention is extremely low, and it can be judged that it is sufficiently safe for use as a medicine.

[0190]

INDUSTRIAL APPLICABILITY The compound of the present invention represented by the general formula (I) has TXA ₂ synthesis inhibition and 5-lipoxygenase inhibition and / or active oxygen scavenging action, and therefore, thrombosis, arteriosclerosis, ischemic heart and It is useful for the prevention and / or treatment of brain disease, bronchial asthma, inflammatory kidney disease, rheumatism, arthritis, gout, psoriasis, ulcerative colitis, ringworm, myocardial infarction, allergy and the like. In order to use the compound of the present invention represented by the general formula (I), a non-toxic salt thereof, an acid addition salt or a hydrate thereof for the above purpose, usually, systemically or locally,
It is administered orally or parenterally. The dose depends on the age,
It depends on the body weight, symptoms, therapeutic effect, administration method, treatment time and the like. Usually, 1 mg per adult per dose
Orally administered in the range of 1,000 mg once to several times a day, or in the range of 100 μg to 100 mg per adult once parenterally once to several times a day, or It is intravenously connected and administered within the range of 1 to 24 hours per day.

Of course, as described above, since the dose varies depending on various conditions, a dose smaller than the above dose may be sufficient in some cases, and a dose exceeding the range may be required in some cases. When the compound of the present invention is administered, it is used as solid compositions, liquid compositions and other compositions for oral administration, injections for parenteral administration, external preparations, suppositories and the like. Solid compositions for oral administration include tablets, pills,
Capsules, powders, granules and the like are included. Capsules include hard capsules and soft capsules.

In such solid compositions, the one or more active substances comprises at least one inert diluent such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, Mixed with magnesium aluminometasilicate. The composition comprises, according to a conventional method, additives other than an inert diluent, for example, a lubricant such as magnesium stearate, a disintegrating agent such as calcium fibrin glycolate, a stabilizer such as lactose, glutamic acid or asparagine. It may contain a solubilizing agent such as an acid. If necessary, the tablets or pills may be coated with a film of a gastric or enteric substance such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, or may be coated with two or more layers. Also included are capsules of absorbable material such as gelatin.

Liquid compositions for oral administration include pharmaceutically acceptable solutions, emulsions, syrups, elixirs and the like, and generally used inert diluents (purified water, ethanol). ) May be included. This composition may contain, in addition to an inert diluent, auxiliary agents such as a wetting agent and a suspending agent, a sweetening agent, a flavoring agent, an aromatic agent and a preservative.
Other compositions for oral administration include spray formulations which contain one or more active substances and are formulated in a manner known per se. The composition may contain, in addition to an inert diluent, a stabilizer such as sodium bisulfite and a buffer such as sodium chloride, sodium citrate or citric acid to provide isotonicity. A method for producing a spray agent is described, for example, in US Pat.
Further details are provided in 8691 and 3095355.

Injections for parenteral administration according to the present invention include sterile aqueous or non-aqueous solutions, suspensions and emulsions. Examples of the aqueous solution and suspension include distilled water for injection and physiological saline. Examples of the non-water soluble solution and suspension include propylene glycol, polyethylene glycol, olive oil, ethanol, polysorbate 80 and the like. Such compositions may also contain adjuvants such as preserving, wetting, emulsifying, dispersing, stabilizing (eg, lactose) and solubilizing agents (eg, glutamic acid, aspartic acid). These are sterilized by, for example, filtration through a bacteria retaining filter, blending of a bactericide or irradiation.
They can also be used in the production of a sterile solid composition, for example, dissolved in sterile water or a sterile solvent for injection before use of the freeze-dried product. Other compositions for parenteral administration include external preparations containing one or more active substances and formulated according to a conventional method, soft-ko, coatings, suppositories, pessaries and the like.

[0195]

Reference Examples and Examples Hereinafter, the present invention will be described in detail with reference to Reference Examples and Examples, but the present invention is not limited thereto. The solvent in parentheses shown at the point of separation by chromatography indicates the elution solvent or developing solvent used, and the ratio indicates the volume ratio. IR is measured by the KBr tablet method unless otherwise specified.

Reference Example 1

[Chemical 173]

2- (2-pivaloyloxyethyl) -3
-Methyl-4-acetoxy-5-isopropyl-6-
(2-Methyl-2-propenyl) phenol (1.74g)
M-chloroperbenzoic acid (2.10 g, 55% content) was added to a methylene chloride (20 ml) solution of the above at 0 ° C under an argon atmosphere, and the mixture was stirred at 0 ° C for 40 minutes. The reaction mixture is
It was poured into a mixed solution of a saturated sodium thiosulfate aqueous solution and a saturated sodium hydrogen carbonate aqueous solution, and extracted with ethyl acetate.
The extract was washed successively with saturated aqueous sodium hydrogen carbonate solution, water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated to obtain the target compound having the following physical properties. TLC: Rf 0.30 (hexane: ethyl acetate = 4:
1).

Reference Example 2

[Chemical 174]

A solution of the compound prepared in Reference Example 1 in methylene chloride (13 ml) was added to boron trifluoride diethyl etherate (0.66 m) at -70 ° C. under an argon atmosphere.
1) was added and stirred for 10 minutes. Ice was added to the reaction mixture at 0 ° C., and the mixture was extracted with ethyl acetate. The extract was washed successively with water, saturated aqueous sodium hydrogen carbonate solution, water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated to give the desired compound (1.83 g) having the following physical data. TLC: Rf 0.16 (hexane: ethyl acetate = 4:
1).

Reference Example 3

[Chemical 175]

Imidazole (364 mg) and t-butyldimethylsilyl chloride (672 mg) were sequentially added to a solution of the compound (1.83 g) produced in Reference Example 2 in dimethylformamide (20 ml), and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The extract was washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 19: 1) to obtain the target compound (1.92 g) having the following physical properties. TLC: Rf 0.53 (hexane: ethyl acetate = 4:
1).

Reference Example 4

[Chemical 176]

Lithium aluminum hydride (420 m
g) in a tetrahydrofuran (4 ml) suspension at 0 ° C. under an argon atmosphere, and the compound (1.92
A solution of g) in tetrahydrofuran (8 ml) was added. The reaction mixture was stirred for 10 minutes and saturated aqueous ammonium chloride solution was added. The mixture was stirred for 20 minutes, anhydrous magnesium sulfate was added, the mixture was stirred at room temperature for 10 minutes, and filtered.
The filtrate was concentrated, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 7: 3) to obtain the target compound (1.32 g) having the following physical properties. TLC: Rf 0.43 (hexane: ethyl acetate = 3:
2).

Reference Example 5

[Chemical 177]

To a solution of the compound (1.32 g) produced in Reference Example 4 in dimethylformamide (10 ml) was added sodium hydride (147 mg) at 0 ° C. under an argon atmosphere, and the mixture was added to 5
After stirring for 1 minute, the mixture was stirred at room temperature for 30 minutes. Chloromethyl methyl ether (0.33 ml) was added to the mixture at 0 ° C and the mixture was added to 10
Stir for minutes. The reaction mixture was extracted with diethyl ether. The extract was washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to obtain the desired compound (1.281 g) having the following physical properties. TLC: Rf 0.36 (hexane: ethyl acetate = 7:
3).

Reference Example 6

[Chemical 178]

Compound prepared in Reference Example 4 (485 mg)
Solution of tetra-n-butylammonium fluoride in tetrahydrofuran (2 ml).
4 ml) solution was added and stirred at room temperature for 3 days. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 1 →
Purification by 1: 2) gave the target compound (188 mg) having the following physical data. TLC: Rf 0.32 (hexane: ethyl acetate = 1: 1
2).

Reference Example 7

[Chemical 179]

Compound prepared in Reference Example 6 (518 mg)
Solution of benzyl bromide (790
mg) and potassium carbonate (766 mg) were sequentially added, and the mixture was stirred at 60 ° C. for 14.5 hours under an argon atmosphere. The reaction mixture was cooled to room temperature and then concentrated. Ethyl acetate was added to the residue, washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated. The residue was washed with hexane and dried under reduced pressure to give the object compound (580 mg) having the following physical data. TLC: Rf 0.29 (hexane: ethyl acetate = 2:
3).

Reference Example 8

[Chemical 180]

Compound produced in Reference Example 7 (573 mg)
In methylene chloride (7.5 ml) solution of imidazole (1
14 mg) was added, and t-butyldiphenylsilyl chloride (0.45 ml) and 4-N, N-dimethylaminopyridine (10 mg) were sequentially added under an argon atmosphere, and the mixture was stirred for 5 hours. After adding ethyl acetate to the reaction mixture, water, 2
The mixture was washed successively with N hydrochloric acid aqueous solution, water, saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 9: 1 →
4: 1) to obtain the target compound (853 mg) having the following physical data. TLC: Rf 0.49 (hexane: ethyl acetate = 4:
1).

Reference Example 9

[Chemical 181]

Compound produced in Reference Example 8 (500 mg)
Diisopropylethylamine (0.2 ml) was added to a methylene chloride (3.8 ml) solution of the above at 0 ° C. under an argon atmosphere, and the mixture was stirred for 5 minutes and then at room temperature for 30 minutes. Chloromethyl methyl ether (0.13 ml) was added to the mixture at 0 ° C., and the mixture was stirred for 10 minutes. The reaction mixture was extracted with diethyl ether. The extract was washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1) to obtain the target compound having the following physical properties. TLC: Rf 0.35 (hexane: ethyl acetate = 9:
1).

Reference Example 10

[Chemical 182]

Compound prepared in Reference Example 9 (543 mg)
The target compound (326 mg) having the following physical data was obtained by the same procedures as in Reference Example 6 using. TLC: Rf 0.22 (hexane: ethyl acetate = 7:
3).

Reference Example 11

[Chemical 183]

Compound prepared in Reference Example 5 (981 mg)
Solution of methylene chloride (6 ml) under argon atmosphere at 0
Pyridine (1.3 ml) and pivaloyl chloride (1.0
ml) was added sequentially. The reaction mixture was stirred at room temperature for 1.5 hours. Water was added to the reaction mixture and the mixture was extracted with diethyl ether. The extract was washed successively with 2N aqueous hydrochloric acid solution, water, saturated aqueous sodium hydrogen carbonate solution, water, and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 17: 3) to obtain the target compound (1.04 g) having the following physical properties. TLC: Rf 0.59 (hexane: ethyl acetate = 17:
3).

Reference Example 12

Embedded image

Using the compound (1.04 g) produced in Reference Example 11 and following the same procedure as in Reference Example 6, the target compound (859 mg) having the following physical data was obtained. TLC: Rf 0.25 (hexane: ethyl acetate = 4:
1).

Reference Example 13

[Chemical 185]

A solution of oxalyl chloride (0.49 ml) in methylene chloride (11 ml) was charged with -6 under an argon atmosphere.
A solution of dimethyl sulfoxide (0.83 ml) in methylene chloride (4 ml) was added dropwise at 0 ° C. After stirring the mixture at the same temperature for 15 minutes, the compound prepared in Reference Example 12 (859 m
A solution of g) in methylene chloride (7.5 ml) was added. The mixture was stirred at the same temperature for 30 minutes and then triethylamine (2.
71 ml) was added. The reaction mixture was stirred at room temperature for 10 minutes. Water (20 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with 1N aqueous hydrochloric acid solution, water, saturated aqueous sodium hydrogen carbonate solution, saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated to give the target compound (834 mg) having the following physical data. TLC: Rf 0.30 (hexane: ethyl acetate = 4:
1).

Reference Example 14

[Chemical 186]

A suspension of sodium hydride (212 mg, containing 60%) in dimethyl sulfoxide (4 ml) was stirred at 70 ° C. for 1 hour under an argon atmosphere. After cooling to room temperature, a solution of methyltriphenylphosphonium bromide (1.97 g) in dimethyl sulfoxide (4 ml) was added to the mixture, and the mixture was stirred for 20 minutes. A solution of the compound (834 mg) produced in Reference Example 13 in dimethyl sulfoxide (4 ml) was added to this mixture, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into ice water and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 17:
Purification by 3) gave the target compound (755 mg) having the following physical data. TLC: Rf 0.45 (hexane: ethyl acetate = 17:
3).

Reference Example 15

[Chemical 187]

The compound prepared in Reference Example 14 (750 m
9-Borabicyclo [3.3.1] nonane (8.58 ml, 0.5 M tetrahydrofuran solution) was added to a tetrahydrofuran (3 ml) solution of g), and the mixture was stirred at room temperature for 2 hours.
Methanol (2.42 ml), 6N sodium hydroxide aqueous solution (0.8 ml), and 30% hydrogen peroxide solution (1.7 ml) were sequentially added to the reaction mixture. Reaction mixture at 50 ° C. for 30
After stirring for a minute, the mixture was cooled to room temperature and concentrated. Water was added to the residue and extracted with ethyl acetate. The extract was washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 7: 3), and the target compound (597 mg) having the following physical properties was obtained.
I got TLC: Rf 0.31 (hexane: ethyl acetate = 7:
3).

Reference Example 16

[Chemical 188]

The compound prepared in Reference Example 15 (300 m
Using g), the same operation as in Reference Example 9 → Reference Example 4 was carried out to obtain the target compound (225 mg) having the following physical data. TLC: Rf 0.18 (hexane: ethyl acetate = 3:
2).

Reference Example 17

[Chemical 189]

To a solution of the compound (2.14 g) prepared in Reference Example 5 in methylene chloride (15 ml) was added diisopropylethylamine (5.0 ml) under an argon atmosphere, and benzyl chloromethyl ether (2.0 ml) was added dropwise to the solution overnight. It was stirred. Ethyl acetate was added to the reaction mixture, which was washed successively with saturated ammonium chloride, water and saturated sodium chloride, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate =
Purification by 97: 3 → 19: 1) gave the desired compound (2.18 g) having the following physical data. TLC: Rf 0.42 (hexane: ethyl acetate = 9:
1).

Reference Example 18

Embedded image

Using the compound (2.18 g) produced in Reference Example 17, the same operation as in Reference Example 6 was carried out to obtain the target compound (1.72 g) having the following physical data. TLC: Rf 0.18 (hexane: ethyl acetate = 4:
1).

Reference Example 19

[Chemical 191]

The compound prepared in Reference Example 18 (350 m
g), pyridine (1.3 ml) in methylene chloride (1.3 ml)
Isobutyryl chloride (0.12 ml) was added to the solution at 0 ° C. under an argon atmosphere, and the mixture was stirred for 15 minutes. Ethyl acetate was added to the reaction mixture, and ice water, 2N hydrochloric acid aqueous solution, water,
The extract was washed successively with saturated aqueous sodium hydrogen carbonate solution, water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1) to obtain the target compound (364 mg) having the following physical properties. TLC: Rf 0.39 (hexane: ethyl acetate = 4:
1).

Reference Example 20

[Chemical 192]

The compound prepared in Reference Example 19 (364 m
g) in ethanol (3 ml) solution with 5% palladium-
Carbon (67 mg) was added. The reaction mixture was stirred under a hydrogen atmosphere at room temperature for 2 hours. The reaction mixture was filtered through Celite (trade name), and the filtrate was concentrated to give the object compound (282 mg) having the following physical data. TLC: Rf 0.22 (hexane: ethyl acetate = 7:
3).

Reference Example 21

[Chemical formula 193]

Using the compound prepared in Reference Example 18, the same operation as in Reference Example 13 was carried out to obtain the target compound having the following physical data. TLC: Rf 0.56 (hexane: ethyl acetate = 4:
1).

Reference Example 22

Embedded image

The compound prepared in Reference Example 21 (280 m
To a solution of g) in benzene (15 ml) was added methyl (triphenylphosphoranidene) acetate (668 mg) under an argon atmosphere. The reaction mixture was stirred at 80 ° C. overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The extract is washed with saturated aqueous sodium chloride solution,
It was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1) to obtain the desired compound (240 mg) having the following physical properties. TLC: Rf 0.31 (hexane: ethyl acetate = 9:
1).

Reference Example 23

[Chemical 195]

Using the compound produced in Reference Example 22 and the same procedure as in Reference Example 20, the desired compound having the following physical data was given. TLC: Rf 0.31 (hexane: ethyl acetate = 9:
1).

Reference Example 24

[Chemical 196]

The compound prepared in Reference Example 19 (500 m
To a solution of g) in dimethylformamide (4 ml) was added sodium hydride (60 mg) under an argon atmosphere, and 2
Stirred for hours. After cooling to 0 ° C., a solution of 1-tetrahydropyranyloxy-2-bromoethane (470 mg) in dimethylformamide (1 ml) was added, and the mixture was stirred for 1 hour.
Diethyl ether was added to the reaction mixture, washed with water, and the aqueous layer was extracted with diethyl ether. The extract was washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give the desired compound (283m) having the following physical data.
g) was obtained. TLC: Rf 0.33 (hexane: ethyl acetate = 4:
1).

Reference Example 25

[Chemical 197]

The compound prepared in Reference Example 24 (400 m
p-Toluenesulfonic acid (7 mg) was added to a solution of g) in methanol (4 ml), and after stirring for 25 minutes, triethylamine (0.02 ml) was added and concentrated. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate =
7: 3) to obtain the target compound (341 mg) having the following physical data. TLC: Rf 0.38 (hexane: ethyl acetate = 3:
2).

Reference Example 26

[Chemical 198]

Using the compound prepared in Reference Example 25 and the same procedure as in Reference Example 9, the desired compound having the following physical data was given. TLC: Rf 0.32 (hexane: ethyl acetate = 3:
2).

Reference Example 27

[Chemical formula 199]

Using the compound prepared in Reference Example 26 and the same procedure as in Reference Example 20, the desired compound having the following physical data was given. TLC: Rf 0.12 (hexane: ethyl acetate = 7:
3).

Reference Example 28

[Chemical 200]

The compound prepared in Reference Example 18 (250 m
g) and ethyl iodide (0.4 ml) in dimethylformamide (1.7 ml) was added sodium hydride (25 mg) under an argon atmosphere, and the mixture was stirred for 4.5 hours. Water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The extract was washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 9).
Purification by 3: 7) gave the target compound (238 mg) having the following physical data. TLC: Rf 0.45 (hexane: ethyl acetate = 4:
1).

Reference Example 29

[Chemical 201]

Using the compound prepared in Reference Example 28 and the same procedure as in Reference Example 20, the desired compound having the following physical data was given. TLC: Rf 0.29 (hexane: ethyl acetate = 7:
3).

Reference Example 30

Embedded image

Using the compound prepared in Reference Example 23 and the same procedure as in Reference Example 17, the desired compound having the following physical data was given. TLC: Rf 0.44 (hexane: ethyl acetate = 3:
1).

Reference Example 31

[Chemical 203]

The compound prepared in Reference Example 30 (160 m
Methyllithium (0.75 ml) was added to a diethyl ether (2 ml) solution of g) at 0 ° C., and the mixture was stirred for 30 minutes.
Ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography (hexane:
Purification with ethyl acetate = 3: 1) gave the target compound (114 mg) having the following physical data. TLC: Rf 0.19 (hexane: ethyl acetate = 3:
1).

Reference Example 32

[Chemical 204]

Using the compound prepared in Reference Example 31 and the same procedure as in Reference Example 9 → Reference Example 20, the desired compound having the following physical data was obtained. TLC: Rf 0.23 (hexane: ethyl acetate = 3:
1).

Reference Example 33

[Chemical 205]

Using the compound prepared in Reference Example 23 and the same procedure as in Reference Example 8, the desired compound having the following physical data was given. TLC: Rf 0.31 (hexane: ethyl acetate = 9:
1).

Reference Example 34

[Chemical 206]

The compound prepared in Reference Example 33 (670 m
To a solution of g) in methanol (3 ml) was added a 1N aqueous sodium hydroxide solution (2.2 ml), and the mixture was stirred at 60 ° C. overnight. A 1N hydrochloric acid aqueous solution was added to the reaction mixture until the pH became 4 to 5, and the mixture was extracted twice with ethyl acetate. The extract was washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give the desired compound (436) having the following physical data.
mg). TLC: Rf 0.49 (chloroform: methanol = 9:
1).

Reference Example 35

Embedded image

The compound prepared in Reference Example 34 (436 m
To a solution of g) in methylene chloride (2.5 ml) was added N-hydroxysuccinimide (125 mg) and 1,3-dicyclohexylcarbodiimide (223 mg) at 0 ° C.,
The mixture was stirred for 0 minutes at the same temperature. A 28% aqueous ammonia solution (2.5 ml) was added to the reaction mixture, and the mixture was stirred at the same temperature for 1 hr. Water was added to the reaction mixture, and extracted with ethyl acetate. The extract is washed successively with water and saturated aqueous sodium chloride solution,
It was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1 → 1: 3) to obtain the desired compound (487 mg) having the following physical properties. TLC: Rf 0.28 (hexane: ethyl acetate = 1: 1
2).

Reference Example 36

[Chemical 208]

Using the compound prepared in Reference Example 35 and the same procedure as in Reference Example 6, the desired compound having the following physical data was given. TLC: Rf 0.28 (chloroform: methanol = 9:
1).

Reference Example 37

[Chemical 209]

Using the compound prepared in Reference Example 23, the same operation as in Reference Example 3 → Reference Example 4 was carried out to obtain the target compound having the following physical data. TLC: Rf 0.38 (hexane: ethyl acetate = 3:
1).

Reference Example 38

[Chemical 210]

Using the compound produced in Reference Example 37 and the same procedure as in Reference Example 9 → Reference Example 6, the desired compound having the following physical data was obtained. TLC: Rf 0.15 (hexane: ethyl acetate = 3:
1).

Reference Example 39

[Chemical 211]

The compound prepared in Reference Example 37 (520 m
g), a solution of triphenylphosphine (0.19 ml) in tetrahydrofuran (4 ml) was added dropwise with a solution of diethyl azodicarboxylate (0.19 ml) in tetrahydrofuran (1 ml) at room temperature under an argon atmosphere, and the mixture was stirred for 30 minutes. Water was added to the reaction mixture, and extracted with ethyl acetate. The extract was washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to obtain the desired compound (687 mg) having the following physical properties. TLC: Rf 0.54 (hexane: ethyl acetate = 3:
1).

Reference Example 40

Embedded image

The compound prepared in Reference Example 39 (682 m
Hydrazine (0.28 ml) was added to an ethanol (5 ml) solution of g) under an argon atmosphere, and the mixture was refluxed for 1.5 hours. The reaction mixture was concentrated and the residue was extracted with chloroform. The extract was washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated to give the desired compound (526 mg) having the following physical data. TLC: Rf 0.30 (chloroform: methanol = 1)
0: 1).

Reference Example 41

[Chemical 213]

Using the compound produced in Reference Example 40 and the same procedure as in Reference Example 19 → Reference Example 6, the desired compound having the following physical data was obtained. TLC: Rf 0.24 (hexane: ethyl acetate = 1: 1
3).

Reference Example 42

[Chemical 214]

The compound prepared in Reference Example 40 (150 m
To a solution of g) in methylene chloride (2 ml) was added mesyl chloride (0.08 ml) and pyridine (0.16 ml) at 0 ° C under an argon atmosphere, and the mixture was stirred at 0 ° C to 5 ° C overnight. Water was added to the reaction mixture, and extracted with ethyl acetate. The extract was washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 3:
Purification by 1 → 2: 1) gave the target compound (189 mg) having the following physical data. TLC: Rf 0.69 (chloroform: methanol = 1)
0: 1).

Reference Example 43

Embedded image

Using the compound produced in Reference Example 42 and the same procedure as in Reference Example 6, the desired compound having the following physical data was given. TLC: Rf 0.11 (hexane: ethyl acetate = 1: 1
1).

Reference Example 44

[Chemical 216]

The compound prepared in Reference Example 40 (180 m
To a solution of g) in methylene chloride (2 ml) was added trifluoroacetic anhydride (0.16 ml) and pyridine (0.16 ml) under an argon atmosphere, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and extracted with ethyl acetate. The extract was washed successively with water, saturated aqueous sodium hydrogen carbonate solution, water and saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate,
Concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to obtain the desired compound (158 mg) having the following physical properties. TLC: Rf 0.95 (chloroform: methanol = 1)
0: 1).

Reference Example 45

Embedded image

Using the compound produced in Reference Example 44 and the same procedure as in Reference Example 6, the desired compound having the following physical data was given. TLC: Rf 0.06 (hexane: ethyl acetate = 4:
1).

Reference Example 46

[Chemical 218]

Using the compound prepared in Reference Example 5, the same operation as in Reference Example 6 → Reference Example 8 was carried out to obtain the target compound having the following physical data. TLC: Rf 0.42 (hexane: ethyl acetate = 4:
1).

Reference Example 47

[Chemical 219]

Using the compound produced in Reference Example 46 and the same procedures as in Reference Example 13, the desired compound having the following physical data was given. TLC: Rf 0.54 (hexane: ethyl acetate = 4:
1).

Reference Example 48

[Chemical 220]

Using the compound prepared in Reference Example 47 and the same procedures as in Reference Example 31, the desired compound having the following physical data was given. TLC: Rf 0.31 (hexane: ethyl acetate = 4:
1).

Reference Example 49

[Chemical 221]

Using the compound prepared in Reference Example 48 and the same procedure as in Reference Example 9 → Reference Example 6, the desired compound having the following physical data was obtained. TLC: Rf 0.11 (hexane: ethyl acetate = 4:
1).

Reference Example 50

Embedded image

The compound prepared in Reference Example 48 (247 m
Dess-Martin periodinate (218 mg) was added to a solution of g) in methylene chloride (4.2 ml), and the mixture was stirred for 20 minutes. The reaction mixture was filtered, the residue was washed with ethyl acetate, the filtrate was washed successively with saturated aqueous sodium hydrogen carbonate solution, water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated. A hexane-ethyl acetate (9: 1) mixed solution was added to the residue, the mixture was filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 93: 7) to obtain the desired compound (198 mg) having the following physical data. TLC: Rf 0.46 (hexane: ethyl acetate = 4:
1).

Reference Example 51

[Chemical formula 223]

Using the compound prepared in Reference Example 50 and the same procedures as in Reference Example 6, the desired compound having the following physical data was given. TLC: Rf 0.20 (hexane: ethyl acetate = 3:
2).

Reference Example 52

[Chemical formula 224]

The compound prepared in Reference Example 47 (510 m
g) in ethanol (3 ml), pyridine (0.37 m
l), O-benzylhydroxyamine hydrochloride (174
mg) were added sequentially, and the mixture was refluxed for 1 hour and stirred. The reaction mixture was concentrated, ethyl acetate was added to the residue, washed successively with saturated aqueous sodium hydrogen carbonate solution, water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography (hexane:
Purification with ethyl acetate = 19: 1) gave the target compound (513 mg) having the following physical data. TLC: Rf 0.56 (hexane: ethyl acetate = 4:
1).

Reference Example 53

Embedded image

The compound prepared in Reference Example 52 (513 m
g) in ethanol (3 ml) solution at 0 ° C with borane-pyridine complex (0.23 ml), 2N aqueous hydrochloric acid solution (1.2 ml)
Were sequentially added, and the mixture was stirred at room temperature for 3 hours. Ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogen carbonate solution, water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 15: 1) to obtain the desired compound (495 mg) having the following physical properties. TLC: Rf 0.49 (hexane: ethyl acetate = 4:
1).

Reference Example 54

[Chemical formula 226]

The compound prepared in Reference Example 53 (325 m
To a solution of g) in diethyl ether (3 ml) was added methylisocyanate (0.37 ml) under an argon atmosphere, and 1
Stir for 0 minutes. Diethyl ether was added to the reaction mixture, and the mixture was washed successively with ice, 2N hydrochloric acid aqueous solution, water, and saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to obtain the desired compound (307 mg) having the following physical properties. TLC: Rf 0.40 (hexane: ethyl acetate = 1: 1
1).

Reference Example 55

[Chemical 227]

Using the compound prepared in Reference Example 54, the same procedure as in Reference Example 6 was carried out to obtain the desired compound having the following physical data. TLC: Rf 0.22 (hexane: ethyl acetate = 3:
7).

Reference Example 56

[Chemical 228]

Using the compound prepared in Reference Example 53 and carrying out the same operation as in Reference Example 42 → Reference Example 43, the desired compound having the following physical data was obtained. TLC: Rf 0.36 (hexane: ethyl acetate = 1: 1
1).

Reference Example 57

[Chemical formula 229]

The compound prepared in Reference Example 47 (498 m
g) in ethanol (3 ml), pyridine (0.36 m
l) and methoxyamine hydrochloride (89 mg) were added, and 2
Reflux for hours. The reaction mixture was concentrated, ethyl acetate was added to the residue, washed successively with saturated aqueous sodium hydrogen carbonate solution, water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 15: 1) to give the desired compound (493m) having the following physical data.
g) was obtained. TLC: Rf 0.58 (hexane: ethyl acetate = 4:
1).

Reference Example 58

[Chemical 230]

Using the compound produced in Reference Example 57 and the same procedures as in Reference Example 53, the desired compound having the following physical data was obtained. TLC: Rf 0.38 (hexane: ethyl acetate = 4:
1).

Reference Example 59

[Chemical formula 231]

Using the compound prepared in Reference Example 58 and the same procedure as in Reference Example 54 → Reference Example 6, the desired compound having the following physical data was given. TLC: Rf 0.21 (chloroform: methanol = 2
0: 1).

Reference Example 60

[Chemical 232]

Using the compound produced in Reference Example 58 and the same procedure as in Reference Example 56, the desired compound having the following physical data was given. TLC: Rf 0.46 (hexane: ethyl acetate = 1: 1
2).

Reference Example 61

[Chemical formula 233]

The compound prepared in Reference Example 47 (447 m
To a solution of g) in benzene (4 ml) was added N, N-dimethylhydrazine (0.067 ml), and under an argon atmosphere, 2
Reflux for hours. The reaction mixture was concentrated to obtain the target compound having the following physical properties. TLC: Rf 0.55 (hexane: ethyl acetate = 3:
1).

Reference Example 62

[Chemical formula 234]

Methyl iodide (1.0 ml) was added to a solution of the compound prepared in Reference Example 61 in benzene (4 ml), and the mixture was refluxed for 7.5 hours. The reaction mixture was cooled to room temperature, concentrated, and the residue was washed with hexane to obtain the target compound (490 mg) having the following physical data. TLC: Rf 0.20 (chloroform: methanol = 9:
1).

Reference Example 63

[Chemical formula 235]

The compound prepared in Reference Example 62 (486 m
Sodium methoxide (39 mg) was added to a solution of g) in methanol (4 ml) at 0 ° C., and the mixture was stirred at room temperature for 1 hr under an argon atmosphere and then refluxed for 2 hrs. The reaction mixture was cooled to room temperature and then concentrated. Ethyl acetate was added to the residue, washed successively with saturated aqueous ammonium chloride solution, water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 93: 7) to obtain the desired compound (344 mg) having the following physical data. TLC: Rf 0.35 (hexane: ethyl acetate = 17:
3).

Reference Example 64

[Chemical 236]

Using the compound produced in Reference Example 63 and the same procedure as in Reference Example 6, the desired compound having the following physical data was given. TLC: Rf 0.32 (hexane: ethyl acetate = 3:
2).

Reference Example 65

[Chemical 237]

Using the compound prepared in Reference Example 47 and the same procedure as in Reference Example 14 → Reference Example 15, the desired compound having the following physical data was given. TLC: Rf 0.23 (hexane: ethyl acetate = 4:
1).

Reference Example 66

[Chemical 238] Using the compound produced in Reference Example 65, the same operation as in Reference Example 6 was carried out to obtain the target compound having the following physical properties. TLC: Rf 0.23 (hexane: ethyl acetate = 2:
1).

Reference Example 67

[Chemical 239]

The compound prepared in Reference Example 65 (272 m
g) in a methylene chloride (2 ml) solution under an argon atmosphere, triethylamine (0.13 ml), triphenylphosphine (149 mg), tetrabromomethane (376 m).
g) was sequentially added, and the mixture was reacted at room temperature for 1 hour. Water was added to the reaction mixture, and extracted with ethyl acetate. The extract was washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 20: 1) to give the desired compound (348) having the following physical data.
mg). TLC: Rf 0.74 (hexane: ethyl acetate = 4:
1).

Reference Example 68

[Chemical 240]

2-Imidazole carboxaldehyde (2
90 mg) in dimethylformamide (1.5 ml) solution under argon atmosphere, sodium hydride (120 m).
g) was added and the mixture was stirred at 50 ° C. for 30 minutes. A solution of the compound (318 mg) produced in Reference Example 67 in dimethylformamide (1.5 ml) was added to the reaction mixture, and the mixture was stirred at 50 ° C. overnight. Water was added to the reaction mixture, and extracted with ethyl acetate. The extract was washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to obtain the desired compound (265 mg) having the following physical data. TLC: Rf 0.13 (hexane: ethyl acetate = 10:
1).

Reference Example 69

[Chemical 241]

Using the compound prepared in Reference Example 68 and the same procedure as in Reference Example 6, the desired compound having the following physical data was given. TLC: Rf 0.33 (ethyl acetate).

Reference Example 70

[Chemical 242]

To a t-butanol-water (3: 1) mixed solution of the compound (1.45 g) produced in Reference Example 47, sodium dihydrogen phosphate (311 mg), 2-methyl-2-butene (1.21 ml), Sodium hypochlorite (980 mg) was sequentially added at 0 ° C, and the mixture was stirred at room temperature for 15 minutes. Ice water was added to the reaction mixture, and a 1N aqueous hydrochloric acid solution was added until the pH reached 4 to 6. It was extracted with ethyl acetate, the extract was washed with water and saturated aqueous sodium chloride solution successively, dried over anhydrous magnesium sulfate, and concentrated to give the target compound having the following physical properties (1.
36 g) was obtained. TLC: Rf 0.45 (chloroform: methanol = 9:
1).

Reference Example 71

Embedded image

To a solution of the compound (1.36 g) prepared in Reference Example 70 in diethyl ether (7 ml) was added a solution of diazomethane in diethyl ether at 0 ° C. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 15: 1) to obtain the target compound (1.39 g) having the following physical properties. TLC: Rf 0.56 (hexane: ethyl acetate = 4:
1).

Reference Example 72

Embedded image

Using the compound prepared in Reference Example 71 and the same procedures as in Reference Example 6, the desired compound having the following physical data was obtained. TLC: Rf 0.49 (hexane: ethyl acetate = 1: 1
1).

Reference Example 73

[Chemical 245]

Using the compound produced in Reference Example 71 and the same procedure as in Reference Example 35 → Reference Example 36, the desired compound having the following physical data was given. TLC: Rf 0.54 (chloroform: methanol = 9:
1).

Reference Examples 73 (a) to (d) The following compounds were obtained in the same manner as in Reference Example 73 using the corresponding amine instead of the 28% aqueous ammonia solution.

Reference Example 73 (a)

[Chemical formula 246] TLC: Rf 0.33 (hexane: ethyl acetate = 2:
1).

Reference Example 73 (b)

Embedded image TLC: Rf 0.27 (hexane: ethyl acetate = 1: 1
1).

Reference Example 73 (c)

[Chemical 248] TLC: Rf 0.19 (hexane: ethyl acetate = 1: 1
2).

Reference Example 73 (d)

Embedded image TLC: Rf 0.27 (hexane: ethyl acetate = 1: 1
1).

Reference Example 74

[Chemical 250]

Using the compound produced in Reference Example 46 and the same procedure as in Reference Example 39 → Reference Example 40, the desired compound having the following physical data was obtained. TLC: Rf 0.54 (chloroform: methanol = 9:
1).

Reference Example 75

[Chemical 251]

The compound prepared in Reference Example 74 (215 m
Pyridine (0.4 ml) and benzenesulfonyl chloride (0.14 ml) were added to a solution of g) in methylene chloride (1.5 ml) at 0 ° C. under an argon atmosphere, and the mixture was stirred for 2 hours.
Water was added to the reaction mixture, and extracted with ethyl acetate. The extract was washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate =
Purification by 4: 1 → 3: 1) gave the target compound (236 mg) having the following physical data. TLC: Rf 0.89 (chloroform: methanol = 2
0: 1).

Reference Example 76

[Chemical 252]

By using the compound produced in Reference Example 75 and performing the same operation as in Reference Example 6, an intended compound having the following physical data was obtained. TLC: Rf 0.21 (hexane: ethyl acetate = 3:
1).

Reference Example 77

[Chemical 253]

The compound prepared in Reference Example 74 (215 m
Pyridine (0.40 ml) and 1-propanesulfonyl chloride (0.12 ml) were added to a solution of g) in methylene chloride (1.5 ml) at 0 ° C. under an argon atmosphere, and the mixture was stirred for 2 hours and then at room temperature for 1 hour. . Water was added to the reaction mixture,
It was extracted with ethyl acetate. The extract was washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1 → 3: 1) to give the desired compound (217m) having the following physical data.
g) was obtained. TLC: Rf 0.88 (chloroform: methanol = 2
0: 1).

Reference Example 78

Embedded image

Using the compound produced in Reference Example 77 and the same procedure as in Reference Example 6, a target compound having the following physical data was obtained. TLC: Rf 0.15 (hexane: ethyl acetate = 3:
2).

Reference Example 79

[Chemical 255]

Using the compound prepared in Reference Example 77 and substituting methyl iodide for ethyl iodide, Reference Example 2
8 → The same operation as in Reference Example 6 was performed to obtain the target compound having the following physical properties. TLC: Rf 0.40 (hexane: ethyl acetate = 1: 1
2).

Reference Example 80

[Chemical 256]

Using the compound produced in Reference Example 74,
The same operation as in Reference Example 42 was performed to obtain an object compound having the following physical properties. TLC: Rf 0.51 (hexane: ethyl acetate = 3:
2).

Reference Example 81

[Chemical 257]

Using the compound produced in Reference Example 80 and the same procedure as in Reference Example 6, the desired compound having the following physical data was obtained. TLC: Rf 0.17 (hexane: ethyl acetate = 1: 1
2).

Reference Example 82

[Chemical 258]

Using the compound produced in Reference Example 80 and the same procedure as in Reference Example 79, the desired compound having the following physical data was given. TLC: Rf 0.19 (hexane: ethyl acetate = 1: 1
2).

Reference Examples 82 (a) to (c) The same operation as in Reference Example 82 was carried out using the corresponding alkyl halide or mesyl chloride instead of methyl iodide to obtain the following compounds. .

Reference Example 82 (a)

[Chemical 259] TLC: Rf 0.08 (hexane: ethyl acetate = 2:
1).

Reference Example 82 (b)

[Chemical 260] TLC: Rf 0.40 (hexane: ethyl acetate = 1: 1
2).

Reference Example 82 (c)

[Chemical 261] TLC: Rf 0.66 (hexane: ethyl acetate = 1: 1
2).

Reference Example 83

[Chemical 262]

Using the compound prepared in Reference Example 74 and following the procedure of Reference Example 41, the desired compound having the following physical data was given. TLC: Rf 0.14 (hexane: ethyl acetate = 1: 1
1).

Reference Example 84

[Chemical 263]

The compound prepared in Reference Example 74 (312 m
g) in methylene chloride (2 ml) at 0 ° C., 4-dimethylaminopyridine (20 mg), pyridine (0.12 m)
l), isopropylsulfonyl chloride (0.09 ml)
Were sequentially added, and the mixture was stirred at room temperature for 3 days. Ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1 → 4: 1 → 2: 1 → chloroform: methanol = 9: 1) to obtain the target compound (197 mg) having the following physical properties. . TLC: Rf 0.46 (hexane: ethyl acetate = 2:
1).

Reference Example 85

[Chemical 264]

Using the compound prepared in Reference Example 84, the same procedure as in Reference Example 6 was carried out to obtain the desired compound having the following physical data. TLC: Rf 0.42 (hexane: ethyl acetate = 1: 1
2).

Reference Example 86

[Chemical 265]

The compound prepared in Reference Example 74 (281 m
g) in a solution of diethyl ether (2 ml) under an argon atmosphere, trimethylsilyl isocyanate (0.29 ml)
Was added and stirred at room temperature for 1 hour. A 2N aqueous hydrochloric acid solution was added to the reaction mixture, which was cooled and then extracted with ethyl acetate. The extract was washed successively with water, a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated to give the desired compound (305) having the following physical data.
mg). TLC: Rf 0.12 (hexane: ethyl acetate = 1: 1
2).

Reference Example 87

[Chemical 266]

Using the compound produced in Reference Example 86 and the same operation as in Reference Example 6, a target compound having the following physical data was obtained. TLC: Rf 0.09 (hexane: ethyl acetate = 1: 1
4).

Reference Example 88

[Chemical 267] In a methylene chloride (1.5 ml) solution of the compound (196 mg) produced in Reference Example 74, at 0 ° C. under an argon atmosphere,
Pyridine (0.28 ml) and 3-pyridinesulfonyl chloride / hydrochloride (230 mg) were added, and after stirring for 30 minutes,
Stir at room temperature for 2 hours. Water and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate =
5: 1 → 2: 1) to obtain the target compound (261 mg) having the following physical data. TLC: Rf 0.33 (hexane: ethyl acetate = 3:
2).

Reference Example 89

[Chemical 268]

Using the compound produced in Reference Example 88 and the same procedure as in Reference Example 6, the desired compound having the following physical data was given. TLC: Rf 0.34 (ethyl acetate).

Reference Example 90

[Chemical 269]

Compound produced in Reference Example 74 (500 m
g) in methylene chloride (3 ml) at 0 ° C., 4-dimethylaminopyridine (54 mg), pyridine (0.22 m)
l), trifluoromethanesulfonyl chloride (0.14
(ml) were sequentially added, and the mixture was stirred at room temperature for 2 hours. Ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1) to give the desired compound (467) having the following physical data.
mg). TLC: Rf 0.49 (hexane: ethyl acetate = 2:
1).

Reference Example 91

[Chemical 270]

Using the compound produced in Reference Example 90 and the same procedure as in Reference Example 6, the desired compound having the following physical data was given. TLC: Rf 0.28 (hexane: ethyl acetate = 2:
1).

Reference Example 92

[Chemical 271]

Using the compound produced in Reference Example 90 and the same procedure as in Reference Example 79, the desired compound having the following physical data was given. TLC: Rf 0.48 (hexane: ethyl acetate = 1: 1
1).

Reference Example 93

Embedded image

Using the compound produced in Reference Example 74 and the same procedure as in Reference Example 59, the desired compound having the following physical data was given. TLC: Rf 0.08 (chloroform: methanol = 2
0: 1).

Reference Example 94

[Chemical 273]

The compound prepared in Reference Example 74 (281 m
g) in acetone (4.2 ml), potassium carbonate (8
3 mg) and methyl chloroformate (0.04 ml) were added sequentially,
The mixture was stirred at 60 ° C for 1 day. Water was added to the reaction mixture, and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography (hexane:
Ethyl acetate = 1: 1 → chloroform: methanol = 9:
Purification by 1) gave the target compound (223 mg) having the following physical data. TLC: Rf 0.92 (hexane: ethyl acetate = 1: 1
4).

Reference Example 95

[Chemical 274]

By using the compound produced in Reference Example 94 and performing the same operation as in Reference Example 6, an intended compound having the following physical data was obtained. TLC: Rf 0.19 (hexane: ethyl acetate = 1: 1
1).

Reference Example 96

[Chemical 275]

The compound prepared in Reference Example 74 (369 m
g) in ethanol (3 ml), S, S'-dimethyl-N-cyanodithioiminocarbonate (128 m
g) was added and the mixture was refluxed for 3 hours. The reaction mixture was concentrated, ethyl acetate was added to the residue, washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1 → 2: 1 → chloroform: methanol = 9: 1) to obtain the desired compound (370 mg) having the following physical properties. TLC: Rf 0.20 (hexane: ethyl acetate = 2:
1).

Reference Example 97

[Chemical 276]

The compound prepared in Reference Example 96 (370 m
g) in methanol (2 ml), methylamine (5
ml) was added and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to obtain the desired compound (350 mg) having the following physical properties. TLC: Rf 0.30 (hexane: ethyl acetate = 1: 1
2).

Reference Example 98

[Chemical 277]

Using the compound produced in Reference Example 97 and the same procedures as in Reference Example 6, the desired compound having the following physical data was obtained. TLC: Rf 0.24 (chloroform: methanol = 9:
1).

Reference Example 99

[Chemical 278]

Using 3-methoxy-4-acetoxy-5-isopropyl-6- (2-methyl-2-propenyl) phenol, the same operation as in Reference Example 1 → Reference Example 2 was carried out to give the following physical data. The target compound having TLC: Rf 0.15 (hexane: ethyl acetate = 3:
1).

Reference Example 100

[Chemical formula 279]

The compound prepared in Reference Example 99 (714 m
g) in methylene chloride (10 ml), pyridine (0.
29 ml), N, N-dimethylaminopyridine (147 m
g) and acetic anhydride (0.34 ml) were sequentially added, and the mixture was stirred at room temperature for 30 minutes. A 1N aqueous hydrochloric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water, saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated to obtain the target compound (714 mg) having the following physical data. TLC: Rf 0.37 (hexane: ethyl acetate = 3:
1).

Reference Example 101

[Chemical 280]

The compound prepared in Reference Example 100 (714 m
Dichloromethyl methyl ether (0.48 ml) and titanium tetrachloride (0.58 ml) were sequentially added to a solution of g) in methylene chloride (5 ml) at 0 ° C., and the mixture was stirred at the same temperature for 10 minutes.
Ice was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate =
Purification by 3: 1) gave the target compound (526 mg) having the following physical data. TLC: Rf 0.50 (hexane: ethyl acetate = 1: 1
1).

Reference Example 102

[Chemical 281]

Using the compound produced in Reference Example 101,
The same operations as in Reference Example 34 → Reference Example 5 → Reference Example 14 → Reference Example 15 were carried out to obtain a target compound having the following physical properties. TLC: Rf 0.14 (hexane: ethyl acetate = 2:
1).

Reference Example 103

[Chemical 282]

Using 3-ethyl-4-acetoxy-5-isopropyl-6- (2-methyl-2-propenyl) phenol, Reference Example 99 → Reference Example 100 → Reference Example 101
→ The same operation as in Reference Example 102 was performed to obtain an object compound having the following physical property values. TLC: Rf 0.44 (hexane: ethyl acetate = 1: 1
1).

Reference Example 103 (a) to (f) 3-Ethyl-4-acetoxy-5-isopropyl-6-
Using the corresponding phenol instead of (2-methyl-2-propenyl) phenol, the same operation as in Reference Example 103 was performed to obtain the compound shown below.

Reference Example 103 (a)

Embedded image TLC: Rf 0.35 (hexane: ethyl acetate = 1: 1
1).

Reference Example 103 (b)

[Chemical 284] TLC: Rf 0.33 (hexane: ethyl acetate = 1: 1
1).

Reference Example 103 (c)

[Chemical 285] TLC: Rf 0.14 (hexane: ethyl acetate = 2:
1).

Reference Example 103 (d)

[Chemical 286] TLC: Rf 0.14 (hexane: ethyl acetate = 2:
1).

Reference Example 103 (e)

[Chemical 287] TLC: Rf 0.18 (hexane: ethyl acetate = 1: 1
1).

Reference Example 103 (f)

Embedded image TLC: Rf 0.17 (hexane: ethyl acetate = 2:
1).

Reference Example 104

[Chemical formula 289]

Using 3-methyl-4-acetoxy-5-isopropyl-6- (2-methyl-2-propenyl) phenol, Reference Example 99 → Reference Example 100 → Reference Example 101
-> Reference example 34-> It carried out similarly to the reference example 5, and obtained the target compound which has the following physical-property values. TLC: Rf 0.70 (hexane: ethyl acetate = 1: 1
1).

Reference Example 105

[Chemical 290]

Using the compound prepared in Reference Example 104,
The same operations as in Reference Example 22 → Reference Example 20 → Reference Example 4 were carried out to obtain a target compound having the following physical properties. TLC: Rf 0.35 (hexane: ethyl acetate = 1: 1
1).

Reference Example 106

[Chemical formula 291]

The compound prepared in Reference Example 104 (140 m
g) in methylene chloride (2 ml) at 0 ° C., sodium borohydride (23 mg), methanol (10 m
1) were added sequentially and stirred for 10 minutes. 1N in the reaction mixture
Aqueous hydrochloric acid was added to adjust the pH to 4 to 6, and the mixture was extracted with ethyl acetate. The extract was washed successively with water, saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 1).
Purification by 1) gave the target compound (135 mg) having the following physical data. TLC: Rf 0.15 (hexane: ethyl acetate = 3:
1).

Reference Example 107

[Chemical 292]

Using 3-propyl-4-acetoxy-5-methyl-6- (2-methyl-2-propenyl) phenol, the same operation as in Reference Example 104 was carried out to give the desired compound having the following physical data. Got TLC: Rf 0.40 (hexane: ethyl acetate = 2:
1).

Reference Example 108

[Chemical formula 293]

Using the compound prepared in Reference Example 107,
The same operation as in Reference Example 14 → Reference Example 15 was carried out to obtain the target compound having the following physical properties. TLC: Rf 0.22 (hexane: ethyl acetate = 2:
1).

Reference Example 109

[Chemical formula 294]

Using the compound prepared in Reference Example 107,
The same operation as in Reference Example 105 was performed to obtain an object compound having the following physical properties. TLC: Rf 0.22 (hexane: ethyl acetate = 2:
1).

Reference Example 110

Embedded image

Using the compound prepared in Reference Example 107,
The same operation as in Reference Example 106 was performed to obtain an object compound having the following physical properties. TLC: Rf 0.20 (hexane: ethyl acetate = 2:
1).

Reference Example 111

[Chemical 296]

2- (2-pivaloyloxyethyl) -3
-Methyl-4-acetoxy-5-t-butyl-6- (2
-Methyl-2-propenyl) phenol was used to perform the same operations as in Reference Example 1-> Reference Example 2-> Reference Example 9-> Reference Example 4-> Reference Example 5 to obtain the target compound having the following physical property values. . TLC: Rf 0.33 (hexane: ethyl acetate = 1: 1
1).

Reference Example 112

[Chemical 297]

Using 2,5-dimethyl-4-methoxymethyloxy-6- (2-methyl-2-propenyl) phenol, Reference Example 1 → Reference Example 2 → Reference Example 13 → Reference Example 1
4 → Reference Example 15 → Reference Example 11 → Reference Example 101 → Reference Example 2
2 → Reference Example 20 → The same operation as in Reference Example 4 was performed to obtain the target compound having the following physical properties. TLC: Rf 0.11 (hexane: ethyl acetate = 1: 1
1).

Reference Example 113

[Chemical 298]

2,5-Dimethyl-4-acetoxy-6-
With (2-methyl-2-propenyl) phenol,
The same operations as in Reference Example 1 → Reference Example 2 → Reference Example 100 → Reference Example 101 → Reference Example 34 → Reference Example 5 were performed to obtain the target compound having the following physical properties. TLC: Rf 0.32 (hexane: ethyl acetate = 2:
1).

Reference Example 114

[Chemical 299]

Using the compound produced in Reference Example 113,
The same operations as in Reference Example 22 → Reference Example 20 → Reference Example 4 were carried out to obtain a target compound having the following physical properties. TLC: Rf 0.38 (hexane: ethyl acetate = 1: 1
1).

Reference Example 115

[Chemical 300]

The compound prepared in Reference Example 114 (200 m
To a solution of g) in methanol (1 ml) was added a 4N hydrochloric acid dioxane solution (0.3 ml), and the mixture was stirred for 30 minutes. Water was added to the reaction mixture, and extracted with ethyl acetate. Extract the water,
The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated to give the desired compound (163 mg) having the following physical data. TLC: Rf 0.19 (hexane: ethyl acetate = 2:
3).

Reference Example 116

[Chemical 301]

Using the compound prepared in Reference Example 115,
The same operations as in Reference Example 5 → Reference Example 8 → Reference Example 39 → Reference Example 40 were performed to obtain the target compound having the following physical properties. TLC: Rf 0.34 (chloroform: methanol = 1
0: 1).

Reference Example 117

[Chemical 302]

Using the compound prepared in Reference Example 116,
The same operation as in Reference Example 42 → Reference Example 43 was performed to obtain the target compound having the following physical properties. TLC: Rf 0.10 (hexane: ethyl acetate = 1: 1
1).

Reference Example 118

[Chemical 303]

To a suspension of sodium hydride (80 mg) in tetrahydrofuran (2 ml) was added triethylphosphonoacetate (0.40 ml) in tetrahydrofuran (2 ml).
The solution was added at -30 ° C and stirred for 30 minutes. A solution of the compound (560 mg) produced in Reference Example 47 in tetrahydrofuran (3 ml) was added to the reaction mixture at -30 ° C to give 20.
Stir for minutes. A saturated ammonium chloride aqueous solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 19: 1 →
9: 1) to obtain the target compound (583 mg) having the following physical data. TLC: Rf 0.52 (hexane: ethyl acetate = 4:
1).

Reference Example 119

[Chemical 304]

The compound prepared in Reference Example 118 (583 m
Diisobutylaluminum hydride (2 ml, 1.0 M toluene solution) was added to a solution of g) in toluene (2 ml) at -78 ° C, and the mixture was stirred for 20 minutes. Methanol (1 ml) and water (0.5 ml) were added to the reaction mixture, and the mixture was stirred at -78 ° C for 20 min, anhydrous sodium sulfate was added, and the mixture was stirred at room temperature for 30 min. After concentrating the organic layer, the residue is subjected to silica gel column chromatography (hexane: ethyl acetate =
4: 1) to obtain the target compound (440 mg) having the following physical data. TLC: Rf 0.21 (hexane: ethyl acetate = 4:
1).

Reference Example 120

[Chemical 305]

Using the compound prepared in Reference Example 119,
The same operation as in Reference Example 9 → Reference Example 6 was carried out to obtain a target compound having the following physical properties. TLC: Rf 0.30 (hexane: ethyl acetate = 1: 1
1).

Reference Example 121

[Chemical 306]

Reference Example 1 using methylhydroquinone
The same operation as in 1 was carried out to obtain the target compound having the following physical properties. TLC: Rf 0.24 (hexane: ethyl acetate = 4:
1).

Reference Example 122

[Chemical 307]

Using the compound produced in Reference Example 121,
Using methyl iodide instead of ethyl iodide and performing the same operation as in Reference Example 28, the target compound having the following physical properties was obtained. TLC: Rf 0.70 (hexane: ethyl acetate = 4:
1).

Reference Example 123

[Chemical 308]

Using the compound prepared in Reference Example 122,
The same operation as in Reference Example 34 was performed to obtain an object compound having the following physical properties. TLC: Rf 0.23 (hexane: ethyl acetate = 5:
1).

Reference Example 124

[Chemical formula 309]

Compound (3.9 g) produced in Reference Example 123
In dimethylformamide (30 ml) solution of β-methallyl chloride (3.7 ml) and potassium carbonate (2.84 g)
Were sequentially added, and the mixture was stirred at 70 ° C. for 5 hours. The reaction mixture was poured into ice water (120 ml) and extracted with a mixed solution of ethyl acetate-ether (1: 1). The extract was washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to obtain the target compound (4.3 g) having the following physical properties. TLC: Rf 0.70 (hexane: ethyl acetate = 5:
1).

Reference Example 125

[Chemical 310]

Compound produced in Reference Example 124 (4.3 g)
Solution of diethylaniline (30 ml) in
Stirred for hours. The reaction mixture was cooled to room temperature and then diluted with ethyl acetate. The diluted solution was washed with a 2N hydrochloric acid aqueous solution until the pH became 1, and further washed with a saturated sodium hydrogen carbonate aqueous solution, water, and a saturated sodium chloride aqueous solution in that order, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 15: 1) to obtain target compound A (1.0 g) and target compound B (2.2 g) having the following physical properties. TLC: A: Rf 0.22 (hexane: ethyl acetate = 1
5: 1). B: Rf 0.11 (hexane: ethyl acetate = 15: 1).

Reference Example 126

[Chemical 311]

Compound A (5 g) prepared in Reference Example 125
In acetonitrile (100 ml), water (50 m
1) was added and cooled to 0 ° C. Cerium ammonium nitrate (CAN, 35.7 g) was added to the reaction mixture in several portions, and the mixture was stirred for 10 minutes. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 15: 1),
The target compound (3.96 g) having the following physical data was obtained. TLC: Rf 0.36 (hexane: ethyl acetate = 10:
1).

Reference Example 127

[Chemical 312]

Using the compound prepared in Reference Example 126,
Reference Example 106 → The same operation as in Reference Example 2 was carried out to obtain the target compound having the following physical properties. TLC: Rf 0.61 (hexane: ethyl acetate = 2:
1).

Reference Example 128

[Chemical 313]

Using the compound prepared in Reference Example 127,
The same operations as in Reference Example 101 → Reference Example 5 → Reference Example 14 → Reference Example 15 were carried out to obtain a target compound having the following physical properties. TLC: Rf 0.84 (hexane: ethyl acetate = 3:
1).

Reference Example 129

[Chemical 314]

Using the compound prepared in Reference Example 128,
The same operation as in Reference Example 3 was carried out to obtain the target compound having the following physical properties. TLC: Rf 0.53 (hexane: ethyl acetate = 10:
1).

Reference Example 130

[Chemical 315]

The compound prepared in Reference Example 129 (770 m
g) in diethyl ether (3 ml) at 0 ° C.
-Butyllithium (3.2 ml, 1.6 M hexane solution) was added dropwise. The reaction mixture was stirred at the same temperature for 1 hr, acetone (0.45 ml) and diethyl ether (3 ml) were added, and the mixture was stirred for 1 hr. The reaction mixture was added to ice water and extracted with ethyl acetate. The extract was washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to obtain the target compound (247 mg) having the following physical properties. TLC: Rf 0.42 (hexane: ethyl acetate = 5:
1).

Reference Example 131

[Chemical 316]

Using the compound produced in Reference Example 130,
The same operation as in Reference Example 6 was performed to obtain an object compound having the following physical properties. TLC: Rf 0.33 (hexane: ethyl acetate = 1: 1
1).

Reference Example 132

[Chemical 317]

Using the compound prepared in Reference Example 127,
The same operation as in Reference Example 5 was carried out to obtain the target compound having the following physical properties. TLC: Rf 0.36 (hexane: ethyl acetate = 9:
1).

Reference Example 133

[Chemical 318]

[0475] The compound prepared in Reference Example 132 (5.43 g)
A small amount of o-phenanthroline (indicator) was added to a solution of tetramethylethylenediamine (4.0 ml) in diethyl ether (50 ml), and n-butyllithium (16.5 ml, 1.6 M hexane solution) was added dropwise at 0 ° C for 45 minutes. It was stirred. After cooling to −70 ° C., ethyl α- was added to the reaction mixture.
Bromoisobutyrate (4.3 ml) was slowly added dropwise to 1
After stirring for 5 minutes, the mixture was stirred at room temperature for 15 minutes. A saturated ammonium chloride aqueous solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated.
The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1) to obtain the target compound (6.99 g) having the following physical properties. TLC: Rf 0.44 (hexane: ethyl acetate = 9:
1).

Reference Example 134

[Chemical 319]

Using the compound prepared in Reference Example 133,
Reference Example 115 → Reference Example 128 → The same operation as in Reference Example 3 was carried out to obtain the target compound having the following physical properties. TLC: Rf 0.53 (hexane: ethyl acetate = 9:
1).

Reference Example 135

[Chemical 320]

Compound (1.5 g) produced in Reference Example 134
A solution of tetramethylethylenediamine (0.59 ml) in diethyl ether (9 ml) was cooled to 0 ° C. N-Butyllithium (2.45 ml, 1.6 M hexane solution) was added dropwise to the reaction mixture, and the mixture was stirred at the same temperature for 1 hr. The reaction mixture was cooled to -40 ° C and tetrahydro-4H-pyran-4
-ON (0.39 ml) was added, and the mixture was stirred at 0 ° C for 1 hr. A saturated ammonium chloride aqueous solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1 → 5: 1) to obtain the target compound (665 mg) having the following physical properties. TLC: Rf 0.68 (hexane: ethyl acetate = 1: 1
1).

Reference Example 136

[Chemical 321]

Using the compound prepared in Reference Example 135,
The same operation as in Reference Example 6 was performed to obtain an object compound having the following physical properties. TLC: Rf 0.25 (hexane: ethyl acetate = 1: 1
1).

Reference Example 137

[Chemical 322]

Using the compound prepared in Reference Example 135,
The same operation as in Reference Example 79 was performed to obtain an object compound having the following physical properties. TLC: Rf 0.14 (hexane: ethyl acetate = 1: 1
1).

Reference Example 138

[Chemical Formula 323]

[0485] The compound prepared in Reference Example 134 (3.73 g)
A small amount of o-phenanthroline (indicator) was added to a solution of tetramethylethylenediamine (1.4 ml) in diethyl ether (16 ml), and n was added at 0 ° C. under an argon atmosphere.
-Butyllithium (5.6 ml, 1.6 M hexane solution) was added dropwise, and after stirring for 30 minutes, dimethylformamide (2.
0 ml) was added dropwise and the mixture was stirred for 40 minutes. After stirring at room temperature for 30 minutes, ice and saturated aqueous ammonium chloride solution were added, and the mixture was extracted with diethyl ether. The extract was washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1) to obtain the target compound (3.02 g) having the following physical properties. TLC: Rf 0.33 (hexane: ethyl acetate = 9:
1).

Reference Example 139

[Chemical 324]

Using the compound prepared in Reference Example 138,
The same operations as in Reference Example 14 → Reference Example 15 → Reference Example 13 → Reference Example 70 → Reference Example 71 were performed to obtain the target compound having the following physical properties. TLC: Rf 0.37 (hexane: ethyl acetate = 4:
1).

Reference Example 140

[Chemical 325]

N-Butyllithium (4.1 ml, 1.6 M hexane solution) was added dropwise to a solution of diisopropylamine (0.92 ml) in tetrahydrofuran (2.5 ml) at 0 ° C. under an argon atmosphere, and the mixture was stirred for 30 minutes. After cooling to −70 ° C., a solution of the compound (1.98 g) produced in Reference Example 139 in tetrahydrofuran (8.5 ml) was added dropwise, and the mixture was stirred for 10 minutes. Methyl iodide (0.55 ml) was added dropwise to the reaction mixture, and the mixture was stirred at 0 ° C for 20 min. A saturated ammonium chloride aqueous solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated to obtain the target compound (2.17 g) having the following physical data. TLC: Rf 0.41 (hexane: ethyl acetate = 4:
1).

Reference Example 141

[Chemical formula 326]

N-Butyllithium (4.1 ml, 1.6 M hexane solution) was added dropwise to a solution of diisopropylamine (0.92 ml) in tetrahydrofuran (2.5 ml) at 0 ° C. under an argon atmosphere, and the mixture was stirred for 30 minutes. After cooling to −40 ° C., a solution of the compound (2.17 g) produced in Reference Example 140 in tetrahydrofuran (8.5 ml) was added dropwise, and the mixture was stirred for 30 minutes. Methyl iodide (0.55 ml) was added dropwise to the reaction mixture, and the mixture was stirred at room temperature for 50 minutes. A saturated ammonium chloride aqueous solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate =
17: 3) to obtain the target compound (2.04 g) having the following physical data. TLC: Rf 0.44 (hexane: ethyl acetate = 17:
3).

Reference Example 142

[Chemical 327]

Using the compound produced in Reference Example 141,
The same operations as in Reference Example 4 → Reference Example 9 → Reference Example 6 were carried out to obtain a target compound having the following physical properties. TLC: Rf 0.18 (hexane: ethyl acetate = 7:
3).

Reference Example 143

[Chemical 328]

Using the compound prepared in Reference Example 141,
The same operation as in Reference Example 6 was performed to obtain an object compound having the following physical properties. TLC: Rf 0.19 (hexane: ethyl acetate = 7:
3).

Reference Example 144

[Chemical 329]

Using the compound prepared in Reference Example 128,
The same operation as in Reference Example 11 → Reference Example 115 was carried out to obtain an object compound having the following physical properties. TLC: Rf 0.43 (hexane: ethyl acetate = 3:
1).

Reference Example 145

[Chemical 330]

Compound prepared in Reference Example 144 (16 g)
Sodium hydride (2.7 g, 60% content) was added to the dimethylformamide (40 ml) solution of. 30 at room temperature
After stirring for minutes, allyl bromide (6.3 ml) was added. The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into ice water (150 ml) and extracted with a hexane-ethyl acetate (2: 1) mixed solution. The extract was washed successively with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated to give the target compound (1
9.1 g) was obtained. TLC: Rf 0.48 (hexane: ethyl acetate = 4:
1).

Reference Example 146

[Chemical 331]

Using the compound prepared in Reference Example 145,
The same operation as in Reference Example 125 → Reference Example 5 was performed to obtain an object compound having the following physical properties. TLC: Rf 0.40 (hexane: ethyl acetate = 10:
1).

Reference Example 147

[Chemical 332]

Palladium dichloride (PdCl ₂ , 12 m
g) dimethylformamide (1 ml) and water (0.2 m
l) In a solution, in an oxygen atmosphere, copper chloride (CuCl, 65 m
g) was added, and the mixture was stirred at room temperature for 30 minutes. A solution of the compound (262 mg) produced in Reference Example 146 in dimethylformamide (1.5 ml) was added to the mixture. The reaction mixture is
The mixture was stirred overnight at room temperature under an oxygen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with a hexane-ethyl acetate (1: 1) mixed solution. The extract was washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to obtain the target compound (233 mg) having the following physical properties. TLC: Rf 0.54 (hexane: ethyl acetate = 3:
2).

Reference Example 148

[Chemical 333]

The compound prepared in Reference Example 147 (509 m
A solution of g) in tetrahydrofuran (3 ml) was cooled to 0 ° C. and methylmagnesium bromide (6.2 ml, 1M tetrahydrofuran solution) was added. The reaction mixture was stirred at room temperature for 20 minutes and 50 ° C. for 30 minutes. Aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 2) to obtain the desired compound (354 mg) having the following physical data. TLC: Rf 0.14 (hexane: ethyl acetate = 3:
2).

Reference Example 149

[Chemical 334]

By using the compound produced in Reference Example 128,
Reference Example 115 → Reference Example 145 → Reference Example 8 → Reference Example 146
-> Reference example 15-> The same operation as in Reference example 6 was performed to obtain the target compound having the following physical properties. TLC: Rf 0.19 (hexane: ethyl acetate = 1: 1
1).

Reference Example 150

[Chemical 335]

Using the compound B produced in Reference Example 125, Reference Example 126-> Reference Example 127-> Reference Example 145-> Reference Example 146-> Reference Example 15-> Reference Example 11-> Reference Example 115-> Reference Example 101-> Reference Example 5 The same operation as the above was performed to obtain the target compound having the following physical properties. TLC: Rf 0.42 (hexane: ethyl acetate = 2:
1).

Reference Example 151

[Chemical 336]

Using the compound produced in Reference Example 150,
The same operation as in Reference Example 14 → Reference Example 15 was carried out to obtain the target compound having the following physical properties. TLC: Rf 0.33 (hexane: ethyl acetate = 2:
1).

Reference Example 152

[Chemical 337]

Using the compound produced in Reference Example 151,
The same operation as in Reference Example 4 was carried out to obtain the target compound having the following physical property values. TLC: Rf 0.13 (hexane: ethyl acetate = 1: 1
2).

Reference Example 153

[Chemical 338]

Using the compound produced in Reference Example 151,
The same operations as in Reference Example 9 → Reference Example 4 were carried out to obtain the target compound having the following physical properties. TLC: Rf 0.30 (hexane: ethyl acetate = 1: 1
2).

Reference Example 154

[Chemical 339]

Using the compound produced in Reference Example 150,
The same operation as in Reference Example 4 was carried out to obtain the target compound having the following physical property values. TLC: Rf 0.29 (hexane: ethyl acetate = 1: 1
3).

Reference Example 155

[Chemical 340]

Using the compound produced in Reference Example 150,
The same operations as in Reference Example 106 → Reference Example 74 → Reference Example 42 were performed to obtain an object compound having the following physical properties. TLC: Rf 0.53 (hexane: ethyl acetate = 1: 1
1).

Reference Example 156

[Chemical 341]

Using the compound produced in Reference Example 155,
The same operation as in Reference Example 4 was carried out to obtain the target compound having the following physical property values. TLC: Rf 0.32 (hexane: ethyl acetate = 1: 1
2).

Reference Example 157

[Chemical 342]

Using the compound produced in Reference Example 155,
The same operation as in Reference Example 122 → Reference Example 4 was carried out to obtain a target compound having the following physical properties. TLC: Rf 0.44 (hexane: ethyl acetate = 1: 1
2).

Reference Example 158

[Chemical 343]

Reference Example 1 using methylhydroquinone
1 → Reference Example 124 → Reference Example 125 → Reference Example 2 → Reference Example 4
-> Reference example 145-> Reference example 125-> Reference example 145-> Reference example 146-> The same operation as reference example 15 was carried out to obtain the target compound having the following physical property values. TLC: Rf 0.07 (hexane: ethyl acetate = 1: 1
1).

Reference Example 159

[Chemical 344]

Reference Example 121 → Reference Example 122 → Reference Example 123 → Reference Example 12 using isopropylhydroquinone
4-> Reference Example 125-> Reference Example 126-> Reference Example 127-> Reference Example 132-> Reference Example 133-> Reference Example 134-> Reference Example 138
-> Reference example 106-> Reference example 9-> It carried out similarly to the reference example 6, and obtained the target compound which has the following physical-property values. TLC: Rf 0.31 (hexane: ethyl acetate = 2:
1).

Reference Example 160

[Chemical 345]

Using 2-isopropylphenol and the same procedure as in Reference Example 145 → Reference Example 125, the desired compound having the following physical data was obtained. TLC: Rf 0.54 (hexane: ethyl acetate = 9:
1).

Reference Example 161

[Chemical 346]

Compound prepared in Reference Example 160 (30 g)
In ethanol (500 ml) solution of salcomine (7.5
g) was added, and the mixture was stirred under an oxygen atmosphere at room temperature for 3 days. The reaction mixture was concentrated, diluted with ethyl acetate, and filtered through Celite (trade name). The filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1) to obtain a mixture (12.3 g) of the objective compound having the following physical properties and phenol. TLC: Rf 0.50 (hexane: ethyl acetate = 9:
1).

Reference Example 162

[Chemical 347]

Using the compound produced in Reference Example 161,
Reference Example 106-> The same operation as in Reference Example 100 was performed to obtain an object compound having the following physical properties. TLC: Rf 0.56 (hexane: ethyl acetate = 3:
1).

Reference Example 163

[Chemical 348]

Compound (4.4 g) prepared in Reference Example 162
In ethanol (60 ml) at 0 ° C., sodium dithionite (800 mg) and sodium hydroxide (733 mg) were added.
mg) in water (7 ml) was added slowly. The reaction mixture was stirred at 0 ° C. for 30 minutes. The reaction mixture was mixed with ice water (20
The mixture was poured into 0 ml) and adjusted to pH 6 with a 1N aqueous hydrochloric acid solution, and extracted with diethyl ether. The extract is washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and the target compound (3.6g) having the following physical data.
I got TLC: Rf 0.47 (hexane: ethyl acetate = 3:
1).

Reference Example 164

[Chemical 349]

Using the compound prepared in Reference Example 163,
Reference Example 124 → Reference Example 125 → Reference Example 2 → Reference Example 34 →
The same operations as in Reference Example 5 → Reference Example 15 → Reference Example 11 → Reference Example 115 → Reference Example 101 were carried out to obtain the target compound having the following physical properties. TLC: Rf 0.50 (hexane: ethyl acetate = 3:
1).

Reference Example 165

[Chemical 350]

Using the compound produced in Reference Example 164,
The same operations as in Reference Example 34 → Reference Example 5 → Reference Example 14 → Reference Example 15 were carried out to obtain a target compound having the following physical properties. TLC: Rf 0.23 (hexane: ethyl acetate = 3:
1).

Reference Example 166

[Chemical 351]

Using the compound prepared in Reference Example 164,
The same operations as in Reference Example 5 → Reference Example 34 → Reference Example 14 → Reference Example 15 were carried out to obtain a target compound having the following physical properties. TLC: Rf 0.08 (hexane: ethyl acetate = 1: 1
1).

Reference Example 167

[Chemical 352]

2- (2-pivaloyloxyethyl) -3
-Ethyl-4-acetoxy-5-propyl-6- (2-
Using methyl-2-propenyl) phenol, the same operations as in Reference Example 1 → Reference Example 2 → Reference Example 3 → Reference Example 4 → Reference Example 5 → Reference Example 46 → Reference Example 9 → Reference Example 6 were performed, The target compound having the following physical properties was obtained. TLC: Rf 0.33 (hexane: ethyl acetate = 2:
1).

Reference Example 167 (a) to (c) 2- (2-pivaloyloxyethyl) -3-ethyl-4
-Acetoxy-5-propyl-6- (2-methyl-2-
Using a corresponding phenol instead of propenyl) phenol, the same operation as in Reference Example 167 was carried out to obtain the following target compound.

Reference Example 167 (a)

[Chemical 353] TLC: Rf 0.34 (hexane: ethyl acetate = 2:
1).

Reference Example 167 (b)

[Chemical 354] TLC: Rf 0.32 (hexane: ethyl acetate = 2:
1).

Reference Example 167 (c)

[Chemical 355] TLC: Rf 0.31 (hexane: ethyl acetate = 1: 1
1).

Reference Example 168

[Chemical 356]

2-Isopropyl-4-acetoxy-5-
Using methyl-6- (2-methyl-2-propenyl) phenol, the procedure of Reference Example 113 → Reference Example 114 was repeated to give the target compound having the following physical properties. TLC: Rf 0.24 (hexane: ethyl acetate = 2:
1).

Reference Example 168 (a)-(b) 2-Isopropyl-4-acetoxy-5-methyl-6-
Using the corresponding phenol instead of (2-methyl-2-propenyl) phenol, the same operation as in Reference Example 168 was performed to obtain the target compound shown below.

Reference Example 168 (a)

[Chemical 357] TLC: Rf 0.42 (hexane: ethyl acetate = 1: 1
1).

Reference Example 168 (b)

[Chemical 358] TLC: Rf 0.31 (hexane: ethyl acetate = 1: 1
1).

Reference Example 169

[Chemical 359]

Using the compound produced in Reference Example 2 and the same procedures as in Reference Example 9 → Reference Example 4 → Reference Example 8 → Reference Example 79, the desired compound having the following physical data was obtained. TLC: Rf 0.25 (hexane: ethyl acetate = 2:
1).

Reference Example 170

[Chemical 360]

2- (2-pivaloyloxyethyl) -3
-Propyl-4-acetoxy-5-methyl-6- (2-
Using methyl-2-propenyl) phenol, the same operations as in Reference Example 1 → Reference Example 2 → Reference Example 3 → Reference Example 4 → Reference Example 5 → Reference Example 46 → Reference Example 74 → Reference Example 42 were performed, The target compound having the following physical properties was obtained. TLC: Rf 0.25 (hexane: ethyl acetate = 2:
1).

Reference Example 171

[Chemical 361]

Using the compound produced in Reference Example 170,
The same operation as in Reference Example 6 was performed to obtain an object compound having the following physical properties. TLC: Rf 0.21 (hexane: ethyl acetate = 1: 1
2).

Reference Example 172

[Chemical 362]

Using the compound prepared in Reference Example 170,
The same operation as in Reference Example 79 was performed to obtain an object compound having the following physical properties. TLC: Rf 0.27 (hexane: ethyl acetate = 1: 1
2).

Reference Example 173

[Chemical Formula 363]

2- (2-pivaloyloxyethyl) -3
-Methyl-4-acetoxy-5-propyl-6- (2-
Using methyl-2-propenyl) phenol, the same operation as in Reference Example 170 → Reference Example 172 was performed to obtain the target compound having the following physical properties. TLC: Rf 0.25 (hexane: ethyl acetate = 1: 1
2).

Reference Example 174

[Chemical 364]

By using the compound produced in Reference Example 114,
The same operations as in Reference Example 8 → Reference Example 115 → Reference Example 5 → Reference Example 13 were carried out to obtain a target compound having the following physical properties. TLC: Rf 0.59 (hexane: ethyl acetate = 2:
1).

Reference Example 175

[Chemical 365]

Using the compound prepared in Reference Example 174,
The same operation as in Reference Example 70 was performed to obtain an object compound having the following physical properties. TLC: Rf 0.39 (chloroform: methanol = 9:
1).

Reference Example 176

[Chemical 366]

Using the compound prepared in Reference Example 175,
The same operation as in Reference Example 73 was performed to obtain an object compound having the following physical properties. TLC: Rf 0.48 (chloroform: methanol = 9:
1).

Reference Example 176 (a)

[Chemical 367]

Using dimethylamine instead of the 28% aqueous ammonia solution, the same operation as in Reference Example 176 was carried out to obtain the target compound having the following physical data. TLC: Rf 0.27 (chloroform: methanol = 5
0: 1).

Reference Example 177

[Chemical 368]

Using the compound produced in Reference Example 174,
The same operation as in Reference Example 57 → Reference Example 53 was carried out to obtain the target compound having the following physical properties. TLC: Rf 0.37 (hexane: ethyl acetate = 3:
1).

Reference Example 178

[Chemical formula 369]

Using the compound prepared in Reference Example 177,
The same operation as in Reference Example 54 → Reference Example 6 was carried out to obtain a target compound having the following physical properties. TLC: Rf 0.41 (chloroform: methanol = 9:
1).

Reference Example 179

[Chemical 370]

Using the compound prepared in Reference Example 177,
Reference Example 42 → The same operation as Reference Example 6 was carried out to obtain the target compound having the following physical properties. TLC: Rf 0.27 (hexane: ethyl acetate = 1: 1
1).

Reference Example 180

[Chemical 371]

[0578]

Using the compound prepared in Reference Example 174,
The same operations as in Reference Example 52 → Reference Example 53 → Reference Example 56 were carried out to obtain the target compound having the following physical properties. TLC: Rf 0.35 (hexane: ethyl acetate = 1: 1
1).

Reference Example 181

[Chemical 372]

2- (2-pivaloyloxyethyl)-
Using 3,5-dimethyl-4-acetoxy-6- (2-methyl-2-propenyl) phenol, the same operation as in Reference Example 1 → Reference Example 2 → Reference Example 9 → Reference Example 4 → Reference Example 5 was performed. Thus, the target compound having the following physical properties was obtained. TLC: Rf 0.34 (hexane: ethyl acetate = 1: 1
1).

Reference Example 182

[Chemical 373]

2- (2-pivaloyloxyethyl)-
Using 3,5-dimethyl-4-acetoxy-6- (2-methyl-2-propenyl) phenol, Reference Example 1 → Reference Example 2 → Reference Example 3 → Reference Example 4 → Reference Example 5 → Reference Example 46 →
The same operations as in Reference Example 74 → Reference Example 42 → Reference Example 6 were carried out to obtain a target compound having the following physical properties. TLC: Rf 0.17 (hexane: ethyl acetate = 1: 1
2).

Reference Example 183

[Chemical 374]

2- (2-pivaloyloxyethyl) -4
Using -acetoxy-5-methyl-6- (2-methyl-2-propenyl) phenol, Reference Example 1 → Reference Example 2 →
Reference example 3 → Reference example 4 → Reference example 5 → Reference example 46 → Reference example 1
15 → Reference Example 9 → Reference Example 160 → The same operation as in Reference Example 5 was carried out to obtain the target compound having the following physical property values. TLC: Rf 0.29 (hexane: ethyl acetate = 4:
1).

Reference Example 184

[Chemical 375]

Using the compound prepared in Reference Example 183,
Perform the same operation as in Reference Example 6 → Reference Example 5 → Reference Example 15,
The target compound having the following physical properties was obtained. TLC: Rf 0.21 (hexane: ethyl acetate = 1: 1
1).

Reference Example 185

[Chemical 376]

By using the compound produced in Reference Example 183,
Perform the same operation as in Reference Example 15 → Reference Example 5 → Reference Example 6,
The target compound having the following physical properties was obtained. TLC: Rf 0.22 (hexane: ethyl acetate = 1: 1
1).

Reference Example 186

[Chemical 377]

Using the compound prepared in Reference Example 74 and carrying out the same operation as in Reference Example 100 → Reference Example 6, a target compound having the following physical data was obtained. TLC: Rf 0.38 (chloroform: methanol = 9:
1).

Reference Example 187

[Chemical 378]

Using the compound produced in Reference Example 74, and the same operation as in Reference Example 44 → Reference Example 122 → Reference Example 34 → Reference Example 186, the desired compound having the following physical data was obtained. TLC: Rf 0.46 (chloroform: methanol = 9:
1).

Reference Example 188

[Chemical 379]

By using the compound produced in Reference Example 116,
Reference Example 75 → The same operation as in Reference Example 6 was performed to obtain the target compound having the following physical properties. TLC: Rf 0.38 (hexane: ethyl acetate = 1: 1
2).

Reference Examples 188 (a) to (d) Substituting the corresponding sulfonyl chloride or the corresponding acyl chloride in place of phenylsulfonyl chloride, the same operation as in Reference Example 188 was conducted, and The target compound was obtained.

Reference Example 188 (a)

[Chemical 380] TLC: Rf 0.14 (hexane: ethyl acetate = 1: 1
2).

Reference Example 188 (b)

[Chemical 381] TLC: Rf 0.42 (hexane: ethyl acetate = 1: 1
2).

Reference Example 188 (c)

[Chemical 382] TLC: Rf 0.29 (hexane: ethyl acetate = 1: 1
2).

Reference Example 188 (d)

[Chemical 383] TLC: Rf 0.10 (hexane: ethyl acetate = 1: 1
2).

Reference Example 189

[Chemical 384]

Using the compound produced in Reference Example 188 (d) and the same procedure as in Reference Example 122, the desired compound having the following physical data was obtained. TLC: Rf 0.22 (chloroform: methanol = 3
0: 1).

Reference Example 190

[Chemical 385]

Using the compound prepared in Reference Example 116,
The same operation as in Reference Example 42 → Reference Example 79 was carried out to obtain the target compound having the following physical properties. TLC: Rf 0.23 (hexane: ethyl acetate = 1: 1
2).

Reference Example 191

[Chemical 386]

By using the compound produced in Reference Example 116,
The same operation as in Reference Example 94 was performed to obtain an object compound having the following physical properties. TLC: Rf 0.51 (hexane: ethyl acetate = 1: 1
2).

Reference Example 192

[Chemical 387]

By using the compound produced in Reference Example 191,
The same operation as in Reference Example 6 was performed to obtain an object compound having the following physical properties. TLC: Rf 0.27 (hexane: ethyl acetate = 1: 1
2).

Reference Example 193

[Chemical 388]

Using the compound prepared in Reference Example 191,
The same operation as in Reference Example 79 was performed to obtain an object compound having the following physical properties. TLC: Rf 0.47 (hexane: ethyl acetate = 1: 1
3).

Reference Example 194

[Chemical 389]

Compound produced in Reference Example 116 (0.8 g)
A solution of dimethylsulfamoyl chloride (0.42 ml) in tetrahydrofuran (5 ml) was cooled to 0 ° C., a solution of potassium carbonate (0.72 g) in water (5 ml) was added, and the mixture was stirred at room temperature for 1 day. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to obtain the desired compound (970 mg) having the following physical data. TLC: Rf 0.65 (hexane: ethyl acetate = 1: 1
2).

Reference Example 195

[Chemical 390]

Using the compound produced in Reference Example 194,
The same operation as in Reference Example 6 was performed to obtain an object compound having the following physical properties. TLC: Rf 0.21 (hexane: ethyl acetate = 1: 1
2).

Reference Example 196

[Chemical 391]

By using the compound produced in Reference Example 194,
The same operation as in Reference Example 79 was performed to obtain an object compound having the following physical properties. TLC: Rf 0.55 (chloroform: methanol = 9:
1).

Reference Example 197

[Chemical 392]

By using the compound produced in Reference Example 116,
The same operation as in Reference Example 100 → Reference Example 79 was carried out to obtain the target compound having the following physical properties. TLC: Rf 0.27 (chloroform: methanol = 3
0: 1).

Reference Example 198

[Chemical 393]

By using the compound produced in Reference Example 116,
The same operations as in Reference Example 44 → Reference Example 122 → Reference Example 34 were carried out to obtain a target compound having the following physical properties. TLC: Rf 0.61 (chloroform: methanol = 9:
1).

Reference Example 199

[Chemical 394]

The compound prepared in Reference Example 198 (650 m
A solution of g) in diethyl ether (5 ml) was added dropwise with benzyl isocyanate (0.14 ml) at 0 ° C. under an argon atmosphere, and the mixture was stirred at the same temperature for 50 minutes. Ice-cooled saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The residue was subjected to silica gel column chromatography (hexane:
Purification with ethyl acetate = 5: 2) gave the target compound (610 mg) having the following physical data. TLC: Rf 0.51 (hexane: ethyl acetate = 1: 1
2).

Reference Example 200

[Chemical 395]

Using the compound produced in Reference Example 199,
The same operation as in Reference Example 6 was performed to obtain an object compound having the following physical properties. TLC: Rf 0.26 (hexane: ethyl acetate = 1: 1
2).

Reference Example 201

Embedded image

Using the compound prepared in Reference Example 198,
The same operation as in Reference Example 54 → Reference Example 79 was performed to obtain an object compound having the following physical properties. TLC: Rf 0.34 (chloroform: methanol = 2
0: 1).

Reference Example 202

[Chemical 397]

Using the compound produced in Reference Example 46 and the same operation as in Reference Example 9 → Reference Example 6, an intended compound having the following physical data was obtained. TLC: Rf 0.13 (hexane: ethyl acetate = 1: 1
2).

Reference Example 203

[Chemical 398]

Using the compound B produced in Reference Example 125, Reference Example 126 → Reference Example 127 → Reference Example 101 → Reference Example 145 → Reference Example 4 → Reference Example 11 → Reference Example 125 → Reference Example 5 → Reference Example 15 → Reference Example 3 → Reference Example 4 → The same operation as Reference Example 74 was carried out to obtain the target compound having the following physical property values. TLC: Rf 0.33 (chloroform: methanol = 1
9: 1).

Reference Example 204

[Chemical 399]

By using the compound produced in Reference Example 203,
The same operation as in Reference Example 100 → Reference Example 6 was carried out to obtain the target compound having the following physical properties. TLC: Rf 0.25 (ethyl acetate).

Reference Example 205

[Chemical 400]

By using the compound produced in Reference Example 203,
Reference Example 199-> The same operation as in Reference Example 6 was performed to obtain the target compound having the following physical properties. TLC: Rf 0.57 (ethyl acetate).

Reference Example 206

[Chemical 401]

4-acetoxy-5-methyl-6- (2-
Using methyl-2-propenyl) phenol, Reference Example 1-> Reference Example 2-> Reference Example 8-> Reference Example 4-> Reference Example 145-> Reference Example 125-> Reference Example 15-> Reference Example 11-> Reference Example 101->
The same operation as in Reference Example 5 → Reference Example 106 was carried out to obtain a target compound having the following physical properties. TLC: Rf 0.23 (hexane: ethyl acetate = 4:
1).

Reference Example 207

[Chemical 402]

[0638] The compound prepared in Reference Example 206 (1.5 g)
To a methylene chloride (15 ml) solution of was added 3,4-dihydro-2H-pyran (0.32 ml) and camphorsulfonic acid (54 mg) under an argon atmosphere, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated. Silica gel column chromatography of the residue (hexane: ethyl acetate = 19: 1)
The target compound (2.18
g) was obtained. TLC: Rf 0.53 (hexane: ethyl acetate = 4:
1).

Reference Example 208

[Chemical 403]

By using the compound produced in Reference Example 207,
The same operation as in Reference Example 4 was carried out to obtain the target compound having the following physical property values. TLC: Rf 0.20 (hexane: ethyl acetate = 2:
1).

Reference Example 209

[Chemical 404]

By using the compound produced in Reference Example 206,
The same operations as in Reference Example 74 → Reference Example 42 → Reference Example 4 were carried out to obtain a target compound having the following physical properties. TLC: Rf 0.25 (hexane: ethyl acetate = 1: 1
1).

Reference Example 210

[Chemical 405]

By using the compound produced in Reference Example 207,
The same operation as in Reference Example 6 → Reference Example 74 → Reference Example 42 → Reference Example 122 → Reference Example 4 was carried out to obtain the target compound having the following physical properties. TLC: Rf 0.56 (ethyl acetate).

Reference Example 211

[Chemical 406]

By using the compound produced in Reference Example 121,
Reference Example 124 → Reference Example 125 → Reference Example 1 → Reference Example 2 → Reference Example 8 → Reference Example 4 → Reference Example 145 → Reference Example 146 → Reference Example 15 → Reference Example 11 → Reference Example 6 → Reference Example 74 → Reference Example Four
The same operation as in 2 was performed to obtain the target compound having the following physical property values. TLC: Rf 0.40 (hexane: ethyl acetate = 1: 1
1).

Reference Example 212

[Chemical 407]

By using the compound produced in Reference Example 211,
The same operation as in Reference Example 4 was carried out to obtain the target compound having the following physical property values. TLC: Rf 0.31 (chloroform: methanol = 2
0: 1).

Reference Example 213

[Chemical 408]

[0650] Using the compound prepared in Reference Example 211,
The same operation as in Reference Example 122 → Reference Example 4 was carried out to obtain a target compound having the following physical properties. TLC: Rf 0.48 (hexane: ethyl acetate = 1: 1
1).

Reference Example 214

[Chemical 409]

Using 3- (2-methylpropyl) -4-acetoxy-5-ethyl-6- (2-methyl-2-propenyl) phenol, Reference Example 1-> Reference Example 2-> Reference Example 11-> Reference Example 101 → The same operation as in Reference Example 106 was carried out to obtain the target compound having the following physical properties. TLC: Rf 0.53 (hexane: ethyl acetate = 2:
1).

Reference Example 215

[Chemical 410]

Using 3-methyl-4-acetoxy-5-propyl-6- (2-methyl-2-propenyl) phenol, Reference Example 1-> Reference Example 2-> Reference Example 100-> Reference Example 1
The procedure of 01 → Reference Example 34 → Reference Example 9 → Reference Example 5 was repeated to obtain the desired compound having the following physical properties. TLC: Rf 0.49 (hexane: ethyl acetate = 3:
1).

Reference Example 216

[Chemical 411]

The compound prepared in Reference Example 202 (250 m
g) in methylene chloride (3 ml) solution at -20 ° C with mesyl chloride (0.06 ml) and triethylamine (0.24 m).
l) were added sequentially. The reaction mixture was stirred at the same temperature for 10 minutes. Water was added to the reaction mixture, and extracted with ethyl acetate.
The extract was washed successively with 1N aqueous hydrochloric acid solution, water, saturated aqueous sodium hydrogen carbonate solution, water, and saturated aqueous sodium chloride solution,
The extract was dried over anhydrous magnesium sulfate and concentrated to obtain the target compound having the following physical properties. TLC: Rf 0.33 (hexane: ethyl acetate = 3:
2).

Example 1

[Chemical 412]

To a solution of the compound prepared in Reference Example 216 in toluene (3 ml) was added imidazole (194 mg). The reaction mixture was stirred at 100 ° C. for 7 hours. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution at room temperature,
It was extracted with diethyl ether. The extract was washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (chloroform: methanol = 60: 1) to give the desired compound (464m) having the following physical data.
g) was obtained. TLC: Rf 0.37 (chloroform: methanol = 1)
9: 1).

Example 2

[Chemical 413]

The compound prepared in Example 1 (223 mg)
To a methanol (3 ml) solution of was added 4N hydrochloric acid dioxane solution (0.3 ml). The reaction mixture was stirred at room temperature for 1 hour and then concentrated. Diethyl ether was added to the residue and filtered. The obtained white powder was washed well with diethyl ether and then dried under reduced pressure to obtain the target compound (126 mg) having the following physical data. TLC: Rf 0.31 (chloroform: methanol = 9:
1); IR: ν 3381, 2866, 1579, 1549, 1431, 1297, 1242,
1078, 1062, 906, 638 cm ^-1 .

Examples 2 (1) to (105) Using the compounds produced in the above Reference Example, Reference Example 21
6 → Example 1 → The same operation as in Example 2 was carried out to obtain the target compound shown below.

Example 2 (1)

[Chemical 414] TLC: Rf 0.31 (chloroform: methanol = 9:
1); IR: ν 3436, 2931, 2934, 1577, 1548, 1430, 1299,
1235, 1078, 900, 835,636 cm ^-1 .

Example 2 (2)

[Chemical 415] TLC: Rf 0.21 (chloroform: methanol = 1
9: 1); IR: ν 3370, 2975, 2932, 2867, 2820, 1427, 1292,
1126, 1083, 903, 819cm ^-1 .

Example 2 (3)

[Chemical 416] TLC: Rf 0.37 (chloroform: methanol = 1)
0: 1); IR: ν 3436, 2955, 1578, 1545, 1425, 1231, 1077,
903, 642 cm ^-1 .

Example 2 (4)

[Chemical 417] TLC: Rf 0.15 (chloroform: methanol = 2
0: 1); IR: ν 3368, 3140, 2964, 2931, 2871, 1736, 1626,
1577, 1545, 1479, 1430, 1376, 1289, 1221, 1084, 1
057, 947, 878, 822 cm ^-1 .

Example 2 (5)

[Chemical 418] TLC: Rf 0.13 (chloroform: methanol = 2
0: 1); IR: ν 3368, 3139, 2965, 2931, 2869, 1626, 1577,
1545, 1427, 1380, 1344, 1289, 1235, 1164, 1088, 1
056, 951, 897, 793 cm ^-1 .

Example 2 (6)

[Chemical 419] TLC: Rf 0.29 (chloroform: methanol = 9:
1); IR: ν 3370, 2953, 1432, 1298, 1242, 1119, 1073,
905 cm ^-1 .

Example 2 (7)

[Chemical 420] TLC: Rf 0.38 (chloroform: methanol =
9: 1); IR: ν 3368, 1577, 1545, 1439, 1407, 1290, 1241,
1058, 903, 806, 675,625 cm ^-1 .

Example 2 (8)

[Chemical 421] TLC: Rf 0.30 (chloroform: methanol = 1)
0: 1); IR: ν 3423, 1639, 1425, 1314, 1150, 522 cm ^-1 .

Example 2 (9)

[Chemical 422] TLC: Rf 0.33 (chloroform: methanol = 1)
0: 1); IR: ν 3401, 2965, 1640, 1545, 1428, 1377, 1254,
1085, 904, 823, 629 cm ^-1 .

Example 2 (10)

[Chemical 423] TLC: Rf 0.37 (chloroform: methanol: isopropylamine = 40: 2: 1); IR: ν 3392, 3098, 2961, 2867, 1626, 1576, 1545,
1426, 1381, 1287, 1245, 1086, 1065, 902, 823, 625
cm ^-1 .

Example 2 (11)

[Chemical formula 424] TLC: Rf 0.51 (chloroform: methanol = 7:
1); IR: ν 3413, 3129, 3035, 2956, 2867, 1577, 1547,
1426, 1296, 1240, 1192, 1086, 1016, 901, 639 c
m ^-1 .

Example 2 (12)

[Chemical 425] TLC: Rf 0.30 (chloroform: methanol = 9:
1); IR: ν 3401, 3142, 2966, 2868, 1626, 1577, 1546,
1426, 1378, 1343, 1289, 1240, 1085, 1065, 998, 90
2, 824 cm ^-1 .

Example 2 (13)

[Chemical 426] TLC: Rf 0.20 (chloroform: methanol = 9:
1); IR: ν 3370, 3140, 2963, 2869, 1626, 1577, 1546,
1427, 1361, 1342, 1293, 1240, 1191, 1167, 1087, 1
055, 994, 936, 903, 828, 794 cm ^-1 .

Example 2 (14)

[Chemical 427] TLC: Rf 0.25 (chloroform: methanol = 1)
0: 1); IR: ν 3400, 2931, 1579, 1545, 1459, 1422, 1226,
1082, 878, 630 cm ^-1 .

Example 2 (15)

[Chemical 428] TLC: Rf 0.61 (chloroform: methanol = 6:
1); IR: ν 3274, 3127, 3090, 2959, 2829, 2607, 1736,
1639, 1576, 1547, 1428, 1376, 1302, 1246, 1206, 1
176, 1119, 1081, 991, 910, 826, 770, 673, 637 c
m ^-1 .

Example 2 (16)

[Chemical 429] TLC: Rf 0.30 (chloroform: methanol = 1)
9: 1); IR: ν 3368, 3136, 3022, 2980, 2936, 2863, 2808,
1741, 1576, 1543, 1427, 1385, 1344, 1312, 1297, 1
270, 1207, 1155, 1099, 1083, 903, 819, 743, 631, 62
1 cm ^-1 .

Example 2 (17)

[Chemical 430] TLC: Rf 0.23 (chloroform: methanol = 9:
1); IR: ν 3370, 1626, 1572, 1544, 1458, 1247, 1219,
1081, 933, 785 cm ^-1 .

Example 2 (18)

[Chemical 431] TLC: Rf 0.29 (chloroform: methanol = 1
0: 1); IR: ν 3405, 1578, 1545, 1459, 1245, 1056, 888,
756, 625 cm ^-1 .

Example 2 (19)

[Chemical 432] TLC: Rf 0.25 (chloroform: methanol = 1)
0: 1); IR: ν 3431, 2966, 1656, 1577, 1547, 1428, 1241,
1076, 904, 761, 635 cm ^-1 .

Example 2 (20)

[Chemical 433] TLC: Rf 0.13 (chloroform: methanol = 2
0: 1); IR: ν 3368, 3137, 2960, 2868, 1639, 1578, 1545,
1427, 1342, 1295, 1240, 1086, 1056, 902, 794 c
m ^-1 .

Example 2 (21)

[Chemical 434] TLC: Rf 0.13 (chloroform: methanol = 9:
1); IR: ν 3370, 2964, 2930, 2869, 1626, 1572, 1543,
1440, 1381, 1343, 1083, 967, 889, 794 cm ^-1 .

Example 2 (22)

[Chemical 435] TLC: Rf 0.52 (chloroform: methanol = 9:
1); IR: ν 3366, 3153, 3024, 2960, 2866, 2804, 2608,
1740, 1626, 1576, 1544, 1429, 1380, 1344, 1290, 1
217, 1164, 1119, 1084, 1041, 906, 823, 748,672, 63
0 cm ^-1 .

Example 2 (23)

[Chemical Formula 436] TLC: Rf 0.28 (chloroform: methanol = 9:
1); IR: ν 3387, 1630, 1578, 1545, 1458, 1289, 1245,
1083, 1053, 850, 625 cm ^-1 .

Example 2 (24)

[Chemical 437] TLC: Rf 0.33 (chloroform: methanol = 1)
0: 1); IR: ν 3145, 2966, 1578, 1545, 1447, 1327, 1245,
1160, 1093, 902, 831, 751, 691, 630, 587 cm ^-1 .

Example 2 (25)

[Chemical 438] TLC: Rf 0.34 (chloroform: methanol = 1)
0: 1); IR: ν 3143, 2967, 1578, 1545, 1426, 1321, 1246,
1142, 1062, 903, 630 cm ^-1 .

Example 2 (26)

[Chemical formula 439] TLC: Rf 0.18 (chloroform: methanol = 1
0: 1); IR: ν 3436, 2929, 1639, 1544, 1425, 1320, 1151,
1084, 761, 625, 523 cm ^-1 .

Example 2 (27)

[Chemical formula 440] TLC: Rf 0.31 (chloroform: methanol = 1)
0: 1); IR: ν 2965, 1736, 1578, 1546, 1426, 1327, 1246,
1148, 1066, 987, 903,789, 630, 521 cm ^-1 .

Example 2 (28)

[Chemical 441] TLC: Rf 0.29 (chloroform: methanol = 9:
1); IR: ν 3402, 1578, 1545, 1459, 1288, 1246, 1086,
1055, 909, 627 cm ^-1 .

Example 2 (29)

[Chemical 442] TLC: Rf 0.43 (chloroform: methanol = 1
0: 1); IR: ν 3270, 2968, 2872, 1656, 1546, 1427, 1381,
1289, 1243, 1067, 902, 794, 631 cm ^-1 .

Example 2 (30)

[Chemical 443] TLC: Rf 0.27 (chloroform: methanol: isopropylamine = 10: 1: 1); IR: ν 3411, 1578, 1545, 1459, 1250, 1087, 895,
625 cm ^-1 .

Example 2 (31)

[Chemical 444] TLC: Rf 0.27 (chloroform: methanol = 1
7: 3); IR: ν 3339, 2965, 1651, 1572, 1427, 1342, 1288,
1246, 1145, 1066 cm ^-1 .

Example 2 (32)

[Chemical formula 445] TLC: Rf 0.57 (chloroform: methanol = 5:
1); IR: ν 3362, 3141, 2963, 2863, 1662, 1612, 1577,
1546, 1426, 1381, 1343, 1288, 1255, 1239, 1163, 1
120, 1083, 1065, 890, 873, 823, 625 cm ^-1 .

Example 2 (33)

[Chemical formula 446] TLC: Rf 0.66 (chloroform: methanol = 5:
1); IR: ν 3248, 2962, 2868, 2613, 1675, 1577, 1548,
1427, 1340, 1278, 1248, 1164, 1119, 1085, 905, 87
3, 778, 634 cm ^-1 .

Example 2 (34)

[Chemical 447] TLC: Rf 0.46 (chloroform: methanol = 9:
1); IR: ν 3393, 3139, 2962, 2867, 1672, 1599, 1531,
1444, 1424, 1320, 1288, 1245, 1192, 1118, 1064, 8
94, 825, 755, 695, 633, 512 cm ^-1 .

Example 2 (35)

[Chemical 448] TLC: Rf 0.41 (chloroform: methanol = 9:
1); IR: ν 3401, 3137, 2961, 2868, 1736, 1626, 1577,
1545, 1425, 1341, 1288, 1252, 1189, 1148, 1105, 1
063, 892, 824, 754, 672, 626 cm ^-1 .

Example 2 (36)

[Chemical 449] TLC: Rf 0.20 (chloroform: methanol = 9:
1); IR: ν 3381, 1577, 1545, 1433, 1290, 1240, 1056,
787, 756 cm ^-1 .

Example 2 (37)

[Chemical 450] TLC: Rf 0.19 (chloroform: methanol = 9:
1); IR: ν 3367, 1577, 1545, 1435, 1289, 1236, 1056,
788, 755, 625 cm ^-1 .

Example 2 (38)

[Chemical 451] TLC: Rf 0.22 (chloroform: methanol = 1)
0: 1); IR: ν 2970, 1626, 1544, 1426, 1344, 1247, 1169,
1119, 1068, 904, 811,677, 624, 569 cm ^-1 .

Example 2 (39)

[Chemical 452] TLC: Rf 0.08 (chloroform: methanol = 1)
0: 1); IR: ν 3415, 1459, 1318, 1151, 1078 cm ^-1 .

Example 2 (40)

[Chemical 453] TLC: Rf 0.37 (chloroform: methanol = 9:
1); IR: ν 3401, 3130, 3053, 2965, 2871, 1619, 1574,
1545, 1424, 1377, 1250, 1232, 1204, 1147, 1083, 1
063, 895, 852, 675, 606, 572 cm ^-1 .

Example 2 (41)

[Chemical 454] TLC: Rf 0.18 (chloroform: methanol = 1
9: 1); IR: ν 3270, 3091, 2931, 2832, 1577, 1428, 1243,
1073, 907, 837 cm ^-1 .

Example 2 (42)

[Chemical 455] TLC: Rf 0.50 (chloroform: methanol = 9:
1); IR: ν 3392, 2964, 2869, 1577, 1546, 1427, 1386,
1288, 1229, 1187, 1131, 1086, 1066, 993, 943, 90
4, 779, 746, 596, 486 cm ^-1 .

Example 2 (43)

[Chemical 456] TLC: Rf 0.26 (chloroform: methanol = 9:
1); IR: ν 3323, 3138, 2964, 2869, 1656, 1577, 1547,
1425, 1382, 1342, 1286, 1246, 1162, 1066, 998, 90
1, 796 cm ^-1 .

Example 2 (44)

[Chemical 457] TLC: Rf 0.45 (chloroform: methanol = 9:
1); IR: ν 3338, 3139, 2961, 2869, 1708, 1574, 1543,
1428, 1382, 1342, 1247, 1193, 1155, 1085, 1067, 1
028, 902, 824, 779 cm ^-1 .

Example 2 (45)

[Chemical formula 458] TLC: Rf 0.55 (chloroform: methanol = 9:
1); IR: ν 3368, 3143, 2932, 2868, 1576, 1547, 1427,
1343, 1288, 1246, 1162, 1120, 1066, 1017, 903, 83
5, 790, 631, 567, 529 cm ^-1 .

Example 2 (46)

[Chemical 459] TLC: Rf 0.21 (chloroform: methanol = 1
9: 1); IR: ν 3274, 3092, 2932, 2835, 1719, 1576, 1428,
1239, 1114, 1076, 902cm ^-1 .

Example 2 (47)

[Chemical 460] TLC: Rf 0.54 (chloroform: methanol = 9:
1); IR: ν 3401, 2965, 2873, 1639, 1577, 1545, 1426,
1324, 1245, 1146, 1085, 1066, 1011, 963, 899, 79
7, 626, 521 cm ^-1 .

Example 2 (48)

[Chemical 461] TLC: Rf 0.37 (chloroform: methanol = 9:
1); IR: ν 3368, 3139, 2963, 2870, 1656, 1576, 1535,
1424, 1380, 1340, 1288, 1240, 1156, 1085, 1066, 9
98, 899, 824, 793 cm ^-1 .

Example 2 (49)

[Chemical 462] TLC: Rf 0.29 (chloroform: methanol = 9:
1); IR: ν 3370, 3139, 2962, 2932, 2870, 1639, 1577,
1545, 1427, 1380, 1344, 1287, 1224, 1058, 892, 83
0 cm ^-1 .

Example 2 (50)

[Chemical 463] TLC: Rf 0.47 (chloroform: methanol = 9:
1); IR: ν 3392, 3144, 2965, 2931, 2868, 1640, 1577,
1546, 1426, 1324, 1289, 1246, 1147, 1119, 1084, 1
066, 1029, 963, 937, 901, 791, 626, 522 cm ^-1 .

Example 2 (51)

[Chemical 464] TLC: Rf 0.43 (chloroform: methanol = 9:
1); IR: ν 3142, 2966, 2932, 2871, 1576, 1546, 1428,
1384, 1317, 1245, 1138, 1085, 1066, 998, 902, 83
1, 757, 692, 631, 575, 511 cm ^-1 .

Example 2 (52)

[Chemical 465] TLC: Rf 0.44 (chloroform: methanol = 6:
1); IR: ν 3284, 3144, 2964, 2868, 2189, 1597, 1425,
1379, 1342, 1289, 1248, 1186, 1119, 1083, 1065, 9
98, 900, 873, 797, 757, 672, 625 cm ^-1 .

Example 2 (53)

[Chemical 466] TLC: Rf 0.21 (chloroform: methanol = 2
0: 1); IR: ν 3392, 3133, 2970, 2933, 2871, 1620, 1546,
1428, 1381, 1363, 1346, 1289, 1247, 1150, 1108, 1
085, 1064, 998, 939, 892, 826 cm ^-1 .

Example 2 (54)

Embedded image TLC: Rf 0.26 (chloroform: methanol = 2
0: 1); IR: ν 3392, 3133, 2933, 2861, 1626, 1576, 1545,
1441, 1342, 1287, 1246, 1212, 1164, 1116, 1086, 1
065, 1015, 943, 903, 854 cm ^-1 .

Example 2 (55)

[Chemical 468] TLC: Rf 0.62 (chloroform: methanol = 7:
1); IR: ν 3547, 3436, 3049, 2971, 1639, 1579, 1430,
1320, 1293, 1226, 1162, 1137, 1003, 933, 900, 80
3, 566 cm ^-1 .

Example 2 (56)

Embedded image TLC: Rf 0.21 (chloroform: methanol = 9:
1); IR: ν 3367, 1630, 1577, 1545, 1431, 1376, 1290,
1240, 1085, 1051, 887, 786, 624 cm ^-1 .

Example 2 (57)

[Chemical 470] TLC: Rf 0.56 (chloroform: methanol = 9:
1); IR: ν 3155, 2924, 1578, 1547, 1426, 1358, 1348,
1326, 1240, 1159, 1085, 1061, 981, 960, 909, 793,
765, 625, 564, 535, 513 cm ^-1 .

Example 2 (58)

[Chemical 471] TLC: Rf 0.18 (chloroform: methanol = 1
9: 1); IR: ν 3083, 2975, 1514, 1398, 1367, 1293, 1260,
1161, 1078, 1058 cm ^-1 .

Example 2 (59)

[Chemical 472] TLC: Rf 0.38 (chloroform: methanol = 9:
1); IR: ν 3445, 1632, 1520, 1428, 1271, 1246, 1113,
1083, 1042, 998, 927,867, 738 cm ^-1 .

Example 2 (60)

[Chemical 473] TLC: Rf 0.32 (chloroform: methanol = 2
0: 1); IR: ν 3120, 2976, 2928, 1630, 1515, 1424, 1370,
1316, 1282, 1256, 1236, 1213, 1155, 1110, 1081, 1
025, 966, 923, 897, 880, 833 cm ^-1 .

Example 2 (61)

[Chemical 474] TLC: Rf 0.10 (chloroform: methanol = 1)
9: 1); IR: ν 3392, 3133, 2960, 2868, 1630, 1575, 1545,
1511, 1429, 1369, 1289, 1257, 1208, 1152, 1084, 1
028, 940, 876, 822 cm ^-1 .

Example 2 (62)

[Chemical 475] TLC: Rf 0.31 (chloroform: methanol = 9:
1); IR: ν 3371, 1576, 1545, 1431, 1376, 1289, 1235,
1085, 1051, 906, 787, 625 cm ^-1 .

Example 2 (63)

[Chemical 476] TLC: Rf 0.26 (chloroform: methanol = 9:
1); IR: ν 3369, 1577, 1545, 1432, 1376, 1289, 1240,
1086, 1055, 891, 756, 625 cm ^-1 .

Example 2 (64)

[Chemical formula 477] TLC: Rf 0.38 (chloroform: methanol = 9:
1); IR: ν 3368, 3140, 2960, 2931, 2869, 1630, 1576,
1546, 1432, 1377, 1289, 1239, 1086, 1056, 942, 89
1, 842, 789 cm ^-1 .

Example 2 (65)

[Chemical 478] TLC: Rf 0.23 (chloroform: methanol = 9:
1); IR: ν 3403, 1635, 1547, 1427, 1380, 1289, 1246,
1066, 901, 630 cm ^-1 .

Example 2 (66)

[Chemical 479] TLC: Rf 0.31 (chloroform: methanol = 9:
1); IR: ν 3402, 1626, 1546, 1424, 1363, 1288, 1245,
1159, 1086, 1065, 1027, 997, 898, 824, 795, 626 c
m ^-1 .

Example 2 (67)

[Chemical 480] TLC: Rf 0.33 (chloroform: methanol = 9:
1); IR: ν 3317, 1573, 1442, 1414, 1359, 1227, 1086,
1062, 1001, 864, 764, 635 cm ^-1 .

Example 2 (68)

[Chemical 481] TLC: Rf 0.43 (chloroform: methanol = 5:
1); IR: ν 3370, 1578, 1545, 1458, 1290, 1244, 1066,
863, 786, 625 cm ^-1 .

Example 2 (69)

[Chemical 482] TLC: Rf 0.45 (chloroform: methanol = 9:
1); IR: ν 3392, 3143, 2961, 2930, 2868, 1630, 1577,
1546, 1456, 1321, 1251, 1220, 1152, 1119, 1080, 9
70, 891, 872, 832, 791, 761, 624, 523 cm ^-1 .

Example 2 (70)

[Chemical 483] TLC: Rf 0.49 (chloroform: methanol = 9:
1); IR: ν 3434, 2963, 1736, 1639, 1545, 1459, 1323,
1220, 1148, 1081, 987, 792, 625, 522 cm ^-1 .

Example 2 (71)

[Chemical 484] TLC: Rf 0.25 (chloroform: methanol = 9:
1); IR: ν 3403, 1449, 1346, 1160, 1074, 586 cm ^-1 .

Example 2 (72)

[Chemical 485] TLC: Rf 0.25 (chloroform: methanol = 9:
1); IR: ν 3338, 2927, 1455, 1320, 1142, 986, 790, 5
21 cm ^-1 .

Example 2 (73)

[Chemical 486] TLC: Rf 0.27 (chloroform: methanol = 9:
1); IR: ν 3423, 1655, 1459, 1244, 1077 cm ^-1 .

Example 2 (74)

[Chemical 487] TLC: Rf 0.48 (chloroform: methanol = 9:
1); IR: ν 3399, 3143, 2950, 2931, 2869, 1630, 1577,
1546, 1433, 1327, 1286, 1243, 1148, 1105, 1068, 9
86, 965, 940, 855, 790, 625, 521, 486 cm ^-1 .

Example 2 (75)

[Chemical 488] TLC: Rf 0.21 (chloroform: methanol = 9:
1); IR: ν 3401, 1460, 1372, 1230, 1196, 1149, 1075,
898, 605 cm ^-1 .

Example 2 (76)

Embedded image TLC: Rf 0.21 (chloroform: methanol = 9:
1); IR: ν 3423, 1459, 1315, 1137, 1077 cm ^-1 .

Example 2 (77)

[Chemical 490] TLC: Rf 0.14 (chloroform: methanol = 9:
1); IR: ν 3401, 1460, 1169, 1077, 589 cm ^-1 .

Example 2 (78)

[Chemical formula 491] TLC: Rf 0.31 (chloroform: methanol = 9:
1); IR: ν 3400, 1703, 1544, 1459, 1250, 1086 cm ^-1 .

Example 2 (79)

[Chemical 492] TLC: Rf 0.31 (chloroform: methanol = 9:
1); IR: ν 3401, 1459, 1323, 1148, 1079 cm ^-1 .

Example 2 (80)

[Chemical 493] TLC: Rf 0.34 (chloroform: methanol = 9:
1); IR: ν 3469, 3295, 3137, 3083, 2937, 2863, 1663,
1576, 1551, 1461, 1446, 1422, 1355, 1293, 1253, 1
218, 1174, 1155, 1072, 946, 905, 778, 618, 594, 56
9 cm ^-1 .

Example 2 (81)

Embedded image TLC: Rf 0.44 (chloroform: methanol = 9:
1); IR: ν 3402, 2936, 1656, 1578, 1535, 1459, 1420,
1379, 1240, 1159, 1079, 1015, 905, 763, 625 c
m ^-1 .

Example 2 (82)

[Chemical formula 495] TLC: Rf 0.46 (chloroform: methanol = 1
0: 1); IR: ν 3415, 2932, 1624, 1458, 1253, 1148, 1087,
907 cm ^-1 .

Example 2 (83)

[Chemical 496] TLC: Rf 0.28 (chloroform: methanol: isopropylamine = 40: 2: 1); IR: (nu) 3415, 1432, 1290, 1086, 624 cm < ^-1 >.

Example 2 (84)

[Chemical 497] TLC: Rf 0.47 (chloroform: methanol = 9:
1); IR: ν 3361, 3087, 3029, 2940, 2849, 1577, 1458,
1340, 1297, 1261, 1168, 1072, 1021, 893, 799, 51
1, 493 cm ^-1 .

Example 2 (85)

[Chemical 498] TLC: Rf 0.42 (chloroform: methanol = 9:
1); IR: ν 3322, 3121, 1671, 1469, 1428, 1324, 752,
673 cm ^-1 .

Example 2 (86)

[Chemical 499] TLC: Rf 0.27 (chloroform: methanol = 1
0: 1); IR: ν 3145, 3103, 2861, 1577, 1546, 1456, 1320,
1240, 1182, 1149, 1070, 1027, 973, 884, 792, 626,
520, 491 cm ^-1 .

Example 2 (87)

[Chemical 500] TLC: Rf 0.40 (chloroform: methanol = 1)
0: 1); IR: ν 3377, 2120, 3086, 3033, 2923, 2859, 1709,
1577, 1491, 1459, 1391, 1305, 1231, 1197, 1174, 1
079, 996, 881, 776 cm ^-1 .

Example 2 (88)

[Chemical 501] TLC: Rf 0.26 (chloroform: methanol: isopropylamine = 40: 2: 1); IR: ν 3402, 1577, 1546, 1451, 1264, 1159, 108
4, 624 cm ^-1 .

Example 2 (89)

[Chemical 502] TLC: Rf 0.24 (chloroform: methanol: isopropylamine = 40: 2: 1); IR: ν 3374, 1578, 1546, 1451, 1425, 1258, 1079,
1040, 626 cm ^-1 .

Example 2 (90)

[Chemical 503] TLC: Rf 0.27 (chloroform: methanol: isopropylamine = 40: 2: 1); IR: ν 3392, 1457, 1230, 1078, 1055, 877, 624 cm
^-1 .

Example 2 (91)

[Chemical 504] TLC: Rf 0.31 (chloroform: methanol = 1)
0: 1); IR: ν 3366, 3118, 3027, 2927, 2845, 1641, 1577,
1455, 1410, 1296, 1265, 1206, 1175, 1079, 878 cm
^-1 .

Example 2 (92)

[Chemical formula 505] TLC: Rf 0.45 (chloroform: methanol = 1
0: 1); IR: ν 3414, 1627, 1545, 1460, 1421, 1354, 1266,
1171, 1082, 986, 902,770, 677, 624, 581 cm ^-1 .

Example 2 (93)

[Chemical formula 506] TLC: Rf 0.30 (chloroform: methanol = 9:
1); IR: ν 3402, 1578, 1545, 1451, 1420, 1362, 1230,
1039, 905, 839, 627 cm ^-1 .

Example 2 (94)

[Chemical 507] TLC: Rf 0.36 (chloroform: methanol = 5:
1); IR: ν 3401, 3138, 2970, 2850, 1626, 1576, 1544,
1456, 1426, 1371, 1276, 1212, 1159, 1082, 1044, 9
31, 879, 842, 761, 679, 625 cm ^-1 .

Example 2 (95)

[Chemical 508] TLC: Rf 0.34 (chloroform: methanol = 4:
1); IR: ν 3367, 1456, 1289, 1241, 1049, 627 cm ^-1 .

Example 2 (96)

[Chemical formula 509] TLC: Rf 0.43 (chloroform: methanol = 4:
1); IR: ν 3371, 1456, 1289, 1234, 1055, 625 cm ^-1 .

Example 2 (97)

[Chemical 510] TLC: Rf 0.24 (chloroform: methanol = 9:
1); IR: ν 3518, 3151, 3045, 2971, 2932, 2809, 2721,
1638, 1574, 1457, 1423, 1360, 1291, 1247, 1196, 1
129, 1103, 1084, 1047, 1038, 1025, 1012, 971, 899,
838, 772, 704, 639, 622, 570, 527, 502 cm ^-1 .

Example 2 (98)

[Chemical 511] TLC: Rf 0.31 (chloroform: methanol = 9:
1); IR: ν 3519, 3045, 2971, 2932, 2809, 1574, 1458,
1422, 1360, 1291, 1247, 1195, 1131, 1085, 1047, 1
035, 971, 899, 838, 773, 704, 639, 622, 527, 502 cm
^-1 .

Example 2 (99)

[Chemical 512] TLC: Rf 0.18 (chloroform: methanol = 1
0: 1); IR: ν 3402, 3138, 2970, 2887, 1630, 1578, 1547,
1451, 1369, 1261, 1213, 1160, 1087, 760, 625 c
m ^-1 .

Example 2 (100)

[Chemical 513] TLC: Rf 0.18 (chloroform: methanol = 2
0: 1); IR: ν 3130, 3063, 3008, 2954, 2863, 2627, 1608,
1581, 1552, 1451, 1408, 1364, 1305, 1244, 1219, 1
155, 1082, 1062, 889, 851, 789, 761, 621 cm ^-1 .

Example 2 (101)

[Chemical 514] TLC: Rf 0.29 (chloroform: methanol = 1
0: 1); IR: ν 3402, 2932, 1618, 1547, 1510, 1458, 1388,
1247, 1147, 1085, 891, 781, 628 cm ^-1 .

Example 2 (102)

[Chemical 515] TLC: Rf 0.37 (chloroform: methanol = 9:
1); IR: ν 3402, 1451, 1423, 1245, 1084, 1051, 625 c
m ^-1 .

Example 2 (103)

[Chemical 516] TLC: Rf 0.54 (chloroform: methanol = 5:
1); IR: ν 3327, 2973, 1646, 1577, 1535, 1453, 1371,
1276, 1152, 1075, 874, 827, 774, 699, 632, 590 cm
^-1 .

Example 2 (104)

[Chemical 517] TLC: Rf 0.25 (chloroform: methanol = 1)
0: 1); IR: ν 3402, 1626, 1578, 1545, 1451, 1317, 1232,
1151, 1083, 972, 898,840, 764, 624, 523 cm ^-1 .

Example 2 (105)

[Chemical 518] TLC: Rf 0.34 (chloroform: methanol = 1)
0: 1); IR: ν 3431, 2932, 1638, 1451, 1232, 1146, 1085,
985, 792, 522 cm ^-1 .

Example 3

[Chemical 519]

Using the compound produced in Reference Example 55 and the same procedure as in Reference Example 216-> Example 1-> Reference Example 20-> Example 2, the target compound having the following physical data was obtained. TLC: Rf 0.20 (chloroform: methanol = 9:
1); IR: ν 3392, 2963, 1636, 1547, 1424, 1341, 1288,
1240, 1157, 1066 cm ^-1 .

Examples 3 (1) to (4) Using the compounds produced in the above-mentioned Reference Example, the same operation as in Example 3 was carried out to obtain the target compounds shown below.

Example 3 (1)

[Chemical 520] TLC: Rf 0.41 (chloroform: methanol = 9:
1); IR: ν 3411, 2965, 2932, 1736, 1639, 1511, 1426,
1384, 1342, 1240, 1161, 1109, 1083, 997, 903, 79
2, 661, 626, 528 cm-1.

Example 3 (2)

[Chemical 521] TLC: Rf 0.50 (chloroform: methanol = 5:
1); IR (neat): ν 3392, 2927, 1635, 1577, 1547, 1456,
1385, 1317, 1246, 1152, 1076, 896, 761, 624, 525
cm ^-1 .

Example 3 (3)

[Chemical 522] TLC: Rf 0.42 (chloroform: methanol = 5:
1); IR: ν 3856, 3401, 2971, 1648, 1579, 1545, 1510,
1459, 1420, 1244, 1083, 885, 785, 624 cm ^-1 .

Example 3 (4)

[Chemical 523] TLC: Rf 0.38 (chloroform: methanol = 5:
1); IR: ν3403, 2947, 1649, 1562, 1453, 1372, 1277,
1155, 1072, 624 cm ^-1 .

Example 4

[Chemical 524]

Using the compound prepared in Reference Example 10 and the same procedure as in Reference Example 216 → Example 1, the desired compound having the following physical data was given. TLC: Rf 0.40 (chloroform: methanol = 1
9: 1).

Example 5

[Chemical 525]

Using the compound produced in Example 4, the same operation as in Reference Example 20 was carried out to obtain the target compound having the following physical data. TLC: Rf 0.23 (chloroform: methanol = 1
9: 1); IR: ν 2954, 1511, 1429, 1381, 1289, 1231, 1151,
1110, 1045, 996, 920, 817, 755, 663 cm ^-1 .

Example 6

[Chemical Formula 526]

Using the compound prepared in Reference Example 45 and the same procedure as in Reference Example 216-> Example 1-> Reference Example 34-> Example 2, the desired compound having the following physical data was obtained. TLC: Rf 0.60 (chloroform: methanol: isopropylamine = 20: 2: 1); IR: ν 3436, 1656, 1639, 1544, 1510, 1459, 1425,
1245 cm ^-1 .

Example 7

[Chemical 527]

Using the compound produced in Reference Example 69 and the same procedure as in Reference Example 216-> Example 1-> Reference Example 106-> Example 2, the desired compound having the following physical data was obtained. TLC: Rf 0.33 (chloroform: methanol = 3:
1); IR: ν 3401, 1639, 1544, 1425, 1240, 1064 cm ^-1 .

Example 8

[Chemical 528]

A solution of 3-pyridylmethyltriphenylphosphonium chloride (220 mg) in tetrahydrofuran (5 ml) was added with n- at −78 ° C. under an argon atmosphere.
Butyl lithium (1.07 ml, 1.6 M hexane solution) was added. After stirring the mixture at 0 ° C. for 1 hour, Reference Example 104.
A tetrahydrofuran (3 ml) solution of the compound (100 mg) produced in 1. was added at 0 ° C. The reaction mixture was stirred at room temperature for 1 hour. A saturated ammonium chloride aqueous solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. Extract the water,
It was washed successively with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate) to give the object compound (83 mg) having the following physical data. TLC: Rf 0.56 (ethyl acetate).

Example 9

[Chemical 529]

The target compound having the following physical data was obtained by the same procedure as in Reference Example 20 using the compound prepared in Example 8. TLC: Rf 0.58 (chloroform: methanol = 3:
1).

Example 10

[Chemical 530]

Using the compound produced in Example 9, the same operation as in Example 2 was carried out to obtain the target compound having the following physical data. TLC: Rf 0.51 (chloroform: methanol = 9:
1); IR: ν 3383, 2962, 2931, 2871, 2678, 1631, 1554,
1468, 1426, 1376, 1341, 1298, 1243, 1166, 1114, 1
051, 897, 828, 797 cm ^-1 .

Reference Example 217

[Chemical 531]

To a solution of 3-bromopyridine (0.19 ml) in diethyl ether (1 ml) was prepared under argon atmosphere at -7.
N-Butyllithium (1.43 ml, 1.4 M hexane solution) was added at 8 ° C. After stirring the mixture at -78 ° C for 30 minutes,
A solution of the compound (352 mg) produced in Reference Example 104 in diethyl ether (2 ml) was added. Reaction mixture at 0 ° C
Then, the mixture was stirred for 1 hour. The reaction mixture was added to water and extracted with ethyl acetate. The extract was washed successively with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (chloroform: methanol = 39: 1) to obtain the desired compound (301 mg) having the following physical properties. TLC: Rf 0.08 (hexane: ethyl acetate = 1: 1
1).

Example 11

[Chemical 532]

The compound prepared in Reference Example 217 (295 m
Triethylsilane (0.33 ml) and trifluoroacetic acid (0.21 ml) were added to a solution of g) in methylene chloride (2 ml) at room temperature under an argon atmosphere. The reaction mixture is allowed to stand at room temperature for 2
It was stirred for a day. Water was added to the reaction mixture, and extracted with ethyl acetate. The extract is water, saturated aqueous sodium hydrogen carbonate solution,
It was washed successively with water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography (chloroform: methanol =
20: 1) to obtain the target compound (120 mg) having the following physical data. TLC: Rf 0.23 (chloroform: methanol = 2
0: 1).

Example 12

[Chemical 533]

Using the compound produced in Example 11 and the same procedures as in Example 2, the desired compound having the following physical data was obtained. TLC: Rf 0.23 (chloroform: methanol = 2
0: 1); IR: ν 3382, 2964, 2931, 2871, 1677, 1630, 1552,
1468, 1429, 1378, 1297, 1241, 1139, 1114, 1049, 9
16, 881, 834, 793 cm ^-1 .

Example 12 (1)

[Chemical 534]

Using the compound prepared in Example 215,
The same operations as in Reference Example 217 → Example 11 → Example 12 were carried out to obtain the target compound having the following physical properties. TLC: Rf 0.56 (chloroform: methanol = 9:
1); IR: ν 3393, 2932, 2870, 2363, 1787, 1630, 1553,
1434, 1377, 1242, 1106, 1046, 870, 790, 680 c
m ^-1 .

Example 13

[Chemical Formula 535]

Using the compound produced in Example 2 (22) and carrying out the same operation as in Reference Example 34 → Example 2 to obtain the desired compound having the following physical data. TLC: Rf 0.20 (chloroform: methanol = 5:
1); IR: ν 3368, 3138, 2965, 2870, 1724, 1576, 1546,
1427, 1382, 1344, 1289, 1238, 1160, 1118, 1086, 1
066, 900, 825, 672, 625 cm ^-1 .

Example 13 (1)

[Chemical Formula 536]

Using the compound produced in Example 2 (15) and the same procedure as in Example 13, the desired compound having the following physical data was obtained. TLC: Rf 0.20 (chloroform: methanol: isopropylamine = 10: 1: 1); IR: ν 3435, 3128, 3093, 3038, 2962, 2833, 1723,
1634, 1577, 1549, 1429, 1341, 1300, 1245, 1188, 1
114, 1077, 910, 635 cm ^-1 .

Reference Example 218

[Chemical 537]

The compound prepared in Reference Example 131 (240 m
g) in methylene chloride (5 ml), pyridine (0.72
ml) was added. P-Toluenesulfonyl chloride (562 mg) was added to the reaction mixture at 0 ° C, and the mixture was stirred at 5 ° C overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to obtain the target compound (454 g) having the following physical properties. TLC: Rf 0.58 (hexane: ethyl acetate = 1: 1
1).

Example 14

[Chemical 538]

Using the compound produced in Reference Example 218,
The same operation as in Example 1 was carried out to obtain the target compound having the following physical properties. TLC: Rf 0.20 (chloroform: methanol = 5:
1).

Example 15

[Chemical 539]

The compound prepared in Example 14 (250 m
To a solution of g) in dioxane (8 ml) was added 1N aqueous hydrochloric acid solution (0.8 ml), and the mixture was stirred at room temperature for 2 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated. The residue was dissolved in ethyl acetate (3 ml), hexane (3 ml) was added, followed by filtration and washing with hexane to obtain the target compound (176 mg) having the following physical properties. TLC: Rf 0.10 (chloroform: methanol = 2
0: 1); IR (thin film method): ν 2973, 1511, 1409, 1368, 1265, 11
60, 1109, 1081, 908, 796, 733, 661 cm ^-1 .

Example 15 (1) to (2) Using the compounds produced in the above-mentioned Reference Example, Reference Example 21
8 → Example 1 → The same operation as in Example 15 was carried out to obtain the target compound shown below.

Example 15 (1)

[Chemical 540] TLC: Rf 0.43 (chloroform: methanol = 1
0: 1); IR: ν 3436, 1639, 1510, 1410, 1271, 1149, 110
3, 585 cm ^-1 .

Example 15 (2)

[Chemical 541] TLC: Rf 0.36 (chloroform: methanol = 1)
0: 1); IR: ν 3468, 3122, 3044, 2970, 2838, 1611, 1579,
1547, 1421, 1377, 1293, 1261, 1216, 1157, 1136, 1
087, 1069, 987, 893, 865, 786, 640 cm ^-1 .

Example 16

[Chemical 542]

Using the compound produced in Reference Example 137,
The same operations as in Reference Example 216-> Example 1-> Example 15 were carried out to obtain a target compound having the following physical properties. TLC: Rf 0.28 (chloroform: methanol = 1
2: 1); IR (thin film method): ν 3294, 2966, 2869, 1509, 1409, 13
69, 1270, 1226, 1151, 1106, 1072, 908, 836, 732, 66
3 cm ^-1 .

Example 17

[Chemical Formula 543]

Using the compound produced in Example 16 and the same procedures as in Example 2, the desired compound having the following physical data was obtained. TLC: Rf 0.23 (chloroform: methanol = 1
2: 1); IR: ν 3343, 3129, 3032, 2929, 2829, 1578, 1547,
1423, 1280, 1227, 1160, 1130, 912, 850, 636 c
m ^-1 .

Example 18

[Chemical 544]

The compound prepared in Example 17 (176m
g) in ethanol (6 ml) solution, platinum dioxide (Pt)
O ₂ , 70 mg) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 9 days. The reaction mixture was filtered through Celite (trade name), and the filtrate was concentrated. The residue was subjected to silica gel column chromatography (chloroform: methanol = 30:
Purification by 1 → 25: 1) gave the target compound having the following physical properties. TLC: Rf 0.48 (chloroform: methanol = 1
0: 1).

Example 19

[Chemical Formula 545]

Using the compound produced in Example 18, the same operation as in Example 2 was carried out to obtain the target compound having the following physical data. TLC: Rf 0.48 (chloroform: methanol = 1
0: 1); IR: ν 3370, 1579, 1545, 1426, 1288, 1131, 1086,
853, 636 cm ^-1 .

Example 20

[Chemical 546]

Using the compound produced in Reference Example 141,
Reference Example 216-> The same operation as in Example 1 was carried out to obtain a target compound having the following physical properties. TLC: Rf 0.37 (chloroform: methanol = 1)
9: 1).

Example 21

[Chemical 547]

Using the compound produced in Example 20 and the same procedure as in Example 2, the desired compound having the following physical data was obtained. TLC: Rf 0.26 (chloroform: methanol = 1)
9: 1); IR: ν 3424, 2973, 1795, 1636, 1412, 1287, 1070,
951 cm ^-1 .

Example 22

[Chemical 548]

Using the compound produced in Reference Example 209,
Reference Example 216-> Example 1-> The same operation as Reference Example 6 was carried out to obtain the target compound having the following physical properties. TLC: Rf 0.53 (chloroform: methanol = 4:
1).

Example 23

[Chemical formula 549]

Using the compound produced in Example 22 and the same procedure as in Example 2, the target compound having the following physical data was obtained. TLC: Rf 0.43 (chloroform: methanol = 4:
1); IR: ν 3367, 1626, 1574, 1552, 1441, 1356, 130
9, 1235, 1152, 1077, 1061, 1045, 976, 889, 837, 77
0, 658, 629, 521 cm ^-1 .

Example 23 (1)

[Chemical 550]

Using the compound produced in Reference Example 208,
The same operation as in Example 22 → Example 23 was carried out to obtain the target compound having the following physical properties. TLC: Rf 0.36 (chloroform: methanol = 4:
1); IR: ν 3436, 1639, 1510, 1459, 1233, 1110, 1080,
887, 751, 663 cm ^-1 .

Reference Example 219

[Chemical 551]

[0828] Using the compound prepared in Reference Example 210,
Reference Example 216-> The same operation as in Example 1 was carried out to obtain a target compound having the following physical properties. TLC: Rf 0.39 (chloroform: methanol = 1)
9: 1).

Example 24

[Chemical 552]

To the ethanol solution of the compound prepared in Reference Example 219, 4N hydrochloric acid dioxane solution was added and concentrated.
The residue was washed with diethyl ether to obtain the target compound having the following physical properties. TLC: Rf 0.43 (chloroform: methanol = 9:
1); IR: ν 3436, 1638, 1545, 1459, 1323, 1148, 108
3, 986, 792, 625, 521 cm ^-1 .

Example 25

[Chemical 553]

Using the compound produced in Reference Example 214:
Reference Example 216-> The same operation as in Example 1 was carried out to obtain a target compound having the following physical properties. TLC: Rf 0.62 (chloroform: methanol = 1)
0: 1).

Example 26

[Chemical formula 554]

Using the compound produced in Example 25 and the same operation as in Reference Example 4 → Example 2, the desired compound having the following physical data was obtained. TLC: Rf 0.42 (chloroform: methanol = 1)
0: 1); IR: ν 3401, 2963, 2869, 1626, 1544, 1435, 1250,
1084, 1054, 784, 626 cm ^-1 .

Reference Example 220

[Chemical 555]

Using 2,6-dimethoxyphenol,
Reference Example 161, Reference Example 106, Reference Example 100, Reference Example 1
63-> Reference Example 124-> Reference Example 125-> Reference Example 1-> Reference Example 2-> Reference Example 100-> Reference Example 101-> Reference Example 34-> Reference Example 9-> Reference Example 5-> Reference Example 14-> Reference Example 15 Thus, the target compound having the following physical properties was obtained. TLC: Rf 0.20 (chloroform: methanol = 9:
1).

Example 27

[Chemical 556]

By using the compound produced in Reference Example 220,
The same operations as in Reference Example 216-> Example 1-> Example 2 were carried out to obtain a target compound having the following physical properties. TLC: Rf 0.45 (chloroform: methanol = 6:
1); IR: ν 3375, 2937, 1627, 1578, 1461, 1431, 137
6, 1320, 1235, 1090, 1055, 965, 898, 764, 627 c
m ^-1 .

[0839]

[Formulation Example] The following components were admixed in a conventional method and punched out to obtain 100 tablets each having 50 mg of active ingredient. 5-hydroxy-2,6-dimethyl-4-isopropyl-2-hydroxymethyl-7- (2- (1-imidazoyl) ethyl) -2,3-dihydrobenzofuran-hydrochloride (of Example 2) Compound) ……………………………………………… 5.0g ・ Fibrin calcium glycolate (disintegrant) …………………… 0.2g ・ Magnesium stearate (lubricant) ……………………………… 0.1g ・ Microcrystalline cellulose …………………………………………………… 4.7g

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location C07D 405/06 237 241 A61K 31/335 ABE 31/34 ACV 31/35 ACG 31/40 ABX 31 / 415 AED 31/44 ACB 31/495 ABR 31/50 ACF 31/55 ABF C07D 307/78 311/04 313/08 405/14 233 407/06 307 (72) Inventor Shuichi Ouchida Shimamoto-cho, Mishima-gun, Osaka Prefecture 3-1-1 Sakurai Minase Research Laboratory, Ono Pharmaceutical Co., Ltd.

Claims (1)

[Claims] 1. A compound of the general formula (I) [In the formula, R ¹ and R ² are the same or different and each represents a sub 1 group or a sub 2 group. Sub 1 group is 1) hydrogen atom, 2) halogen atom, 3) trifluoromethyl group, 4) cyano group, 5) C1-10 alkyl group, 6) C1-4 alkoxy group, 7) C3-7 cycloalkyl. Group, 8) C7-10 phenylalkyl group, 9) C1-10 alkyl group substituted by C1-4 alkoxy group, 10) C1-4 alkyl group substituted by C3-7 cycloalkyl group, 11) Substituted by phenylthio group Cl to 6 alkyl groups, 12) Cl to 6 alkyl group in which the phenyl group is substituted, 13) -COOH group, 14) -COOR ⁶ group (wherein, R ⁶ represents a Cl to 6 alkyl group.), 15) C2-10 alkenyl group, or 16) when they are in the ortho position to each other, R ¹ and R ² together represent a —CH═CH—CH═CH— group, and the sub 2 group is —D. ^1- E ¹ group (in the group, D ¹ represents a single bond, a C1-8 alkylene group, or a C2-8 alkenylene group, and E ¹ is 1) -NR ⁷¹ R ⁸¹ group (in the groups, R ⁷¹ and R ⁸¹ are the same or different and each represents a hydrogen atom, a C1-4 alkyl group or a phenyl group.), 2) -OR ⁹¹ group (in which R ⁹¹ is a hydrogen atom, a C1-4 alkyl group, a C1-4 group). It represents a hydroxyalkyl group, a C2-5 acyl group, a phenylcarbonyl group, a C7-10 phenylalkyl group, a carbonyl group substituted with a C7-10 phenylalkyl group, or a C2-4 alkoxyalkyl group, provided that R ⁹¹ is C1- When it is a 4-alkyl group, D ¹ does not represent a single bond or a C1-8 alkylene group.), 3) —NR ¹⁰¹ —SO ₂ —R ¹¹¹ group (in the group, R ¹⁰¹ is a hydrogen atom, C 1-6). Alkyl group, C2 6 alkenyl group,
C1~4 alkoxy group, a -SO ₂ -R ¹¹¹ group or a hydroxyl group, R ¹¹¹ is C1~6 alkyl group, -NR ⁷¹ R
^{It represents an 81} group (in which R ⁷¹ and R ⁸¹ have the same meanings as described above), a phenyl group, a pyridyl group or a trifluoromethyl group. ), 4) -NR ¹²¹ -COR ¹³¹ group (in which R ¹²¹ represents a hydrogen atom, a C1-4 alkyl group, a hydroxyl group or a C1-4 alkoxy group, and R ¹³¹ represents a C1-6 alkyl group, C1
~ 4 alkoxy group, phenyl group or -NR ⁷¹ R ⁸¹ group (in the group, R ⁷¹ and R ⁸¹ have the same meanings as described above).
Represents ), 5) -COOR ¹⁴¹ group (in the group, R ¹⁴¹ represents a hydrogen atom or a C1-6 alkyl group, provided that E ¹ is -COO.
In the case of the R ¹⁴¹ group, D ¹ does not represent a single bond. ), 6) -CONR ¹⁵¹ R ¹⁶¹ group (in which R ¹⁵¹ and R
¹⁶¹ is the same or different and is a hydrogen atom, C1
~ 4 alkyl group, phenyl group, R ¹⁵¹ and R ^{161 are-} (C
H ₂ ) _l -group (wherein l represents an integer of 4 to 7) or a nitrogen atom to which R ¹⁵¹ and R ¹⁶¹ are bonded. Represents ), 7) -COR ¹⁷¹ group (wherein R ¹⁷¹ represents a C1-4 alkyl group or a phenyl group), 8) cyano group (provided that E ¹ is a cyano group, D ¹ represents a single bond). Not exist.), 9) [Chemical Formula 3] (In the group, R ¹⁸¹ represents a hydrogen atom or a C1-4 hydroxyalkyl group.), 10) (In the group, R ¹⁹¹ , R ²¹¹ and R ²²¹ are the same or different and each represents a hydrogen atom, a C1-4 alkyl group or a phenyl group, and R ²⁰¹ is a hydrogen atom, a C1-4 alkyl group, a phenyl group or a cyano group. Represents a group), 11) (In the group, R ¹⁹¹ , R ²¹¹ and R ²²¹ have the same meanings as described above.), 12) (In the group, R ²³¹ is a hydrogen atom, C1-4 alkyl group, C1
~ 4 represents an alkoxy group or a hydroxyl group. ) 13) [Chemical 7] Or 14) when R ¹ and R ² and —OR ³¹ in the G group are in the ortho position relative to each other, R ¹ and R ² and the —OR ³¹ group are taken together. (In the group, R ²⁴¹ and R ²⁵¹ are a hydrogen atom or C1-4.
Represents an alkyl group. ) And), A is 1) C1-8 alkylene group, 2) C2-8 alkenylene group, 3) C1-6 oxyalkylene group (provided that an oxygen atom is bonded to B). , Or 4) (In the group, m represents an integer of 1 to 6 and B is bonded to the phenylene group), and B represents a nitrogen atom 1
Or, it represents a 5- to 7-membered monocyclic heterocyclic group containing two, and G is —OR ³¹ or —NR ³² R ³³ (wherein R ³¹ ,
R ³² and R ³³ are the same or different and each is a hydrogen atom, a C1-4 alkyl group, a C7-10 phenylalkyl group, a C2-5 acyl group, a phenylcarbonyl group, C
7-10 represents a carbonyl group substituted with a phenylalkyl group or a C2-4 alkoxyalkyl group. ), And R ⁴ and R ⁵ are the same or different, 1) a hydrogen atom, 2) a C1-8 alkyl group, 3) a C7-10 phenylalkyl group, and 4) a -D ² -E ² group (group). In the above, D ² has the same meaning as D ^1, and E ² is a (1) -NR ⁷² R ⁸² group (in which R ⁷² and R ⁸² are the same or different, and each is a hydrogen atom, C
1 to 4 represents an alkyl group or a phenyl group. ),
(2) -OR ⁹² group (wherein R ⁹² is a hydrogen atom, a C1-4 alkyl group, a C1-4 hydroxyalkyl group, a C2-5 acyl group, a phenylcarbonyl group, a C7-10 phenylalkyl group, C7-10 A carbonyl group substituted with a phenylalkyl group or a C2-4 alkoxyalkyl group), (3) -NR ¹⁰² -SO ₂ -R ¹¹² group (in the group,
R ¹⁰² represents a hydrogen atom, a C 1-6 alkyl group, a C 2-6 alkenyl group, a C 1-4 alkoxy group, —SO ₂ —R ¹¹² group or a hydroxyl group, and R ¹¹² represents a C 1-6 alkyl group,
-NR ⁷² R ⁸² group (in the group, R ⁷² and R ⁸² have the same meanings as described above), phenyl group, pyridyl group or trifluoromethyl group. ), (4) -NR ¹²² -CO
R ¹³² group (in which R ¹²² represents a hydrogen atom, a C1-4 alkyl group, a hydroxyl group or a C1-4 alkoxy group,
¹³² is a C1-6 alkyl group, a C1-4 alkoxy group,
Phenyl group or -NR ⁷² R ⁸² group (wherein R ⁷² and R
⁸² has the same meaning as above. ) Is represented. ), (5)
-COOR ¹⁴² group (wherein R ¹⁴² is a hydrogen atom or C1
~ 6 represents an alkyl group. ), (6) -CONR ¹⁵² R
¹⁶² group (wherein R ¹⁵² and R ¹⁶² are the same or different, and each is a hydrogen atom, a C1-4 alkyl group, a phenyl group, and R ¹⁵² and R ¹⁶² are a-(CH ₂ ) l-group (wherein l is
Represents an integer of 4 to 7. ) Or together with the nitrogen atom to which R ¹⁵² and R ¹⁶² are attached: Represents ), (7) -COR ¹⁷² group (in the group, R ¹⁷² represents a C1-4 alkyl group or a phenyl group),
(8) cyano group, (9) (In the group, R ¹⁸² represents a hydrogen atom or a C1-4 hydroxyalkyl group.), (10) (In the group, R ¹⁹² , R ²¹² and R ²²² are the same or different and each represents a hydrogen atom, a C1-4 alkyl group or a phenyl group, and R ²⁰² is a hydrogen atom, a C1-4 alkyl group, a phenyl group or a cyano group. Represents a group) or (11) (In the group, R ¹⁹² , R ²¹² and R ²²² have the same meanings as described above.) (12) (In the group, R ²³² is a hydrogen atom, C1-4 alkyl group, C1
~ 4 represents an alkoxy group or a hydroxyl group. ), Or (13) Or 5) R ⁴ and R ⁵ together with the carbon atom to which they are attached represent a C4-7 cycloalkyl group, and n represents an integer from 1 to 3. Provided that R ⁴ and R ⁵ are the same or different and each represents a hydrogen atom, a C1-8 alkyl group, C
7-10 phenylalkyl groups, or when R ⁴ and R ⁵ together with the carbon atom to which they are attached represent a C 4-7 cycloalkyl group, R ¹ and R ² shall not represent sub 1 groups . ] The condensed phenol derivative shown by these, those nontoxic salts, those acid addition salts, or those hydrate salts.