JP2884153B2 - Tricyclic compound, its production method and agent - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a tricyclic compound having excellent melatonin receptor affinity, a method for producing the same, and an agent.

[0002]

2. Description of the Related Art Melatonin (N-acetyl-5-methoxytryptamine) is a hormone synthesized and secreted mainly by the pineal gland of the brain, and increases in a dark environment and decreases in a bright environment. Melatonin acts on pigment cells and female gonads in an inhibitory manner, and is involved in photoperiodic signaling to act as a biological clock synchronizing factor. Therefore, melatonin is considered to be used for treating diseases related to melatonin activity, such as reproductive and endocrine disorders, sleep-wake rhythm disorders, jet lag, and various disorders associated with aging. Recently, it has been revealed that the amount of melatonin produced decreases with aging, and it has been reported that aging itself can be prevented by maintaining the amount of melatonin produced [Annals of the New York Academy of Sciences (Ann) NY Acad. Sci.), Volume 719, pp. 456-460 (199)
4)]. However, melatonin is easily metabolized by metabolic enzymes in the body [Clinical Tests 38, 11
No., pp. 282-284, 1994].

[0003] As a melatonin agonist or an antagonist thereof, (1) EP-A-578620

Embedded image Is represented by (2) US-411675.

Embedded image The compound represented by the following formula (3):

Embedded image Is represented by (4) FR-014630:

Embedded image Is represented by (5) EP-A-591057.

Embedded image Is represented by (6) EP-A-527687.

Embedded image Is represented by (7) EP-A-506538.

Embedded image Are disclosed, respectively. Examples of the tricyclic or higher polycyclic compound having a cyclic ether moiety include (1) Tetrahedron Letters.
Lett.), 36, 7019 (1995)

Embedded image Is represented by (2) Journal of Medicinal Chemistry (J. Med. Chem.), 35, 36
25 pages (1992)

Embedded image Is a compound represented by (3) Tetrahed
ron), 48, 1039 (1992)

Embedded image Is represented by (4) Tetrahedron Lett., Vol. 32, p. 3345 (199)
1 year)

Embedded image Is represented by (5) Bioorganic Chemistry (Bioorg.Chem.), 18, 291 (199).
0)

Embedded image Is further represented by (6) Journal of
Electroanalytical Chemistry of Interface Electrochemistry (J.Electr
oanal.Chem.Interfacial Electrochem.) Volume 278, 2
Page 49 (1990)

Embedded image Are described. However, there is no report on the relationship between these compounds and the melatonin receptor.

As a tricyclic melatonin receptor affinity compound,

Embedded image [Wherein, R ¹ is a hydrogen atom, a halogen atom or a C _1-6 alkyl group, and R ² is —CR ³ R ⁴ (CH ₂ ) pNR ⁵ COR ⁶ [R
³ , R ⁴ and R ⁵ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, and R ⁶ represents a C _1-6 alkyl group or a C _3-7 cycloalkyl group. ], N represents an integer of 2 to 4 and p represents an integer of 1 to 4. ] (WO-A-9517405) and

Embedded image [Wherein, R ¹ represents —CR ³ R ⁴ (CH ₂ ) pNR ⁵ COR ⁶ [R
³ , R ⁴ and R ⁵ are the same or different and each represents a hydrogen atom or a C _1-6 alkyl group, and R ⁶ represents a C _1-6 alkyl group or a C _3-7 cycloalkyl group. And R ² is a hydrogen atom, a halogen atom, a C _1-6 alkyl group, OR ⁷ or CO
₂ R ⁷ [R ⁷ represents a hydrogen atom or a C _1-6 alkyl group. ]
(However, when q is 2, R ² is the same or different and is a hydrogen atom, a halogen atom, a C _1-6 alkyl group, OR ⁷ or C ⁷
O ₂ R ⁷ ), n is an integer of 0 to 2, p is an integer of 1 to 4 and q is 1 or 2] (WO-A-9529173).

[0005]

A melatonin agonist which is different in structure from melatonin, has an excellent affinity for a melatonin receptor, and has excellent brain transportability and metabolic stability.
It can be expected to be more effective than melatonin in treatment. At present, melatonin receptor activity, metabolic stability,
And those which are sufficiently satisfactory in terms of their ability to be transferred into the brain have not been found. Therefore, development of compounds that differ in chemical structure from the above-mentioned known compounds, have excellent melatonin receptor agonistic activity or antagonistic activity, and are sufficiently satisfactory as pharmaceuticals has been desired.

[0006]

The present inventors have made various studies and found that the formula

Embedded image [Wherein each symbol has the same meaning as described below], a Y in the basic skeleton represented by R ¹ -CO-amino-C _1-4 alkylene group (R ¹ has the following meaning). Having the chemical structural characteristics of having

Embedded image [Wherein, R ¹ is a hydrocarbon group which may have a substituent,
An amino group which may have a substituent or a heterocyclic group which may have a substituent, R ² is a hydrogen atom or a hydrocarbon group which may have a substituent, R ³ is a hydrogen atom, A hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent, X is CHR ⁴ , NR ⁴ , O or S
(R ⁴ represents a hydrogen atom or a hydrocarbon group which may have a substituent.),

Embedded image Ring A is a heterocyclic ring containing a 5- to 7-membered oxygen atom which may have a substituent, ring B is a benzene ring which may have a substituent, and m is an integer of 1 to 4.] And succeeded for the first time in the creation of a novel compound or a salt thereof (hereinafter abbreviated as compound (I)), and this compound (I) unexpectedly has excellent properties as a melatonin agonist. The present invention was found to be sufficiently satisfactory as a medicine, and the present invention was completed based on these findings.

That is, the present invention relates to (1) a compound (I):
(2) R¹Is (i) a halogen atom, a nitro group, a cyano group,
Hydroxy group, optionally halogenated C_1-6Al
Kill group, C_1-6Alkoxy group, amino group, mono-C_1-6A
Alkylamino group, di-C_1-6Alkylamino group, carbo
Xyl group, C_1-6Alkyl-carbonyl group, C_1-6Arco
Xy-carbonyl group, carbamoyl group, mono-C_1-6A
Alkyl-carbamoyl group, di-C_1-6Alkyl-carba
Moyl group, C_6-10Aryl-carbamoyl group, C_6-10A
Reel base, C_6-10Aryloxy group or halogenated
C that may be_1-6With an alkyl-carbonylamino group
1 to 5 optionally substituted (a) C_1-6Alkyl
Group, (b) C_2-6Alkenyl group, (c) C_2-6Alkynyl
Group, (d) C_3-6Cycloalkyl group or (e) C_6-14A
Reel group, (ii) halogen atom, nitro group, cyano group,
Hydroxy group, optionally halogenated C_1-6Al
Kill group, C_1-6Alkoxy group, amino group, mono-C_1-6A
Alkylamino group, di-C_1-6Alkylamino group, carbo
Xyl group, C_1-6Alkyl-carbonyl group, C_1-6Arco
Xy-carbonyl group, carbamoyl group, mono-C_1-6A
Alkyl-carbamoyl group, di-C_1-6Alkyl-carba
Moyl group, C_6-10Aryl-carbamoyl group, C_6-10A
Reel base, C_6-10Aryloxy group or halogenated
C that may be_1-6With an alkyl-carbonylamino group
1 to 5 optionally substituted (a) C_1-6Alkyl
Group, (b) C_2-6Alkenyl group, (c) C_2-6Alkynyl
Group, (d) C_3-6Cycloalkyl group or (e) C_6-14A
An amino group which may have one or two reel groups, or
Or (iii) a halogen atom, C_1-6Alkyl group, C_3-6Shi
Chloroalkyl group, C_2-6Alkynyl group, C_2-6Alkenyl
Group, C_7-11Aralkyl group, C_6-10Aryl group, C_1-6A
Lucoxy group, C_6-10Aryloxy group, formyl group, C
_1-6Alkyl-carbonyl group, C_6-10Aryl-carbo
Nyl group, formyloxy group, C_1-6Alkyl-carboni
Roxy group, C_6-10Aryl-carbonyloxy group,
Ruboxyl group, C _1-6Alkoxy-carbonyl group, C
_7-11Aralkyloxy-carbonyl group, carbamoyl
Group, optionally halogenated C_1-4Alkyl group, e
Oxo group, amidino group, imino group, amino group, mono-C
_1-4Alkylamino group, di-C_1-4Alkylamino group, 3
A 6-membered cyclic amino group, C_1-3Alkylenedioxy
Group, hydroxy group, nitro group, cyano group, mercapto
Group, sulfo group, sulfino group, phosphono group, sulfamo
Il group, Mono-C_1-6Alkylsulfamoyl group, di-
C_1-6Alkylsulfamoyl group, C_1-6Alkylthio
Group, C_6-10Arylthio group, C_1-6Alkylsulfini
Group, C_6-10Arylsulfinyl group, C_1-6Alkyl
Sulfonyl group or C_6-10An arylsulfonyl group
5 or more optionally substituted carbon atoms other than nitrogen
Heteroatom selected from atoms, oxygen atoms and sulfur atoms
A 5- to 14-membered heterocyclic group containing 1 to 3^TwoBut
(I) a hydrogen atom or (ii) a halogen atom, a nitro group,
Cyano group, hydroxy group, may be halogenated
C_1-6Alkyl group, C_1-6Alkoxy group, amino group, mono
-C_1-6Alkylamino group, di-C_1-6Alkylamino
Group, carboxyl group, C_1-6An alkyl-carbonyl group,
C_1-6Alkoxy-carbonyl group, carbamoyl group,
No-C_1-6Alkyl-carbamoyl group, di-C_1-6Archi
Ru-carbamoyl group, C_6-10Aryl-carbamoyl
Group, C_6-10Aryl group, C_6-10Aryloxy group or
Optionally halogenated C_1-6Alkyl-carboni
May be substituted with 1 to 5 amino groups (a)
C_1-6Alkyl group, (b) C_2-6Alkenyl group, (c) C
_2-6Alkynyl group, (d) C_3-6A cycloalkyl group or
(E) C_6-14Aryl group; R^ThreeIs (i) a hydrogen atom, (ii)
Halogen atom, nitro group, cyano group, hydroxy group, ha
C which may be formed into a log_1-6Alkyl group, C_1-6Al
Coxy group, amino group, mono-C_1-6Alkylamino group,
Di-C_1-6Alkylamino group, carboxyl group, C_1-6A
Alkyl-carbonyl group, C_1-6Alkoxy-carbonyl
Group, carbamoyl group, mono-C_1-6Alkyl-carbamo
Il group, di-C_1-6Alkyl-carbamoyl group, C_6-10
Aryl-carbamoyl group, C_6-10Aryl group, C_6-10
An aryloxy group or an optionally halogenated C
_1-6Substitute 1 to 5 alkyl-carbonylamino groups
(A) C_1-6Alkyl group, (b) C_2-6A
Lucenyl group, (c) C_2-6Alkynyl group, (d) C_3-6Shiku
Loalkyl group or (e) C_6-14An aryl group, or (i
ii) halogen atom, C_1-6Alkyl group, C_3-6Cycloal
Kill group, C_2-6Alkynyl group, C_2-6Alkenyl group, C
_7-11Aralkyl group, C_6-10Aryl group, C_1-6Alkoki
Si group, C_6-10Aryloxy group, formyl group, C_1-6A
Alkyl-carbonyl group, C_6-10Aryl-carbonyl
Group, formyloxy group, C_1-6Alkyl-carbonyl
Xy group, C_6-10Aryl-carbonyloxy group, carbo
Xyl group, C_1-6Alkoxy-carbonyl group, C_7-11A
Aralkyloxy-carbonyl group, carbamoyl group, halo
C which may be genated_1-4Alkyl group, oxo group,
Amidino group, imino group, amino group, mono-C_1-4Archi
Ruamino group, di-C_1-4Alkylamino group, 3 to 6
Membered cyclic amino group, C_1-3Alkylenedioxy group, hydrid
Roxy, nitro, cyano, mercapto, sulfo
Group, sulfino group, phosphono group, sulfamoyl group,
No-C_1-6Alkylsulfamoyl group, di-C_1-6Archi
Rusulfamoyl group, C_1-6Alkylthio group, C_6-10A
Reelthio group, C_1-6Alkylsulfinyl group, C_6-10
Arylsulfinyl group, C_1-6Alkylsulfonyl group
Or C_6-101 to 5 arylsulfonyl groups
Other than carbon atom, nitrogen atom, oxygen atom
1 to 3 heteroatoms selected from
A 5- to 14-membered heterocyclic group including R;^FourIs (i) a hydrogen atom
Or (ii) a halogen atom, a nitro group, a cyano group, a hydride
Roxy group, optionally halogenated C_1-6Alkyl
Group, C_1-6Alkoxy group, amino group, mono-C_1-6Archi
Ruamino group, di-C_1-6Alkylamino group, carboxy
Group, C_1-6Alkyl-carbonyl group, C_1-6Alkoxy
-Carbonyl group, carbamoyl group, mono-C_1-6Archi
Ru-carbamoyl group, di-C_1-6Alkyl-carbamoy
Group, C_6-10Aryl-carbamoyl group, C_6-10Ally
Group, C_6-10Aryloxy or halogenated
May be C_1-6An alkyl-carbonylamino group
(A) C which may be substituted by 5_1-6Alkyl group,
(B) C_2-6Alkenyl group, (c) C_2-6Alkynyl group,
(D) C_3-6Cycloalkyl group or (e) C_6-14Ally
Ring: A ring is (i) halogen atom, nitro group, cyano
Group, hydroxy group, optionally halogenated C_1-6
Alkyl group, C_1-6Alkoxy group, amino group, mono-C
_1-6Alkylamino group, di-C_1-6Alkylamino group,
Ruboxyl group, C_1-6Alkyl-carbonyl group, C_1-6A
Lucoxy-carbonyl group, carbamoyl group, mono-C
_1-6Alkyl-carbamoyl group, di-C_1-6Alkyl-ka
Rubamoyl group, C_6-10Aryl-carbamoyl group, C
_6-10Aryl group, C_6-10Aryloxy group or halogen
C which may be_1-6Alkyl-carbonylamido
(A) C which may be substituted with 1 to 5 amino groups_1-6A
Alkyl group, (b) C_2-6Alkenyl group, (c) C_2-6Archi
Nyl group, (d) C_3-6Cycloalkyl group or (e) C
_6-14Aryl group, (ii) halogen atom, (iii) C_1-6A
Alkoxy group, (iv) C_6-10Aryloxy group, (v)
Rumyl group, (vi) C_1-6An alkyl-carbonyl group, (vi
i) C_6-10Aryl-carbonyl group, (viii) formyl
Oxy wear, (ix) C_1-6Alkyl-carbonyloxy
Group, (x) C_6-10An aryl-carbonyloxy group, (x
i) carboxyl group, (xii) C_1-6Alkoxy-carbo
Nyl group, (xiii) C_7-11Aralkyloxy-carbonyl
Group, (xiv) carbamoyl group, (xv) halogenated
May be C_1-4Alkyl group, (xvi) oxo group, (xvi
i) amidino group, (xviii) imino group, (xix) amino
Group, (xx) mono-C_1-4Alkylamino group, (xxi) di-
C_1-4Alkylamino group, (xxii) 3- to 6-membered cyclic
Amino group, (xxiii) C_1-3Alkylenedioxy group, (xx
iv) hydroxy group, (xxv) nitro group, (xxvi) cyano
Group, (xxvii) mercapto group, (xxviii) sulfo group, (x
xix) sulfino group, (xxx) phosphono group, (xxxi) sulf
Famoyl group, (xxxii) mono-C_1-6Alkyl sulfa
Moyl group, (xxxiii) di-C_1-6Alkylsulfamoy
Group, (xxxiv) C_1-6Alkylthio group, (xxxv) C_6-10
Arylthio group, (xxxvi) C_1-6Alkylsulfinyl
Group, (xxxvii) C_6-10Arylsulfinyl group, (xxxv
iii) C_1-6Alkylsulfonyl group or (xxxix) C
_6-101 to 4 substituted with arylsulfonyl groups
A carbon atom and an oxygen atom, a nitrogen atom,
One heteroatom selected from oxygen and sulfur
A 5- to 7-membered heterocyclic ring optionally containing 3 members; and
And ring B are (i) a halogen atom, (ii) a halogen atom,
Toro, cyano, hydroxy, halogenated
May be C_1-6Alkyl group, C_1-6Alkoxy group, amino
Group, mono-C_1-6Alkylamino group, di-C_1-6Alkyl
Amino group, carboxyl group, C_1-6Alkyl-carboni
Group, C_1-6Alkoxy-carbonyl group, carbamoyl
Group, mono-C_1-6Alkyl-carbamoyl group, di-C_1-6
Alkyl-carbamoyl group, C_6-10Aryl-carbamo
Il group, C_6-10Aryl group, C_6-10Aryloxy group
Or optionally halogenated C_1-6Alkyl-cal
1 to 5 bonylamino groups may be substituted
(A) C_1-6Alkyl group, (b) C_2-6Alkenyl group,
(C) C_2-6Alkynyl group, (d) C_3-6Cycloalkyl group
Or (e) C_6-14An aryl group, (iii) a halogen atom,
Nitro, cyano, hydroxy, halogenated
May be C_1-6Alkyl group, C_1-6Alkoxy group, amide
No group, mono-C_1-6Alkylamino group, di-C_1-6Archi
Ruamino group, carboxyl group, C_1-6Alkyl-carbo
Nyl group, C_1-6Alkoxy-carbonyl group, carbamoy
Group, mono-C_1-6Alkyl-carbamoyl group, di-C
_1-6Alkyl-carbamoyl group, C_6-10Aryl-cal
Bamoyl group, C_6-10Aryl group, C_6-10Aryloxy
Group or optionally halogenated C_1-6Alkyl-
1 to 5 carbonylamino groups may be substituted
I (a) C_1-6Alkyl group, (b) C_2-6Alkenyl group,
(C) C_2-6Alkynyl group, (d) C_3-6Cycloalkyl group
Or (e) C_6-14Having one or two aryl groups
Optionally an amino group, (iv) C_1-6Alkanoylamino
Group, (v) halogen atom, nitro group, cyano group, hydro
Xy group, optionally halogenated C_1-6Alkyl
Group, C_1-6Alkoxy group, amino group, mono-C_1-6Archi
Ruamino group, di-C_1-6Alkylamino group, carboxy
Group, C_1-6Alkyl-carbonyl group, C_1-6Alkoxy
-Carbonyl group, carbamoyl group, mono-C_1-6Archi
Ru-carbamoyl group, di-C_1-6Alkyl-carbamoy
Group, C_6-10Aryl-carbamoyl group, C_6-10Ally
Group, C_6-10Aryloxy or halogenated
May be C_1-6An alkyl-carbonylamino group
Three or more optionally substituted C_1-6An alkoxy group or
Is (vi) C_1-31 or 2 alkylenedioxy groups
The benzene ring according to the above (1), which is an optionally substituted benzene ring.
Compound,

(3)

Embedded image Wherein R ⁴ ′ represents a hydrocarbon group which may have a substituent, and other symbols have the same meanings as described above;

Embedded image [Wherein the ring A ′ is a heterocyclic ring containing an oxygen atom which may have a substituent, n is an integer of 0 to 2,

Embedded imageThe other symbols are as defined above.]
(1) The compound described in (1), (5) R¹Has (i) a substituent
May be C_1-6Alkyl group, (ii) having a substituent
May be C_3-6A cycloalkyl group, (iii) having a substituent
May be C _2-6An alkenyl group, (iv) having a substituent
May be C_6-14Aryl group, having (v) a substituent
May be mono- or di-C_1-6Alkylamino
Group, (vi) C optionally having substituent (s)_6-14Aryla
5 or which may have a amino group or (vii)
Is a compound according to the above (1), which is a 6-membered nitrogen-containing heterocyclic group,
(6) R¹May be halogenated C_1-6Alkyl
A compound according to the above (1), wherein (7) R^TwoIs a hydrogen source
C or an optionally substituted C_1-6With an alkyl group
A compound according to the above (1), (8) R^TwoIs a hydrogen atom
A compound according to the above (1), (9) R^ThreeIs a hydrogen atom
Or a hydrocarbon group optionally having a substituent
(1) The compound described in (1), (10) R^ThreeBefore is a hydrogen atom
The compound according to the above (1), (11) R^FourIs a hydrogen atom or
C which may have a substituent_1-6The alkyl group is
(12) The compound according to (1), wherein X is CHR^Four(R^FourIs
The compound according to the above (1), which has the same meaning as
3) X is CHR^Four(R^FourIs as defined above) and

Embedded image (14) The compound according to the above (13), wherein X is CH ₂ ,
(15) the compound according to (1), wherein X is NR ⁴ (R ⁴ has the same meaning as described above); (16) the compound according to (1), wherein Y is C or CH; (17) Y Is CH, (18) the compound according to (1), wherein m is 2, (19) the compound according to (1), wherein A ring is a tetrahydrofuran ring, (20) A A compound according to (1), wherein the ring is unsubstituted; (21) a compound according to (1), wherein ring B is unsubstituted; (22) a compound according to (4), wherein n is 0 or 1. Equation (23)

Embedded image R ^3a is a hydrogen atom or a phenyl group, E ^a is CH ₂ CH ₂ ,
CH = CH, CH ₂ O, CH = N, CONH or CH
₂ NH, n ^a is 0 or 1, A '' ring 5 or 6 membered heterocyclic containing good oxygen atom optionally having two 1 or even a C _1-6 alkyl group substituted by a hydroxy group The ring and the B ′ ring each represent a benzene ring which may be substituted with a halogen atom].
4)

Embedded image (25) The above (1), which is (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide. (26) N- [2- (1,6,7,8-tetrahydro-2H-furo [3,2-e] indol-8-yl) ethyl] propionamide The compound according to (1), wherein the compound is (27) N- [2- (1,6,7,8-tetrahydro-2H-furo [3,2-e] indol-8-yl) ethyl] butylamide. (28) The compound according to the above (1), which is N- [2- (7-phenyl-1,6-dihydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide, 29) N- [2- (7-phenyl-1,6-
Dihydro-2H-indeno [5,4-b] furan-8-
Yl) ethyl] butyramide, the compound according to the above (1),

Equation (30)

Embedded image Or (ii)

Embedded image [Wherein each symbol has the same meaning as described above] or a salt thereof, and a compound represented by the formula R ¹ COOH (wherein R ¹ has the same meaning as described above), a salt thereof, or Reacting the compound with the reactive derivative and, if desired, further carrying out a reduction reaction and / or an alkylation reaction;

Embedded image [In the formula, R ⁵ represents a hydrogen atom, a halogen atom, a hydrocarbon group which may have a substituent, an alkoxy group which may have a substituent, a hydroxy group, a nitro group, a cyano group or a substituent. An amino group which may be possessed, L is a leaving group, and other symbols have the same meanings as described above], or a salt thereof is subjected to a ring closure reaction, and if desired, further subjected to a reduction reaction. A process for producing the compound according to the above (4), wherein

Embedded image Wherein each symbol is as defined above, or a salt thereof;

Embedded image Wherein, X ^a is (showing the R ^4a is a hydrogen atom or an optionally substituted hydrocarbon group) CHR ^4a, NR ^4a, O or S, Y ^a is C, CH or N (provided that When X ^a represents NH, Y ^a is CH or N), and other symbols have the same meanings as described above], or a salt thereof, (34) the compound described in (1) above. A pharmaceutical composition comprising: (35) a composition according to (34), which is a melatonin receptor affinity composition; (36) a composition according to (35), which is a biological rhythm regulator; The composition according to the above (35), which is a sleep / wake rhythm regulator,
(38) The composition according to (35), which is a jet lag regulator, and (39) the therapeutic agent for sleep disorder.
And the like.

The term "hydrocarbon group" in the term "optionally substituted hydrocarbon group" as used herein includes, for example, aliphatic hydrocarbon groups, monocyclic saturated hydrocarbon groups and Examples thereof include an aromatic hydrocarbon group, and a group having 1 to 16 carbon atoms is preferable. Specifically, for example, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group and an aryl group are used. "Alkyl group"
Is preferably, for example, a lower alkyl group. For example, a C _1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, pentyl and hexyl is generally used. The “alkenyl group” is preferably a lower alkenyl group, for example, and C _2-6 alkenyl groups such as vinyl, 1-propenyl, allyl, isopropenyl, butenyl, and isobutenyl are generally used. The “alkynyl group” is preferably, for example, a lower alkynyl group, for example, ethynyl,
C _2-6 alkynyl groups such as propargyl and 1-propynyl are widely used. The “cycloalkyl group” is preferably, for example, a lower cycloalkyl group, and for example, a C _3-6 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl is generally used. The “aryl group” is preferably a C _6-14 aryl group such as phenyl, 1-naphthyl, 2-naphthyl, biphenylyl and 2-anthryl, and for example, a phenyl group is generally used.

"Hydrocarbon group optionally having substituent (s)"
As the substituent which the “hydrocarbon group” may have,
For example, a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), a nitro group, a cyano group, a hydroxy group, a lower alkyl group which may be halogenated (eg, methyl, chloromethyl, difluoromethyl, trichloromethyl, trichloromethyl) Fluoromethyl, ethyl, 2-bromoethyl,
2,2,2-trifluoroethyl, pentafluoroethyl, propyl, 3,3,3-trifluoropropyl, isopropyl, butyl, isobutyl, sec-butyl, tert-
Optionally halogenated C ₁ such as butyl, 4,4,4-trifluorobutyl, pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl, 6,6,6-trifluorohexyl _-6 alkyl group),
Lower alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentyloxy, a C _1-6 alkoxy group such as hexyloxy), an amino group, a mono - lower alkylamino group (e.g., methylamino, Mono-C _1-6 such as ethylamino
Alkylamino group), di-lower alkylamino group (for example, di-amino such as dimethylamino and diethylamino).
A C _1-6 alkylamino group, a carboxyl group, a lower alkylcarbonyl group (eg, a C _1-6 alkyl-carbonyl group such as acetyl and propionyl), a lower alkoxycarbonyl group (eg, methoxycarbonyl,
C _1-6 alkoxy-carbonyl group such as ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.), carbamoyl group, mono-lower alkylcarbamoyl group (eg, mono-C _1-6 alkyl-carbamoyl group such as methylcarbamoyl, ethylcarbamoyl) ), Di-lower alkylcarbamoyl groups (eg, dimethylcarbamoyl, diethylcarbamoyl, etc.
_1-6 alkyl-carbamoyl group and the like), arylcarbamoyl group (for example, C _6-10 aryl-carbamoyl group such as phenylcarbamoyl and naphthylcarbamoyl),
Aryl groups (eg, C _6-10 such as phenyl, naphthyl, etc.)
An aryl group), an aryloxy group (for example, a C _6-10 aryloxy group such as phenyloxy and naphthyloxy), an _optionally halogenated lower alkylcarbonylamino group (for example, acetylamino, trifluoroacetylamino and the like) Optionally halogenated C
_1-6 alkyl-carbonylamino group), oxo group and the like. The "hydrocarbon group" of the "hydrocarbon group optionally having substituent (s)" has 1 to 5, preferably 1 to 3 of the above-mentioned substituents at substitutable positions of the hydrocarbon group. When the number of substituents is two or more, each substituent may be the same or different.

The "heterocyclic group" of the term "heterocyclic group optionally having substituent (s)" used herein is, for example, selected from a nitrogen atom, an oxygen atom and a sulfur atom other than a carbon atom. 5 or 14 membered (preferably 5 to 10 membered) (monocyclic to tricyclic, preferably monocyclic) containing 1 to 4 (preferably 1 to 3) heteroatoms Or a bicyclic) heterocyclic group. For example, 2- or 3-thienyl, 2- or 3-furyl, 1-, 2- or 3-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, 2-, 4- or 5-oxazolyl, 3-, 4- Or 5-isoxazolyl, 2-, 4
-Or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 3-, 4- or 5-pyrazolyl, 2-3
-Or 4-pyrazolidinyl, 2-, 4- or 5-imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1H- or 2H-tetrazolyl other than carbon atoms such as oxygen atom, sulfur atom and 5-membered ring groups containing 1 to 4 heteroatoms selected from nitrogen atoms, for example 2
-, 3- or 4-pyridyl, N-oxide-2-, 3
-Or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, N-oxide-2-, 4- or 5-pyrimidinyl, thiomorpholinyl, morpholinyl, piperidino, 2
-, 3- or 4-piperidyl, thiopyranyl, 1,4
-Oxazinyl, 1,4-thiazinyl, 1,3-thiazinyl, piperazinyl, triazinyl, 3- or 4-pyridazinyl, pyrazinyl, N-oxide-3- or 4-
6-membered ring group containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen atoms in addition to carbon atoms such as pyridazinyl, for example, indolyl, benzofuryl, benzothiazolyl, benzoxazolyl, benzimidazolyl, quinolyl, isoquinolyl , Phthalazinyl, quinazolinyl, quinoxalinyl, indolizinyl, quinolizinyl, 1,8-naphthyridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenanthridinyl, chromanyl, phenothiazinyl, phenoxazinyl and the like, in addition to oxygen, sulfur and nitrogen A bicyclic or tricyclic fused ring group having 1 to 4 hetero atoms selected from the group consisting of 1 to 4 atoms 5 or 6 that may contain
And a group formed by condensing with one or two membered ring groups). Among them, a 5- to 7-membered (preferably 5- or 6-membered) heterocyclic group containing 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen atoms in addition to carbon atoms is preferable.

Said "heterocyclic group optionally having substituent (s)"
Examples of the substituent which the “heterocyclic group” may have include, for example, a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.) and a lower alkyl group (eg, methyl, ethyl,
Propyl, isopropyl, butyl, isobutyl, sec-
C such as butyl, tert-butyl, pentyl and hexyl
_1-6 alkyl group, etc.), cycloalkyl group (eg, C _3-6 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), lower alkynyl group (eg, ethynyl, 1-propynyl, propargyl, etc. _2-6 alkynyl group, etc.), lower alkenyl group (eg, C _2-6 alkenyl group such as vinyl, allyl, isopropenyl, butenyl, isobutenyl, etc.), and aralkyl group (eg, C _2-6 such as benzyl, α-methylbenzyl, phenethyl and the like). _7-11 aralkyl group, etc.), aryl group (for example, C _6-10 aryl group such as phenyl, naphthyl and the like, preferably phenyl group), lower alkoxy group (for example, methoxy, ethoxy, propoxy, isopropoxy,
C _1-6 alkoxy groups such as butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc., aryloxy groups (eg, C _6-10 aryloxy groups such as phenoxy), lower alkanoyl groups (eg, formyl; acetyl) C _1-6 such as, propionyl, butyryl and isobutyryl
Alkyl-carbonyl group, etc., arylcarbonyl (for example, C _6-10 aryl-carbonyl group such as benzoyl group, naphthoyl group, etc.), lower alkanoyloxy group (for example, formyloxy; acetyloxy, propionyloxy, butyryloxy, isobutyi) A C _1-6 alkyl-carbonyloxy group such as riloxy, an arylcarbonyloxy group (eg, a C _6-10 aryl-carbonyloxy group such as benzoyloxy and naphthoyloxy), a carboxyl group, a lower alkoxycarbonyl group (Eg, methoxycarbonyl, ethoxycarbonyl,
C _1-6 alkoxy-carbonyl groups such as propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, etc., aralkyloxycarbonyl (eg, C _7-11 aralkyloxycarbonyl groups such as benzyloxycarbonyl) Carbamoyl, mono-, di- or tri-halogeno-lower alkyl groups (e.g. chloromethyl, dichloromethyl, trifluoromethyl, 2,2,2-
A mono-, di- or tri-halogeno-C _1-4 alkyl group such as trifluoroethyl), an oxo group, an amidino group, an imino group, an amino group, a mono-lower alkylamino group (eg, methylamino, ethylamino Mono-C such as propylamino, isopropylamino, butylamino, etc.
_1-4 alkylamino groups), di-lower alkylamino groups (e.g., dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino,
Di-C _1-4 alkylamino groups such as methylethylamino), one or three heteroatoms selected from oxygen, sulfur and nitrogen in addition to carbon and one nitrogen atom. Good 3- to 6-membered cyclic amino groups (eg aziridinyl, azetidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, imidazolyl, pyrazolyl, imidazolidinyl, piperidyl, morpholinyl, dihydropyridyl, pyridyl, N-methylpiperazinyl, N-ethylpiperazinyl A 3- to 6-membered cyclic amino group, etc.), an alkylenedioxy group (eg, a C _1-3 alkylenedioxy group such as methylenedioxy, ethylenedioxy, etc.),
Hydroxy group, nitro group, cyano group, mercapto group, sulfo group, sulfino group, phosphono group, sulfamoyl group, monoalkylsulfamoyl group (for example, N-methylsulfamoyl, N-ethylsulfamoyl, N-propyl Mono-C _1-6 alkylsulfamoyl groups such as sulfamoyl, N-isopropylsulfamoyl, N-butylsulfamoyl and the like, dialkylsulfamoyl group (for example, N, N-dimethylsulfamoyl, Di-C _1-6 alkylsulfamoyl groups such as N, N-diethylsulfamoyl, N, N-dipropylsulfamoyl, N, N-dibutylsulfamoyl and the like; alkylthio groups (for example, methylthio, ethylthio , propylthio, isopropylthio, butylthio, sec- butylthio, a C _1-6 alkylthio group such as tert- butylthio), arylthio groups (e.g. If, phenylthio, etc. C _6-10 arylthio group such as naphthylthio), a lower alkylsulfinyl group (e.g., methylsulfinyl, ethylsulfinyl, propyl sulfinyl, butylsulfinyl a C _1-6 alkylsulfinyl group Le etc.), arylsulfinyl group ( For example, a C _6-10 arylsulfinyl group such as phenylsulfinyl and naphthylsulfinyl, a lower alkylsulfonyl group (eg, a C _1-6 alkylsulfonyl group such as methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl and the like), aryl A sulfonyl group (for example, a C _6-10 arylsulfonyl group such as phenylsulfonyl and naphthylsulfonyl) and the like are used. The “heterocyclic group” of the “heterocyclic group optionally having substituent (s)” is such that the above-mentioned substituent has 1 to 5, preferably 1 to 3 at the substitutable position of the heterocyclic group. And the number of substituents is 2
In the case of more than one, each substituent may be the same or different.

The term "amino group optionally having substituent (s)" as used herein means, for example, one or two of the above-mentioned "hydrocarbon group optionally having substituent (s)". And an amino group which may be present. Preferred examples of the substituent which the “amino group” may have include, for example, a C _1-6 alkyl group which may have a substituent, and a C _6-10 which may have a substituent. And an aryl group. As the substituents that the “C _1-6 alkyl group” and “C _6-10 aryl group” may have, the same substituents as those that the “hydrocarbon group” may have Used. As used herein, the term "lower alkyl group" of the term "optionally substituted lower alkyl group" refers to
For example, it represents a C _1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, and may have, for example, the aforementioned `` hydrocarbon group '' as a substituent. Substituents such as 1
Or may have three. As used herein, the term "lower alkoxy group" of the "optionally substituted lower alkoxy group" includes, for example, methoxy, ethoxy,
Propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy and the like to indicate a <sub>C1-6</sub> alkoxy group and the like, as a substituent, for example, a substituent which the `` hydrocarbon group '' may have 1 to 3
You may have one.

As used herein, the term "optionally substituted benzene ring" includes, for example, a halogen atom (for example, fluorine, chlorine, bromine, iodine, etc.) and a substituent. A hydrocarbon group, an amino group which may have a substituent, an amide group (for example, formamide,
A C _1-3 acylamino group such as acetamide), a lower alkoxy group which may have a substituent, a lower alkylenedioxy group (for example, a C _1-3 alkylenedioxy group such as methylenedioxy and ethylenedioxy) Benzene ring which may have one or two substituent (s) selected at the position which can be substituted. Examples of the "optionally substituted hydrocarbon group", "optionally substituted amino group" and "optionally substituted lower alkoxy group" include the aforementioned The same ones as described in detail above are used. These "hydrocarbon groups",
When "amino group" and "lower alkoxy group" have two or more substituents, each substituent may be the same or different. The “optionally substituted benzene ring” includes, for example, a halogen atom (eg, fluorine, chlorine, etc.), a C _1-6 alkyl group (eg, methyl, ethyl, etc.), and mono-C _1-6. A benzene ring which may be substituted with one or two substituents selected from an alkylamino group is preferred.

In the above formula, R ¹ represents a hydrocarbon group which may have a substituent, an amino group which may have a substituent, or a heterocyclic group which may have a substituent. Preferred examples of the “hydrocarbon group” of the “hydrocarbon group optionally having substituent (s)” represented by R ¹ include, for example, an alkyl group (for example, C 4 such as methyl, ethyl, propyl and isopropyl).
_An alkenyl group (eg, a C _2-6 alkenyl group such as vinyl), an alkynyl group (eg, a C _2-6 alkynyl group such as ethynyl), a cycloalkyl group (eg, cyclopropyl) , Cyclobutyl,
Cyclopentyl, C _3-6 cycloalkyl groups such as cyclohexyl) and aryl groups (e.g., etc.) C _6-14 aryl groups such as phenyl, particularly alkyl groups (e.g., C _1-6 alkyl group such as methyl) And cycloalkyl groups (eg, C _3-6 cyclopropyl such as cyclopropyl) and the like are widely used. Examples of the “alkyl group”, “alkenyl group”, “alkynyl group”, “cycloalkyl group”, and “aryl group” include, for example, a substituent (preferably, fluorine, etc.) that the “hydrocarbon group” may have. And the like, 1 to 5, preferably 1 to 3 halogen atoms.

Preferred examples of the substituent of the "amino group optionally having substituent (s)" for R ¹ include a lower alkyl group optionally having substituent (s) and a substituent (s) having substituent (s). One or two aryl groups or the like may be used, and in particular, one lower alkyl group which may have a substituent is used. The "lower alkyl group" is, for example, C _1-6 such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.
An alkyl group or the like is used. The "lower alkyl group"
May have, for example, 1 to 3 substituents and the like which the “hydrocarbon group” may have. As the “aryl group”, for example, a C _6-10 aryl group such as a phenyl group is used. The “aryl group” is, for example, a substituent (preferably, a halogen atom such as fluorine or chlorine, a C _1-6 alkoxy group such as methoxy or ethoxy, etc.) which the “hydrocarbon group” may have. It may have from 5 to 5, preferably from 1 to 3. The “amino group optionally having substituent (s)” includes, for example, a phenylamino group substituted with 1 to 3 lower alkoxy groups (eg, a C _1-4 alkoxy group such as methoxy), or a lower amino group. Alkyl group (eg, methyl, ethyl, propyl, butyl,
Monoalkylamino groups substituted with C _1-4 alkyl groups such as tert-butyl, etc. are widely used.

Preferred examples of the “heterocyclic group” of the “heterocyclic group optionally having substituent (s)” for R ¹ include:
For example, a 5- or 6-membered heterocyclic group containing 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom is used. Specifically, for example, 1-, 2- or 3-pyrrolidinyl, 2- or 4-imidazolinyl, 2-, 3- or 4-pyrazolidinyl,
Piperidino, 2-, 3- or 4-piperidyl, 1- or 2-piperazinyl, morpholinyl, 2- or 3-
Thienyl, 2-, 3- or 4-pyridyl, 2-furyl or 3-furyl, pyrazinyl, 2-pyrimidinyl, 3
-Pyrrolyl, 3-pyridazinyl, 3-isothiazolyl,
3-isoxazolyl and the like. Particularly preferably, a 6-membered nitrogen-containing heterocyclic group (eg, pyridyl and the like) is used. Preferred examples of the substituent of the “heterocyclic group optionally having substituent (s)” represented by R ¹ include a halogen atom (eg, chlorine, fluorine, etc.) and a C _1-6 alkyl group (eg, methyl, ethyl And the like, a C _1-6 alkoxy group (for example, methoxy and ethoxy), an aralkyloxycarbonyl group (for example, C _7-12 aralkyloxy-carbonyl such as benzyloxycarbonyl) and the like.

R ¹ is, for example, (i) a lower alkyl group optionally having a substituent, (ii) a lower cycloalkyl group optionally having a substituent, or (iii) a substituent. (Iv) optionally substituted lower alkenyl group, (iv) optionally substituted aryl group, (v) optionally substituted mono or di lower alkylamino group, (vi) optionally substituted And an optionally substituted arylamino group or (vii) an optionally substituted 5- or 6-membered nitrogen-containing heterocyclic group. The “lower alkyl group” is preferably, for example, a C _1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, pentyl and hexyl. As the “lower cycloalkyl group”, for example, a C _3-6 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl is preferable. The “lower alkenyl group” is preferably a C _2-6 alkenyl group such as vinyl, 1-propenyl and butenyl. The “aryl group” is preferably a C _6-10 aryl group such as phenyl, 1-naphthyl and 2-naphthyl. "Lower alkylamino group"
For example, methylamino, ethylamino, propylamino,
Mono- or di-C _1-6 alkylamino groups such as isopropylamino, butylamino, tert-butylamino, dimethylamino, diethylamino and methylethylamino are preferred. The “arylamino group” is preferably a C _6-10 arylamino group such as phenylamino. "5- or 6-membered nitrogen-containing heterocyclic group" is, for example, 2-,
A 5- or 6-membered nitrogen-containing heterocyclic group such as 3- or 4-pyridyl is preferred. As the substituents that these groups may have, for example, 1 to 5 substituents that the aforementioned “hydrocarbon group” may have are used.

[0020] More preferred examples of R ¹ are, i) halogen or C _1-6 alkoxy C _1-6 alkyl group optionally substituted 1-4 respectively group, ii) C _3-6 cycloalkyl group, iii) a C _2-6 alkenyl group, iv) a C _1-6 alkoxy,
A nitro, a halogeno C _1-6 alkyl-carbonylamino or a C _6-10 aryl group optionally substituted with 1 to 4 halogen atoms, v) a mono- or di-C _1-6 alkylamino group, vi) A C _6-10 arylamino group optionally substituted with 1 to 3 C _1-6 alkoxy groups or vi
i) a 6-membered nitrogen-containing heterocyclic group which may be substituted with one or two C _7-11 aralkyloxycarbonyl groups; Particularly, an optionally halogenated C _1-6 alkyl group (for example, methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, pentane Fluoroethyl, propyl, 3,3,3-trifluoropropyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, 4,4,4-trifluorobutyl, pentyl, isopentyl, neopentyl, 5,5,5 - trifluoro pentyl, hexyl, 6,6,6-trifluoro hexyl, etc.), C _3-6 cycloalkyl group (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.) or mono -C _1-6 alkylamino group ( For example, methylamino, ethylamino, propylamino, isopropylamino, butyric Amino, tert- butylamino, etc.), etc. are generic, inter alia, optionally halogenated C _1-6 alkyl group or a mono -C _1-6 alkylamino group, which may be especially halogenated C _{1- 6} alkyl groups, especially C _1-3 alkyl groups (eg methyl,
Ethyl, propyl, etc.).

In the above formula, R ² represents a hydrogen atom or a hydrocarbon group which may have a substituent. As R ² , a hydrogen atom or a lower (C _1-6 ) alkyl group which may have a substituent is preferably used, more preferably a hydrogen atom or a lower (C _1-6 ) alkyl group, particularly a hydrogen atom. Is commonly used. In the above formula, R ³ represents a hydrogen atom, a hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent. Preferred examples of the “hydrocarbon group” of the “optionally substituted hydrocarbon group” represented by R ³ include an alkyl group (for example, C _1-6 alkyl such as methyl, ethyl, propyl, isopropyl, etc.). group etc.), an alkenyl group (e.g., C _2-6 alkenyl group such as vinyl), alkynyl groups (e.g., C _2-6, such as ethynyl
Such as an alkynyl group, a cycloalkyl group (eg, a C _3-6 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl) and an aryl group (eg, a C _6-14 aryl group such as phenyl). Alkyl groups (eg, C such as methyl)
_{A 1-6} alkyl group or the like and an aryl group (eg, a C _6-14 aryl group such as phenyl) are widely used.
Examples of the “alkyl group”, “alkenyl group”, “alkynyl group”, “cycloalkyl group”, and “aryl group” include, for example, a substituent (preferably, fluorine, etc.) that the “hydrocarbon group” may have. And the like, 1 to 5, preferably 1 to 3 halogen atoms.

Preferred examples of the “heterocyclic group” of the “heterocyclic group optionally having substituent (s)” for R ³ include:
For example, a 5- or 6-membered heterocyclic group containing 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom is used. Specifically, for example, 1-, 2- or 3-pyrrolidinyl, 2- or 4-imidazolinyl, 2-, 3- or 4-pyrazolidinyl,
Piperidino, 2-, 3- or 4-piperidyl, 1- or 2-piperazinyl, morpholinyl, 2- or 3-
Thienyl, 2-, 3- or 4-pyridyl, 2- or 3-furyl, pyrazinyl, 2-pyrimidinyl, 3-pyrrolyl, 3-pyridazinyl, 3-isothiazolyl, 3-isoxazolyl and the like. Particularly preferably, 6
A membered nitrogen-containing heterocyclic group (eg, pyridyl and the like) and the like are used. Preferred examples of the substituent of the “heterocyclic group optionally having substituent (s)” represented by R ³ include a halogen atom (eg, chlorine, fluorine, etc.) and a C _1-6 alkyl group (eg, methyl, ethyl Etc.), a C _1-6 alkoxy group (eg, methoxy, ethoxy, etc.), an aralkyloxycarbonyl group (eg, C _7-12 aralkyloxy-carbonyl such as benzyloxycarbonyl), an amino group, mono-C _1-6
An alkylamino group (eg, methylamino, ethylamino, etc.), a di-C _1-6 alkylamino group (eg, dimethylamino, diethylamino, etc.) and the like are used. R
³ includes, for example, (i) a hydrogen atom, (ii) a lower alkyl group optionally having a substituent, (iii) an aryl group optionally having a substituent, and (iv) a group having a substituent. And a 5- or 6-membered heterocyclic group which may be preferable. Further, for example, (i) a hydrogen atom, (ii) a lower alkyl group, (iii) a C _6-10 aryl group which may have a substituent, (iv) 6) A 6-membered nitrogen-containing heterocyclic group which may have a substituent is preferable. Examples of the substituent include a halogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group, an amino group, a mono-C _1-6 alkylamino group, and a di-C _1-6 alkylamino group. More preferably, R ³ is a hydrogen atom, a phenyl group, 2-, 3- or 4-pyridyl group. Particularly preferred is a hydrogen atom.

In the above formula, X represents CHR ⁴ , NR ⁴ , O or S (R ⁴ represents a hydrogen atom or a hydrocarbon group which may have a substituent). X ^a is CHR ^4a, NR ^4a, O
Or S (R ^4a represents a hydrogen atom or a hydrocarbon group which may have a substituent). R ⁴ or R ^4a is preferably a hydrogen atom or a lower (C _1-6 ) alkyl group which may have a substituent, and a hydrogen atom is widely used. X is preferably CHR ⁴ (R ⁴ is as defined above), O or S. Alternatively, X is preferably CHR ⁴ or NR ⁴ (R ⁴ is as defined above). X
^a is preferably CHR ^4a or NR ^4a (R ^4a has the same meaning as described above). In the above formula, Y represents C, CH or N. Preferably it is C or CH. Y ^a represents a C, CH or N. Preferably it is C or CH.

In the above formula, ring A or ring A 'is a heterocyclic ring containing a 5- to 7-membered oxygen atom which may have a substituent. The "heterocycle containing a 5- to 7-membered oxygen atom" means one or two or more selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom and an oxygen atom (preferably one to three). Or 2) which may contain a 5- to 7-membered (preferably 5- or 6-membered) heterocyclic ring. The ring has the formula

Embedded image [Wherein E is (i) CH ₂ CH ₂ , (ii) CH ＝ CH, (i
ii) CH ₂ O, (iv) OCH ₂ , (v) CH ₂ S (O) q ′
(Q 'is an integer of 0 to 2), (vi) S (O) q'CH
₂ (q ′ is as defined above), (vii) CH ₂ NH, (viii)
NHCH ₂ , (ix) N = N, (x) CH = N, (xi) N =
CH or (xii) CONH 2, wherein n ′ is 0 to 2
And a ring represented by the following formula: E is (i)
_{CH 2 CH 2, (ii)} CH = CH, (iii) CH 2 O, (i
v) OCH ₂ , (v) CH ₂ NH, (vi) NHCH ₂ , (vi
i) N = N, (viii) CH = N or (ix) N = CH is preferred, and in particular (i) CH ₂ CH ₂ or (ii) CH = C
H is preferred. Specifically, for example, 2,3-dihydrofuran, furan, 1,3-dioxole, oxazoline,
5-membered heterocycles containing an oxygen atom such as isoxazole, 1,2,3-oxadiazole and oxazole, for example, 2H
A 6-membered heterocyclic ring containing an oxygen atom such as -3,4-dihydropyran, 2H-pyran, 2,3-dehydro-1,4-dioxane, and 2,3-dehydromorpholine is preferable. More preferably, the formula

Embedded image [Wherein, n has the same meaning as described above. ] The ring represented by this. Specifically, for example, 2,3-dihydrofuran,
Furan, 2H-3,4-dihydropyran and 2H-pyran are widely used.

Examples of the substituent on the ring A and the ring A 'include a halogen atom (for example, fluorine, chlorine, bromine, iodine, etc.), a lower alkyl group which may have a substituent, and a substituent. Cycloalkyl group which may be substituted, lower alkynyl group which may have a substituent, lower alkenyl group which may have a substituent, aryl group which may have a substituent, lower alkoxy group (for example, Methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy and other C _1-6 alkoxy groups, etc., aryloxy groups (eg, C _6-10 aryloxy groups such as phenoxy, etc.), lower alkanoyl groups (e.g., formyl; acetyl, propionyl, butyryl, C _1-6 alkyl isobutyryl etc. - carbonyl group), arylcarbonyl (E.g., benzoyl group,
A C _6-10 aryl-carbonyl group such as a naphthoyl group; a lower alkanoyloxy group (eg, formyloxy; a C _1-6 alkyl-carbonyloxy group such as acetyloxy, propionyloxy, butyryloxy, isobutyryloxy); An arylcarbonyloxy group (e.g., benzoyloxy, naphthoyloxy and the like;
_6-10 aryl-carbonyloxy group, etc.), carboxyl group, lower alkoxycarbonyl group (for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,
C _1-6 alkoxy-carbonyl groups such as isobutoxycarbonyl, tert-butoxycarbonyl and the like), aralkyloxycarbonyl (eg C _7-11 aralkyloxy-carbonyl groups such as benzyloxycarbonyl), carbamoyl group, mono-, Di- or tri-halogeno-lower alkyl groups (for example, mono-, di- or tri-halogeno-C _1-4 alkyl groups such as chloromethyl, dichloromethyl, trifluoromethyl, 2,2,2-trifluoroethyl and the like) Oxo group, amidino group, imino group, amino group, mono-lower alkylamino group (for example, mono-C _1-4 alkylamino group such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, etc.) ), Di-lower alkylamino groups (e.g., dimethylamino, diethylamino, Ropiruamino, diisopropylamino, dibutylamino, and di -C _1-4 alkylamino group such as a methyl ethylamino), carbon and oxygen atoms in addition to one nitrogen atom, a hetero atom selected from sulfur atom and a nitrogen atom A 3- to 6-membered cyclic amino group optionally containing 1 to 3 (eg aziridinyl,
Azetidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl,
Imidazolyl, pyrazolyl, imidazolidinyl, piperidyl, morpholinyl, dihydropyridyl, pyridyl, N-
A 3- to 6-membered cyclic amino group such as methylpiperazinyl, N-ethylpiperazinyl, etc.), an alkylenedioxy group (for example, a C such as methylenedioxy, ethylenedioxy, etc.)
_1-3 alkylenedioxy group, etc.), hydroxy group, nitro group, cyano group, mercapto group, sulfo group, sulfino group, phosphono group, sulfamoyl group, monoalkylsulfamoyl group (for example, N-methylsulfamoyl, Mono-C _1-6 alkylsulfamoyl groups such as N-ethylsulfamoyl, N-propylsulfamoyl, N-isopropylsulfamoyl, N-butylsulfamoyl and the like, dialkylsulfamoyl group (for example, Di-C _1-6 alkylsulfamoyl groups such as N, N-dimethylsulfamoyl, N, N-diethylsulfamoyl, N, N-dipropylsulfamoyl and N, N-dibutylsulfamoyl ), Alkylthio groups (eg, methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio,
a C _1-6 alkylthio group such as tert-butylthio and the like; an arylthio group (eg, a C _6-10 arylthio group such as phenylthio and naphthylthio); a lower alkylsulfinyl group (eg, methylsulfinyl, ethylsulfinyl, propylsulfinyl, butyl) C such as sulfinyl
_1-6 alkylsulfinyl group), arylsulfinyl group (eg, C _6-10 arylsulfinyl group such as phenylsulfinyl and naphthylsulfinyl), lower alkylsulfonyl group (eg, methylsulfonyl,
Examples thereof include a C _1-6 alkylsulfonyl group such as ethylsulfonyl, propylsulfonyl and butylsulfonyl, and an arylsulfonyl group (eg, a C _6-10 arylsulfonyl group such as phenylsulfonyl and naphthylsulfonyl). The “lower alkyl group”, “lower alkenyl group”, “lower alkynyl group”, “lower cycloalkyl group”, “aryl group” are, for example, the aforementioned “hydrocarbon group”
May have 1 to 5, preferably 1 to 3, substituents and the like which may be possessed.

The substituent on the ring A and the ring A 'is preferably a halogen atom, a C _1-6 alkyl group which may have a substituent or a C _1-6 alkoxy group which may have a substituent. A hydroxyl group, a nitro group, a cyano group, an amino group which may have a substituent, an oxo group, and the like. The "optionally substituted C _1-6 alkyl group", "optionally substituted C _1-6 alkoxy group", "optionally substituted amino group" The “substituent” in the above indicates, for example, a substituent that the “hydrocarbon group” may have. Said A
The ring and the A ′ ring may have 1 to 4, preferably 1 to 2 substituents at the substitutable positions according to the size of the ring, and the number of substituents is 2 or more. In the case of each substituent may be the same or different. As the A ring and the A ′ ring, for example,

Embedded image [N has the same meaning as described above, and R ⁵ represents a hydrogen atom or one or two substituents represented by the above-mentioned “preferable substituents on ring A and ring A ′”]. Above all, R
⁵ is a hydrogen atom and a C _1-6 alkyl group which may have a substituent, especially those wherein R ⁵ is hydrogen atom (unsubstituted ring A and unsubstituted ring A ') are generally used.

In the above formula, the ring B represents a benzene ring which may have a substituent. Examples of the substituent on the ring B include the “substituent” of the “benzene ring optionally having substituent (s)”. Among them, a halogen atom or a lower (C _1-6 ) alkyl group which may have a substituent is preferable, and a halogen atom or a lower (C _1-6 ) alkyl group (preferably methyl) is widely used. “Substituent” of the “lower (C _1-6 ) alkyl group _optionally having substituent (s)”
Represents a substituent which the “hydrocarbon group” may have, for example. Ring B may have one or two, preferably one, substituent at a substitutable position, and the number of substituents is 2
In this case, each substituent may be the same or different.
As the ring B, for example,

Embedded image [R ⁶ represents a hydrogen atom, a halogen atom, a lower (C _1-6 ) alkyl group which may have a substituent or a lower (C _1-6 ) alkoxy group which may have a substituent] Are preferred. R ⁶ is preferably, for example, a hydrogen atom, a halogen atom or a lower (C _1-6 ) alkyl group (preferably methyl). More preferably, it is a hydrogen atom.

In the above formula, m represents an integer of 1 to 4.
m is preferably an integer of 1 to 3. Further, m is preferably 2 or 3, and particularly preferably m is 2. In the above formula, n represents an integer of 0 to 2. n is preferably an integer of 0 or 1. In particular, n is preferably 0.

Embedded image [Wherein, R ⁴ ′ represents a hydrocarbon group which may have a substituent, and other symbols have the same meanings as described above]. R ⁴ ′ is preferably lower (C _1-3 ) alkyl which may have a substituent.

[0029]

Embedded image Wherein each symbol is as defined above. Among them,

Embedded image Wherein each symbol is as defined above.

Embedded image Wherein each symbol has the same meaning as described above. this house,

Embedded image Wherein each symbol is as defined above. Particularly preferably

Embedded image Wherein each symbol is as defined above.

[0030]

Embedded image Wherein each symbol is as defined above.

Embedded image Wherein each symbol is as defined above. Among them,

Embedded image Wherein each symbol is as defined above.

[0031]

Embedded image Wherein each symbol has the same meaning as described above. this house,

Embedded image Wherein each symbol is as defined above. Also,

Embedded image Wherein each symbol is as defined above. Particularly preferably

Embedded image Wherein each symbol is as defined above.

As the compound (I) of the present invention, for example, those having the following structural formulas are widely used.

Embedded image [Wherein the symbols have the same meanings as described above] As a preferred example of the compound (I), a compound represented by the formula

Embedded image [Wherein the symbols have the same meanings as described above], and the like.

Preferred examples of the compound (I) include those wherein R ¹ is (i) a lower alkyl group which may have a substituent, and (ii) a lower cycloalkyl group which may have a substituent. (Iii) a lower alkenyl group optionally having a substituent, (iv) an aryl group optionally having a substituent, (v)
A mono- or di-lower alkylamino group optionally having a substituent, (vi) an arylamino group optionally having a substituent, or (vii) 5 or 6 optionally having a substituent
Membered nitrogen-containing heterocyclic group, R ² has a hydrogen atom or a lower (C _1-6 ) alkyl group which may have a substituent, R ³ has (i) a hydrogen atom, and (ii) a substituent. An optionally substituted lower alkyl group or (iii) an optionally substituted aryl group,
X is CHR ⁴ or NR ⁴ (R ⁴ represents a hydrogen atom or a lower (C _1-6 ) alkyl group optionally substituted with an oxo group);

Embedded image Heterocycles containing a 5- to 7-membered oxygen atom in which ring A may have a substituent, benzene rings in which ring B may have a substituent, compounds in which m is 1 or 2, and the like. No.

[0034] More preferably, optionally substituted 1-4 respectively R ¹ is i) halogen or C _1-6 alkoxy C _1-6 alkyl group, ii) C _3-6 cycloalkyl group, iii ) C _2-6 alkenyl groups, iv) C _1-6 alkoxy,
A nitro, a halogeno C _1-6 alkyl-carbonylamino or a C _6-10 aryl group optionally substituted with 1 to 4 halogen atoms, v) a mono- or di-C _1-6 alkylamino group, vi) A C _6-10 arylamino group optionally substituted with 1 to 3 C _1-6 alkoxy groups or vi
i) a 6-membered nitrogen-containing heterocyclic group optionally substituted by 1 to 2 C _7-11 aralkyloxy-carbonyl groups, R ² is a hydrogen atom or a lower (C _1-6 ) alkyl group, and R ³ is (I) a hydrogen atom, (ii) a lower (C _1-6 ) alkyl group or (iii) C
_6-14 aryl group, X is CHR ⁴ or NR ⁴ (R ⁴ is a hydrogen atom or an oxo group optionally substituted with lower (C
_1-6 ) represents an alkyl group),

Embedded image A ring

Embedded image [Each symbol is as defined above. The ring B is

Embedded image [R ^6a is a hydrogen atom, a halogen atom or lower (C _1-6 )
An alkyl group], and compounds wherein m is 1 or 2.

Of these, the expression

Embedded image Also, the formula

Embedded image As the compound (I), for example, N- [2- (1,6,
7,8-tetrahydro-2H-indeno [5,4-b]
Furan-8-yl) ethyl] acetamide, N- [2-
(1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] butylamide, N- [2- (1,6,7,8-tetrahydro-2H
-Indeno [5,4-b] furan-8-yl) ethyl]
Propionamide, N- [2- (3,7,8,9-tetrahydropyrano [3,2-e] indol-1-yl)
Ethyl] propionamide, N- [2- (5-fluoro-3,7,8,9-tetrahydrocyclopenta [f]
[L] benzopyran-9-yl) ethyl] propionamide, N- [2- (3,7,8,9-tetrahydropyrano [3,2-e] indol-1-yl) ethyl] butylamide, N- [2- (1,2,3,7,8,9-hexahydropyrano [3,2-e] indol-1-yl)
Ethyl] propionamide, N- [2- (1,2,3,
7,8,9-hexahydropyrano [3,2-e] indol-1-yl) ethyl] butylamide, N- [2-
(4-fluoro-1,6,7,8-tetrahydro-2H
-Indeno [5,4-b] furan-8-yl) ethyl]
Butyramide, N- [2- (4-fluoro-1,6,6,
7,8-tetrahydro-2H-indeno [5,4-b]
Furan-8-yl) ethyl] propionamide, (S)
-N- [2- (1,6,7,8-tetrahydro-2H-
Indeno [5,4-b] furan-8-yl) ethyl] propionamide, (R) -N- [2- (1,6,7,8
-Tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide, N- [2-
(1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] butylamide, N- [2- (1,6-dihydro-2H-indeno [5,4 -B] furan-8-yl) ethyl] acetamide, N- [2- (1,6-dihydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide, N- [2 -(1,6-dihydro-2H-indeno [5,4-b] furan-8-yl) ethyl] butylamide, N- [2- (7,8-dihydro-6H-indeno [4,5-d] -1,3-dioxol-8-yl) ethyl] propionamide, N- [2- (7,8-dihydro-6H-indeno [4,5-d] -1,3-dioxol-8-yl) ethyl ] Butyramide, N- [2-
(2,3,8,9-tetrahydro-7H-indeno [4,5-b] -1,4-dioxin-9-yl) ethyl] propionamide, N- [2- (2,3,8,9 −
Tetrahydro-7H-indeno [4,5-b] -1,4
-Dioxin-9-yl) ethyl] butylamide, N-
[2- (1,6,7,8-tetrahydro-2H-furo [3,2-e] indol-8-yl) ethyl] propionamide, N- [2- (1,6,7,8-tetrahydro -2H-furo [3,2-e] indol-8-yl)
Ethyl] butyramide, N- [2- (7-phenyl-
1,6-dihydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide, N- [2-
(7-phenyl-1,6-dihydro-2H-indeno [5,4-b] furan-8-yl) ethyl] butylamide is preferred.

More preferably, N- [2- (1,6,
7,8-tetrahydro-2H-indeno [5,4-b]
Furan-8-yl) ethyl] acetamide, N- [2-
(1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide, N- [2- (5-fluoro-3,7,8,9-
Tetrahydrocyclopenta [f] [1] benzopyran-
9-yl) ethyl] propionamide, N- [2- (5
-Fluoro-1,2,3,7,8,9-hexahydrocyclopenta [f] [1] benzopyran-9-yl) ethyl] propionamide, (S) -N- [2- (1,6,
7,8-tetrahydro-2H-indeno [5,4-b]
Furan-8-yl) ethyl] propionamide, (R)
-N- [2- (1,6,7,8-tetrahydro-2H-
Indeno [5,4-b] furan-8-yl) ethyl] propionamide, N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ) Ethyl] butyramide, N- [2- (1,6-dihydro-2H-indeno [5,4-b] furan-8-yl) ethyl] acetamide, N- [2- (1,6-dihydro-2H) -Indeno [5,4-b] furan-8-yl) ethyl] propionamide, N- [2- (1,6-
Dihydro-2H-indeno [5,4-b] furan-8-
Yl) ethyl] butylamide, N- [2- (1,6,
7,8-tetrahydro-2H-furo [3,2-e] indol-8-yl) ethyl] propionamide, N-
[2- (1,6,7,8-tetrahydro-2H-furo [3,2-e] indol-8-yl) ethyl] butylamide, N- [2- (7-phenyl-1,6-dihydro- 2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide, N- [2- (7-phenyl-
1,6-dihydro-2H-indeno [5,4-b] furan-8-yl) ethyl] butylamide. Particularly preferably, (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide, N- [2- (1,6
7,8-tetrahydro-2H-furo [3,2-e] indol-8-yl) ethyl] propionamide, N-
[2- (1,6,7,8-tetrahydro-2H-furo [3,2-e] indol-8-yl) ethyl] butylamide, N- [2- (7-phenyl-1,6-dihydro- 2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide, N- [2- (7-phenyl-
1,6-dihydro-2H-indeno [5,4-b] furan-8-yl) ethyl] butylamide.

As the salt of compound (I) of the present invention, for example, pharmacologically acceptable salts and the like are used. For example,
Examples thereof include salts with inorganic bases, salts with organic bases, salts with inorganic acids, salts with organic acids, and salts with basic or acidic amino acids. Preferable examples of the salt with an inorganic base include, for example, alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, and aluminum salt and ammonium salt. Preferred examples of the salt with an organic base include, for example, trimethylamine, triethylamine, pyridine, picoline,
2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine,
Salts with dicyclohexylamine, N, N'-dibenzylethylenediamine and the like can be mentioned. Preferred examples of the salt with an inorganic acid include, for example, salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like. Preferred examples of salts with organic acids include, for example, formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfone Acids and salts with p-toluenesulfonic acid and the like. Preferred examples of the salt with a basic amino acid include, for example, salts with arginine, lysine, ornithine, and preferred examples of the salt with an acidic amino acid include, for example, salts with aspartic acid, glutamic acid, and the like. Can be Among them, pharmaceutically acceptable salts are preferable, and examples thereof include, when the compound (I) has a basic functional group, an inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, and phosphoric acid. Salts of, for example, acetic acid, phthalic acid,
Fumaric acid, tartaric acid, maleic acid, citric acid, succinic acid,
Examples thereof include salts with organic acids such as methanesulfonic acid and p-toluenesulfonic acid, and when having an acidic functional group, for example, alkali metal salts such as sodium salt and potassium salt,
Examples thereof include alkaline earth metal salts such as calcium salts and magnesium salts, and ammonium salts. The compound (I) of the present invention may be a hydrate or a non-hydrate.

The method for producing the compound (I) of the present invention is described below. The compound (I) of the present invention can be obtained, for example, by a method represented by the following reaction formula or a method analogous thereto. Compounds (III) to (LXXIV) in the formula include those in the form of a salt, and examples of such a salt include those similar to the salt of compound (I). The schematic diagram of the reaction formula is shown below, and each symbol of the compound in the schematic diagram has the same meaning as described above.

(Reaction 1)

Embedded image

Embedded image

Embedded image

Compound (III) is produced according to a method known per se, for example, the method described in Experimental Chemistry Course, 4th edition, Vol. 21, pp. 1-148 (edited by The Chemical Society of Japan), or a method analogous thereto. be able to. Compound (VI) [wherein L represents a halogen atom, a leaving group such as alkylsulfonyl, alkylsulfonyloxy or arylsulfonyloxy, and R ⁷ represents an optionally substituted hydrocarbon group], a method known per se; For example, Bulletin of the Chemical Society of Japan (Bull. Chem. Soc. Jp.
n.), 64, 1410 (1991), Journal of the Indian Chemical Society (J. Indian Ch.
em. Soc.), 66, 656 (1989), Journal of
Medicinal Chemistry (J. Med. Chem.), Vol. 29,
It can be produced according to the method described on page 1586, page 1904 (1986) or a method analogous thereto.

Compound (XIII) can be prepared by a method known per se, for example, the method of Journal of the Chemical Society (J. Che
m. Soc.), p. 4691 (1963), Chemistry Letters (Chem. Lett.), p. 165 (1986), or a method analogous thereto. Examples of the halogen atom represented by L include fluorine, chlorine, bromine and iodine. Examples of the alkylsulfonyl group represented by L include a C _1-5 alkylsulfonyl group (eg, methanesulfonyl, ethanesulfonyl, etc.). Examples of the alkylsulfonyloxy group represented by L include an optionally halogenated C _1-5 alkylsulfonyloxy group (eg, methanesulfonyloxy, ethanesulfonyloxy, trichloromethanesulfonyloxy, etc.). Examples of the arylsulfonyloxy group represented by L include an optionally substituted benzenesulfonyloxy group (for example, p-toluenesulfonyloxy, benzenesulfonyloxy, and the like). When the compound in the formula is commercially available, a commercially available product can be used as it is.

Compound (IV) is produced from compound (III) and malonic acid by Knoevenagel condensation in the presence of a base. Malonic acid is added in an amount of about 1.0 to 1 mol per mole of compound (III).
5.0 moles, preferably about 1.0 to 2.0 moles are used.
As the base, for example, sodium hydroxide, inorganic bases such as potassium hydroxide, sodium carbonate, potassium carbonate,
Basic salts such as cesium carbonate and sodium hydrogen carbonate,
Aromatic amines such as pyridine and lutidine, triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine And other tertiary amines. The amount of the base to be used is about 0.1-10.0 per 1 mol of compound (III).
Mole, preferably about 0.1-5.0 mole. This reaction is advantageously performed using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds. For example, alcohols such as methanol, ethanol and propanol, hydrocarbons such as benzene, toluene, cyclohexane and hexane, N, N-dimethylformamide, N, N- Solvents such as amides such as dimethylacetamide, organic acids such as formic acid and acetic acid, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, and 1,2-dichloroethane, and mixed solvents thereof are preferable. The reaction time varies depending on the reagent and solvent used, but is usually 30 minutes to 24 hours, preferably 30 minutes to
8 hours. The reaction temperature is generally 0-150 ° C, preferably 0-130 ° C. The product (IV) can be used in the next reaction as a reaction solution or as a crude product, but it can also be isolated from the reaction mixture according to a conventional method, and can be easily separated by separation means such as recrystallization, distillation, and chromatography. Can be purified.

Compound (VIII) (wherein R ⁹ represents a hydrocarbon group) is obtained by treating a phosphonate carbanion formed by the base treatment of an alkylphosphonic diester with a compound (II)
By reacting with (I), a configurational isomer of E or Z form alone or a mixture of E and Z isomers is obtained. R
Examples of the “hydrocarbon group” represented by ⁹ include the above-mentioned “hydrocarbon group” and the like, and among them, lower alkyl groups (for example, C _1-6 such as methyl, ethyl, isopropyl, etc.)
And benzyl group which may have a substituent. The “benzyl group optionally having substituent (s)” may have 1 to 3 substituents such as a halogen atom and C _1-3 alkyl at a substitutable position of the benzyl group. As specific examples, for example, benzyl,
p-chlorobenzyl, p-methylbenzyl and the like. As the alkyl phosphonic acid diester, for example, ethyl diethylphosphonoacetate or the like is used. The alkylphosphonic acid diester is used in an amount of about 1.0-3.0 mol, preferably about 1.0-1.5 mol, per 1 mol of compound (III). Examples of the base include alkali metal hydrides such as sodium hydride and potassium hydride, metal amides such as sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide, sodium methoxide, sodium ethoxide, and potassium tertiary salt. And metal alkoxides such as butoxide. The amount of the base to be used is about 1. 1 mol per 1 mol of compound (III).
It is 0 to 5.0 moles, preferably about 1.0 to 1.5 moles. This reaction is advantageously performed using a solvent inert to the reaction. Although not particularly limited as long as the reaction proceeds as such a solvent, for example, methanol, ethanol, alcohols such as propanol, diethyl ether, tetrahydrofuran, dioxane, ethers such as 1,2-dimethoxyethane, benzene, toluene, cyclohexane, Solvents such as hydrocarbons such as hexane, amides such as N, N-dimethylformamide and N, N-dimethylacetamide, sulfoxides such as dimethylsulfoxide, and a mixed solvent thereof are preferable. The reaction time is generally 1 hour to 50 hours, preferably 1 hour to 10 hours.
Time. The reaction temperature is usually -78 to 200C, preferably 0 to 150C. The isomer mixture of compound (VIII) can be used in the next reaction as a reaction solution or as a crude product, but can also be isolated from the reaction mixture according to a conventional method, and can be separated by recrystallization, distillation, chromatography, etc. It can be easily purified by means.

Compound (IX) is produced by hydrolyzing the ester group of compound (VIII) using an acid or a base. Acid hydrolysis generally involves mineral acids such as hydrochloric acid and sulfuric acid, Lewis acids such as boron trichloride and boron tribromide, combined use of Lewis acids with thiols or sulfides, and organic acids such as trifluoroacetic acid and p-toluenesulfonic acid. Is used. Alkaline hydrolysis includes inorganic bases such as sodium hydroxide, potassium hydroxide and barium hydroxide, basic salts such as sodium carbonate and potassium carbonate,
Metal alkoxides such as sodium methoxide, sodium ethoxide and potassium tert-butoxide, and organic bases such as triethylamine, imidazole and formamidine are used. These acids and bases are used in an amount of about 0.5 to 10 mol, preferably about 0.5 to 6.0 mol, per 1 mol of compound (VIII). This reaction is advantageously carried out without a solvent or using a solvent inert to the reaction.
Such a solvent is not particularly limited as long as the reaction proceeds, for example, alcohols such as methanol, ethanol and propanol, benzene, aromatic hydrocarbons such as toluene, cyclohexane, saturated hydrocarbons such as hexane, formic acid, Organic acids such as acetic acid, ethers such as tetrahydrofuran, dioxane and 1,2-dimethoxyethane, amides such as N, N-dimethylformamide and N, N-dimethylacetamide, dichloromethane,
Halogenated hydrocarbons such as chloroform, carbon tetrachloride, and 1,2-dichloroethane; nitriles such as acetonitrile and propionitrile; ketones such as acetone and methyl ethyl ketone; sulfoxides such as dimethyl sulfoxide; and solvents such as water and the like Are preferred. The reaction time is generally 10 minutes to 60 hours, preferably 10 minutes to 12 hours. The reaction temperature is usually -10
-200 ° C, preferably 0-120 ° C. The product (IX) can be used in the next reaction as a reaction solution or as a crude product. Can be purified. Compound (VII) (wherein R ⁹ represents a hydrocarbon group) is represented by compound (VI) and a compound represented by the formula R ³ CH ₂ COOR ⁹ (wherein R ³ and R ⁹ are as defined above). And the ester derivative to be
It is produced by reacting in the presence of a base.

The ester derivative is used in an amount of about 1.0 to 5.0 mol, preferably about 1.0 to 2.0 mol, per 1 mol of compound (VI).
Use 0 mol. As the base, for example, inorganic bases such as sodium hydroxide and potassium hydroxide, basic salts such as sodium carbonate, potassium carbonate, cesium carbonate and sodium hydrogen carbonate, aromatic amines such as pyridine and lutidine, triethylamine, tripropyl Amine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N, N-dimethylaniline, N
Tertiary amines such as -methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, alkali metal hydrides such as sodium hydride and potassium hydride, sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide, etc. And metal alkoxides such as sodium methoxide, sodium ethoxide and potassium tert-butoxide. The amount of the base to be used is about 1.0-5.0 mol, preferably about 1.0-2.0 mol, per 1 mol of compound (VI). This reaction is advantageously performed using a solvent inert to the reaction. Although not particularly limited as long as the reaction proceeds as such a solvent, for example, methanol, ethanol, alcohols such as propanol, diethyl ether, tetrahydrofuran, dioxane, ethers such as 1,2-dimethoxyethane, benzene, toluene, cyclohexane, Hydrocarbons such as hexane, amides such as N, N-dimethylformamide, N, N-dimethylacetamide, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, acetonitrile, propio Nitriles such as nitriles, ketones such as acetone and methyl ethyl ketone,
Solvents such as sulfoxides such as dimethyl sulfoxide or a mixed solvent thereof are preferable. The reaction time is generally 30 minutes to 48 hours, preferably 30 minutes to 5 hours. The reaction temperature is usually -20 to 200 ° C, preferably -1.
0-150 ° C. The product (VII) can be used in the next reaction as a reaction solution or as a crude product, but can also be isolated from the reaction mixture according to a conventional method, and can be easily separated by separation means such as recrystallization, distillation, and chromatography. Can be purified.

Among the compounds (VII), those in which R ³ and R ⁴ are hydrogen can also be produced by subjecting the compound (VIII) to a catalytic reduction reaction in a hydrogen atmosphere in the presence of various catalysts. Examples of the catalyst used include platinum oxide, activated carbon with platinum, activated carbon with palladium, barium sulfate with palladium, nickel, copper-chromium oxide, rhodium, cobalt, ruthenium and the like. The amount of the catalyst to be used is about 5 to 1000% by weight relative to compound (VIII),
Preferably it is about 5-300% by weight. This reaction is advantageously performed using a solvent inert to the reaction. The solvent is not particularly limited as long as the reaction proceeds, for example, alcohols such as methanol, ethanol and propanol, ethers such as diethyl ether, tetrahydrofuran, dioxane and 1,2-dimethoxyethane, and saturated solvents such as cyclohexane and hexane. Hydrocarbons,
Amides such as N, N-dimethylformamide and N, N-dimethylacetamide; organic acids such as formic acid and acetic acid;
A solvent such as water or a mixed solvent thereof is preferable. The reaction time varies depending on the activity and amount of the catalyst used, but is usually 30 minutes to 24 hours, preferably 30 minutes to 6 hours. The reaction temperature is usually 0 to 120 ° C, preferably 2
0-80 ° C. The pressure is usually 1 to 100 atm.
An additive (promoter) for increasing the catalytic ability may be added to the reaction system. As the acidic additive, for example, inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, perchloric acid, hydrobromic acid, phosphoric acid, acetic acid, trifluoroacetic acid, oxalic acid, phthalic acid, fumaric acid, tartaric acid, citric acid, Organic acids such as succinic acid, methanesulfonic acid, p-toluenesulfonic acid, and 10-camphorsulfonic acid are preferred. As the basic additive, sodium hydroxide, potassium hydroxide and the like are preferable. The product (VII) can be used in the next reaction as a reaction solution or as a crude product, but can also be isolated from the reaction mixture according to a conventional method, and can be easily separated by separation means such as recrystallization, distillation, and chromatography. Can be purified.

Among the compounds (V), compounds in which R ³ and R ⁴ are hydrogen can be obtained by subjecting the compound (IV) or the compound (IX) to a catalytic reduction reaction in a hydrogen atmosphere in the same manner as in the step of producing the compound (VII). It is manufactured by attaching to. Compound (V) is also produced by hydrolyzing the ester group of compound (VII) using an acid or a base. In general, acid hydrolysis includes mineral acids such as hydrochloric acid and sulfuric acid, Lewis acids such as boron trichloride and boron tribromide, a combination of Lewis acid and thiol or sulfide, trifluoroacetic acid, p-
Organic acids such as toluenesulfonic acid are used. Alkaline hydrolysis includes inorganic bases such as sodium hydroxide, potassium hydroxide and barium hydroxide, basic salts such as sodium carbonate and potassium carbonate, and metal alkoxides such as sodium methoxide, sodium ethoxide and potassium tert-butoxide. And organic bases such as triethylamine, imidazole and formamidine. These acids and bases are used in an amount of about 0.5-10 mol, preferably about 0.5-6. Mol, per 1 mol of compound (VII).
Use 0 mol. This reaction is advantageously carried out without a solvent or using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds, for example, alcohols such as methanol, ethanol and propanol, benzene, aromatic hydrocarbons such as toluene, cyclohexane, saturated hydrocarbons such as hexane, formic acid,
Organic acids such as acetic acid; ethers such as tetrahydrofuran, dioxane and 1,2-dimethoxyethane;
Amides such as N-dimethylformamide, N, N-dimethylacetamide, dichloromethane, chloroform,
Solvents such as halogenated hydrocarbons such as carbon tetrachloride and 1,2-dichloroethane, nitriles such as acetonitrile and propionitrile, ketones such as acetone and methyl ethyl ketone, sulfoxides such as dimethyl sulfoxide, water and the like, or a mixture thereof. Solvents and the like are preferred.
The reaction time is generally 10 minutes to 60 hours, preferably 10 minutes to
12 hours. The reaction temperature is usually -10 to 200C, preferably 0 to 120C. The product (V) can be used in the next reaction as a reaction solution or as a crude product,
It can be isolated from the reaction mixture according to a conventional method, and can be easily purified by separation means such as recrystallization, distillation, and chromatography.

Compound (XIV) is obtained by subjecting compound (XIII) to an aldehyde derivative represented by the formula R ⁴ CHO [R ⁴ is as defined above] in the presence of a base by aldol condensation,
It is produced as an E- or Z-configuration isomer alone or as a mixture of E- and Z-isomers. The aldehyde derivative is used in an amount of about 1.0-5.0 mol, preferably about 1.0-2.0 mol, per 1 mol of compound (XIII). As the base,
For example, inorganic bases such as sodium hydroxide and potassium hydroxide, for example, basic salts such as sodium carbonate, potassium carbonate, cesium carbonate and sodium hydrogencarbonate, aromatic amines such as pyridine and lutidine, triethylamine, tripropylamine, triethylamine Butylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine,
N, N-dimethylaniline, N-methylpiperidine, N
Tertiary compounds such as -methylpyrrolidine and N-methylmorpholine
Primary amines, alkali metal hydrides such as sodium hydride and potassium hydride, metal amides such as sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide, sodium methoxide, sodium ethoxide, potassium tert-butoxide And other metal alkoxides. The amount of the base to be used is about 1.0-5.0 mol, preferably about 1.0-2.5 mol, per 1 mol of compound (XIII). This reaction is advantageously performed using a solvent inert to the reaction. Although not particularly limited as long as the reaction proceeds as such a solvent, for example, methanol, ethanol, alcohols such as propanol, diethyl ether, tetrahydrofuran, dioxane, ethers such as 1,2-dimethoxyethane, benzene, toluene, cyclohexane, Hydrocarbons such as hexane, N, N-dimethylformamide,
Amides such as N, N-dimethylacetamide; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, and 1,2-dichloroethane; nitriles such as acetonitrile and propionitrile; and sulfoxides such as dimethylsulfoxide. A solvent or a mixed solvent thereof is preferred. Reaction time is usually 30 minutes or more.
48 hours, preferably 30 minutes to 5 hours. The reaction temperature is usually -78 to 200C, preferably -10 to 150C.
It is. Further, it can also be produced by dehydrating an aldol-type intermediate obtained in the presence of a base such as lithium diisopropylamide in the presence of an acid catalyst such as p-toluenesulfonic acid at room temperature to heating. Product (XIV)
Can be used in the next reaction as a reaction solution or as a crude product, but can also be isolated from the reaction mixture according to a conventional method, and can be easily purified by separation means such as recrystallization, distillation, and chromatography. it can.

Compound (X) is produced by subjecting compound (V) or compound (XIV) to a ring-closing reaction known per se. For example, a method by heating, a method using an acidic substance, a method of reacting with a halogenating agent and then cyclizing in the presence of a Lewis acid, and a method analogous thereto are used. When the ring is closed by heating, it is advantageous to carry out the reaction without a solvent or using a solvent inert to the reaction. The solvent is not particularly limited as long as the reaction proceeds. For example, solvents such as high-boiling hydrocarbons such as 1,2,3,4-tetrahydronaphthalene, high-boiling ethers such as diphenyl ether and diethylene glycol dimethyl ether, or solvents such as Are preferred. The reaction time is generally 10 minutes to 24 hours, preferably 10 minutes to 10 hours. The reaction temperature is usually 100 to 300 ° C, preferably 1
00 to 200 ° C. In the case of ring closure using an acidic substance, for example, phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride,
Acidic substances such as thionyl chloride, hydrochloric acid, sulfuric acid, polyphosphoric acid and p-toluenesulfonic acid are used. The acidic substance is added in an amount of about 0.5 to 1 mol of the compound (V) or (XIV).
To 100 mol, preferably about 5.0 to 20 mol.
This reaction is advantageously carried out without a solvent or using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds, for example, benzene, aromatic hydrocarbons such as toluene, cyclohexane, saturated hydrocarbons such as hexane, tetrahydrofuran, dioxane, 1,2-dimethoxyethane and the like Ethers,
Amides such as N, N-dimethylformamide and N, N-dimethylacetamide; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane; acid anhydrides such as acetic anhydride; dimethyl sulfoxide Solvents such as sulfoxides or a mixed solvent thereof are preferred. Reaction time is usually 30
Minutes to 12 hours, preferably 30 minutes to 6 hours. The reaction temperature is generally 0-200 ° C, preferably 0-150 ° C.

When the ring is closed in the presence of a Lewis acid after the reaction with a halogenating agent, examples of the halogenating agent include thionyl halides such as thionyl chloride and thionyl bromide, and halogens such as phosphoryl chloride and phosphoryl bromide. Phosphoryls, phosphorus pentachloride, phosphorus trichloride, phosphorus pentabromide,
Examples include phosphorus halides such as phosphorus tribromide, oxalyl halides such as oxalyl chloride, and phosgene. The halogenating agent is used in an amount of about 1.0-30 mol, preferably about 1.0-10 mol, per 1 mol of compound (V). This reaction is advantageously carried out without a solvent or using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds, for example, benzene,
Aromatic hydrocarbons such as toluene, saturated hydrocarbons such as cyclohexane and hexane, ethers such as tetrahydrofuran, dioxane and 1,2-dimethoxyethane, amides such as N, N-dimethylformamide and N, N-dimethylacetamide And a solvent such as a halogenated hydrocarbon such as dichloromethane, chloroform, carbon tetrachloride, and 1,2-dichloroethane, or a mixed solvent thereof. The reaction time is usually 10 minutes to 12 hours,
Preferably, it is 10 minutes to 5 hours. The reaction temperature is usually -1
The temperature is from 0 to 200C, preferably from -10 to 120C. The product can be used as a reaction solution or as a crude product in the next reaction, but can also be isolated from the reaction mixture according to a conventional method, and is easily purified by separation means such as recrystallization, distillation, and chromatography. be able to. Examples of the Lewis acid used in the next cyclization reaction include anhydrous aluminum chloride, anhydrous zinc chloride, anhydrous iron chloride and the like. The Lewis acid is added in an amount of about 0.1 to 1 mol of the compound (V).
20 moles, preferably about 0.2-5.0 moles are used. This reaction is advantageously carried out without a solvent or using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds. For example, aromatic hydrocarbons such as benzene and toluene, monochlorobenzene, o-
Dichlorobenzene, 1,2,4-trichlorobenzene,
Dichloromethane, chloroform, carbon tetrachloride, 1,2-
Solvents such as halogenated hydrocarbons such as dichloroethane or a mixed solvent thereof are preferred. The reaction time is generally 30 minutes to 12 hours, preferably 30 minutes to 6 hours. The reaction temperature is usually -20 to 200 ° C, preferably -5.
~ 120 ° C. The product (X) obtained by the above cyclization reaction can be used in the next reaction as a reaction solution or as a crude product. And can be easily purified by separation means such as chromatography.

Compound (XII) is produced by reacting compound (X) with a carbanion formed by treating acetonitrile with a base to obtain compound (XI) and then subjecting it to a dehydration reaction. Compound (XII) can be obtained as a configuration isomer of E or Z form alone or as a mixture of E and Z forms. Acetonitrile is used in an amount of about 1.0 to 3.0 mol, preferably about 1.0 to 1.3 mol, per 1 mol of compound (X). Examples of the base include alkali metal hydrides such as sodium hydride and potassium hydride, metal amides such as sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide, sodium methoxide, sodium ethoxide, and potassium tertiary salt. Metal alkoxides such as butoxide; and the like, and the amount of the base to be used is about 1.0-1.0 mol per 1 mol of compound (X).
5.0 mol, preferably about 1.0-1.5 mol.
This reaction is advantageously performed using a solvent inert to the reaction. Although not particularly limited as long as the reaction proceeds as such a solvent, for example, methanol, ethanol, alcohols such as propanol, diethyl ether, tetrahydrofuran, dioxane, ethers such as 1,2-dimethoxyethane, benzene, toluene, cyclohexane, Hydrocarbons such as hexane, amides such as N, N-dimethylformamide and N, N-dimethylacetamide, dichloromethane, chloroform, carbon tetrachloride,
Solvents such as halogenated hydrocarbons such as 2-dichloroethane or a mixed solvent thereof are preferable. The reaction time is generally 30 minutes to 48 hours, preferably 30 minutes to 5 hours. The reaction temperature is usually -78 to 100C, preferably -78 to 50C. The product can be used as a reaction solution or as a crude product in the next reaction, but can also be isolated from the reaction mixture according to a conventional method, and is easily purified by separation means such as recrystallization, distillation, and chromatography. be able to.

Examples of the catalyst used for the dehydration reaction include hydrochloric acid, sulfuric acid, phosphoric acid, potassium hydrogen sulfate, oxalic acid,
Examples thereof include acidic catalysts such as p-toluenesulfonic acid, 10-camphorsulfonic acid, and boron trifluoride ether complex; and basic catalysts such as sodium hydroxide and potassium hydroxide. For example, a dehydrating agent such as alumina, sodium dioxide, phosphorus oxychloride, thionyl chloride, and methanesulfonyl chloride may be used. This reaction is advantageously carried out without a solvent or using a solvent inert to the reaction. Although not particularly limited as long as the reaction proceeds as such a solvent, for example, methanol, ethanol, alcohols such as propanol, diethyl ether, tetrahydrofuran, dioxane, ethers such as 1,2-dimethoxyethane, benzene, toluene, cyclohexane, Solvents such as hydrocarbons such as hexane, amides such as N, N-dimethylformamide and N, N-dimethylacetamide, sulfoxides such as dimethylsulfoxide, and a mixed solvent thereof are preferable. The reaction time is generally 30 minutes to 24 hours, preferably 30 minutes to 5 hours. The reaction temperature is usually 0 to 200 ° C, preferably 0 to 200 ° C.
150 ° C.

The compound (XII) is reacted with a phosphonate carbanion generated by the base treatment of an alkylphosphonic diester with the compound (X) to give an E-form or a Z-form.
It can also be obtained as a single isomer of the isomer or as a mixture of E and Z isomers. As the alkyl phosphonic acid diester, for example, diethyl cyanomethyl phosphonate or the like is used. The alkylphosphonic acid diester is used in an amount of about 1.0-3.0 mol, preferably about 1.0-1.5 mol, per 1 mol of compound (X). As the base, for example, sodium hydride, alkali metal hydrides such as potassium hydride, sodium amide, lithium diisopropylamide, metal amides such as lithium hexamethyldisilazide, sodium methoxide, sodium ethoxide,
Metal alkoxides such as potassium tert-butoxide and the like are used. The amount of these bases to be used is about 1.0-5.0 mol, preferably about 1.0-5.0 mol, per 1 mol of compound (X).
1.5 mole is preferred. This reaction is advantageously performed using a solvent inert to the reaction. The solvent is not particularly limited as long as the reaction proceeds, for example, alcohols such as methanol, ethanol and propanol, diethyl ether, tetrahydrofuran, dioxane,
Ethers such as 1,2-dimethoxyethane, hydrocarbons such as benzene, toluene, cyclohexane and hexane; amides such as N, N-dimethylformamide and N, N-dimethylacetamide; and sulfoxides such as dimethylsulfoxide. A solvent or a mixed solvent thereof is preferred. The reaction time is generally 1 hour to 50 hours, preferably 1 hour to 10 hours. The reaction temperature is usually -78 to 200C, preferably 0 to 150C.
The mixture of isomers of compound (XII) can be used as is in the reaction mixture or as a crude product in the next reaction. It can be easily purified by means.

The extension of the carbon chain of the side chain of the compound (XII) may be carried out according to a known carbon chain extension reaction. For example, a cyano group is hydrolyzed under alkaline or acidic conditions to form a carboxyl group. After that, or after the carboxyl group is converted into an ester form, a reduction reaction is performed to form an alcohol form, and then a reaction through halogenation and cyanation is employed. Compound (XV) is produced by subjecting compound (XII) to a reduction reaction. Examples of the reducing agent used include metal hydrides such as aluminum hydride and diisobutylaluminum hydride; metal hydride complex compounds such as lithium aluminum hydride and sodium borohydride; and Raney nickel and Raney as hydrogenation catalysts. A catalyst such as cobalt is used. The amount of the reducing agent used is, for example, in the case of a metal hydride, about 1.0 to 10 mol, preferably about 1.0 to 3.0 mol, per 1 mol of the compound (XII). In the case of hydrogenation, a catalyst such as Raney nickel or Raney cobalt is used in an amount of about 1.0 to 10 mol, preferably about 1.0 to 3.0 mol, per 1 mol of compound (XII). 10-1000% by weight, preferably about 80-3
00% by weight. This reaction is advantageously performed using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds. For example, alcohols such as methanol, ethanol, and propanol, diethyl ether, tetrahydrofuran, dioxane, and 1,2-
Solvents such as ethers such as dimethoxyethane, hydrocarbons such as benzene, toluene and cyclohexane, amides such as N, N-dimethylformamide and N, N-dimethylacetamide, and organic acids such as formic acid and acetic acid, or a mixture thereof. Solvents and the like are preferred. When a Raney nickel or Raney cobalt catalyst is used, amines such as ammonia may be further added to suppress side reactions.
The reaction time varies depending on the activity and amount of the catalyst used, but is usually 1 hour to 100 hours, preferably 1 hour to 50 hours.
Time. The reaction temperature is generally 0-120 ° C, preferably 20-80 ° C. When a catalyst such as Raney nickel or Raney cobalt is used, the pressure of hydrogen is usually 1 to 100.
Atmospheric pressure. The product (XV) can be used in the next reaction as a reaction solution or as a crude product, but it can also be isolated from the reaction mixture according to a conventional method, and can be easily separated by separation means such as recrystallization, distillation, and chromatography. Can be purified.

The compound of the formula (XVI) wherein m = 2 or 3 is produced by treating the compound (XV) with an acid and isomerizing it. Examples of the acid catalyst include hydrochloric acid, sulfuric acid,
Inorganic acids such as nitric acid, hydrobromic acid, phosphoric acid, acetic acid, trifluoroacetic acid, oxalic acid, phthalic acid, fumaric acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid, Organic acids such as 10-camphorsulfonic acid, and boron trifluoride etherate are preferred. The amount of the acid catalyst to be used is about 0.01-10 mol, preferably about 0.01 mol, per 1 mol of compound (XV).
~ 5.0 mol. This reaction is advantageously carried out without a solvent or using a solvent inert to the reaction. Although not particularly limited as long as the reaction proceeds as such a solvent, for example, methanol, ethanol, alcohols such as propanol, diethyl ether, tetrahydrofuran, dioxane, ethers such as 1,2-dimethoxyethane, benzene, toluene, cyclohexane, Hydrocarbons such as hexane, N, N-dimethylformamide, N,
Preferred are amides such as N-dimethylacetamide, sulfoxides such as dimethylsulfoxide, solvents such as water, and mixed solvents thereof. Reaction time is usually 1
0 minutes to 12 hours, preferably 10 minutes to 2 hours. The reaction temperature is usually -10 to 200C, preferably -10 to 1C.
00 ° C. The product (XVI) can be used in the next reaction as a reaction solution or as a crude product, but it can also be isolated from the reaction mixture according to a conventional method, and is easily separated by separation means such as recrystallization, distillation, or chromatography. Can be purified. Compound (m = 1) of compound (XVI) is
It is produced by treating compound (X) with trimethylsilyl cyanide in the presence of a Lewis acid, eliminating the resulting trimethylsilyloxy group with an acid, and subsequently reducing the cyano group. Examples of the Lewis acid include zinc iodide, anhydrous aluminum chloride, anhydrous zinc chloride, anhydrous iron chloride, and the like. The amount of the Lewis acid catalyst to be used is about 0.01 to 10 mol, preferably about 0.01 to 10 mol, per 1 mol of compound (X).
1.0 mole. This reaction is advantageously carried out without a solvent or using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds, for example, diethyl ether, tetrahydrofuran, dioxane, ethers such as 1,2-dimethoxyethane, benzene, toluene, cyclohexane, and solvents such as hydrocarbons such as hexane or the like. Preferred are mixed solvents thereof. The reaction time is usually 10 minutes to 12 hours, preferably 3 minutes.
0 minutes to 3 hours. The reaction temperature is usually -10 to 200
° C, preferably -10 to 100 ° C. The product can be used in the next reaction as a reaction solution or as a crude product, but can also be isolated from the reaction mixture according to a conventional method,
It can be easily purified by separation means such as recrystallization, distillation and chromatography. Next, treatment is performed using an acid. As the acid, for example, inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, acetic acid, trifluoroacetic acid,
Oxalic acid, phthalic acid, fumaric acid, tartaric acid, maleic acid,
Organic acids such as citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid, 10-camphorsulfonic acid, and boron trifluoride ether complex are preferred. These acids are used in an amount of about 1 to 100 with respect to 1 mol of the compound (X).
Mol, preferably about 1 to 10 mol. This reaction is advantageously carried out without a solvent or using a solvent inert to the reaction. The solvent is not particularly limited as long as the reaction proceeds, for example, diethyl ether, tetrahydrofuran, dioxane, ethers such as 1,2-dimethoxyethane, benzene, toluene, cyclohexane,
Hydrocarbons such as hexane, amides such as N, N-dimethylformamide and N, N-dimethylacetamide;
Solvents such as sulfoxides such as dimethyl sulfoxide or a mixed solvent thereof are preferable. The reaction time is generally 30 minutes to 12 hours, preferably 30 minutes to 5 hours. The reaction temperature is generally 0-200 ° C, preferably 20-1.
50 ° C. The reduction of the cyano group can be performed under the conditions used for producing compound (XV) from compound (XII). The product (XVI) can be used in the next reaction as a reaction solution or as a crude product, but it can also be isolated from the reaction mixture according to a conventional method, and is easily separated by separation means such as recrystallization, distillation, or chromatography. Can be purified.

The compound (XVII) is produced by reacting the compound (XVI) with a carboxylic acid, a salt thereof or a reactive derivative thereof. Examples of the carboxylic acid include compounds represented by the formula R ¹ —COOH (wherein R ¹ has the same meaning as described above). Examples of the reactive derivative of the carboxylic acid include acid halides (eg, acid chlorides,
Acid bromides), acid amides (eg, acid amides with pyrazole, imidazole, benzotriazole, etc.), acid anhydrides (eg, C _1-6 aliphatic carboxylic acid anhydrides such as acetic anhydride, propionic anhydride, butyric anhydride) Products), acid azides,
Active esters (eg, diethoxy phosphate, diphenoxy phosphate, p-nitrophenyl ester,
2,4-dinitrophenyl ester, cyanomethyl ester, pentachlorophenyl ester, ester with N-hydroxysuccinimide, ester with N-hydroxyphthalimide, ester with 1-hydroxybenzotriazole, 6-chloro-1-hydroxybenzotriazole , An ester with 1-hydroxy-1H-2-pyridone, and an active thioester (eg, 2
-Pyridylthioester, 2-benzothiazolylthioester, etc.).

Instead of using the reactive derivative, the carboxylic acid or a salt thereof may be directly reacted with the compound (XVI) in the presence of a suitable condensing agent. As a condensing agent,
For example, N, N'-dicyclohexylcarbodiimide, 1
N, N'-disubstituted carbodiimides such as -ethyl-3- (3-dimethylaminopropyl) carbodiimide (WSC) hydrochloride, azolides such as N, N'-carbonyldiimidazole, N-ethoxycarbonyl-2- Dehydrating agents such as ethoxy-1,2-dihydroquinoline, phosphorus oxychloride and alkoxyacetylene, and 2-halogenopyridinium salts such as 2-chloromethylpyridinium iodide and 2-fluoro-1-methylpyridinium iodide are used. When these condensing agents are used, the reaction is thought to proceed via a reactive derivative of the carboxylic acid.
A carboxylic acid represented by the formula R ¹ —COOH (R ¹ has the same meaning as described above) or a reactive derivative thereof is a compound (XVI) 1
It is generally used in an amount of about 1.0-5.0 mol, preferably about 1.0-2.0 mol, per mol. This reaction is advantageously performed using a solvent inert to the reaction. The solvent is not particularly limited as long as the reaction proceeds. Examples of the solvent include diethyl ether, tetrahydrofuran, dioxane, 1,2 and
Ethers such as dimethoxyethane, hydrocarbons such as benzene, toluene and cyclohexane, amides such as N, N-dimethylformamide and N, N-dimethylacetamide, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane Preferred are halogenated hydrocarbons such as, for example, nitriles such as acetonitrile and propionitrile, sulfoxides such as dimethyl sulfoxide, solvents such as water, and a mixed solvent thereof. When an acid halide is used as the reactive derivative of the carboxylic acid, the reaction can be performed in the presence of a deoxidizing agent for the purpose of removing released hydrogen halide from the reaction system. Examples of such a deacidifying agent include basic salts such as sodium carbonate, potassium carbonate and sodium hydrogen carbonate, pyridine, aromatic amines such as lutidine, triethylamine, tripropylamine, tributylamine, and the like.
It is desirable to add tertiary amines such as cyclohexyldimethylamine, 4-dimethylaminopyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine and N-methylmorpholine. The reaction time varies depending on the reagents and solvents used, but is usually from 30 minutes to
24 hours, preferably 30 minutes to 4 hours. The reaction temperature is generally 0-100 ° C, preferably 0-70 ° C.

Compound (XVII) is prepared by adding a carboxylic acid represented by the formula R ¹ —COOH (R ¹ is as defined above) or a reactive derivative thereof to compound (XV),
Minutes to 3 hours, preferably 10 minutes to 1 hour, 0 to 100
After stirring at 0 ° C., preferably 0 to 70 ° C., the above-mentioned deoxidizing agent is added and the mixture is subjected to an acylation reaction, whereby the compound can be produced with isomerization in the system. The carboxylic acid or its reactive derivative is generally used in an amount of about 1.0 to 5.0 mol, preferably about 1.0 to 2.0 mol, per 1 mol of compound (XV).
Use moles. This reaction is advantageously performed using a solvent inert to the reaction. The solvent is not particularly limited as long as the reaction proceeds. Examples thereof include ethers such as diethyl ether, tetrahydrofuran, dioxane, and 1,2-dimethoxyethane; hydrocarbons such as benzene, toluene, and cyclohexane; and N, N-dimethyl. Amides such as formamide and N, N-dimethylacetamide, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane, nitriles such as acetonitrile and propionitrile, and sulfoxides such as dimethyl sulfoxide Or a mixed solvent thereof is preferred. The product (XVII) thus obtained can be used in the next reaction as a reaction solution or as a crude product, but it can also be isolated from the reaction mixture according to a conventional method, and can be used for recrystallization, distillation, chromatography, etc. It can be easily purified by separation means.

In order to produce the optically active compound (XVII), the compound (XV) is reduced using an asymmetric reduction catalyst such as a transition metal-optically active phosphine complex, followed by acylation. Used. The transition metal-optically active phosphine complex includes, for example, a ruthenium-optically active phosphine complex, and is preferably diruthenium tetrachlorobis [2,2'-bis (diphenylphosphino) -1,1'-binaphthyl] triethylamine. ,
[2,2'-bis (diphenylphosphino) -1,1 '
-Binaphthyl] ruthenium-2,2'-bis (diphenylphosphino) -1, such as diacetate,
1′-binaphthyl derivatives and the like are used. The reaction conditions are
The conditions are the same as those for producing an optically active aminoalkyl compound from compound (XXXV) described later. As the conditions for acylation of the obtained optically active aminoalkyl compound, the same conditions as those for producing compound (I) from compound (XXXVI) described later are used. In addition, in order to produce the optically active compound (XVII), a method of acylating the compound (XV) and then performing reduction using an asymmetric reduction catalyst such as a transition metal-optically active phosphine complex is also used. The transition metal-optically active phosphine complex includes, for example, a ruthenium-optically active phosphine complex, and is preferably diruthenium tetrachlorobis [2,2'-bis (diphenylphosphino) -1,1'-binaphthyl] triethylamine. ,
[2,2'-bis (diphenylphosphino) -1,1 '
-Binaphthyl] ruthenium-2,2'-bis (diphenylphosphino) -1, such as diacetate,
1′-binaphthyl derivatives and the like are used. The reaction conditions are
The conditions are the same as those for producing an optically active aminoalkyl compound from compound (XXXV) described later. As the conditions for the acylation of the compound (XV), the same conditions as those for producing the compound (I) from the compound (XXXVI) described later are used.

Further, when R ² in the compound (XVII) is an alkyl group, after the above acylation, a base is prepared by using a corresponding alkylating agent (eg, alkyl halide, sulfonic ester of alcohol, etc.). To perform an alkylation reaction. The alkylating agent is used in an amount of about 1.0 to 5.0 mol, preferably about 1.0 to 2.0 mol, per 1 mol of compound (XVII).
Use 0 mol. As the base, for example, inorganic bases such as sodium hydroxide and potassium hydroxide, basic salts such as sodium carbonate, potassium carbonate, cesium carbonate and sodium hydrogen carbonate, aromatic amines such as pyridine and lutidine, triethylamine, tripropyl Amine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N, N-dimethylaniline, N
Tertiary amines such as -methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, alkali metal hydrides such as sodium hydride and potassium hydride, sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide, etc. And metal alkoxides such as sodium methoxide, sodium ethoxide and potassium tert-butoxide. The base is added in an amount of about 1.0 to 5.about.1 mol of the compound (XVII).
0 mol, preferably about 1.0 to 2.0 mol is used. This reaction is advantageously performed using a solvent inert to the reaction.
Although not particularly limited as long as the reaction proceeds as such a solvent, for example, methanol, ethanol, alcohols such as propanol, diethyl ether, tetrahydrofuran, dioxane, ethers such as 1,2-dimethoxyethane, benzene, toluene, cyclohexane, Hydrocarbons such as hexane, amides such as N, N-dimethylformamide, N, N-dimethylacetamide, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, acetonitrile, propio Solvents such as nitrites such as nitriles, sulfoxides such as dimethyl sulfoxide, and mixed solvents thereof are preferable. The reaction time is generally 30 minutes to 48 hours, preferably 30 minutes to 6 hours. The reaction temperature is usually -20 to 200C, preferably -10 to 150.
° C. The product (XVII) can be used in the next reaction as a reaction solution or as a crude product. Can be purified.

In the case of producing a compound (XVII) in which the double bond is reduced, the compound (XVII) can be prepared in the same manner as in the production of compound (VII) from compound (VIII). It is produced by catalytic reduction of the binding moiety. Compound (XVIII) is produced by deprotecting the hydroxyl-protecting group of compound (XVII). This deprotection step is performed based on a general known operation. For example, T. W. Green Protective Groups in Organ
ic Synthesis "(2nd edition, 1991).
ion for Phenols and Catechols. Compound (XIX) is produced by reacting compound (XVIII) with a corresponding alkylating agent (eg, alkyl halide, sulfonic acid ester of alcohol, etc.) in the presence of a base. Compound (XVIII) 1
The alkylating agent is used in an amount of about 1.0-5.0 mol, preferably about 1.0-2.0 mol, per mol. As the base, for example, inorganic bases such as sodium hydroxide and potassium hydroxide, basic salts such as sodium carbonate, potassium carbonate, cesium carbonate and sodium hydrogen carbonate, aromatic amines such as pyridine and lutidine, triethylamine, tripropyl Tertiary amines such as amine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine;
Alkali metal hydrides such as sodium hydride and potassium hydride; metal amides such as sodium amide, lithium diisopropylamide and lithium hexamethyldisilazide; metal alkoxides such as sodium methoxide, sodium ethoxide and potassium tert-butoxide And the like. The base is used in an amount of about 1.0 to 5.0 mol, preferably about 1.0 to 2.0 mol, per 1 mol of compound (XVIII).
Use moles. This reaction is advantageously performed using a solvent inert to the reaction. Although not particularly limited as long as the reaction proceeds as such a solvent, for example, methanol, ethanol, alcohols such as propanol, diethyl ether, tetrahydrofuran, dioxane, ethers such as 1,2-dimethoxyethane, benzene, toluene, cyclohexane, Hydrocarbons such as hexane, amides such as N, N-dimethylformamide, N, N-dimethylacetamide, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, acetonitrile, propio Solvents such as nitrites such as nitriles, sulfoxides such as dimethyl sulfoxide, and mixed solvents thereof are preferable. The reaction time is usually 30 minutes to 48 hours, preferably 1 hour to 24 hours.
Time. The reaction temperature is usually -20 to 200C, preferably 0 to 150C. The product (XIX) can be used in the next reaction as a reaction solution or as a crude product, but it can also be isolated from the reaction mixture according to a conventional method, and is easily separated by separation means such as recrystallization, distillation, or chromatography. Can be purified.

Compound (XX) wherein R ⁸ is a hydrogen atom, a halogen atom, a hydrocarbon group which may have a substituent, an alkoxy group which may have a substituent, a hydroxy group,
A nitro group, a cyano group or an amino group which may have a substituent, R ⁹ represents a hydrocarbon group, and other symbols have the same meanings as described above.] Is α corresponding to the compound (XVIII)
-Haloketones (eg, α-chloroketone, α-bromoketone, α-iodoketone, etc.) in the presence of a base. The α-haloketone is used in an amount of about 1.0 to 5.0 mol, preferably about 1.0 to 2.0 mol, per 1 mol of compound (XVIII). As the base, for example, inorganic bases such as sodium hydroxide and potassium hydroxide,
Basic salts such as sodium carbonate, potassium carbonate, cesium carbonate and sodium hydrogencarbonate; aromatic amines such as pyridine and lutidine; triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N, N Tertiary amines such as dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, alkali metal hydrides such as sodium hydride and potassium hydride, sodium amide, lithium diisopropylamide, lithium hexamine; Metal amides such as methyldisilazide, sodium methoxide, sodium ethoxide,
Metal alkoxides such as potassium tert-butoxide; The base is used in an amount of about 1.0-5.0 mol, preferably about 1.0-2.0 mol, per 1 mol of compound (XVIII). This reaction is advantageously performed using a solvent inert to the reaction. The solvent is not particularly limited as long as the reaction proceeds, for example, methanol, ethanol,
Alcohols such as propanol, diethyl ether,
Ethers such as tetrahydrofuran, dioxane, 1,2-dimethoxyethane, hydrocarbons such as benzene, toluene, cyclohexane and hexane; ketones such as acetone and methyl ethyl ketone; N, N-dimethylformamide; N, N-dimethylacetamide Amides, dichloromethane, chloroform, carbon tetrachloride, 1,
Solvents such as halogenated hydrocarbons such as 2-dichloroethane, nitriles such as acetonitrile and propionitrile, sulfoxides such as dimethyl sulfoxide, and a mixed solvent thereof are preferable. The reaction time is generally 30 minutes to 48 hours, preferably 1 hour to 24 hours. The reaction temperature is usually -20 to 200C, preferably 0 to 200C.
150 ° C. The product (XX) can be used in the next reaction as a reaction solution or as a crude product. Can be purified.

Compound (XXI) is produced by reacting compound (XVIII) with a corresponding alkylating agent (eg, substituted acetylene alkyl halide, substituted acetylene alcohol sulfonate, etc.) in the presence of a base. You. The alkylating agent is used in an amount of about 1.0 to 20.0 mol, preferably about 1.0 to 1 mol, per 1 mol of compound (XVIII).
Use 0.0 mol. As the base, for example, inorganic bases such as sodium hydroxide and potassium hydroxide, basic salts such as sodium carbonate, potassium carbonate, cesium carbonate and sodium hydrogen carbonate, aromatic amines such as pyridine and lutidine, triethylamine, tripropyl Amine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N, N-dimethylaniline, N
Tertiary amines such as -methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, alkali metal hydrides such as sodium hydride and potassium hydride, sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide, etc. And metal alkoxides such as sodium methoxide, sodium ethoxide and potassium tert-butoxide. About 1.0 to 1 base is added per 1 mol of compound (XVIII).
0.0 mol, preferably about 1.0 to 5.0 mol is used.
This reaction is advantageously performed using a solvent inert to the reaction. Although not particularly limited as long as the reaction proceeds as such a solvent, for example, methanol, ethanol, alcohols such as propanol, diethyl ether, tetrahydrofuran, dioxane, ethers such as 1,2-dimethoxyethane, benzene, toluene, cyclohexane, Hydrocarbons such as hexane, amides such as N, N-dimethylformamide and N, N-dimethylacetamide, dichloromethane, chloroform, carbon tetrachloride,
Solvents such as halogenated hydrocarbons such as 2-dichloroethane, nitriles such as acetonitrile and propionitrile, sulfoxides such as dimethyl sulfoxide, and a mixed solvent thereof are preferable. The reaction time is generally 30 minutes to 48 hours, preferably 1 hour to 24 hours. The reaction temperature is usually -20 to 200C, preferably 0 to 200C.
150 ° C. The product (XXI) can be used in the next reaction as the reaction solution or as a crude product, but can also be isolated from the reaction mixture according to a conventional method, and can be recrystallized, distilled,
It can be easily purified by separation means such as chromatography.

Compound (I) is produced by subjecting compound (XIX), (XX) or (XXI) to a ring-closing reaction known per se. For example, a method using heating, a method using an acidic substance,
A method using a basic substance, a method similar thereto, and the like are used. When the ring is closed by heating, it is advantageous to carry out the reaction without a solvent or using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds. For example, high-boiling hydrocarbons such as 1,2,3,4-tetrahydronaphthalene and bromobenzene; high-boiling ethers such as diphenyl ether and diethylene glycol dimethyl ether; , N-dimethylaniline, N, N-diethylaniline and the like, or a mixed solvent thereof is preferable. The reaction time is usually from 10 minutes to
24 hours, preferably 10 minutes to 10 hours. The reaction temperature is usually 100 to 300 ° C, preferably 150 to 250.
° C. In the case of ring closure using an acidic substance, for example, phosphorus oxychloride, phosphorus pentachloride, phosphorus pentoxide, phosphorus trichloride, thionyl chloride, hydrobromic acid, hydrochloric acid, sulfuric acid, phosphoric acid, polyphosphoric acid, p-toluenesulfonic acid, etc. Is used. The acidic substance is used in an amount of about 0.5-100 mol, preferably about 5.0-20 mol, per 1 mol of compound (XIX), (XX) or (XXI). This reaction is carried out without solvent,
It is advantageous to use a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds.For example, benzene, aromatic hydrocarbons such as toluene, cyclohexane, saturated hydrocarbons such as hexane,
Ethers such as tetrahydrofuran, dioxane and 1,2-dimethoxyethane, amides such as N, N-dimethylformamide and N, N-dimethylacetamide, halogenation such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane Preferred are hydrocarbons, acid anhydrides such as acetic anhydride, sulfoxides such as dimethyl sulfoxide, solvents such as water, and mixed solvents thereof. The reaction time is generally 30 minutes to 12 hours, preferably 30 minutes to 6 hours. The reaction temperature is usually 0 to 200
° C, preferably from 0 to 150 ° C.

In the case of ring closure using a basic substance, for example, sodium hydroxide, potassium hydroxide, sodium carbonate,
Basic substances such as potassium carbonate and sodium hydrogen carbonate are used. The basic substance is used in an amount of about 0.5-100 mol, preferably about 5.0-20 mol, per 1 mol of compound (XIX), (XX) or (XXI). This reaction is advantageously carried out without a solvent or using a solvent inert to the reaction.
The solvent is not particularly limited as long as the reaction proceeds, but is preferably, for example, an alcohol such as methanol, ethanol, or propanol, a ketone such as acetone or methyl ethyl ketone, a solvent such as water, or a mixed solvent thereof. The reaction time is usually 30 minutes to 12 hours,
Preferably, it is 30 minutes to 6 hours. The reaction temperature is usually 0 to
The temperature is 200 ° C, preferably 0 to 150 ° C. The product (I) obtained by the cyclization reaction can be isolated from the reaction mixture according to a conventional method, and can be easily purified by separation means such as recrystallization, distillation, and chromatography. When producing a compound in which the double bond portion of the compound (I) is reduced, the double bond portion of the compound (I) is produced by the same operation as that for producing the compound (VII) from the compound (VIII). It is produced by catalytic reduction.

(Reaction 2)

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Compound (XXII) is produced by subjecting compound (X) to an alkylation reaction and then treating with hydrobromic acid. In the alkylation reaction, a Grignard reagent prepared from cyclopropyl bromide and magnesium is diluted with an inert solvent and then reacted with compound (X). The method for preparing the Grignard reagent from cyclopropyl bromide may be performed according to a known method. About 1 mole of magnesium is added to 1 mole of cyclopropyl bromide.
0 to 5.0 mol, preferably about 1.0 to 1.5 mol is used. This reaction is advantageously performed using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds. For example, aromatic hydrocarbons such as benzene and toluene, saturated hydrocarbons such as cyclohexane and hexane, tetrahydrofuran, dioxane, 1,2
-Solvents such as ethers such as dimethoxyethane and the like and a mixed solvent thereof are preferable. Reaction time is usually 1
0 minute to 10 hours, preferably 15 minutes to 3 hours. The reaction temperature is generally 0-150 ° C, preferably 40-80 ° C. During the reaction, a small amount of iodine may be present.
After completion of the reaction, the Grignard reagent produced is allowed to stand at room temperature to complete the reaction, and then the solvent is distilled off, or the solvent is added without dilution to dilute the mixture, and the compound (X) is added dropwise to react. Compound (X) is used in an amount of about 0.4-3.0 mol, preferably about 0.4-3.0 mol, per 1 mol of the Grignard reagent.
Use 1.0 mole. The solvent used for dilution is not particularly limited as long as the reaction proceeds, for example, benzene,
Solvents such as aromatic hydrocarbons such as toluene, saturated hydrocarbons such as cyclohexane and hexane, halogenated hydrocarbons such as chlorotoluene, and ethers such as tetrahydrofuran, dioxane and 1,2-dimethoxyethane, or a mixture thereof. Solvents and the like are preferred. The amount of the solvent used for dilution is about 1.0 to 30 times, preferably about 1.0 to 15 times the volume of the Grignard reagent. The reaction time is generally 10 minutes to 10 hours, preferably 1 minute.
5 minutes to 3 hours. The reaction temperature is generally 0 to 150 ° C, preferably 40 to 100 ° C. The product can be used in the next reaction as a reaction solution or as a crude product, but can also be isolated from the reaction mixture according to a conventional method, and recrystallized.
It can be easily purified by separation means such as distillation and chromatography. The amount of hydrobromic acid to be used is about 1.0-30 mol, preferably about 1.0-5.0 mol, per 1 mol of compound (X). This reaction is advantageously performed using a solvent inert to the reaction. The solvent is not particularly limited as long as the reaction proceeds, for example, alcohols such as methanol, ethanol and propanol, formic acid, organic acids such as acetic acid, benzene, toluene,
Hydrocarbons such as cyclohexane and hexane, sulfoxides such as dimethyl sulfoxide, solvents such as water, and mixed solvents thereof are preferable. The reaction time is generally 1 hour to 60 hours, preferably 1 hour to 15 hours. The reaction temperature is generally 0-200 ° C, preferably 0-80 ° C.
° C. The product (XXII) can be used in the next reaction as a reaction solution or as a crude product, but it can also be isolated from the reaction mixture according to a conventional method, and can be easily separated by separation means such as recrystallization, distillation, and chromatography. Can be purified.

Compound (XXIII) is produced by reacting compound (XXII) with potassium phthalimide. Potassium phthalimide is used in an amount of about 1.0-5.0 mol, preferably about 1.0-1.5 mol, per 1 mol of compound (XXII).
Use moles. The condensation of compound (XXII) with potassium phthalimide is advantageously carried out in the presence of a base, if desired, using no solvent or an inert solvent. As the base,
For example, sodium hydroxide, inorganic bases such as potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate,
Basic salts such as sodium hydrogencarbonate, aromatic amines such as pyridine and lutidine, triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N, N-dimethylaniline, N-methylpiperidine; Tertiary amines such as N-methylpyrrolidine and N-methylmorpholine; alkali metal hydrides such as sodium hydride and potassium hydride; metal amides such as sodium amide, lithium diisopropylamide and lithium hexamethyldisilazide And metal alkoxides such as sodium methoxide, sodium ethoxide, and potassium tert-butoxide.
The base is used in an amount of about 1.0 to 5.0 mol, preferably about 1.0 to 2.0 mol, per 1 mol. Examples of the solvent include alcohols such as methanol, ethanol, and propanol; ethers such as diethyl ether, tetrahydrofuran, dioxane, and 1,2-dimethoxyethane; hydrocarbons such as benzene, toluene, cyclohexane, and hexane; Amides such as dimethylformamide and N, N-dimethylacetamide; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane; nitriles such as acetonitrile and propionitrile; and sulfoxides such as dimethylsulfoxide. And the like, or a mixed solvent thereof. The reaction time is generally 30 minutes to 20 hours, preferably 30 minutes to 8 hours. The reaction temperature is usually 0 to 15
0 ° C, preferably 20 to 80 ° C. Product (XXII
I) can be used in the next reaction as a reaction solution or as a crude product, but it can also be isolated from the reaction mixture according to a conventional method, and easily purified by a separation means such as recrystallization, distillation, or chromatography. be able to.

Compound (XXIV) is produced by reacting compound (XXII) with a cyano compound. Examples of the cyano compound include sodium cyanide, potassium cyanide, and a mixture thereof. It can also be prepared and used by reacting hydrogen cyanide with a basic substance such as, for example, sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate in a reaction system. The cyano compound is used in an amount of about 0.8 to 10 mol, preferably about 1.0 to 2.0 mol, per 1 mol of compound (XXII). This reaction is advantageously performed using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds, for example, diethyl ether,
Ethers such as tetrahydrofuran, dioxane, 1,2-dimethoxyethane, hydrocarbons such as benzene, toluene, cyclohexane and hexane; amides such as N, N-dimethylformamide and N, N-dimethylacetamide; dichloromethane, chloroform; Solvents such as halogenated hydrocarbons such as carbon tetrachloride, 1,2-dichloroethane, chlorobenzene and orthodichlorobenzene, sulfoxides such as dimethyl sulfoxide, and a mixed solvent thereof are preferable. In the presence of a phase transfer catalyst, water and the above-mentioned organic solvent insoluble or hardly soluble in water can also be used. Examples of the phase transfer catalyst include quaternary ammonium salts such as tetrabutylammonium bromide and benzyltriethylammonium chloride, and quaternary phosphonium salts. The amount of the phase transfer catalyst to be used is about 0.001-10 mol, preferably about 0.005-0.5 mol, per 1 mol of compound (XXII). The reaction time is generally 30 minutes to 20 hours, preferably 30 minutes to 8 hours. The reaction temperature is generally 0-200 ° C, preferably 20-1.
50 ° C. The product (XXIV) can be used as is in the reaction solution or as a crude product in the next reaction, but can also be isolated from the reaction mixture according to a conventional method, and can be easily separated by separation means such as recrystallization, distillation, and chromatography. Can be purified.

Compound (XVI) is produced by decomposing the imide group of compound (XXIII). Compound (XXII
I) Usually, about 1 mole of amines such as methylamine and ethylamine, hydrazines such as hydrazine and phenylhydrazine, alkali metal sulfides such as sodium sulfide and potassium sulfide, and mineral acids such as hydrochloric acid and sulfuric acid are used for about 1 mole. 0.0 mol to 20 mol, preferably about 1.0 mol to
Use 5.0 moles. This reaction is advantageously performed using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds. For example, alcohols such as methanol, ethanol, and propanol, diethyl ether, tetrahydrofuran, dioxane, and 1,2-
Ethers such as dimethoxyethane, hydrocarbons such as benzene, toluene, cyclohexane and hexane;
Solvents such as amides such as N-dimethylformamide and N, N-dimethylacetamide, sulfoxides such as dimethyl sulfoxide, and a mixed solvent thereof are preferable. The reaction time is generally 30 minutes to 12 hours, preferably 30 minutes to 5 hours. The reaction temperature is usually 0 to 200
° C, preferably 20 to 100 ° C. Product (XVI)
Can be used in the next reaction as a reaction solution or as a crude product, but can also be isolated from the reaction mixture according to a conventional method, and can be easily purified by separation means such as recrystallization, distillation, and chromatography. it can. Compound (XVI)
Is also produced by reducing the cyano group of compound (XXIV) by the same operation as that for producing compound (XV) from compound (XII).

(Reaction 3)

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Compound (XXV) can be prepared by a method known per se, for example, the method of Journal of Organic Chemistry (J. Or
g. Chem.), 49, 409 (1984), Journal of
The Indian Chemical Society (J. India
n Chem. Soc.), 36, 76 (1959), etc.
Alternatively, it can be produced according to a method according to these. Compound (XXVIII) [wherein L represents a leaving group such as a halogen atom, an alkylsulfonyl group, an alkylsulfonyloxy group or an arylsulfonyloxy group] can be obtained by a method known per se, for example, a method described in Journal of the Chemical Society (J. Chem. Soc.), 2455 (1956), 4665
Page (1958), or a method analogous thereto.

Examples of the halogen atom represented by L include fluorine, chlorine, bromine and iodine. Examples of the alkylsulfonyl group represented by L include C _1-5
Examples include an alkylsulfonyl group (eg, methanesulfonyl, ethanesulfonyl, and the like). Examples of the alkylsulfonyloxy group represented by L include an optionally halogenated C _1-5 alkylsulfonyloxy group (eg, methanesulfonyloxy, ethanesulfonyloxy, trichloromethanesulfonyloxy, etc.). The arylsulfonyloxy group represented by L includes, for example, an optionally substituted benzenesulfonyloxy group (for example, p-toluenesulfonyloxy,
Benzenesulfonyloxy, etc.). When the compound in the formula is commercially available, a commercially available product can be used as it is. Compound (XXVI) is produced from compound (XXV) and malonic acid in the presence of a base by Knoevenagel condensation in the same manner as in the method for producing compound (IV) from compound (III). Malonic acid is used in an amount of about 1.0-5.0 mol, preferably about 1.0-2.0 mol, per 1 mol of compound (XXV). As the base, for example, inorganic bases such as sodium hydroxide and potassium hydroxide, basic salts such as sodium carbonate, potassium carbonate, cesium carbonate and sodium hydrogen carbonate, aromatic amines such as pyridine and lutidine, triethylamine, tripropyl Amine, tributylamine, cyclohexyldimethylamine, pyridine, 4-dimethylaminopyridine, N, N-
Tertiary amines such as dimethylaniline, piperidine, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine and the like. The amount of these bases to be used is about 0.1-10.0 mol per 1 mol of compound (XXV).
Mole, preferably about 0.1-5.0 mole. This reaction is advantageously performed using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds. For example, alcohols such as methanol, ethanol and propanol, hydrocarbons such as benzene, toluene, cyclohexane and hexane, N, N-dimethylformamide, N, N- Solvents such as amides such as dimethylacetamide, organic acids such as formic acid and acetic acid, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, and 1,2-dichloroethane, and mixed solvents thereof are preferable. The reaction time varies depending on the reagent and solvent used, but is usually 30 minutes to 24 hours, preferably 30 minutes to
8 hours. The reaction temperature is generally 0-150 ° C, preferably 0-130 ° C. The product (XXVI) can be used as is in the reaction solution or as a crude product in the next reaction, but can also be isolated from the reaction mixture according to a conventional method, and recrystallized.
It can be easily purified by separation means such as distillation and chromatography.

Compound (XXX) is obtained by reacting compound (XXV) with a phosphonate carbanion formed by the base treatment of alkyl phosphonic acid diester in the same manner as in the production of compound (VIII) from compound (III). hand,
It is obtained as an E- or Z-configuration isomer alone or as a mixture of E- and Z-isomers. As the alkyl phosphonic acid diester, for example, ethyl diethylphosphonoacetate or the like is used as described above. Alkyl phosphonic acid diester is used in an amount of about 1.0 to 3 based on 1 mol of compound (XXV).
0 mol, preferably about 1.0-1.5 mol. Examples of the base include alkali metal hydrides such as sodium hydride and potassium hydride, metal amides such as sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide, sodium methoxide, sodium ethoxide, and potassium tertiary salt. And metal alkoxides such as butoxide. The amount of these bases to be used is about 1.0-5.0 mol, preferably about 1.0-1.5 mol, per 1 mol of compound (XXV). This reaction is advantageously performed using a solvent inert to the reaction. Although not particularly limited as long as the reaction proceeds as such a solvent, for example, methanol, ethanol, alcohols such as propanol, diethyl ether, tetrahydrofuran, dioxane, ethers such as 1,2-dimethoxyethane, benzene, toluene, cyclohexane, Hydrocarbons such as hexane, N, N-dimethylformamide,
Solvents such as amides such as N, N-dimethylacetamide, sulfoxides such as dimethylsulfoxide, and mixed solvents thereof are preferable. Reaction time is usually 1
The time is from 50 to 50 hours, preferably from 1 to 10 hours.
The reaction temperature is usually -78 to 200 ° C, preferably 0 to 15 ° C.
0 ° C. The isomer mixture of the compound (XXX) can be used in the next reaction as a reaction solution or as a crude product, but can also be isolated from the reaction mixture according to a conventional method.
It can be easily purified by separation means such as recrystallization, distillation and chromatography.

Compound (XXXI) is the same as compound (VI)
It is produced by hydrolyzing the ester group of compound (XXX) using an acid or a base in the same manner as in the method for producing compound (IX) from II). Acid hydrolysis generally involves mineral acids such as hydrochloric acid and sulfuric acid, Lewis acids such as boron trichloride and boron tribromide, combined use of Lewis acids with thiols or sulfides, and organic acids such as trifluoroacetic acid and p-toluenesulfonic acid. Is used. Alkaline hydrolysis includes metal hydroxides such as sodium hydroxide, potassium hydroxide, barium hydroxide, metal carbonates such as sodium carbonate and potassium carbonate, sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc. Metal alkoxides, organic bases such as triethylamine, imidazole and formamidine are used. These acids and bases are used in an amount of about 0.1 to 1 mol of the compound (XXX).
5 to 10 moles, preferably about 0.5 to 3.0 moles are used. This reaction is advantageously carried out without a solvent or using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds, for example, alcohols such as methanol, ethanol and propanol, benzene, aromatic hydrocarbons such as toluene, cyclohexane, saturated hydrocarbons such as hexane, formic acid, Organic acids such as acetic acid, tetrahydrofuran, dioxane, 1,2
Ethers such as -dimethoxyethane, amides such as N, N-dimethylformamide and N, N-dimethylacetamide, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane, acetonitrile, Preference is given to nitriles such as pionitrile, ketones such as acetone and methylethylketone, sulfoxides such as dimethylsulfoxide, solvents such as water, and mixtures thereof. The reaction time is generally 10 minutes to 60 hours, preferably 10 minutes to 12 hours. The reaction temperature is usually -10 to 200C, preferably 0 to 120C. The product (XXXI) can be used in the next reaction as a reaction solution or as a crude product, but it can also be isolated from the reaction mixture according to a conventional method, and can be easily separated by separation means such as recrystallization, distillation, or chromatography. Can be purified.

Compound (XXIX) can be prepared by reacting a compound of formula R ³ C in the same manner as in the production of compound (VII) from compound (VI).
An ester derivative represented by H ₂ COOR ⁹ (wherein R ³ and R ⁹ have the same meanings as described above) and a compound (XXVII
Is produced by reacting I) in the presence of a base. The “hydrocarbon group” represented by R ⁹ includes, for example, the above-mentioned “hydrocarbon group” and the like, and among them, lower alkyl groups (for example, C 4 such as methyl, ethyl and isopropyl)
_{And a} benzyl group which may have a substituent. The “benzyl group which may have a substituent (s)” is a group that can be substituted with 1 to 3 at a substitutable position of the benzyl group.
May have a substituent such as a halogen atom and C _1-3 alkyl, and specific examples include benzyl, p-chlorobenzyl, p-methylbenzyl and the like. The ester derivative is used in an amount of about 1.0-5.0 mol, preferably about 1.0-5.0 mol, per 1 mol of compound (XXVIII).
Use 2.0 moles. As the base, for example, inorganic bases such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, pyridine, aromatic amines such as lutidine, triethylamine, tripropylamine, tributylamine,
Tertiary amines such as cyclohexyldimethylamine, 4-dimethylaminopyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, and alkali metals such as sodium hydride and potassium hydride Hydrides, sodium amide,
Metal amides such as lithium diisopropylamide and lithium hexamethyldisilazide; and metal alkoxides such as sodium methoxide, sodium ethoxide and potassium tert-butoxide. The amount of the base to be used is about 1.0-1.0 mol per 1 mol of compound (XXVIII).
5.0 moles, preferably about 1.0 to 2.0 moles are used.
This reaction is advantageously performed using a solvent inert to the reaction. Although not particularly limited as long as the reaction proceeds as such a solvent, for example, methanol, ethanol, alcohols such as propanol, diethyl ether, tetrahydrofuran, dioxane, ethers such as 1,2-dimethoxyethane, benzene, toluene, cyclohexane, Hydrocarbons such as hexane, amides such as N, N-dimethylformamide and N, N-dimethylacetamide, dichloromethane, chloroform, carbon tetrachloride,
Solvents such as halogenated hydrocarbons such as 2-dichloroethane, nitriles such as acetonitrile and propionitrile, ketones such as acetone and methyl ethyl ketone, sulfoxides such as dimethyl sulfoxide, and a mixed solvent thereof are preferable. The reaction time is generally 30 minutes to 48 hours, preferably 30 minutes to 5 hours. The reaction temperature is usually -20 to 200C, preferably -10 to 150.
° C. The product (XXIX) can be used as is in the reaction solution or as a crude product in the next reaction, but can also be isolated from the reaction mixture according to a conventional method, and is easily separated by separation means such as recrystallization, distillation, and chromatography. Can be purified.

Compound (XXIX) is the same as compound (VIII)
In the same manner as in the method for producing compound (VII) from compound (VII), compound (XXX) is subjected to a catalytic reduction reaction in the presence of various catalysts in a hydrogen atmosphere. Examples of the catalyst used include platinum oxide, activated carbon with platinum, activated carbon with palladium, barium sulfate with palladium, nickel, copper-chromium oxide, rhodium, cobalt, ruthenium and the like. The amount of the catalyst to be used is about 5-1000% by weight, preferably about 5-300% by weight, relative to compound (XXX).
% By weight. This reaction is advantageously performed using a solvent inert to the reaction. The solvent is not particularly limited as long as the reaction proceeds, for example, alcohols such as methanol, ethanol and propanol, ethers such as diethyl ether, tetrahydrofuran, dioxane and 1,2-dimethoxyethane, and saturated solvents such as cyclohexane and hexane. Amides such as hydrocarbons, N, N-dimethylformamide, N, N-dimethylacetamide;
Organic acids such as formic acid and acetic acid, solvents such as water, and mixed solvents thereof are preferable. The reaction time varies depending on the activity and amount of the catalyst used, but is usually 30 minutes to 24 hours, preferably 30 minutes to 6 hours. The reaction temperature is generally 0-120 ° C, preferably 20-80 ° C. The pressure is usually 1 to 100 atm. An additive (promoter) that increases the catalytic ability by adding to the reaction system may be added. Examples of acidic additives include hydrochloric acid, sulfuric acid,
Inorganic acids such as nitric acid, perchloric acid, hydrobromic acid, phosphoric acid,
Acetic acid, trifluoroacetic acid, oxalic acid, phthalic acid, fumaric acid, tartaric acid, citric acid, succinic acid, methanesulfonic acid,
Organic acids such as p-toluenesulfonic acid and 10-camphorsulfonic acid are preferred. As the basic additive, sodium hydroxide, potassium hydroxide and the like are preferable. The product (XXIX) can be used as is in the reaction solution or as a crude product in the next reaction, but can also be isolated from the reaction mixture according to a conventional method, and is easily separated by separation means such as recrystallization, distillation, and chromatography. Can be purified.

Compound (XXVII) is the same as compound (IV)
Alternatively, in the same manner as the method for producing compound (V) from compound (IX) or the method for producing compound (XXIX) from compound (XXX), compound (XXVI) or compound (XXXI) is subjected to catalytic reduction reaction under a hydrogen atmosphere. ). Compound (XXVII) is a compound of the aforementioned compound (VI
It is also produced by hydrolyzing the ester group of compound (XXIX) using an acid or a base in the same manner as in the method for producing compound (V) from I). For acid hydrolysis,
In general, mineral acids such as hydrochloric acid and sulfuric acid, Lewis acids such as boron trichloride and boron tribromide, combined use of Lewis acids with thiol or sulfide, and organic acids such as trifluoroacetic acid and p-toluenesulfonic acid are used. Alkaline hydrolysis includes metal hydroxides such as sodium hydroxide, potassium hydroxide, barium hydroxide, metal carbonates such as sodium carbonate and potassium carbonate, sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc. Metal alkoxides, organic bases such as triethylamine, imidazole and formamidine are used. These acids and bases are used in an amount of about 0.5 to 10 mol, preferably about 0.5 to 6.0 mol, per 1 mol of compound (XXIX). This reaction is advantageously carried out without a solvent or using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds, for example, alcohols such as methanol, ethanol and propanol, benzene, aromatic hydrocarbons such as toluene, cyclohexane, saturated hydrocarbons such as hexane, formic acid, Organic acids such as acetic acid, tetrahydrofuran, dioxane, 1,2
Ethers such as -dimethoxyethane, amides such as N, N-dimethylformamide and N, N-dimethylacetamide, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane, acetonitrile, Preference is given to nitriles such as pionitrile, ketones such as acetone and methylethylketone, sulfoxides such as dimethylsulfoxide, solvents such as water, and mixtures thereof. The reaction time is generally 10 minutes to 60 hours, preferably 10 minutes to 12 hours. The reaction temperature is usually -10 to 200C, preferably 0 to 120C. The product (XXVII) can be used as is in the reaction solution or as a crude product in the next reaction, but it can also be isolated from the reaction mixture according to a conventional method,
It can be easily purified by separation means such as distillation and chromatography.

Compound (XXXII) is produced by subjecting compound (XXVII) to a ring-closing reaction known per se in the same manner as in the above-mentioned method for producing compound (X) by subjecting compound (V) to a ring-closing reaction. Is done. For example, a method by heating, a method using an acidic substance, a method of reacting with a halogenating agent and then cyclizing in the presence of a Lewis acid, and a method analogous thereto are used. When the ring is closed by heating, do it without solvent,
It is advantageous to use a solvent inert to the reaction. The solvent is not particularly limited as long as the reaction proceeds. For example, solvents such as high-boiling hydrocarbons such as 1,2,3,4-tetrahydronaphthalene, high-boiling ethers such as diphenyl ether and diethylene glycol dimethyl ether, or solvents such as Are preferred. The reaction time is generally 10 minutes to 24 hours, preferably 10 minutes.
Minutes to 10 hours. The reaction temperature is usually 100 to 300
° C, preferably 100 to 200 ° C. In the case of ring closure using an acidic substance, for example, an acidic substance such as phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, thionyl chloride, hydrochloric acid, sulfuric acid, polyphosphoric acid, p-toluenesulfonic acid or the like is used. The acidic substance is used in an amount of about 0.5-100 mol, preferably about 5.0-20 mol, per 1 mol of compound (XXVII). This reaction is advantageously carried out without a solvent or using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds, for example, benzene, aromatic hydrocarbons such as toluene, cyclohexane, saturated hydrocarbons such as hexane, tetrahydrofuran, dioxane, 1,2-dimethoxyethane and the like Amides such as ethers, N, N-dimethylformamide, N, N-dimethylacetamide, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, and acid anhydrides such as acetic anhydride ,
Solvents such as sulfoxides such as dimethyl sulfoxide or a mixed solvent thereof are preferable. The reaction time is generally 30 minutes to 12 hours, preferably 30 minutes to 6 hours. The reaction temperature is generally 0-200 ° C, preferably 0-15.
0 ° C.

When the ring is closed in the presence of a Lewis acid after the reaction with a halogenating agent, examples of the halogenating agent include thionyl halides such as thionyl chloride and thionyl bromide, and halogens such as phosphoryl chloride and phosphoryl bromide. Phosphoryls, phosphorus pentachloride, phosphorus trichloride, phosphorus pentabromide,
Examples include phosphorus halides such as phosphorus tribromide, oxalyl halides such as oxalyl chloride, and phosgene. The halogenating agent is used in an amount of about 1.0-30 mol, preferably about 1.0-10 mol, per 1 mol of compound (XXVII). This reaction is advantageously carried out without a solvent or using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds, for example, benzene, aromatic hydrocarbons such as toluene, cyclohexane, saturated hydrocarbons such as hexane, tetrahydrofuran, dioxane, 1,2-dimethoxyethane and the like Solvents such as ethers, amides such as N, N-dimethylformamide, N, N-dimethylacetamide, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, and 1,2-dichloroethane, or a mixed solvent thereof. Is preferred. The reaction time is generally 10 minutes to 12 hours, preferably 10 minutes to 5 hours. The reaction temperature is usually -10 to 200C, preferably -10 to 120C. The product can be used as a reaction solution or as a crude product in the next reaction, but can also be isolated from the reaction mixture according to a conventional method, and is easily purified by separation means such as recrystallization, distillation, and chromatography. be able to. Examples of the Lewis acid used in the next cyclization reaction include anhydrous aluminum chloride, anhydrous zinc chloride, anhydrous iron chloride and the like. The Lewis acid is used in an amount of about 0.1-20 mol, preferably about 0.1-20 mol, per 1 mol of compound (XXVII). 0.2 to 5.0 mol is used. This reaction is advantageously carried out without a solvent or using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds, but examples thereof include aromatic hydrocarbons such as benzene and toluene, monochlorobenzene, o-dichlorobenzene, 1,2,4-trichlorobenzene, dichloromethane, chloroform and tetrachlorobenzene. Solvents such as halogenated hydrocarbons such as carbon chloride and 1,2-dichloroethane, and mixed solvents thereof are preferable. The reaction time is usually 30 minutes to 12 hours, preferably 30 minutes.
Minutes to 6 hours. The reaction temperature is usually -20 to 200 ° C,
Preferably it is -5 to 120C. The product (XXXII) obtained by the above cyclization reaction can be used in the next reaction as a reaction solution or as a crude product, but it can also be isolated from the reaction mixture according to a conventional method, and can be recrystallized or distilled. And can be easily purified by separation means such as chromatography.

In order to preferentially perform ring closure in a desired direction in these ring closure reactions, an undesired position on the benzene ring may be substituted with a halogen atom, followed by ring closure reaction. Examples of the halogenation in this case include a normal halogenation method using a halogenating agent (eg, a halogen such as bromine or chlorine), halogenation using a metal catalyst such as iron together with the halogenating agent, titanium tetrachloride. Methods such as chlorination using trifluoroacetic acid, halogenation using copper halide, and chlorination using sulfuryl chloride-aluminum chloride are also used. Of these, the first halogenation is preferably carried out by a usual method, and if necessary, the halogenation in the next step is preferably carried out by a method using iron as a catalyst. The amount of the halogenating agent used in this reaction is determined based on the compound (XXVI
I) 0.8-3 mol, preferably 1-2, per 1 mol
Is a mole. The amount of iron used as the catalyst is 0.01 to 0.5 equivalent, preferably 0.05 to 0.2 equivalent, per 1 mol of compound (XXVII). This reaction is carried out without a solvent or using a solvent inert to the reaction.
The solvent is not particularly limited as long as the reaction proceeds, for example, hydrocarbons such as cyclohexane and hexane,
Ethers such as tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diethyl ether, amides such as N, N-dimethylformamide, N, N-dimethylacetamide, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, etc. Halogenated hydrocarbons, organic acids such as acetic acid and propionic acid, and mixed solvents thereof. The reaction time is usually 10 minutes to 10
Time, preferably 20 minutes to 5 hours. The reaction temperature is usually -20 to 120C, preferably -10 to 80C. It is also possible to carry out two or three stages of halogenation in one step, and in this case, the halogenating agent is used in an amount twice as large as the above-mentioned amount.

Compound (XXXIV) is obtained by reacting compound (XXXII) with a carbanion formed by treating acetonitrile with a base in the same manner as in the method for producing compound (XII) from compound (X). XXXIII) and then subjected to a dehydration reaction. Compound (XX
XIV) is obtained as an E- or Z-configurational isomer alone or as a mixture of E- and Z-isomer. Compound (XXXII) 1
Acetonitrile is used in an amount of about 1.0 to 3.0 mol, preferably about 1.0 to 1.3 mol, per mol. As the base,
For example, sodium hydride, alkali metal hydrides such as potassium hydride, metal amides such as sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide, and metals such as sodium methoxide, sodium ethoxide, and potassium tert-butoxide Alkoxides and the like can be mentioned, and the amount of the base to be used is about 1.0-5.0 mol, preferably about 1.0-1.5 mol, per 1 mol of compound (XXXII). This reaction is advantageously performed using a solvent inert to the reaction. Although not particularly limited as long as the reaction proceeds as such a solvent, for example, methanol, ethanol, alcohols such as propanol, diethyl ether, tetrahydrofuran, dioxane, ethers such as 1,2-dimethoxyethane, benzene, toluene, cyclohexane, Hydrocarbons such as hexane, amides such as N, N-dimethylformamide and N, N-dimethylacetamide, dichloromethane,
Solvents such as halogenated hydrocarbons such as chloroform, carbon tetrachloride, and 1,2-dichloroethane, and mixed solvents thereof are preferable. The reaction time is usually 30 minutes to 48
Time, preferably 30 minutes to 5 hours. The reaction temperature is usually -78 to 100C, preferably -78 to 50C. The product can be used as a reaction solution or as a crude product in the next reaction, but can also be isolated from the reaction mixture according to a conventional method, and is easily purified by separation means such as recrystallization, distillation, and chromatography. be able to.

Examples of the catalyst used in the dehydration reaction include hydrochloric acid, sulfuric acid, phosphoric acid, potassium hydrogen sulfate, oxalic acid,
Examples include acidic catalysts such as p-toluenesulfonic acid, 10-camphorsulfonic acid, and boron trifluoride ether complex, and basic catalysts such as sodium hydroxide and potassium hydroxide. Further, for example, N, N-cyclohexylcarbodiimide and the like Dehydrating agent, alumina, sodium dioxide, phosphorus oxychloride, thionyl chloride, methanesulfonyl chloride, and the like. This reaction is advantageously carried out without a solvent or using a solvent inert to the reaction.
Although not particularly limited as long as the reaction proceeds as such a solvent, for example, methanol, ethanol, alcohols such as propanol, diethyl ether, tetrahydrofuran, dioxane, ethers such as 1,2-dimethoxyethane, benzene, toluene, cyclohexane, Solvents such as hydrocarbons such as hexane, amides such as N, N-dimethylformamide and N, N-dimethylacetamide, sulfoxides such as dimethylsulfoxide, and a mixed solvent thereof are preferable. The reaction time is generally 30 minutes to 24 hours, preferably 30 minutes to 5 hours. The reaction temperature is generally 0-200 ° C, preferably 0-15.
0 ° C.

Compound (XXXIV) is obtained by reacting compound (XXXII) with a phosphonate carbanion produced by treating alkyl phosphonate diester with a base in the same manner as in the method for producing compound (XII) from compound (X). As a result, a configurational isomer of E or Z form alone or a mixture of E and Z isomers can be obtained. As the alkyl phosphonic acid diester, for example, diethyl cyanomethyl phosphonate or the like is used. The alkylphosphonic acid diester is used in an amount of about 1.0 to 3 per 1 mol of the compound (XXXII).
0 mol, preferably about 1.0-1.5 mol. Examples of the base include alkali metal hydrides such as sodium hydride and potassium hydride, metal amides such as sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide, sodium methoxide, sodium ethoxide, and potassium tertiary salt. Metal alkoxides such as butoxide are exemplified, and the amount of these bases to be used is about 1.0-5.0 mol, preferably about 1.0-1.5 mol, per 1 mol of compound (XXXII). This reaction is advantageously performed using a solvent inert to the reaction.
Although not particularly limited as long as the reaction proceeds as such a solvent, for example, methanol, ethanol, alcohols such as propanol, diethyl ether, tetrahydrofuran, dioxane, ethers such as 1,2-dimethoxyethane, benzene, toluene, cyclohexane, Solvents such as hydrocarbons such as hexane, amides such as N, N-dimethylformamide and N, N-dimethylacetamide, sulfoxides such as dimethylsulfoxide, and a mixed solvent thereof are preferable. The reaction time is generally 1 hour to 50 hours, preferably 1 hour to 10 hours. The reaction temperature is usually -78 to 200 ° C, preferably 0 to
150 ° C. The isomer mixture of compound (XXXIV) can be used as a reaction solution or as a crude product in the next reaction, but can also be isolated from the reaction mixture according to a conventional method, and can be separated by recrystallization, distillation, chromatography, etc. It can be easily purified by means. Compound (XXXIV)
When the carbon chain of the side chain is extended, it may be carried out according to a known carbon chain extension reaction.For example, after a cyano group is hydrolyzed under alkaline or acidic conditions to form a carboxyl group, or After conversion to an ester form, a reduction reaction is performed to form an alcohol form, and then a reaction through halogenation and cyanation is employed.

Compound (XXXV) is the same as compound (XII)
By subjecting compound (XXXIV) to a reduction reaction in the same manner as in the method for producing compound (XV) from
Examples of the reducing agent used include metal hydrides such as aluminum hydride and diisobutylaluminum hydride; metal hydride complex compounds such as lithium aluminum hydride and sodium borohydride; and Raney nickel and Raney as hydrogenation catalysts. A catalyst such as cobalt is used. The amount of the reducing agent to be used is, for example, about 1.0 to about 1 mol of the compound (XXXIV) in the case of a metal hydride.
10 mol, preferably about 1.0 to 3.0 mol, in the case of a metal hydride complex compound, about 1.0 to 10 mol, preferably about 1.0 to 3.0 mol, per 1 mol of compound (XXXIV). ,
In the case of hydrogenation, the catalyst such as Raney nickel and Raney cobalt is used in an amount of about 10 to 1000% by weight, preferably about 80 to 300% by weight, based on the compound (XXXIV). This reaction is advantageously performed using a solvent inert to the reaction. The solvent is not particularly limited as long as the reaction proceeds, for example, alcohols such as methanol, ethanol and propanol, diethyl ether, tetrahydrofuran, dioxane, ethers such as 1,2-dimethoxyethane, benzene, toluene, cyclohexane and the like. And solvents such as amides such as hydrocarbons, N, N-dimethylformamide and N, N-dimethylacetamide, organic acids such as formic acid and acetic acid, and mixed solvents thereof. When a Raney nickel or Raney cobalt catalyst is used, amines such as ammonia may be further added to suppress side reactions. The reaction time varies depending on the activity and amount of the catalyst used, but is usually 1 hour to 100 hours,
Preferably, it is 1 hour to 50 hours. The reaction temperature is usually 0
To 120 ° C, preferably 20 to 80 ° C. When a catalyst such as Raney nickel or Raney cobalt is used, the pressure of hydrogen is usually 1 to 100 atm. The product (XXXV) can be used as is in the reaction solution or as a crude product in the next reaction, but can also be isolated from the reaction mixture according to a conventional method, and is easily separated by separation means such as recrystallization, distillation, and chromatography. Can be purified. In addition, the compound (XX
By strengthening the reaction conditions (eg, increasing the reaction temperature, increasing the reaction time, etc.) for producing XV), it is also possible to simultaneously reduce the cyano group and reduce the double bond portion.

In order to produce the optically active compound (I), a method of subjecting the compound (XXXV) to a reduction reaction using an asymmetric reduction catalyst or the like, followed by an acylation reaction or the like is used. Examples of the asymmetric reduction catalyst include a transition metal-optically active phosphine complex. Examples of the transition metal-optically active phosphine complex include a ruthenium-optically active phosphine complex, among which, for example, diruthenium tetrachlorobis [2,2′-bis (diphenylphosphino) -1,1′-binaphthyl] triethylamine Ruthenium-2,2'-bis (diphenylphosphino)-
1,1′-Binaphthyl derivatives and the like are widely used. The optically active tertiary phosphine in the ruthenium-optically active phosphine complex has two optical isomers of the (R) configuration and the (S) configuration. (R) configuration or (S) of optically active tertiary phosphine in ruthenium-optically active phosphine complex
By selecting one of the optical isomers in the configuration as appropriate, the desired optically active compound can be selectively (substantially pure) obtained. The reduction reaction can be carried out by heating and stirring in an autoclave or the like under pressurized conditions under a hydrogen pressure described below. The amount of the ruthenium-optically active phosphine catalyst is from 1/2 to 1 based on the compound (XXXV).
/ 1000-fold molar, preferably 1/10 to 1 / 500-fold molar.

This reaction can be carried out in an organic solvent. Examples of the organic solvent include toluene, benzene,
Aromatic hydrocarbons such as chlorobenzene, ethyl acetate,
Aliphatic esters such as n-propyl acetate, n-butyl acetate, isopropyl ether, diethyl ether, ethers such as tetrahydrofuran, dichloromethane, halogenated hydrocarbons such as dichloroethane, methanol,
Alcohols such as ethanol and isopropanol,
Solvents such as amides such as N, N-dimethylformamide or a mixed solvent thereof. Of these, alcohols are preferable, and methanol is more preferable. In the reaction, the amount of the organic solvent to be used is generally 1-1000 based on 1 part by weight of compound (XXXV).
Double volume, preferably 2 to 20 times volume. The reaction temperature is generally 0 to 150 ° C, preferably 5 to 100 ° C, more preferably 10 to 80 ° C. The hydrogen pressure in the reaction is usually 5 to 150 kg / cm ² , preferably 30 to 11 kg / cm ² .
It is 0 kg / cm ² . The reaction time is generally 0.5 to 100 hours, preferably 1 to 50 hours, more preferably 5 to 2 hours.
5 hours. In the reaction, a Lewis acid, a proton acid, or the like may be added to the reaction solution, if desired. In the reaction, the desired optically active compound of the product compound is usually added in an amount of 1/200 to 1/5 times, preferably 1/100 times 1 part by weight of the starting compound (XXXV). The reaction may be performed by adding 100 to 1/10 times the weight in advance.

The conversion from the compound (XXXV) to the desired optically active compound can be determined by the following method. That is, for example, an appropriate amount of the reaction solution after the reaction is sampled, and an appropriate chiral column (for example, Chi
ralpak AS (manufactured by Daicel Chemical Industries, Ltd.), ULTRONS-
OVM (SHINWA CHEMICAL INDUSTRIES LTD.) And other high-performance liquid chromatography (HPLC) methods
The respective amounts of the raw material compound (XXXV) or the target optically active compound can be measured. From the reaction solution obtained by the above reaction, a method known per se (eg, solvent extraction, phase transfer, crystallization, recrystallization, chromatography, etc.)
Thereby, an optically active amine derivative can be obtained. The optically active compound (I) is produced by acylating the optically active amine thus obtained. The reaction conditions and the like are the same as those used for producing compound (I) from compound (XXXVI) described below.

The compound (XXXVI) wherein m = 2 or 3 is obtained by treating the compound (XXXV) with an acid in the same manner as in the method for producing the compound (XVI) from the compound (XV),
It is produced by isomerization. As the acid catalyst,
For example, inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, acetic acid, trifluoroacetic acid, oxalic acid, phthalic acid, fumaric acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, p -Toluenesulfonic acid, 10
-Organic acids such as camphorsulfonic acid, and boron trifluoride etherate are preferred. The amount of the acid catalyst to be used is about 0.01-10 mol per 1 mol of compound (XXXV),
Preferably it is about 0.01-5.0 mol. This reaction is advantageously carried out without a solvent or using a solvent inert to the reaction. Although not particularly limited as long as the reaction proceeds as such a solvent, for example, methanol, ethanol, alcohols such as propanol, diethyl ether, tetrahydrofuran, dioxane, ethers such as 1,2-dimethoxyethane, benzene, toluene, cyclohexane, Hydrocarbons such as hexane, amides such as N, N-dimethylformamide and N, N-dimethylacetamide, sulfoxides such as dimethyl sulfoxide;
A solvent such as water or a mixed solvent thereof is preferable. The reaction time is usually 10 minutes to 12 hours, preferably 10 minutes.
Minutes to 2 hours. Reaction temperature is usually -10 to 200 ° C,
Preferably it is -10 to 100C. Product (XXXVI)
Can be used in the next reaction as a reaction solution or as a crude product, but can also be isolated from the reaction mixture according to a conventional method, and can be easily purified by separation means such as recrystallization, distillation, and chromatography. it can.

Among the compounds (XXXVI), the compound where m = 1 is
Compound (XXXII) is treated with trimethylsilyl cyanide in the presence of a Lewis acid in the same manner as in the above-mentioned method for producing compound (XVI) from compound (X), and the resulting trimethylsilyloxy group is eliminated with an acid. It is produced by reducing a cyano group. Examples of the Lewis acid include zinc iodide, anhydrous aluminum chloride, anhydrous zinc chloride, anhydrous iron chloride, and the like. The amount of the Lewis acid catalyst to be used is about 0.01-10 mol per 1 mol of compound (XXXII),
Preferably it is about 0.01-1.0 mol. This reaction is advantageously carried out without a solvent or using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds, for example, diethyl ether, tetrahydrofuran, dioxane, ethers such as 1,2-dimethoxyethane, benzene, toluene, cyclohexane, and solvents such as hydrocarbons such as hexane or the like. Preferred are mixed solvents thereof. The reaction time is usually from 10 minutes to
12 hours, preferably 30 minutes to 3 hours. The reaction temperature is usually -10 to 200C, preferably -10 to 100C.
It is. The product can be used as a reaction solution or as a crude product in the next reaction, but can also be isolated from the reaction mixture according to a conventional method, and is easily purified by separation means such as recrystallization, distillation, and chromatography. be able to.
Next, treatment is performed using an acid. As the acid, for example, inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, acetic acid,
Organic acids such as trifluoroacetic acid, oxalic acid, phthalic acid, fumaric acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid, 10-camphorsulfonic acid, and boron trifluoride etherate Are preferred. The amount of these acids used is Compound (XXXII) 1
It is about 1-100 mol, preferably about 1-10 mol, per mol. This reaction is advantageously carried out without a solvent or using a solvent inert to the reaction. The solvent is not particularly limited as long as the reaction proceeds. Examples of the solvent include diethyl ether, tetrahydrofuran, dioxane, 1,2 and
Ethers such as dimethoxyethane, hydrocarbons such as benzene, toluene, cyclohexane and hexane;
Solvents such as amides such as N, N-dimethylformamide and N, N-dimethylacetamide, sulfoxides such as dimethylsulfoxide, and mixed solvents thereof are preferable. The reaction time is generally 30 minutes to 12 hours, preferably 30 minutes to 5 hours. The reaction temperature is usually 0 to 20
0 ° C., preferably 20 to 150 ° C. The reduction of the cyano group can be performed under the conditions used for producing compound (XV) from compound (XII). Product (XXXVI)
Can be used in the next reaction as a reaction solution or as a crude product, but can also be isolated from the reaction mixture according to a conventional method, and can be easily purified by separation means such as recrystallization, distillation, and chromatography. it can.

Compound (I) can also be produced by reacting compound (XXXVI) with a carboxylic acid, a salt thereof or a reactive derivative thereof. Examples of the carboxylic acid include compounds represented by the formula R ¹ —COOH (wherein R ¹ has the same meaning as described above). Examples of the reactive derivative of the carboxylic acid include acid halides (eg, acid chlorides, acid bromides, etc.), acid amides (eg, acid amides with pyrazole, imidazole, benzotriazole, etc.), acid anhydrides (eg, , acetic anhydride, propionic anhydride, a C _1-6 aliphatic carboxylic acid anhydrides such as anhydrous acid), acid azides, active esters (e.g., Jietokishirin acid esters, diphenoxyphosphoric cylinder ester, p- nitrophenyl ester, 2 , 4-dinitrophenyl ester, cyanomethyl ester, pentachlorophenyl ester, N-
Ester with hydroxysuccinimide, ester with N-hydroxyphthalimide, ester with 1-hydroxybenzotriazole, ester with 6-chloro-1-hydroxybenzotriazole, 1-hydroxy-1
Examples thereof include an ester with H-2-pyridone, an active thioester (eg, 2-pyridylthioester, 2-benzothiazolylthioester, and the like).

Instead of using the reactive derivative, the carboxylic acid or a salt thereof may be directly reacted with the compound (XXXVI) in the presence of a suitable condensing agent. Examples of the condensing agent include N, N′-dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl)
N, N′-disubstituted carbodiimides such as carbodiimide (WSC) hydrochloride, azolides such as N, N′-carbonyldiimidazole, N-ethoxycarbonyl-2
Dehydrating agents such as -ethoxy-1,2-dihydroquinoline, phosphorus oxychloride, and alkoxyacetylene; and 2-halogenopyridinium salts such as 2-chloromethylpyridinium iodide and 2-fluoro-1-methylpyridinium iodide. . When these condensing agents are used, the reaction is thought to proceed via a reactive derivative of the carboxylic acid. The carboxylic acid represented by the formula R ¹ —COOH (R ¹ is as defined above) or a reactive derivative thereof is a compound (XX)
XVI) Usually, about 1.0 to 5.0 mol, preferably about 1.0 to 2.0 mol, per 1 mol. This reaction is advantageously performed using a solvent inert to the reaction. The solvent is not particularly limited as long as the reaction proceeds, for example, diethyl ether, tetrahydrofuran, dioxane,
Ethers such as 1,2-dimethoxyethane, hydrocarbons such as benzene, toluene, and cyclohexane;
Amides such as N-dimethylformamide, N, N-dimethylacetamide, dichloromethane, chloroform,
Preferred are halogenated hydrocarbons such as carbon tetrachloride and 1,2-dichloroethane, nitriles such as acetonitrile and propionitrile, sulfoxides such as dimethylsulfoxide, solvents such as water, and mixed solvents thereof. When an acid halide is used as the reactive derivative of the carboxylic acid, the reaction can be performed in the presence of a deoxidizing agent for the purpose of removing released hydrogen halide from the reaction system. Examples of such a deoxidizing agent include carbonates such as sodium carbonate, potassium carbonate and sodium hydrogen carbonate, pyridine, aromatic amines such as lutidine, triethylamine, tripropylamine, tributylamine, and the like.
Tertiary amines such as cyclohexyldimethylamine, 4-dimethylaminopyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine and N-methylmorpholine are used. The reaction time varies depending on the reagents and solvents used, but is usually 30 minutes to 24 hours, preferably 30 minutes to 4 hours. The reaction temperature is usually 0 to 1
00 ° C, preferably 0-70 ° C.

Compound (I) is obtained by converting compound (XXXV) to a compound of the formula R ¹
-COOH (R ¹ is as defined above), a salt thereof or a reactive derivative thereof is added, and the mixture is added under acidic conditions for 5 minutes to 3 hours, preferably 10 minutes to 1 hour,
After stirring at 0 ° C., preferably at 0 to 70 ° C., the above-mentioned deoxidizing agent is added and the mixture is subjected to an acylation reaction, whereby the compound can be produced with isomerization in the system. The carboxylic acid or a reactive derivative thereof is generally used in an amount of about 1.0 to 5.0 mol, preferably about 1.0 to 5.0 mol, per 1 mol of compound (XXXV).
Use 2.0 moles. This reaction is advantageously performed using a solvent inert to the reaction. The solvent is not particularly limited as long as the reaction proceeds. Examples thereof include ethers such as diethyl ether, tetrahydrofuran, dioxane, and 1,2-dimethoxyethane; hydrocarbons such as benzene, toluene, and cyclohexane; and N, N-dimethyl. Amides such as formamide and N, N-dimethylacetamide, dichloromethane, chloroform, carbon tetrachloride,
Solvents such as halogenated hydrocarbons such as 2-dichloroethane, nitriles such as acetonitrile and propionitrile, sulfoxides such as dimethyl sulfoxide, and a mixed solvent thereof are preferable. The product (I) thus obtained can be isolated from the reaction mixture according to a conventional method, and can be easily purified by separation means such as recrystallization, distillation, and chromatography.

Further, when R ² in the compound (I) is an alkyl group, after the above acylation, a base is prepared by using a corresponding alkylating agent (for example, an alkyl halide or a sulfonic acid ester of an alcohol). To perform an alkylation reaction. The alkylating agent is used in an amount of about 1.0-5.0 mol, preferably about 1.0-2.0 mol, per 1 mol of compound (I). As the base, for example, inorganic bases such as sodium hydroxide and potassium hydroxide, basic salts such as sodium carbonate, potassium carbonate, cesium carbonate and sodium hydrogencarbonate, aromatic amines such as pyridine and lutidine, triethylamine, tripropyl Tertiary amines such as amine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, sodium hydride, hydrogenation Alkali metal hydrides such as potassium, metal amides such as sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide, and metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide Etc., and the like. The base is used in an amount of about 1.0-5.0 mol, preferably about 1.0-2.0 mol, per 1 mol of compound (I). This reaction is advantageously performed using a solvent inert to the reaction. Although not particularly limited as long as the reaction proceeds as such a solvent, for example, methanol, ethanol, alcohols such as propanol, diethyl ether, tetrahydrofuran, dioxane, ethers such as 1,2-dimethoxyethane,
Hydrocarbons such as benzene, toluene, cyclohexane, hexane, N, N-dimethylformamide, N, N-
Solvents such as amides such as dimethylacetamide, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, and 1,2-dichloroethane, nitriles such as acetonitrile and propionitrile, and sulfoxides such as dimethylsulfoxide or the like. A mixed solvent is preferred. The reaction time is generally 30 minutes to 48 hours, preferably 30 minutes to 6 hours. The reaction temperature is usually -20 to 200C, preferably -10 to 150C. The product (I) can be isolated from the reaction mixture according to a conventional method, and can be easily purified by separation means such as recrystallization, distillation, and chromatography.

In the case of producing a compound in which the double bond is reduced among the compounds (I), the double operation of the compound (I) is carried out in the same manner as in the production of the compound (VII) from the compound (VIII). It is produced by catalytic reduction of the binding moiety.

(Reaction 4)

Embedded image

Compound (XXXVII) can be produced by a method known per se, for example, the method of Journal of the Chemical Society (J. Che
m. Soc.), 2525 (1952), 1165 (1954), Journal of Organic Chemistry (J. Org. Che)
m.), 49, 4833 (1984), Journal of Heterocyclic Chemistry (J. Heterocyclic Che)
m.), 24, 941 (1987), Journal of Medicinal Chemistry (J. Med. Chem.), 17, 747
(1974), Helvetica Kimica Acta (Helv. Chim. Act)
a), vol. 48, p. 252 (1965), or a method analogous thereto.

Compound (XXXVIII) is compound (XXXVII)
And a corresponding alkylating agent (eg, an alkyl halide,
And a sulfonic acid ester of an alcohol) in the presence of a base. Compound (XXXV
II) About 0.5 to 5.0 mol, preferably about 0.8 to 2.0 mol, of the alkylating agent is used per 1 mol. As the base, for example, inorganic bases such as sodium hydroxide and potassium hydroxide, basic salts such as sodium carbonate, potassium carbonate, cesium carbonate and sodium hydrogencarbonate, aromatic amines such as pyridine and lutidine, triethylamine, tripropyl Amine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine,
N, N-dimethylaniline, N-methylpiperidine, N
Tertiary compounds such as -methylpyrrolidine and N-methylmorpholine
Primary amines, alkali metal hydrides such as sodium hydride and potassium hydride, metal amides such as sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide, sodium methoxide, sodium ethoxide, potassium tert-butoxide And other metal alkoxides. The base is used in an amount of about 1.0 to 5.0 mol, preferably about 1.0 to 2.0 mol, per 1 mol of compound (XXXVII). This reaction is advantageously performed using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds, for example, alcohols such as methanol, ethanol, and propanol;
Diethyl ether, tetrahydrofuran, dioxane,
Ethers such as 1,2-dimethoxyethane, hydrocarbons such as benzene, toluene, cyclohexane and hexane; amides such as N, N-dimethylformamide and N, N-dimethylacetamide; dichloromethane, chloroform, carbon tetrachloride; Solvents such as halogenated hydrocarbons such as 1,2-dichloroethane, nitriles such as acetonitrile and propionitrile, sulfoxides such as dimethylsulfoxide, and a mixed solvent thereof are preferable. The reaction time is generally 30 minutes to 48 hours, preferably 1 hour to 24 hours. The reaction temperature is usually -20 to
The temperature is 200 ° C, preferably 0 to 150 ° C. Product (XX
XVIII) can be used in the next reaction as a reaction solution or as a crude product, but can also be isolated from the reaction mixture according to a conventional method, and is easily purified by separation means such as recrystallization, distillation, and chromatography. be able to.

Compound (XXXIX) is produced by reacting compound (XXXVII) with the corresponding α-haloketone in the presence of a base. The α-haloketone is used in an amount of about 1.0 to 5.0 mol, preferably about 1.0 to 2.0 mol, per 1 mol of compound (XXXVII). As the base, for example, inorganic bases such as sodium hydroxide and potassium hydroxide, basic salts such as sodium carbonate, potassium carbonate, cesium carbonate and sodium hydrogencarbonate, aromatic amines such as pyridine and lutidine, triethylamine, tripropyl Tertiary amines such as amine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, sodium hydride, hydrogenation Alkali metal hydrides such as potassium, sodium amide, lithium diisopropylamide, metal amides such as lithium hexamethyldisilazide, sodium methoxide, sodium ethoxide,
Metal alkoxides such as potassium tert-butoxide; The base is used in an amount of about 1.0 to 5.0 mol, preferably about 1.0 to 2.0 mol, per 1 mol of compound (XXXVII). This reaction is advantageously performed using a solvent inert to the reaction. The solvent is not particularly limited as long as the reaction proceeds, for example, methanol, ethanol,
Alcohols such as propanol, diethyl ether,
Ethers such as tetrahydrofuran, dioxane, 1,2-dimethoxyethane, hydrocarbons such as benzene, toluene, cyclohexane and hexane; ketones such as acetone and methyl ethyl ketone; N, N-dimethylformamide; N, N-dimethylacetamide Amides, dichloromethane, chloroform, carbon tetrachloride, 1,
Solvents such as halogenated hydrocarbons such as 2-dichloroethane, nitriles such as acetonitrile and propionitrile, sulfoxides such as dimethyl sulfoxide, and a mixed solvent thereof are preferable. The reaction time is generally 30 minutes to 48 hours, preferably 1 hour to 24 hours. The reaction temperature is usually -20 to 200C, preferably 0 to 200C.
150 ° C. The product (XXXIX) can be used in the next reaction as a reaction solution or as a crude product, but it can also be isolated from the reaction mixture according to a conventional method, and can be easily separated by separation means such as recrystallization, distillation, or chromatography. Can be purified.

Compound (XL) is produced by reacting compound (XXXVII) with a corresponding alkylating agent (for example, a substituted acetylene alkyl halide, a sulfonate of substituted acetylene alcohol, etc.) in the presence of a base. You. The alkylating agent is used in an amount of about 1.0 to 20.0 mol, preferably about 1.0 to 1 mol, per 1 mol of compound (XXXVII).
Use 0.0 mol. As the base, for example, inorganic bases such as sodium hydroxide and potassium hydroxide, base salts such as sodium carbonate, potassium carbonate, cesium carbonate and sodium hydrogen carbonate, aromatic amines such as pyridine and lutidine, triethylamine, tripropylamine , Tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N, N-dimethylaniline, N-
Tertiary amines such as methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, sodium hydride,
Alkali metal hydrides such as potassium hydride; metal amides such as sodium amide, lithium diisopropylamide and lithium hexamethyldisilazide; and metal alkoxides such as sodium methoxide, sodium ethoxide and potassium tert-butoxide. Can be
The base is added in an amount of about 1.0 to 10 per 1 mol of the compound (XXXVII).
0 mol, preferably about 1.0 to 5.0 mol. This reaction is advantageously performed using a solvent inert to the reaction.
Although not particularly limited as long as the reaction proceeds as such a solvent, for example, methanol, ethanol, alcohols such as propanol, diethyl ether, tetrahydrofuran, dioxane, ethers such as 1,2-dimethoxyethane, benzene, toluene, cyclohexane, Hydrocarbons such as hexane, amides such as N, N-dimethylformamide, N, N-dimethylacetamide, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, acetonitrile, propio Solvents such as nitrites such as nitriles, sulfoxides such as dimethyl sulfoxide, and mixed solvents thereof are preferable. The reaction time is generally 30 minutes to 48 hours, preferably 1 hour to 24 hours. The reaction temperature is usually −20 to 200 ° C., preferably 0 to 150 ° C.
It is. The product (XXXX) can be used in the next reaction as a reaction solution or as a crude product, but it can also be isolated from the reaction mixture according to a conventional method, and can be easily separated by separation means such as recrystallization, distillation, or chromatography. Can be purified.

In the above-mentioned alkylation reaction, when the alkylation to the hydroxyl group does not proceed selectively, the amino group is protected and deprotected as necessary. The step of protecting and deprotecting the amino group is performed based on general known operations. For example, T. W. Green Protecting Groups in Org
anic Synthesis ”(2nd edition, 1991),“ Prot
Section for the Amino Group. Compound (XLI) is compound (XXXVIII), (XXXI
It is produced by subjecting X) or (XL) to a ring closure reaction known per se. For example, a method using heating, a method using an acidic substance, a method using a basic substance, a method analogous thereto, and the like are used. When the ring is closed by heating, it is advantageous to carry out the reaction without a solvent or using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds. For example, high-boiling hydrocarbons such as 1,2,3,4-tetrahydronaphthalene and bromobenzene; high-boiling ethers such as diphenyl ether and diethylene glycol dimethyl ether; , N-dimethylaniline, N, N-diethylaniline and the like, or a mixed solvent thereof is preferable. Reaction time is usually 1
0 minutes to 24 hours, preferably 10 minutes to 10 hours.
The reaction temperature is usually 100 to 300 ° C, preferably 100 to 300 ° C.
250 ° C.

In the case of ring closure using an acidic substance, for example, phosphorus oxychloride, phosphorus pentachloride, phosphorus pentoxide, phosphorus trichloride,
Thionyl chloride, hydrobromic acid, hydrochloric acid, sulfuric acid, phosphoric acid,
Acidic substances such as polyphosphoric acid and p-toluenesulfonic acid are used. Compound (XXXVIII), (XXXIX) or (X
L) about 0.5 to 100 mol of the acidic substance per 1 mol,
Preferably, about 5.0 to 20 mol is used. This reaction is advantageously carried out without a solvent or using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds. For example, aromatic hydrocarbons such as benzene and toluene, saturated hydrocarbons such as cyclohexane and hexane, tetrahydrofuran, dioxane, and 1,2-
Ethers such as dimethoxyethane, amides such as N, N-dimethylformamide and N, N-dimethylacetamide, dichloromethane, chloroform, carbon tetrachloride,
Halogenated hydrocarbons such as 1,2-dichloroethane,
Acid anhydrides such as acetic anhydride, sulfoxides such as dimethyl sulfoxide, solvents such as water, and mixed solvents thereof are preferable. The reaction time is generally 30 minutes to 12 hours, preferably 30 minutes to 6 hours. The reaction temperature is generally 0-200 ° C, preferably 0-150 ° C.

In the case of ring closure using a basic substance, for example, sodium hydroxide, potassium hydroxide, sodium carbonate,
Basic substances such as potassium carbonate and sodium hydrogen carbonate are used. Compound (XXXVIII), (XXXIX) or (X
L) The basic substance is used in an amount of about 0.5 to 100 mol, preferably about 5.0 to 20 mol, per 1 mol. This reaction is advantageously carried out without a solvent or using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds. For example, methanol, ethanol,
Preferred are alcohols such as propanol, ketones such as acetone and methyl ethyl ketone, solvents such as water, and mixed solvents thereof. Reaction time is usually 30 minutes or more.
12 hours, preferably 30 minutes to 6 hours. The reaction temperature is generally 0-200 ° C, preferably 0-150 ° C.
The double bond part of the ring newly formed by the cyclization reaction can be reduced, if necessary, by the same operation as in the production of compound (VII) from compound (VIII). The product obtained by the above cyclization reaction (XL
I) can be used in the next reaction as a reaction solution or as a crude product, but it can also be isolated from the reaction mixture according to a conventional method, and easily purified by a separation means such as recrystallization, distillation, or chromatography. be able to.

The compound (XLII) can be produced by a known method, for example, The Chemistry of Heterocyclic Compounds, 2
Volume 5, Part 3 (WJ Houlihan, ed, John Wiley and
Sons, Inc., New York), 361 pages (1979), Journal
Of the Chemical Society (J. Chem. Soc.), 3
842 (1954), Tetrahedron, 36
Vol. 2505 (1980), Monashefte Fuer Chemie (Mo
natsh. Chem.), 117, 375 (1986) and the like, or a method analogous thereto and the compound (XLI).
Can be manufactured from Compound (XLIII) is produced from compound (XLII) and nitromethane in the presence of a base catalyst by aldol condensation as a single isomer of configuration E or Z or a mixture of E and Z isomers. About 1.0 to 1 nitromethane is added to 1 mole of compound (XLII).
00 mol, preferably about 1.0 to 50 mol. As the base, for example, inorganic bases such as sodium hydroxide and potassium hydroxide, basic salts such as sodium carbonate, potassium carbonate, cesium carbonate and sodium hydrogen carbonate, methylamine, propylamine, butylamine, benzylamine, aniline and the like Primary amines, ammonium acetate, alumina and the like can be mentioned. The amount of the base to be used is about 0.01-5.0 mol, preferably about 0.1-1.0 mol, per 1 mol of compound (XLII). This reaction is advantageously performed using a solvent inert to the reaction. The solvent is not particularly limited as long as the reaction proceeds, for example, alcohols such as methanol, ethanol and propanol, hydrocarbons such as benzene, toluene, cyclohexane and hexane, N, N-dimethylformamide, N, N- Preferred are amides such as dimethylacetamide, solvents such as water, and mixed solvents thereof. The reaction time is usually 30 minutes to 72 hours, preferably 3 minutes.
0 minutes to 24 hours. The reaction temperature is usually -20 to 200.
° C, preferably -10 to 150 ° C. Product (XLII
I) can be used in the next reaction as a reaction solution or as a crude product, but it can also be isolated from the reaction mixture according to a conventional method, and easily purified by a separation means such as recrystallization, distillation, or chromatography. be able to.

Compound (XLIV) is the same as compound (XLII)
It is produced by subjecting I) to a reduction reaction. Examples of the reducing agent used include aluminum hydride, metal hydrides such as diisobutylaluminum hydride, lithium aluminum hydride, sodium borohydride,
Metal hydride complexes such as lithium borohydride, sodium cyanoborohydride, or hydrogenation catalysts such as Raney nickel, platinum oxide, activated carbon with platinum, activated carbon with palladium, barium sulfate with palladium, nickel, copper-chromium oxide, A catalyst such as rhodium, cobalt, ruthenium or the like is used. Additives (promoters) that increase the catalytic ability by being added to the reaction system, for example.
May be added. As the acidic additive, for example, inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, perchloric acid, hydrobromic acid, phosphoric acid, acetic acid, trifluoroacetic acid, oxalic acid, phthalic acid, fumaric acid, tartaric acid, maleic acid, Citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid, 10
-Organic acids such as camphorsulfonic acid are preferred. As the basic additive, sodium hydroxide, potassium hydroxide and the like are preferable. The amount of the reducing agent used is, for example, in the case of a metal hydride, about 1.0 to 10 mol, preferably about 1.0 to 3.0 mol, per 1 mol of the compound (XLIII).
In the case of a metal hydrogen complex compound, about 1.0 to 10 mol, preferably about 1.0 to 3.0 mol, per 1 mol of compound (XLIII).
In the case of molar or hydrogenation, the catalyst such as Raney nickel is used in an amount of about 10 to 1000% by weight, preferably about 100 to 300% by weight, based on the compound (XLIII). This reaction is advantageously performed using a solvent inert to the reaction. Although not particularly limited as long as the reaction proceeds as such a solvent, for example, methanol, ethanol, alcohols such as propanol, diethyl ether, tetrahydrofuran, dioxane, ethers such as 1,2-dimethoxyethane,
Solvents such as hydrocarbons such as benzene, toluene, and cyclohexane, amides such as N, N-dimethylformamide and N, N-dimethylacetamide, and organic acids such as formic acid and acetic acid, or a mixed solvent thereof are preferable. The reaction time varies depending on the activity and amount of the reducing agent or catalyst used, but is usually 1 hour to 100 hours, preferably 1 hour.
Hours to 50 hours. The reaction temperature is usually 0 to 120 ° C,
Preferably it is 20-80 degreeC. When a catalyst such as Raney nickel is used, the pressure of hydrogen is usually 1 to 100 atm. The product (XLIV) can be used as is in the reaction solution or as a crude product in the next reaction. Can be purified. Compound (XLIV) can be prepared by a method known per se, for example, Journal of Medicinal Chemistry (J. Med.
Chem.), 35, 3625 (1992), tetrahedron (Tetr
ahedron), vol. 48, p. 1039 (1992) and the like, or a method analogous thereto.

Compound (I) is produced by reacting compound (XLIV) with a carboxylic acid, a salt thereof or a reactive derivative thereof. As the carboxylic acid, for example, a compound represented by the formula R ¹ —COOH (wherein R ¹ has the same meaning as described above)
The compound represented by these is mentioned. Examples of the reactive derivative of the carboxylic acid include acid halides (eg, acid chlorides, acid bromides, etc.), acid amides (eg, acid amides with pyrazole, imidazole, benzotriazole, etc.), acid anhydrides (eg, , acetic anhydride, propionic anhydride, a C _1-6 aliphatic carboxylic acid anhydrides such as anhydrous acid), acid azides, active esters (e.g., Jietokishirin acid esters, diphenoxyphosphoric cylinder ester, p- nitrophenyl ester, 2 , 4-dinitrophenyl ester, cyanomethyl ester, pentachlorophenyl ester, N-
Ester with hydroxysuccinimide, ester with N-hydroxyphthalimide, ester with 1-hydroxybenzotriazole, ester with 6-chloro-1-hydroxybenzotriazole, 1-hydroxy-1
Examples thereof include an ester with H-2-pyridone, an active thioester (eg, 2-pyridylthioester, 2-benzothiazolylthioester, and the like).

Instead of using the reactive derivative, the carboxylic acid or a salt thereof may be directly reacted with the compound (XLIV) in the presence of a suitable condensing agent. As a condensing agent,
For example, N, N'-dicyclohexylcarbodiimide, 1
N, N'-disubstituted carbodiimides such as -ethyl-3- (3-dimethylaminopropyl) carbodiimide (WSC) hydrochloride, azolides such as N, N'-carbonyldiimidazole, N-ethoxycarbonyl-2- Dehydrating agents such as ethoxy-1,2-dihydroquinoline, phosphorus oxychloride and alkoxyacetylene, and 2-halogenopyridinium salts such as 2-chloromethylpyridinium iodide and 2-fluoro-1-methylpyridinium iodide are used. When these condensing agents are used, the reaction is thought to proceed via a reactive derivative of the carboxylic acid.
A carboxylic acid represented by the formula R ¹ —COOH (R ¹ has the same meaning as described above) or a reactive derivative thereof is represented by compound (XLIV) 1
It is generally used in an amount of about 1.0-5.0 mol, preferably about 1.0-2.0 mol, per mol. This reaction is advantageously performed using a solvent inert to the reaction. The solvent is not particularly limited as long as the reaction proceeds. Examples of the solvent include diethyl ether, tetrahydrofuran, dioxane, 1,2 and
Ethers such as dimethoxyethane, hydrocarbons such as benzene, toluene and cyclohexane, amides such as N, N-dimethylformamide and N, N-dimethylacetamide, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane Preferred are halogenated hydrocarbons such as, for example, nitriles such as acetonitrile and propionitrile, sulfoxides such as dimethyl sulfoxide, solvents such as water, and a mixed solvent thereof. When an acid halide is used as the reactive derivative of the carboxylic acid, the reaction can be performed in the presence of a deoxidizing agent for the purpose of removing released hydrogen halide from the reaction system. Examples of such a deoxidizing agent include carbonates such as sodium carbonate, potassium carbonate and sodium hydrogen carbonate, pyridine, aromatic amines such as lutidine, triethylamine, tripropylamine, tributylamine, and the like.
Tertiary amines such as cyclohexyldimethylamine, 4-dimethylaminopyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine and N-methylmorpholine are used. The reaction time varies depending on the reagents and solvents used, but is usually 30 minutes to 24 hours, preferably 30 minutes to 4 hours. The reaction temperature is usually 0 to 1
00 ° C, preferably 0-70 ° C.

Further, when R ² in the compound (I) is an alkyl group, after the above acylation, a base is prepared by using a corresponding alkylating agent (for example, an alkyl halide or a sulfonic acid ester of an alcohol). To perform an alkylation reaction. The alkylating agent is used in an amount of about 1.0-5.0 mol, preferably about 1.0-2.0 mol, per 1 mol of compound (I). As the base, for example, inorganic bases such as sodium hydroxide and potassium hydroxide, basic salts such as sodium carbonate, potassium carbonate, cesium carbonate and sodium hydrogencarbonate, aromatic amines such as pyridine and lutidine, triethylamine, tripropyl Tertiary amines such as amine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, sodium hydride, hydrogenation Alkali metal hydrides such as potassium, metal amides such as sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide, and metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide Etc., and the like. The base is used in an amount of about 1.0-5.0 mol, preferably about 1.0-2.0 mol, per 1 mol of compound (I). This reaction is advantageously performed using a solvent inert to the reaction. Although not particularly limited as long as the reaction proceeds as such a solvent, for example, methanol, ethanol, alcohols such as propanol, diethyl ether, tetrahydrofuran, dioxane, ethers such as 1,2-dimethoxyethane,
Hydrocarbons such as benzene, toluene, cyclohexane, hexane, N, N-dimethylformamide, N, N-
Solvents such as amides such as dimethylacetamide, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, and 1,2-dichloroethane, nitriles such as acetonitrile and propionitrile, and sulfoxides such as dimethylsulfoxide or the like. A mixed solvent is preferred. The reaction time is generally 30 minutes to 48 hours, preferably 30 minutes to 6 hours. The reaction temperature is usually -20 to 200C, preferably -10 to 150C. The product (I) can be isolated from the reaction mixture according to a conventional method, and can be easily purified by separation means such as recrystallization, distillation, and chromatography. In the case of producing a compound in which the double bond portion of the compound (I) is reduced, the compound is produced by the same operation as that for producing the compound (VII) from the compound (VIII).

(Reaction 5)

Embedded image

Compound (XLV) is produced, for example, by protecting the primary amino group of 5-hydroxytryptamine (5-HT). R ¹⁰ represents a protecting group, and examples of the “protecting group” include a “protecting group for an amino group” described below. The protection of the amino group is performed based on general known operations. For example, T. W. Green Protecting Groups in Org
anic Synthesis ”(2nd edition, 1991),“ Prot
Section for the AminoGroup ”. Compound (XLVI) is produced from compound (XLV) by the same operation as that for producing compound (XXXVIII) from compound (XXXVII). Compound (XLVII) is produced from compound (XLV) by the same operation as that for producing compound (XXXIX) from compound (XXXVII). Compound (XLIII) is produced from compound (XLV) by the same operation as that for producing compound (XL) from compound (XXXVII). Compound (XLIX) is compound (XXXVIII),
It is produced from compound (XLVI), (XLVII) or (XLVIII) by the same operation as that for producing compound (XLI) from (XXXIX) or (XL). A method known per se,
For example, Tetrahedron Lets
t.), Vol. 36, p. 7019 (1995) and the like, or a method analogous thereto. Further, the compound in which the double bond portion is reduced is the compound (VII
It is produced by the same operation as that for producing compound (VII) from I).

Compound (I) can be prepared by removing the protecting group for the side chain amino group of compound (XLIX) from the compound (XLIV) to produce compound (I). It is manufactured by attaching. Deprotection of an amino group is performed based on a general known operation. For example,
T. W. Green Protecting Groups in OrganicSy
nthesis "(2nd edition, 1991)," Protection
for the Amino Group.

(Reaction 6)

Embedded image Compound (L) is produced by reacting compound (XVIII) with a corresponding alkylating agent (eg, substituted allyl halide, sulfonate of substituted allyl alcohol, etc.) in the presence of a base. The alkylating agent is used in an amount of about 1.0-20.0 mol, preferably about 1.0-10.0 mol, per 1 mol of compound (XVIII). As the base,
For example, sodium carbonate, potassium carbonate, cesium carbonate,
Basic salts such as sodium hydrogen carbonate, inorganic bases such as sodium hydroxide and potassium hydroxide, aromatic amines such as pyridine and lutidine, triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine Tertiary amines such as N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine and N-methylmorpholine; alkali metal hydrides such as sodium hydride and potassium hydride; sodium amide; lithium diisopropyl Examples include metal amides such as amide and lithium hexamethyldisilazide, and metal alkoxides such as sodium methoxide, sodium ethoxide and potassium tert-butoxide. The base is used in an amount of about 1.0 to 5.0 mol, preferably about 1.0 to 5.0 mol, per 1 mol of compound (XVIII).
Use 2.0 moles. This reaction is advantageously performed using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds. For example, alcohols such as methanol, ethanol, and propanol, diethyl ether, tetrahydrofuran, dioxane, and 1,2-
Ethers such as dimethoxyethane, hydrocarbons such as benzene, toluene, cyclohexane and hexane;
Amides such as N-dimethylformamide, N, N-dimethylacetamide, dichloromethane, chloroform,
Solvents such as halogenated hydrocarbons such as carbon tetrachloride and 1,2-dichloroethane, nitriles such as acetonitrile and propionitrile, sulfoxides such as dimethyl sulfoxide, and a mixed solvent thereof are preferable. The reaction time is generally 30 minutes to 48 hours, preferably 1 hour to 24 hours. The reaction temperature is usually -20 to 200.
° C, preferably from 0 to 150 ° C. The product (L) can be used as is in the reaction solution or as a crude product in the next reaction, but can also be isolated from the reaction mixture according to a conventional method, and can be easily separated by separation means such as recrystallization, distillation, and chromatography. Can be purified.

Compound (LI) is produced by subjecting compound (L) to a Claisen rearrangement reaction. The Claisen rearrangement reaction is performed by a method known per se, for example, New Experimental Chemistry Course, Chapter 14
Volume, Synthesis and Reaction of Organic Compounds (I), 3.2 Phenol, 559 pages (The Chemical Society of Japan), Organic Reactions, 2, 1-48, 22, 22, 1
It can be produced according to the method described on page 252 or a method analogous thereto. Specifically, compound (LI)
Is heated in the absence of a solvent or N- in a solvent, whereby the rearrangement reaction proceeds. As such a solvent, a high boiling point solvent such as N, N-diethylaniline, diphenyl ether, 1,2,3,4-tetramethylbenzene is used. The reaction time is usually 30 minutes to 48 hours, preferably 1 hour to 24 hours.
Time. The reaction temperature is usually from 150 to 250C, preferably from 180 to 220C. The product (LI) can be used in the next reaction as a reaction solution or as a crude product.
It can be isolated from the reaction mixture according to a conventional method, and can be easily purified by separation means such as recrystallization, distillation, and chromatography.

Compound (LII) can be produced by oxidatively cleaving the double bond of compound (LI) and subsequently subjecting it to reduction. The leaving group represented by L in compound (LII) is preferably a leaving group such as hydroxy, a halogen atom, an alkylsulfonate and an arylsulfonate. The method of oxidative cleavage, by a method known per se, for example permanganate, permanganate - periodate, chromic acid, lead tetraacetate -N ₃ complex, ozone, osmium tetroxide - hydrogen peroxide, Osmium tetroxide-periodic acid, ruthenium tetroxide, iodosyl compounds, oxygen, hydrogen peroxide or organic peroxides, organic peracids, nitrobenzene, methods using anodic oxidation, for example, New Experimental Chemistry, Vol. 15, Oxidation and reduction (edited by the Chemical Society of Japan) or the like or a method analogous thereto. For example, in the case of ozone oxidation, the solvent is not particularly limited as long as the reaction proceeds.For example, alcohols such as methanol, ethanol, and propanol, diethyl ether, tetrahydrofuran, dioxane, ethers such as 1,2-dimethoxyethane, benzene, Hydrocarbons such as toluene, cyclohexane, hexane, esters such as ethyl acetate, amides such as N, N-dimethylformamide, N, N-dimethylacetamide, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, etc. Solvents such as halogenated hydrocarbons, nitriles such as acetonitrile and propionitrile, ketones such as acetone, and sulfoxides such as dimethyl sulfoxide, and a mixed solvent thereof are used. The reaction time depends on the ozone generating capacity of the ozone generator, but is usually from 5 minutes to
48 hours, preferably 5 minutes to 12 hours. The reaction temperature is generally -100 to 0C, preferably -75 to -20C. As the reducing agent used in the subsequent reduction reaction, for example, metal hydrides such as aluminum hydride and diisobutylaluminum hydride, and metal hydrogen complex compounds such as lithium aluminum hydride and sodium borohydride are used. For example, in the case of a metal hydride, the amount of the reducing agent used is about 1.0 to 1 mol of the compound (LI).
To 20 mol, preferably about 1.0 to 10 mol, in the case of a metal hydride complex compound, about 1.0 mol per 1 mol of the compound (LI).
２０20 mol, preferably about 1.0-10 mol. This reaction is advantageously performed using a solvent inert to the reaction. The solvent is not particularly limited as long as the reaction proceeds, for example, alcohols such as methanol, ethanol and propanol, diethyl ether, tetrahydrofuran, dioxane, ethers such as 1,2-dimethoxyethane, benzene, toluene, cyclohexane and the like. Hydrocarbons, N, N-dimethylformamide,
Amides such as N, N-dimethylacetamide, formic acid,
Solvents such as organic acids such as acetic acid or a mixed solvent thereof are preferred. The reaction time varies depending on the activity and amount of the reagent used, but is usually 5 minutes to 100 hours, preferably 5 minutes to 50 hours. The reaction temperature is usually -78 ° C to 1
The temperature is 20C, preferably -78C to 50C. The product (LII) can be used in the next reaction as a reaction solution or as a crude product. Can be purified.

Compound (Ia) is compound (LII) (eg, L
Is a hydroxy compound), converted to a sulfonate compound or a halide, and then subjected to a ring closure reaction. The sulfonate compound is obtained by reacting the compound (LII) with a corresponding sulfonyl chloride compound (for example, benzenesulfonyl chloride, toluenesulfonyl chloride, alkylsulfonyl chloride having 1 to 4 carbon atoms, such as methanesulfonyl chloride) in the presence of a base. It is manufactured by The sulfonyl chloride compound is used in an amount of about 1.0-10.0 mol, preferably about 1.0-1.5 mol, per 1 mol of compound (LII). As the base,
For example, sodium carbonate, potassium carbonate, basic salts such as sodium bicarbonate, pyridine, aromatic amines such as lutidine, triethylamine, tripropylamine,
Tributylamine, cyclohexyldimethylamine, 4
-Dimethylaminopyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N
Tertiary amines such as methyl morpholine, alkali metal hydrides such as sodium hydride and potassium hydride, metal amides such as sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide, sodium methoxide, sodium Metal alkoxides such as ethoxide and potassium tert-butoxide; About 1 mol of the base is used per 1 mol of the compound (LII).
0 to 50.0 mol, preferably about 1.0 to 20 mol is used. This reaction is advantageously performed using a solvent inert to the reaction. The solvent is not particularly limited as long as the reaction proceeds, for example, diethyl ether, tetrahydrofuran, dioxane, ethers such as 1,2-dimethoxyethane, benzene, toluene, cyclohexane,
Hydrocarbons such as hexane, amides such as N, N-dimethylformamide and N, N-dimethylacetamide;
Dichloromethane, chloroform, carbon tetrachloride, 1,2-
Solvents such as halogenated hydrocarbons such as dichloroethane, nitriles such as acetonitrile and propionitrile, sulfoxides such as dimethyl sulfoxide, and a mixed solvent thereof are preferable. Reaction time is usually 10
Minutes to 6 hours, preferably 10 minutes to 2 hours. The reaction temperature is usually -78 to 150C, preferably -30 to 30C.
It is. The obtained sulfonate compound can be used in the next reaction as a reaction solution or as a crude product, but can also be isolated from the reaction mixture according to a conventional method, and can be easily separated by separation means such as recrystallization, distillation, and chromatography. Can be purified.

The halide is a compound (LII) and a halogenating agent (for example, phosphorus halide such as phosphorus trichloride, phosphorus oxychloride, phosphorus pentachloride, phosphorus tribromide, halogen,
And thionyl chloride). About 1 mole of the halogenating agent is used per 1 mol of the compound (LII).
0 to 100 mol, preferably about 1.0 to 10 mol is used. This reaction is advantageously performed without a solvent or with an inert solvent. The solvent is not particularly limited as long as the reaction proceeds. Examples thereof include ethers such as diethyl ether, tetrahydrofuran, dioxane, and 1,2-dimethoxyethane; hydrocarbons such as benzene, toluene, cyclohexane, and hexane; Amides such as -dimethylformamide and N, N-dimethylacetamide; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane; nitriles such as acetonitrile and propionitrile; dimethylsulfoxide and the like. Solvents such as sulfoxides or mixed solvents thereof are preferred. The reaction time is generally 10 minutes to 24 hours, preferably 30 minutes to 12 hours.
Time. The reaction temperature is generally 0-200 ° C, preferably 10-100 ° C. The obtained halide can be used in the next reaction as a reaction solution or as a crude product, but can also be isolated from the reaction mixture according to a conventional method,
It can be easily purified by separation means such as recrystallization, distillation and chromatography.

Compound (Ia) is produced by subjecting the thus obtained sulfonate compound or halide to a ring-closing reaction in the presence of a base. Examples of the base include inorganic bases such as sodium hydroxide and potassium hydroxide, basic salts such as sodium acid, potassium carbonate, cesium carbonate and sodium hydrogen carbonate, pyridine,
Aromatic amines such as lutidine, triethylamine, tripropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N, N
Tertiary amines such as dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, alkali metal hydrides such as sodium hydride and potassium hydride, sodium amide, lithium diisopropylamide, lithium hexane Metal amides such as methyldisilazide, and metal alkoxides such as sodium methoxide, sodium ethoxide, and potassium tert-butoxide. The base is used in an amount of about 1.0 to 50 mol, preferably about 1.0 to 10 mol, per 1 mol of the sulfonate compound or the halide. This reaction is advantageously performed using a solvent inert to the reaction. Although not particularly limited as long as the reaction proceeds as such a solvent, for example, methanol, ethanol, alcohols such as propanol, diethyl ether, tetrahydrofuran, dioxane, ethers such as 1,2-dimethoxyethane,
Hydrocarbons such as benzene, toluene, cyclohexane, hexane, N, N-dimethylformamide, N, N-
Amides such as dimethylacetamide, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane, nitriles such as acetonitrile and propionitrile, esters such as ethyl acetate, and sulfoxides such as dimethylsulfoxide Kind,
A solvent such as water or a mixed solvent thereof is preferable. The reaction time is generally 10 minutes to 6 hours, preferably 10 minutes to 2 hours. The reaction temperature is generally 0-250 ° C, preferably 10-120 ° C. The product (Ia) can be isolated from the reaction mixture according to a conventional method, and can be easily purified by separation means such as recrystallization, distillation, and chromatography.

(Reaction 7)

Embedded image Compound (LIII) can be prepared by a method known per se, for example, a journal
Of the Chemical Society (J. Chem. Soc.), 5
48 (1927), Tetrahedron, 25
Volume, 5475 (1969), 34, 1435 (1978), 39, 28
The compound can be produced according to the method described in page 03 (1983), Canadian Journal of Chemistry (Can. J. Chem.), Vol. 57, page 1598 (1979), or a method analogous thereto. Compound (LIV) is compound (XVI
It is produced by removing the hydroxyl-protecting group of compound (LIII) in the same manner as in the production of compound (XVIII) from I). This deprotection reaction is performed based on a general known operation. For example, T. W. Green Protective
Groups in Organic Synthesis ”(2nd edition, 1991)
It can be carried out according to the method described in the chapter of “Protection for Phenols and Catechols”. Compound (Ib) is
It is produced by performing a ring-forming reaction on the diol moiety of the compound (LIV). The reaction is carried out based on a generally known operation. W. Green Protecti
ve Groups in Organic Synthesis ”(2nd edition, 1991
Year) "Protection for 1,2- and 1,3-diols" chapter, Synthesis, 839 (1986), Tetrahedron Letters, 32, 2461 (1991), 33, 4165 pages (1992), Journal of
Heterocyclic chemistry (J. Heterocyclic. C
hem.), 26, 193 (1989), or a method analogous thereto.

(Reaction 8)

Embedded image Compound (LV) is produced by nitrating compound (X). The nitration reaction is performed according to a method known per se, for example, a method described in Chapter 14 of New Experimental Chemistry Course Vol. be able to. Specifically, for example, (1) synthesis using a mixed acid obtained by combining nitric acid and sulfuric acid,
(2) Synthesis with acetyl nitrate, (3) Synthesis with nitric acid, (4) Synthesis with nitronium trifluoromethanesulfonate, or (5) Synthesis with a nitrate such as sodium nitrate or potassium nitrate and a mineral acid is used. Among them, a nitration reaction using a nitrate and a mineral acid is widely used. In this case, the nitrate is used in an amount of about 0.8 to 3.0 mol, preferably about 1.0 to 2.0 mol, per 1 mol of compound (X). Sulfuric acid is widely used as a mineral acid, and 10 to 2000% by weight of the compound (X) is used. This reaction is advantageously performed using a solvent inert to the reaction. The solvent is not particularly limited as long as the reaction proceeds, but usually a mineral acid of the catalyst is used also as the solvent. The reaction time is usually 5 minutes to 1
0 hours, preferably 10 minutes to 3 hours. The reaction temperature is usually -20 to 120C, preferably -10 to 20C. The product (LV) can be isolated from the reaction mixture according to a conventional method, and can be easily purified by separation means such as recrystallization, distillation, and chromatography.

Compound (LVII) can be prepared by reacting compound (LV) with a carbanion formed by treating acetonitrile with a base in the same manner as in the method for producing compound (XII) from compound (X). (LVI) and then subjected to a dehydration reaction. Compound (LVII) can be obtained as a configuration isomer of E-form or Z-form alone or as a mixture of E-form and Z-form. Acetonitrile is used in an amount of about 1.0 to 3.0 mol, preferably about 1.0 to 1.3 mol, per 1 mol of compound (LV). As the base, for example, sodium hydride, alkali metal hydrides such as potassium hydride, sodium amide, lithium diisopropylamide, metal amides such as lithium hexamethyldisilazide, sodium methoxide, sodium ethoxide,
Metal alkoxides such as potassium tert-butoxide and the like can be used. The amount of the base to be used is about 1.0-5.0 mol, preferably about 1.0-5.0 mol, per 1 mol of compound (LV).
1.5 mol. This reaction is advantageously performed using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds. For example, alcohols such as methanol, ethanol, and propanol, diethyl ether, tetrahydrofuran, dioxane, and 1,2-
Ethers such as dimethoxyethane, hydrocarbons such as benzene, toluene, cyclohexane and hexane;
Amides such as N-dimethylformamide, N, N-dimethylacetamide, dichloromethane, chloroform,
Solvents such as halogenated hydrocarbons such as carbon tetrachloride and 1,2-dichloroethane, and mixed solvents thereof are preferable. The reaction time is generally 30 minutes to 48 hours, preferably 30 minutes to 5 hours. The reaction temperature is usually -78 to 10
0 ° C, preferably -78 to 50 ° C. The product can be used in the next reaction as a reaction solution or as a crude product, but can also be isolated from the reaction mixture according to a conventional method,
It can be easily purified by separation means such as recrystallization, distillation and chromatography.

The catalyst used in the dehydration reaction includes, for example, hydrochloric acid, sulfuric acid, phosphoric acid, potassium hydrogen sulfate, oxalic acid,
Examples thereof include acidic catalysts such as p-toluenesulfonic acid, 10-camphorsulfonic acid, and boron trifluoride ether complex; and basic catalysts such as sodium hydroxide and potassium hydroxide. Dehydrating agent, alumina, sodium dioxide, phosphorus oxychloride, thionyl chloride, methanesulfonyl chloride, and the like. This reaction is advantageously carried out without a solvent or using a solvent inert to the reaction.
Although not particularly limited as long as the reaction proceeds as such a solvent, for example, methanol, ethanol, alcohols such as propanol, diethyl ether, tetrahydrofuran, dioxane, ethers such as 1,2-dimethoxyethane, benzene, toluene, cyclohexane, Solvents such as hydrocarbons such as hexane, amides such as N, N-dimethylformamide and N, N-dimethylacetamide, sulfoxides such as dimethylsulfoxide, and a mixed solvent thereof are preferable. The reaction time is generally 30 minutes to 24 hours, preferably 30 minutes to 5 hours. The reaction temperature is generally 0-200 ° C, preferably 0-15.
0 ° C.

Compound (LVII) is obtained by reacting compound (LV) with a phosphonate carbanion formed by base treatment of alkyl phosphonic acid diester in the same manner as in the method for producing compound (XII) from compound (X). Let me
It can also be obtained as an E- or Z-configuration isomer alone or as a mixture of E and Z-isomers. As the alkyl phosphonic acid diester, for example, diethyl cyanomethyl phosphonate or the like is used. About 1.0 to 3.0 mol of alkylphosphonic acid diester per 1 mol of compound (LV),
Preferably, about 1.0 to 1.5 mol is used. Examples of the base include alkali metal hydrides such as sodium hydride and potassium hydride, metal amides such as sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide, sodium methoxide, sodium ethoxide, and potassium tertiary salt. Metal alkoxides such as butoxide are exemplified, and the amount of the base to be used is about 1.0-5.0 mol, preferably about 1.0-1.5 mol, per 1 mol of compound (LV). This reaction is advantageously performed using a solvent inert to the reaction. Although not particularly limited as long as the reaction proceeds as such a solvent, for example, methanol, ethanol, alcohols such as propanol, diethyl ether, tetrahydrofuran, dioxane, ethers such as 1,2-dimethoxyethane,
Hydrocarbons such as benzene, toluene, cyclohexane, hexane, N, N-dimethylformamide, N, N-
Solvents such as amides such as dimethylacetamide, sulfoxides such as dimethylsulfoxide, and mixed solvents thereof are preferable. The reaction time is usually 1 hour to 5 hours.
0 hour, preferably 1 hour to 10 hours. The reaction temperature is usually -78 to 200C, preferably 0 to 150C. The isomer mixture of compound (LVII) can be used as a reaction solution or as a crude product in the next reaction, but can also be isolated from the reaction mixture according to a conventional method, and can be separated by recrystallization, distillation, chromatography, or the like. It can be easily purified by means.

When extending the carbon chain of the side chain of the compound (LVII), the reaction may be carried out according to a known carbon chain extension reaction. Alternatively, if necessary, the carboxyl group is converted into an ester form, then subjected to a reduction reaction to form an alcohol form, and then a reaction through halogenation and cyanation is employed. Compound (LVIII) is described in (LXI
It is prepared from compound (LVII) by using the method used for the reduction of the nitro group of I) and the reduction method using Raney nickel. Examples of the reducing agent used include metal hydrides such as aluminum hydride and diisobutylaluminum hydride, metal hydrogen complex compounds such as lithium aluminum hydride and sodium borohydride, and hydrogenation catalysts used. For example, a catalyst such as Raney nickel and Raney cobalt, or a method combining them is used. The amount of the reducing agent used is, for example, in the case of a metal hydride, about 1.0 to 1 with respect to 1 mol of the compound (LVII).
0 mol, preferably about 1.0 to 3.0 mol, and the amount of the metal hydride complex compound to be used is about 1.0 to 10 mol, preferably about 1.0 to 3.0 mol, per 1 mol of compound (LVII). 0 moles,
In the case of hydrogenation, the amount of the catalyst such as Raney nickel and Raney cobalt is about 10 to 100 relative to the compound (LVII).
0% by weight, preferably about 80-300% by weight. This reaction is advantageously performed using a solvent inert to the reaction. The solvent is not particularly limited as long as the reaction proceeds, for example, alcohols such as methanol, ethanol and propanol, diethyl ether, tetrahydrofuran, dioxane, ethers such as 1,2-dimethoxyethane, benzene, toluene, cyclohexane and the like. Hydrocarbons, N, N-dimethylformamide,
Amides such as N, N-dimethylacetamide, formic acid,
Solvents such as organic acids such as acetic acid or a mixed solvent thereof are preferred. When a Raney nickel or Raney cobalt catalyst is used, amines such as ammonia may be further added to suppress side reactions. The reaction time varies depending on the activity and amount of the reagent to be used, but is usually 1 hour to 1 hour.
00 hours, preferably 1 hour to 50 hours. The reaction temperature is generally 0-120 ° C, preferably 20-80 ° C. When a catalyst such as Raney nickel or Raney cobalt is used, the pressure of hydrogen is usually 1 to 100 atm. The product (LVIII) can be used as a reaction solution or as a crude product in the next reaction, but it can also be isolated from the reaction mixture according to a conventional method, and can be easily separated by separation means such as recrystallization, distillation, or chromatography. Can be purified.

Among the compounds (LIX), the compound in which m = 1 is
Compound (LV) is treated with trimethylsilyl cyanide in the presence of a Lewis acid in the same manner as in the method for producing compound (XVI) from compound (X), and the resulting trimethylsilyloxy group is eliminated with an acid. It is produced by reducing a cyano group and a double bond portion and acylating the obtained amine compound. Examples of the Lewis acid used in the first step include zinc iodide, anhydrous aluminum chloride, anhydrous zinc chloride, anhydrous iron chloride and the like. These Lewis acid catalysts are used in an amount of about 0.01 to 1 mole of compound (LV).
10 to 10 mol, preferably about 0.01 to 1.0 mol. This reaction is advantageously carried out without a solvent or using a solvent inert to the reaction. The solvent is not particularly limited as long as the reaction proceeds, for example, diethyl ether, tetrahydrofuran, dioxane, ethers such as 1,2-dimethoxyethane, benzene, toluene,
Solvents such as hydrocarbons such as cyclohexane and hexane, and mixed solvents thereof are preferable. The reaction time is generally 10 minutes to 12 hours, preferably 30 minutes to 3 hours. The reaction temperature is usually -10 to 200C, preferably -1.
0-100 ° C. The product can be used as a reaction solution or as a crude product in the next reaction, but can also be isolated from the reaction mixture according to a conventional method, and is easily purified by separation means such as recrystallization, distillation, and chromatography. be able to. Examples of the acid used for the subsequent elimination of the trimethylsilyloxy group include inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, acetic acid, trifluoroacetic acid, oxalic acid, phthalic acid, fumaric acid, and tartaric acid , Maleic acid, citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid, organic acids such as 10-camphorsulfonic acid, and boron trifluoride ether complex.
The amount of the acid to be used is about 1-100 based on 1 mol of compound (LV).
Mol, preferably about 1 to 10 mol. This reaction is advantageously carried out without a solvent or using a solvent inert to the reaction. The solvent is not particularly limited as long as the reaction proceeds, for example, diethyl ether, tetrahydrofuran, dioxane, ethers such as 1,2-dimethoxyethane, benzene, toluene, cyclohexane,
Hydrocarbons such as hexane, amides such as N, N-dimethylformamide and N, N-dimethylacetamide;
Solvents such as sulfoxides such as dimethyl sulfoxide or a mixed solvent thereof are preferable. The reaction time is generally 30 minutes to 12 hours, preferably 30 minutes to 5 hours. The reaction temperature is generally 0-200 ° C, preferably 20-1.
50 ° C. Reduction of the cyano group and the double bond moiety
The same can be carried out under the conditions used for producing compound (XV) from compound (XII). The acylation in the next step can be performed in the same manner under the conditions used for producing compound (XVII) from compound (XVI). Product (LI
X) can be used in the next reaction as a reaction solution or as a crude product, but can also be isolated from the reaction mixture according to a conventional method, and easily purified by a separation means such as recrystallization, distillation, or chromatography. be able to.

Acylation of a compound of m = 2 or 3 among the compounds (LIX) is carried out by converting the compound (XVI) to the compound (XVII)
Can be carried out under the conditions used in the production of The product (LIX) can be used in the next reaction as a reaction solution or as a crude product, but can also be isolated from the reaction mixture according to a conventional method, and can be easily separated by separation means such as recrystallization, distillation, and chromatography. Can be purified. Compound (Ic) after deprotection of the R ⁷ is a protective group of a phenolic hydroxyl group of compound (LIX), is made by forming an oxazole ring subjected to cyclization reaction. Deprotection is
Usually, the reaction is carried out in the presence of an acid catalyst. Examples of such an acid include Lewis acids such as boron tribromide and anhydrous aluminum chloride, and mineral acids such as hydrochloric acid and hydrobromic acid. The amount of these acids to be used is about 0.1-10 per 1 mol of compound (LIX).
0 mol, preferably about 1 to 10 mol. This reaction is advantageously carried out without a solvent or using a solvent inert to the reaction. Although not particularly limited as long as the reaction proceeds as such a solvent, for example, dichloroethane, chloroform, carbon tetrachloride, halogenated hydrocarbons such as 1,2-dichloroethane, benzene, toluene, cyclohexane, hydrocarbons such as hexane, Preferred are amides such as N, N-dimethylformamide and N, N-dimethylacetamide, sulfoxides such as dimethylsulfoxide, solvents such as water, and mixed solvents thereof. The reaction time is usually 30 minutes to 12 hours, preferably 30 minutes to 5 hours.
Time. The reaction temperature is usually -10 to 120C, preferably 0 to 80C. The product can be used as a reaction solution or as a crude product in the next reaction, but can also be isolated from the reaction mixture according to a conventional method, and is easily purified by separation means such as recrystallization, distillation, and chromatography. be able to. The cyclization reaction is carried out by a method known per se, for example, Synthetic Communication (Synth.Commun.), 16
Volume, p. 365 (1986), Organic Preparation
Proceeding International (Org. Prep. Pr.
oc. Int.), Vol. 22, p. 613 (1990), etc.
Alternatively, it can be performed according to a method according to these.

Further, when R ² in the compound (Ic) is an alkyl group, after the above-mentioned cyclization reaction, a corresponding alkylating agent (for example, alkyl halide, sulfonic acid ester of alcohol, etc.) is used. The alkylation reaction is performed in the presence of a base. The alkylating agent is used in an amount of about 1.0-5.0 mol, preferably about 1.0-2.0 mol, per 1 mol of compound (Ic). Examples of the base include inorganic bases such as sodium hydroxide and potassium hydroxide, basic salts such as sodium carbonate, potassium carbonate and sodium hydrogencarbonate, aromatic amines such as pyridine and lutidine, triethylamine, tripropylamine, and triethylamine. Butylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine,
N, N-dimethylaniline, N-methylpiperidine, N
Tertiary compounds such as -methylpyrrolidine and N-methylmorpholine
Primary amines, alkali metal hydrides such as sodium hydride and potassium hydride, metal amides such as sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide, sodium methoxide, sodium ethoxide, potassium tert-butoxide And other metal alkoxides. The base is added in an amount of about 1.0-5.0 mol, preferably about 1.0 mol, per 1 mol of compound (Ic).
Use up to 2.0 moles. This reaction is advantageously performed using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds, for example, methanol,
Alcohols such as ethanol and propanol, diethyl ether, tetrahydrofuran, dioxane, 1,2
Ethers such as dimethoxyethane, hydrocarbons such as benzene, toluene, cyclohexane and hexane;
Amides such as N, N-dimethylformamide and N, N-dimethylacetamide; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane; nitriles such as acetonitrile and propionitrile; dimethyl Solvents such as sulfoxides such as sulfoxide or a mixed solvent thereof are preferable. The reaction time is usually 30 minutes to 48 hours, preferably 3 minutes.
0 minutes to 6 hours. The reaction temperature is usually -20 to 200.
° C, preferably -10 to 150 ° C. Product (Ic)
Can be isolated from the reaction mixture according to a conventional method, and can be easily purified by separation means such as recrystallization, distillation, and chromatography.

(Reaction 9)

Embedded image Compound (LXI) is produced from compound (LX) by the same operation as that for producing compound (LV) from compound (X). Compound (LXII) is converted to the corresponding α by the same operation as that for producing compound (XX) from compound (XVIII).
-Compound (LX) by reaction with an alkyl agent such as a haloester
Manufactured from I). Compound (LXII) to compound (LXIII)
Is prepared by reducing or catalytically reducing the nitro group of compound (LXII) with a reducing agent and then cyclizing.
The reduction reaction is performed by a method known per se, for example, a new experimental chemistry course,
The method may be carried out according to the method described in Volume 15, Oxidation and Reduction (edited by The Chemical Society of Japan), or a method analogous thereto. For example, metals such as zinc, iron and tin, and metal halides such as tin (II) chloride A reduction method using a reducing agent such as sodium sulfide, sodium hydrosulfide, sodium dithionite, a sulfide such as ammonium sulfide, a metal hydride complex compound such as lithium aluminum hydride, or platinum,
A catalytic reduction method using a catalyst such as Raney nickel, Raney cobalt, platinum black, palladium carbon, and rhodium-alumina is used. The amount of the reducing agent used is, for example, in the case of a metal hydride complex compound, about 1.0 to 10 mol, preferably about 1.0 to 3.0 mol, per 1 mol of compound (LXII). The amount of the catalyst used is about 10 to the compound (LXII).
１０００1000% by weight, preferably about 80-300% by weight. This reaction is advantageously performed using a solvent inert to the reaction. The solvent is not particularly limited as long as the reaction proceeds, for example, alcohols such as methanol, ethanol and propanol, diethyl ether, tetrahydrofuran, dioxane, ethers such as 1,2-dimethoxyethane, benzene, toluene, cyclohexane and the like. And solvents such as amides such as hydrocarbons, N, N-dimethylformamide and N, N-dimethylacetamide, organic acids such as formic acid and acetic acid, and mixed solvents thereof. The reaction time varies depending on the activity and amount of the reagent used, but is usually 1 hour to 100 hours, preferably 1 hour to 50 hours. The reaction temperature is usually 0 to
120 ° C, preferably 20 to 80 ° C. When a catalyst such as palladium carbon, Raney nickel, Raney cobalt or the like is used, the pressure of hydrogen is usually 1 to 100 atm. The product can be used as a reaction solution or as a crude product in the next reaction, but can also be isolated from the reaction mixture according to a conventional method, and is easily purified by separation means such as recrystallization, distillation, and chromatography. be able to. The subsequent cyclization reaction is performed under heating or under a base catalyst. Examples of the base include metal alkoxides such as sodium methoxide, sodium ethoxide and potassium tert-butoxide; metal hydrides such as sodium hydride and potassium hydride; lithium reagents such as butyllithium and phenyllithium; methylmagnesium bromide; phenyl A Grignard reagent such as magnesium bromide is used, and the amount is usually 0.01 to 5 equivalents, preferably 0.05 to 0.5 equivalents. This reaction is advantageously performed using a solvent inert to the reaction. Although not particularly limited as long as the reaction proceeds as such a solvent, for example, methanol, ethanol, alcohols such as propanol, diethyl ether, tetrahydrofuran, dioxane, ethers such as 1,2-dimethoxyethane, benzene, toluene, cyclohexane, Hydrocarbons such as hexane, amides such as N, N-dimethylformamide, N, N-dimethylacetamide, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, acetonitrile, propio Solvents such as nitrites such as nitriles, sulfoxides such as dimethyl sulfoxide, and mixed solvents thereof are preferable. The reaction time is usually 30 minutes to 48 hours, preferably 30 minutes to 12 hours.
Time. The reaction temperature is usually -20 to 200C, preferably -10 to 150C. The product (LXIII) can be isolated from the reaction mixture by a conventional method,
It can be easily purified by separation means such as distillation and chromatography.

Compound (LXIV) is produced from compound (LXIII) by the same operation as that for producing compound (XII) from compound (X). When extending the carbon chain of the side chain of the compound (LXIV), the reaction may be performed according to a known carbon chain extension reaction. If necessary, the carboxyl group is converted into an ester, and then subjected to a reduction reaction to form an alcohol, followed by halogenation.
A reaction through cyanation is employed. Compound (LXV)
Is produced from compound (LXIV) by the same operation as that for producing compound (XV) from compound (XII).
(LXVI) is produced by subjecting (LXV) to a catalytic hydrogenation reaction. Compound (LXVI) can also be obtained directly from compound (LXIV) by further increasing the reaction conditions when producing (LXV) from (LXIV) (eg, increasing the temperature, increasing the reaction time, etc.). it can. Compound (LXVII) is produced by reducing the amide moiety of compound (LXVI). As the reducing agent, a metal hydride complex compound (such as lithium aluminum hydride) is used. Usually, ether solvents such as diethyl ether and tetrahydrofuran, or a mixture of ethers and an inert solvent (eg, hexane, cyclohexane, etc.) are used as the solvent. The reducing agent used for the reaction is usually 1 to
30 equivalents, preferably 3 to 10 equivalents. The reaction temperature is -20 to 150C, preferably 10 to 100C.
The product (LXVII) can be isolated from the reaction mixture according to a conventional method, and can be easily purified by separation means such as recrystallization, distillation, and chromatography. Compounds (Id) and (Ie) are converted from compound (XVI) to compound (XVI
It is produced from compound (LXVI) and compound (LXVII) by the same operation as that for producing I).

(Reaction 10)

Embedded image Compound (LXVIII) can be produced by a known method, or for example, commercially available serotonin or a salt thereof can be used. Compound (LXIX) is obtained by converting compound (XVI) to compound (X
VII), the compound (LXV
III). Compound (LXX) is compound (XVII)
It is produced from compound (LXIX) by the same operation as that for producing compound (L) from I). Compound (LXXI)
Is produced from compound (LXX) by the same operation as that for producing compound (LI) from compound (L).

Compound (LXXII) is produced by subjecting compound (LXXI) to a reduction reaction, followed by formylation. As the reducing agent, metal hydrogen complex compounds such as sodium cyanoborohydride are widely used. Usually, as the solvent, for example, organic acids such as acetic acid and propionic acid and a mixed solvent thereof with an inert solvent (eg, ethers such as diethyl ether and tetrahydrofuran, and hydrocarbons such as hexane and cyclohexane) are used.
The reducing agent used in the reaction is usually 1 to 30 equivalents, preferably 3 to 10 equivalents. Reaction temperature is -20 to 100
° C, preferably from 0 to 80 ° C. Reaction time is usually 3
0 minutes to 12 hours, preferably 30 minutes to 3 hours. The subsequent formylation reaction is carried out by a method known per se, for example, Protective Groups in Organic Synthesis using TW Green.
nthesis "(2nd edition, 1991)," Protection for the
Amino Group ”section. The product (LXXII) can be isolated from the reaction mixture according to a conventional method, and can be easily purified by separation means such as recrystallization, distillation, and chromatography.

Compound (LXXIII) is produced from compound (LXXII) by the same operation as that for producing compound (LII) from compound (LI). Compound (LXXIV) is produced from compound (LXXIII) by the same operation as that for producing compound (Ia) from compound (LII). Compound (LXXIV) can be prepared by subjecting compound (LXXII) to a known method, for example, an acid catalyst (eg, hydrochloric acid, sulfuric acid, boron trifluoride diethyl ether complex, etc.), an organic peracid (eg, m-chloroperbenzoic acid, etc.) , And halogen (eg, iodine, bromine, etc.). Compound (If)
Is produced by removing the formyl group of the compound (LXXIV) with an acid catalyst or a base catalyst. The reaction is performed by a method known per se, for example, Protective Groups in Organic Synthesis (2) by TW Green.
Edition, 1991), "Protection for the Amino Grou
The method may be performed according to the method described in the chapter “p” or the like. If desired, the desired product may be obtained by alkylation or oxidation of indoline to indole.

The compounds (XII), (XV) and (XXXI)
For the configuration isomers (E, Z) of (V), (XXXV), (LVII), (LXIV) or (LXV), when isomerization occurs, for example, extraction, recrystallization, distillation, chromatography, etc. It can be isolated and purified by ordinary separation means,
Pure compounds can be prepared. Heating, acid catalysis, and transition metal are performed according to the method described in New Experimental Chemistry Course 14 (edited by the Chemical Society of Japan), pages 251-253, and the fourth edition of Experimental Chemistry Lecture 19 (edited by the Chemical Society of Japan), pages 273-274 and a method analogous thereto. The double bond isomerization can be advanced by a complex, a metal catalyst, a radical species catalyst, light irradiation or a strong base catalyst to obtain a corresponding pure isomer. The compound (I) produces a stereoisomer depending on the kind of the substituent, but not only this isomer alone but also a mixture thereof is included in the present invention. In the above reaction step, if desired, a known deprotection reaction, acylation reaction, alkylation reaction, hydrogenation reaction, oxidation reaction, reduction reaction, carbon chain extension reaction, and substituent exchange reaction may be used alone or in combination with each other. Compound (I) can also be synthesized by combining the above. These reactions are described in, for example, “New Experimental Chemistry Course Vol.
It may be performed according to the method described in “Year issue”.

In each of the above-mentioned reactions of the present invention and each of the reactions for synthesizing the starting material, when the starting compound has an amino group, a carboxyl group, or a hydroxy group as a substituent, these groups may be generally used in peptide chemistry or the like. Such a protecting group may be introduced, and the target compound can be obtained by removing the protecting group as necessary after the reaction. Examples of the amino-protecting group include a formyl group,
A C _1-6 alkyl-carbonyl group (eg, acetyl, propionyl, etc.), a C _1-6 alkyloxycarbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, etc.), a C _6-10 arylcarbonyl group (eg, benzoyl, etc.), C _7-11 aralkyl-carbonyl group (eg, benzylcarbonyl, etc.), trityl group, phthaloyl group, N, N
A dimethylaminomethylene group or the like is used. These groups may be substituted with 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.), nitro groups and the like. Examples of the carboxyl protecting group include, for example, C
_{A 1-6} alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.), a C _6-10 aryl group (eg, phenyl, etc.), a trityl group, a silyl group and the like are used. These groups include one to three halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.), a formyl group, a C _1-6 alkyl-carbonyl group (eg, acetyl,
Propionyl, butylcarbonyl, etc.), nitro group and the like. Examples of the hydroxy-protecting group include a C _1-6 alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.),
C _6-10 aryl group (eg, phenyl, etc.), C _7-11 aralkyl group (eg, benzyl, etc.), C _1-6 alkyl-carbonyl group (eg, acetyl, propionyl, etc.), C _6-10 arylcarbonyl group (Eg, benzoyl group), C _7-11 aralkyl-carbonyl group (eg, benzylcarbonyl), tetrahydropyranyl group, tetrahydrofuranyl group, silyl group and the like are used. These groups include one to three halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.), a C _1-6 alkyl group (eg, methyl, ethyl, propyl, etc.), a C _6-10 aryl group (eg, , Phenyl and the like), a C _7-11 aralkyl group (eg, benzyl and the like), a nitro group and the like. As a method for removing these protecting groups, a method known per se or a method analogous thereto is used.For example, an acid, a base, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride,
A method using palladium acetate or the like, reduction and the like are used.

The compound (I) of the present invention can be isolated and purified by known means, for example, solvent extraction, liquid conversion, phase transfer, crystallization, recrystallization, chromatography and the like.
The raw material compound of the compound (I) of the present invention or a salt thereof can be isolated and purified by the same known means as described above, but can be used as a raw material in the next step as a reaction mixture without isolation. May be provided. When the compound (I) is purified by recrystallization, for example, water, alcohols (eg, methanol, ethanol, n-propanol, isopropanol, etc.), aromatic hydrocarbons (eg, benzene, toluene, xylene, etc.), halogens Hydrocarbons (eg, dichloromethane, chloroform, etc.), saturated hydrocarbons (eg, hexane, heptane, cyclohexane, etc.), ethers (eg, diethyl ether, isopropyl ether, tetrahydrofuran, dioxane, etc.), ketones (eg, Acetone, methyl ethyl ketone, etc.), nitriles (for example,
Acetonitrile, etc.), sulfoxides (eg, dimethyl sulfoxide), acid amides (eg, N, N
-Dimethylformamide, etc.), esters (e.g.,
Ethyl acetate, etc.), carboxylic acids (eg, acetic acid, propionic acid, etc.) and the like can be used, and these can be used alone or, if necessary, two or more of them in an appropriate ratio such as 1: 1. You may mix and use it by the ratio of 1:10. When the target product is obtained in a free state by the above reaction, it may be converted to a salt according to a conventional method, and when obtained as a salt, it may be converted to a free form or another salt according to a conventional method. Can also. The compound (I) thus obtained can be isolated and purified from the reaction solution by a known means such as phase transfer, concentration, solvent extraction, fractionation, crystallization, recrystallization, chromatography and the like. When the compound (I) exists as a configurational isomer (configuration isomer), a diastereomer, a conformer, or the like, each can be isolated by the above separation and purification means, if desired. When compound (I) is an optically active form, the racemic form can be separated into a + form and a − form by a usual optical resolution means.

Formula (i) obtained in the reaction step for obtaining compound (I)

Embedded image Wherein each symbol is as defined above or (ii)

Embedded image [Wherein each symbol has the same meaning as described above] or a salt thereof is a novel compound and can be used as a raw material of the compound of the present invention. Of these, preferred compounds include 2- (1,6-dihydro-2H-indeno [5,4-b] furan-8-yl) ethylamine,
(1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethylamine or a salt thereof.

The compound (I) of the present invention has a high affinity for the melatonin receptor, and the compound (I) is particularly useful for ML-
High selectivity for one receptor. Further, it is useful as a pharmaceutical because it has low toxicity and few side effects. The compound (I) of the present invention acts as a melatonin agonist or antagonist on mammals (eg, mice, rats, hamsters, rabbits, cats, dogs, cows, sheep, monkeys, humans, etc.), and acts as a melatonin receptor. Diseases that are useful as affinity compositions, particularly melatonin receptor agonistic compositions, and which may be affected by melatonin, such as dysregulation of biological rhythms, eg, sleep-wake rhythm disorders, jet lag, triple shift work Modulation of physical condition, seasonal depression, reproductive and neuroendocrine diseases, senile dementia, Alzheimer's disease, various disorders associated with aging (eg, aging prevention), cerebral circulation disorders (such as stroke), head trauma, bone marrow Damage, stress, epilepsy, convulsions, anxiety,
Can be used for the prevention and treatment of depression, Parkinson's disease, hypertension, glaucoma, cancer, insomnia, diabetes, etc., and is also effective for immunomodulation, cognition, mental stability or ovulation adjustment (eg, contraception) It is. The compound (I) of the present invention may be, for example, a biological rhythm regulator, preferably a therapeutic agent for sleep disorder (eg, a sleep inducer), a sleep-wake rhythm regulator (including a sleep-wake rhythm regulating action), a time zone change syndrome, It is used as a so-called jet lag treatment agent and the like.

The compound (I) of the present invention has low toxicity and is a pharmaceutical composition, for example, a tablet (including sugar-coated tablets and film-coated tablets) mixed with a pharmacologically acceptable carrier as it is or according to a method known per se. , Powders, granules,
Oral or parenteral (eg, topical, rectal, etc.) as capsules (including soft capsules), liquids, injections, suppositories, sustained-release preparations,
Intravenous administration, etc.). The content of the compound (I) in the preparation of the present invention is about 0.0
It is 1 to 100% by weight. The dose depends on the administration subject,
Depending on the administration route, disease, etc., for example, when administered as an oral agent to an adult as a therapeutic agent for sleep disorders, about 0.000 as compound (I) as an active ingredient
5 to 2 mg / kg body weight, preferably about 0.001 to 1 mg / kg body weight, more preferably about 0.001 to 0.5 mg / kg body weight, which can be administered once or several times a day. it can. Furthermore, other active ingredients (for example, benzodiazepines such as triazolam, diazepam, alprazolam and estazolam which are benzodiazepines, sleep rhythm regulators such as fatty acid derivatives butoctamide or salts thereof, cis-9,10-
Octadecenoamide, etc.). The other active ingredient and compound (I) are mixed according to a method known per se, and a pharmaceutical composition (for example, tablet,
Powders, granules, capsules (including soft capsules),
Liquid, injection, suppository, sustained release agent, etc.), or may be separately formulated and administered to the same subject simultaneously or with a time lag.

The pharmacologically acceptable carriers which may be used in the production of the preparation of the present invention include various organic or inorganic carrier substances commonly used as preparation materials, such as excipients for solid preparations, lubricants and the like. Agents, binders, disintegrants; solvents in liquid preparations, solubilizing agents, suspending agents, isotonic agents, buffers, soothing agents and the like. If necessary, ordinary additives such as preservatives, antioxidants, coloring agents, sweeteners, adsorbents, wetting agents and the like can also be used. Examples of the excipient include lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, light anhydrous silicic acid, and the like. As the lubricant, for example, magnesium stearate, calcium stearate, talc,
Colloidal silica and the like. Examples of the binder include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, sodium carboxymethylcellulose and the like. Disintegrators include, for example, starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, sodium carboxymethyl starch, L-hydroxypropyl cellulose and the like. Examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, olive oil and the like.

Examples of the solubilizer include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like. As a suspending agent, for example, stearyl triethanolamine,
Surfactants such as sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate; for example, polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxy And hydrophilic polymers such as propylcellulose. Examples of the tonicity agent include glucose, D-sorbitol, sodium chloride,
Glycerin, D-mannitol and the like can be mentioned. Examples of the buffer include buffers such as phosphate, acetate, carbonate, and citrate. Examples of the soothing agent include benzyl alcohol and the like. Examples of the preservative include paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.
Antioxidants include, for example, sulfites, ascorbic acid,
α-tocopherol and the like.

[0140]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention further includes the following reference examples,
The present invention will be described in detail with reference to Examples, Formulation Examples and Experimental Examples, which are merely examples, do not limit the present invention, and may be changed without departing from the scope of the present invention. The following reference examples, "room temperature" in the examples
Usually indicates about 10 ° C to 35 ° C. % Indicates weight percent unless otherwise specified. Abbreviations used in other texts have the following meanings. s: singlet d: doublet t: triplet q: quartet m: multiplet br: broad J: coupling constant Hz: hertz ( Hertz) CDCl ₃ : heavy chloroform d ₆ -DMSO: heavy dimethyl sulfoxide D ₂ O: heavy water NMR: proton nuclear magnetic resonance BINAP: 2,2'-bis (diphenylphosphino) -1,1'-bina
phthyl T-BINAP: 2,2'-bis [di (4-methylphenyl) phosphino]
-1,1'-binaphthyl DM-BINAP: 2,2'-bis [di (3,5-dimethylphenyl) phosph
ino] -1,1'-binaphthyl

[0141]

【Example】

Reference Example 1 2,3-dihydrobenzofuran-5-carbaldehyde 2,3-dihydrobenzofuran (10.0 g, 83.2
mmol) and dichloromethyl methyl ether (1
1.3 mL (0.125 mol) of dichloromethane (1
Titanium tetrachloride (28 mL) under ice-cooling
Was added dropwise. After the mixture was stirred for 1 hour under ice cooling, water was added. After the dichloromethane was concentrated under reduced pressure, the residue was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give the title compound (11.4 g, 92% yield). Oily. NMR (CDCl ₃ ) δ: 3.28 (2H, t, J = 8.8Hz), 4.70
(2H, t, J = 8.8Hz), 6.88 (1H, d, J = 8.4Hz), 7.67 (1H, d
d, J = 1.0Hz, 8.4Hz), 7.75 (1H, d, J = 1.0Hz), 9.83 (1H,
s).

Reference Example 2 Ethyl (E) -3- (2,3-dihydrobenzofuran-5-yl) -2-propenoate Triethyl phosphonoacetate (19.0 g, 84.6 mmol)
1) 60% solution in tetrahydrofuran (150 mL)
Sodium hydride (3.39 g, 84.6 mmol) was added under ice cooling, and the mixture was stirred for 20 minutes. To this,
3-dihydrobenzofuran-5-carbaldehyde (1
A solution of 1.4 g (76.9 mmol) in tetrahydrofuran (15 mL) was added dropwise, and the mixture was further stirred for 1 hour.
After water was added to the reaction solution, the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95: 5 to 9: 1) to give the title compound (14.7 g, 88% yield). Oily. NMR (CDCl ₃ ) δ: 1.33 (3H, t, J = 7.2 Hz), 3.23
(2H, t, J = 8.8Hz), 4.25 (2H, q, J = 7.2Hz), 4.63 (2H,
t, J = 8.8Hz), 6.28 (1H, d, J = 16.0Hz), 6.79 (1H, d, J =
8.4Hz), 7.31 (1H, d, J = 8.4Hz), 7.41 (1H, s), 7.64
(1H, d, J = 16.0Hz).

Reference Example 3 Ethyl 3- (2,3-dihydrobenzofuran-5-yl) propionate Ethyl (E) -3- (2,3-dihydrobenzofuran-5-yl) -2-propenoate (14. 7g, 66.7m
mol) of ethanol (150 mL) was added 5% palladium on carbon (1 g, 50% water-containing product), and the mixture was stirred under a hydrogen atmosphere at room temperature for 2 hours. After the reaction solution was filtered, the solution was concentrated under reduced pressure to give the title compound (yield 14.6).
g, yield 99%). Oily. NMR (CDCl ₃ ) δ: 1.24 (3H, t, J = 7.2 Hz), 2.57
(2H, t, J = 7.8Hz), 2.88 (2H, t, J = 7.8Hz), 3.18 (2H,
t, J = 8.6Hz), 4.13 (2H, q, J = 7.2Hz), 4.55 (2H, t, J = 8.
6Hz), 6.70 (1H, d, J = 8.2Hz), 6.94 (1H, d, J = 8.2H)
z), 7.05 (1H, s). The obtained title compound was used for the next reaction without further purification.

Reference Example 4 Ethyl 3- (7-bromo-2,3-dihydrobenzofuran-5-yl) propionate Ethyl 3- (2,3-dihydrobenzofuran-5-yl) propionate (14.5 g, 65 .8 mmol) and sodium acetate (5.94 g, 72.4 mmol) in acetic acid (150 mL) were added to bromine (10.5 g, 65.8).
mmol) was added dropwise and the mixture was stirred at room temperature for 1 hour. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. Water was added to the residue and extracted with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous magnesium sulfate.
Concentration under reduced pressure gave the title compound (19.2 g, 97% yield). Oily. NMR (CDCl ₃ ) δ: 1.25 (3H, t, J = 7.2 Hz), 2.57
(2H, t, J = 7.6Hz), 2.85 (2H, t, J = 7.6Hz), 3.28 (2H,
t, J = 8.8Hz), 4.13 (2H, q, J = 7.2Hz), 4.65 (2H, t, J = 8.
8Hz), 6.97 (1H, s), 7.11 (1H, s). The obtained title compound was used for the next reaction without further purification.

Reference Example 5 3- (7-bromo-2,3-dihydrobenzofuran-5-yl) propionic acid 3- (7-bromo-2,3-dihydrobenzofuran-5
-Yl) ethyl propionate (19.1 g, 63.8 m)
mol) in a solution of sodium hydroxide (15 g) in tetrahydrofuran (20 mL).
The mixture was stirred at room temperature for 3 hours. The reaction solution was acidified by adding hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate / hexane to give the title compound (12.8 g, 73% yield). 117-118 ° C. NMR (CDCl ₃ ) δ: 2.64 (2H, t, J = 7.4 Hz), 2.87
(2H, t, J = 7.4Hz), 3.82 (2H, t, J = 8.8Hz), 4.65 (2H,
t, J = 8.8Hz), 6.97 (1H, s), 7.11 (1H, s), 1H are hidden and invisible.

Reference Example 6 4-bromo-1,2,6,7-
Tetrahydro-8H-indeno [5,4-b] furan-
8-one 3- (7-bromo-2,3-dihydrobenzofuran-5
-Yl) propionic acid (12.7 g, 46.2 mmol)
l) to thionyl chloride (10.1 mL, 0.139 mol)
1) was added, and the mixture was stirred at 75 ° C. for 30 minutes, and then the reaction solution was concentrated under reduced pressure to obtain an acid chloride. Anhydrous aluminum chloride (6.77 g, 50.8 mmol) in 1,
The acid chloride prepared above was added dropwise to a suspension of 2-dichloroethane (100 mL) under ice-cooling, and the mixture was stirred for 30 minutes. After the reaction solution was poured into water, it was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate =
8: 2), followed by recrystallization from ethyl acetate / isopropyl ether to give the title compound (1.00 g, 9% yield). 149-150 ° C. NMR (CDCl ₃ ) δ: 2.64-2.72 (2H, m), 3.08 (2
H, t, J = 5.8Hz), 3.57 (2H, t, J = 9.0Hz), 4.76 (2H, t, J =
9.0Hz), 7.41-7.43 (1H, m).

Reference Example 7 (E)-(4-bromo-1,
6,7,8-tetrahydro-2H-indeno [5,4-
b] Furan-8-ylidene) acetonitrile diethyl cyanomethylphosphonate (0.77 g, 4.3
5 mmol) in a solution of tetrahydrofuran (20 mL) in 60% sodium hydride (0.17 g, 4.35 mmol).
l) was added under ice cooling and the mixture was stirred for 20 minutes. To this, 4-bromo-1,2,6,7-tetrahydro-8H-
Indeno [5,4-b] furan-8-one (1.00
g, 3.95 mmol) in tetrahydrofuran (10 m
L) The solution was added and the mixture was further stirred at room temperature for 2 hours. Water was added to the reaction solution, which was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 85: 15 to 8: 2) and recrystallized from ethyl acetate / isopropyl ether to give the title compound (0.47 g, 43% yield). Was. 200-203 ° C. NMR (CDCl ₃ ) δ: 3.02-3.18 (4H, m), 3.41 (2
H, t, J = 8.8Hz), 4.77 (2H, t, J = 8.8Hz), 5.42-5.46 (1
H, m), 7.31 (1H, s).

Reference Example 8 3- (3-fluoro-4-methoxyphenyl) propionic acid 3-fluoro-4-methoxybenzaldehyde (10.
Malonic acid (7.5 g, 72.1 mmol) and piperidine (0.84 g, 9.83 mmol) were added to a solution of 1 g (65.5 mmol) in pyridine (20 mL), and the mixture was heated and stirred at 120 ° C. for 7 hours. After the reaction solution was poured into ice water, the precipitated powder was collected by filtration. After drying, the powder was dissolved in acetic acid (300 mL) without further purification, 5% palladium on carbon (3 g, 50% water-containing product) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. After filtering the reaction solution, the solution was concentrated under reduced pressure to obtain the title compound (8.54 g, yield 66%). 114-117 ° C. NMR (CDCl ₃ ) δ: 2.65 (2H, t, J = 7.5 Hz), 2.89
(2H, t, J = 7.5Hz), 3.87 (3H, s), 6.80-7.00 (3H,
m), 1H is hidden and invisible.

Reference Example 9 5-fluoro-6-methoxy-
1-Indanone In the same manner as in Reference Example 6, 3- (3-fluoro-4
The title compound was obtained from (-methoxyphenyl) propionic acid (yield 91%). 152-153 ° C (recrystallized from methanol / ethyl acetate). NMR (CDCl ₃ ) δ: 2.71 (2H, t, J = 5.7 Hz), 3.08
(2H, t, J = 5.7Hz), 3.92 (3H, s), 7.17 (1H, d, J = 10.3H)
z), 7.29 (1H, d, J = 8.1Hz). Elemental analysis: C ₁₀ H ₉ FO ₂ Calculated: C, 66.66; H, 5.03. Found: C, 66.82; H, 5.06.

Reference Example 10 (E)-(5-Fluoro-6
-Methoxyindane-1-ylidene) acetonitrile In the same manner as in Reference Example 7, the title compound was obtained from 5-fluoro-6-methoxy-1-indanone and diethyl cyanomethylphosphonate (yield 75%). 197-199 ° C (recrystallized from hexane / ethyl acetate). NMR (CDCl ₃ ) δ: 3.00-3.19 (4H, m), 3.92 (3
H, s), 5.53 (1H, t, J = 2.2Hz), 7.02 (1H, d, J = 7.6H)
z), 7.07 (1H, d, J = 10.3Hz). Elemental analysis: C ₁₂ H ₁₀ FNO Calculated: C, 70.93; H, 4.96; N, 6.89. Found: C, 70.65; H, 5.13; N, 6.99.

Reference Example 11 2- (5-Fluoro-6-methoxyindan-1-yl) ethylamine By the same method as in Example 18 described later, (E)-(5-
The title compound was obtained from fluoro-6-methoxyindane-1-ylidene) acetonitrile (88% yield). Oily. NMR (CDCl ₃ ) δ: 1.50-1.80 (2H, m), 1.90-2.
08 (1H, m), 2.20-2.40 (1H, m), 2.67-2.90 (4H, m),
3.00-3.20 (1H, m), 3.87 (3H, s), 6.80 (1H, d, J = 8.1H
z), 6.92 (1H, d, J = 11.0Hz) and 2H are hidden and invisible.

Reference Example 12 N- [2- (5-fluoro-
6-Methoxyindan-1-yl) ethyl] propionamide 2- (5-fluoro-6-methoxyindan-1-yl) ethylamine (4.35 g, 20.8 mmol) and triethylamine (4.21 g, 41.6 mmol)
To a solution of 1) in tetrahydrofuran (20 mL), propionyl chloride (2.5 g, 27.0 mmol) was gradually added dropwise under ice-cooling. After stirring at room temperature for 2 hours, the reaction solution was poured into water, and the organic matter was extracted with ethyl acetate. The extract was washed with brine and water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane = 90: 10) to give the title compound (yield 4.
87 g, yield 88%). 76-78 ° C. NMR (CDCl ₃ ) δ: 1.16 (3H, t, J = 7.7 Hz), 1.47
-1.81 (2H, m), 1.94-2.41 (2H, m), 2.21 (2H, q, J = 7.7H
z), 2.70-2.90 (2H, m), 3.00-3.20 (1H, m), 3.38 (2
H, q, J = 7.3Hz), 3.87 (3H, s), 5.50 (1H, brs), 6.82
(1H, d, J = 8.1Hz), 6.92 (1H, d, J = 11.4Hz). Elemental analysis: C ₁₅ H ₂₀ NFO ₂ Calculated: C, 67.90; H, 7.60; N, 5.28. Found: C, 67.83; H, 7.27; N, 5.25.

Reference Example 13 N- [2- (5-fluoro-
6-Hydroxyindan-1-yl) ethyl] propionamide N- [2- (5-fluoro-6-methoxyindan-1)
-Yl) ethyl] propionamide (4.18 g, 1
Boron tribromide (7.9 g, 31.5 mmol) was slowly added dropwise to a solution of 5.8 mmol) in dichloromethane (100 mL) under ice-cooling. After stirring for 2 hours under ice cooling, the reaction solution was poured into ice water, further stirred at room temperature for 3 hours, and the organic matter was extracted with ethyl acetate. The extract was washed with brine and water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane = 9: 1) to give the title compound (3.68 g, 93% yield).
I got 93-96 ° C (recrystallized from ethyl acetate / hexane). NMR (CDCl ₃ ) δ: 1.20 (3H, t, J = 7.7 Hz), 1.47
-1.80 (2H, m), 1.88-2.10 (1H, m), 2.22 (2H, q, J = 7.7H
z), 2.20-2.40 (1H, m), 2.65-2.90 (2H, m), 2.95-3.
13 (1H, m), 3.37 (2H, q, J = 7.5Hz), 5.59 (1H, br
s), 6.09 (1H, br s), 6.83 (1H, d, J = 8.4Hz), 6.89
(1H, d, J = 10.6Hz). Elemental analysis: C ₁₄ H ₁₈ NFO ₂ Calculated: C, 66.91; H, 7.22; N, 5.57. Found: C, 66.84; H, 7.10; N, 5.54.

Reference Example 14 N- [2- (5-fluoro-
6- (2-propynyloxy) indan-1-yl) ethyl] propionamide N- [2- (5-fluoro-6-hydroxyindan-
1-yl) ethyl] propionamide (0.5 g, 1.
99 mmol) in dimethylformamide (10 mL) solution, potassium carbonate (1.37 g, 9.95 mmol)
And propargyl bromide (2.4 g, 19.9 mmol
l) was added and the mixture was stirred at 120 ° C for 2 hours. The reaction solution was poured into water, and the organic matter was extracted with ethyl acetate. The extract was washed with brine and water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate) to give the title compound (0.56 g, 97% yield). 78-81 ° C (recrystallized from ethyl acetate). NMR (CDCl ₃ ) δ: 1.16 (3H, t, J = 7.5 Hz), 1.50
-1.83 (2H, m), 1.91-2.11 (1H, m), 2.21 (2H, q, J = 7.5
Hz), 2.20-2.41 (1H, m), 2.55 (1H, t, J = 2.3Hz), 2.6
5-2.95 (2H, m), 3.00-3.20 (1H, m), 3.38 (2H, q, J = 7.
5Hz), 4.74 (2H, d, J = 2.2Hz), 5.47 (1H, brs), 6.91
(1H, s), 6.96 (1H, s).

Reference Example 15 3- (6,7-dibromo-
Ethyl 2,3-dihydrobenzofuran-5-yl) propionate 3- (7-bromo-2,3-dihydrobenzofuran-5
-Yl) ethyl propionate (1.0 g, 3.34 mm
ol) and iron (10 mg) in acetic acid (10 mL) were added dropwise with bromine (0.80 g, 5.01 mmol).
The reaction mixture was heated and stirred at 50 ° C. for 5 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. Water was added to the residue, and the organic matter was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium bicarbonate, saturated saline and water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate: hexane =
1: 3) to give the title compound (0.67 g, 53% yield). Melting point 42-43 ° C. NMR (CDCl ₃ ) δ: 1.25 (3H, t, J = 7.3 Hz), 2.60 (2
H, t, J = 7.7Hz), 3.07 (2H, t, J = 7.7Hz), 3.27 (2H, t, J = 8.8H
z), 4.14 (2H, q, J = 7.3Hz), 4.68 (2H, t, J = 8.8Hz), 7.06 (1H,
s).

Reference Example 16 3- (6,7-dibromo-
2,3-dihydrobenzofuran-5-yl) propionic acid In the same manner as in Reference Example 5, the title compound was obtained from ethyl 3- (6,7-dibromo-2,3-dihydrobenzofuran-5-yl) propionate. (93% yield). 177-178 ° C (recrystallized from ethyl acetate / hexane). NMR (CDCl ₃ ) δ: 2.67 (2H, t, J = 7.5 Hz), 3.08 (2
H, t, J = 7.5Hz), 3.27 (2H, t, J = 8.8Hz), 4.68 (2H, t, J = 8.8H)
z), 7.07 (1H, s).

Reference Example 17 4,5-dibromo-1,2,2
6,7-tetrahydro-8H-indeno [5,4-b]
Furan-8-one The title compound was obtained from 3- (6,7-dibromo-2,3-dihydrobenzofuran-5-yl) propionic acid in the same manner as in Reference Example 6 (88% yield). 224-226 ° C (recrystallized from chloroform / isopropyl ether). NMR (CDCl ₃ ) δ: 2.72 (2H, t, J = 5.9 Hz), 3.05 (2
H, t, J = 5.9Hz), 3.55 (2H, t, J = 9.0Hz), 4.79 (2H, t, J = 9.0H
z).

Reference Example 18 1,2,6,7-tetrahydro-8H-indeno [5,4-b] furan-8-one 4,5-dibromo-1,2,6,7-tetrahydro-8
H-indeno [5,4-b] furan-8-one (29.
0 g, 87.4 mmol) in a solution of acetic acid (550 mL) in 5% palladium carbon (50% water content, 2.9 g).
And sodium acetate (17.9 g, 0.22 mol) were added, and the mixture was catalytically reduced under a hydrogen atmosphere at normal temperature and normal pressure. After the calculated amount of hydrogenation, the palladium carbon was removed by filtration and the solvent was distilled off under reduced pressure. Water was added to the residue, and the organic matter was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium bicarbonate, saturated saline and water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane = 15: 85) to give the title compound (yield 1).
3.5 g, 89%). 133-134 ° C (recrystallized from ethyl acetate / hexane). NMR (CDCl ₃ ) δ: 2.68 (2H, t, J = 5.9 Hz), 3.08 (2
H, t, J = 5.9Hz), 3.47 (2H, t, J = 8.8Hz), 4.65 (2H, t, J = 8.8H)
z), 7.01 (1H, d, J = 8.1 Hz), 7.21 (1H, d, J = 8.1 Hz). Elemental analysis: C ₁₁ H ₁₀ O ₂ Calculated: C, 75.84; H, 5.79. Found: C, 75.69; H, 5.75.

Reference Example 19 (E)-(1,6,7,8-
Tetrahydro-2H-indeno [5,4-b] furan-
8-Ylidene) acetonitrile In the same manner as in Reference Example 7, the title compound was obtained from 1,2,6,7-tetrahydro-8H-indeno [5,4-b] furan-8-one and diethyl cyanomethylphosphonate. (60% yield). 149-151 ° C (recrystallized from methanol). NMR (CDCl ₃ ) δ: 3.00-3.20 (4H, m), 3.31 (2H, t,
J = 8.8Hz), 4.67 (2H, t, J = 8.8Hz), 5.45 (1H, t, J = 2.4Hz), 6.8
6 (1H, d, J = 8.1Hz), 7.11 (1H, d, J = 8.1Hz). Elemental analysis: C ₁₃ H ₁₁ NO Calculated: C, 79.17; H, 5.62; N, 7.10. Found: C, 79.21; H, 5.82; N, 7.18.

Reference Example 20 (S) -2- (1,6,7,
8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethylamine hydrochloride In a Hastelloy autoclave (200 mL), (E)-
2- (1,6,7,8-tetrahydro -2H- indeno [5,4-b] furan-8-ylidene) ethylamine _{(1.00g, 5.00mmol), Ru 2} Cl
₄ [(R) -BINAP] ₂ NEt ₃ (21.0 mg),
Methanol (10 mL) was inserted under a nitrogen atmosphere, and then hydrogen gas was injected to 100 atm. After heating and stirring at 50 ° C. for 20 hours, the reaction solution was returned to normal pressure, and the reaction conversion and the product ((S) -2- (1,6,7,8-tetrahydro-2H-indeno [5,4- b] The optical purity of furan-8-yl) ethylamine) was measured by high performance liquid chromatography.
It was 8.8% ee. Toluene (10 mL) was added to the residue (1.02 g) obtained by concentration under reduced pressure, and 2% hydrochloric acid (10 mL) was added while stirring and cooling in an ice bath. After stirring the reaction solution for 30 minutes, it was concentrated under reduced pressure to obtain a residue (1.21 g). This residue was dissolved in methanol (5 mL), and acetone (10 mL) was added to the resulting solution.
mL), cooled to 0 ° C., and filtered to give the title compound (0.64 g). The filtrate was concentrated under reduced pressure, and the residue (0.34 g) obtained was recrystallized from a mixed solvent of methanol (1.5 mL) and acetone (3.0 mL) to give the title compound (0.17 g, total yield 0.81 g). , Yield 68
%). This hydrochloride was treated with a 5% aqueous sodium hydroxide solution to obtain (S) -2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8.
The optical purity of -yl) ethylamine was measured by high performance liquid chromatography and found to be 100% ee.

Reference Example 21 (S) -2- (1,6,7,
8-Strahydro-2H-indeno [5,4-b] furan-8-yl) ethylamine (S)-in a Hastelloy autoclave (200 mL).
2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethylamine (0.
_{20g, 1.00mmol), Ru 2 Cl} 4 [(R) -B
INAP] ₂ NEt ₃ (0.42 g), methanol (20
mL) and methylene chloride (5 mL) were inserted under a nitrogen atmosphere, heated to 50 ° C., and then pressurized with hydrogen gas to 50 atm. After heating and stirring at 50 ° C. for 15 minutes, the mixture was cooled to room temperature,
After returning to normal pressure, (E) -2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8
-Ylidene) ethylamine (20.0 g, 99.4 mm
ol) in methanol (30 mL) was added, and hydrogen gas was injected again to 100 atm. After heating and stirring at 55 ° C. for 20 hours, the reaction solution was returned to normal pressure, and the reaction conversion and the product ((S) -2- (1,6,7,8-tetrahydro-2H-indeno [5,4- When the optical purity of b] furan-8-yl) ethylamine) was measured by high performance liquid chromatography, the reaction conversion was 100% and the optical purity was 90.3% ee.

Reference Example 22 (S) -2- (1,6,7,
8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethylamine In a Hastelloy autoclave (100 mL), (E)-
2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-ylidene) ethylamine (0.50 g, 2.50 mmol), Ru ₂ Cl
₄ [(R) -T-BINAP] ₂ NEt ₃ (5.0 m
g) and methanol (5.0 mL) were inserted under a nitrogen atmosphere, and then hydrogen gas was injected to 100 atm. 50 ℃
After heating and stirring at room temperature for 20 hours, the reaction solution was returned to normal pressure, the reaction conversion rate and the product (S) -2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan When the optical purity of -8-yl) ethylamine was measured by high performance liquid chromatography, the conversion of the reaction was 100% and the optical purity was 74.0% ee.

Reference Examples 23 to 25 Only the catalyst in Reference Example 22 was replaced with Ru (OCOCH ₃ )
₂ [(R) -BINAP], Ru (OCOCH ₃ ) ₂ [(R) -T-
BINAP] or Ru ₂ Cl ₄ [(R) -DM-BINAP] ₂
A hydrogenation reaction was carried out in the same manner as in Reference Example 22 with the replacement of NEt ₃ , and the following results were obtained. Catalyst conversion ratio Optical purity Reference example 23 Ru (OAc) ₂ ((R) -BINAP) 100% 75.4% ee Reference example 24 Ru (OAc) ₂ ((R) -T-BINAP) 100% 74.0% ee Reference example 25 Ru ₂ Cl ₄ ((R) -DM-BINAP) ₂ NEt ₃ 100% 36.4% ee

The following conditions were used for measuring the reaction conversion and the optical purity by high performance liquid chromatography in the above-mentioned Reference Examples 20 to 25. High performance liquid chromatography: SHIMAZU SCL-10A Column: ULTRON ES-OVM (4.6 mm x 150 mm, SHINWA
CHEMICAL INDUSTRIESLTD.) Mobile phase: 40 mmol / L KH ₂ PO ₄ aqueous solution / ethanol = 9
0/10 (pH = 7.5 NaOH) Wavelength: UV 280 nm Flow rate: 1.0 mL / min

Reference Example 26 (E)-(6-Methoxyindane-1-ylidene) acetonitrile The title compound was obtained from 6-methoxy-1-indanone and diethyl cyanomethylphosphonate in the same manner as in Reference Example 7. Rate 73%). 92-95 ° C (recrystallized from ethyl acetate). NMR (CDCl ₃ ) δ: 2.97-3.20 (4H, m), 3.84 (3
H, s), 5.61 (1H, t, J = 2.6Hz), 6.95-7.03 (2H, m), 7.
26 (1H, dd, J = 0.7Hz, 8.1Hz). Elemental analysis: C ₁₂ H ₁₁ NO Calculated: C, 77.81; H, 5.99; N, 7.56. Found: C, 77.79; H, 6.01; N, 7.58.

Reference Example 27 (E) -2- (6-Methoxyindane-1-ylidene) ethylamine hydrochloride (E)-(6-Methoxyindane-1-ylidene) acetonitrile (5.0 g, 27 mmol) in ethanol ( 50 mL) solution, a saturated ammonia / ethanol solution (250 mL) and Raney cobalt (10 g) were added, and the reaction mixture was placed under a hydrogen atmosphere (5 kgf / cm ² ).
Stir at room temperature for 5 hours. After removing Raney cobalt,
The solvent was distilled off under reduced pressure to obtain (E) -2- (6-methoxyindan-1-ylidene) ethylamine. After dissolving this oily residue in ethanol (20 mL),
After cooling to ° C, a saturated hydrogen chloride / ethanol solution was added.
The precipitated crystals were collected by filtration to give the title compound (4.3 g, 71% yield). Melting point 177-179 [deg.] C. NMR (d ₆ -DMSO, D ₂ O) δ: 2.76-3.00 (4H,
m), 3.40-3.65 (2H, m), 3.77 (3H, s), 5.98 (1H, t, J
= 7.5Hz), 6.85 (1H, dd, J = 2.2Hz, 8.4Hz), 7.01 (1H, d,
J = 2.2Hz), 7.22 (1H, d, J = 8.4Hz), 8.22 (2H, brs). Elemental analysis: C ₁₂ H ₁₅ NO · HCl Calculated: C, 63.85; H, 7.14; N, 6.21; Cl, 15.7
1. Found: C, 63.53; H, 6.85; N, 6.16; Cl, 15.4.
0.

Reference Example 28 (E) -N- [2- (6-Methoxyindane-1-ylidene) ethyl] propionamide In the same manner as in Reference Example 12, (E) -2- (6-methoxyindane- The title compound was obtained from 1-ylidene) ethylamine and propionyl chloride (78% yield). 129-131 ° C (recrystallized from ethyl acetate). NMR (CDCl ₃ ) δ: 1.18 (3H, t, J = 7.5 Hz), 2.24
(2H, q, J = 7.5Hz), 2.73-2.86 (2H, m), 2.90-3.20 (2
H, m), 3.81 (3H, s), 4.04 (2H, t, J = 6.2Hz), 5.55 (1
H, brs), 5.88 (1H, m), 6.79 (1H, dd, J = 2.4Hz, 8.1H
z), 6.93 (1H, d, J = 2.4Hz), 7.14 (1H, d, J = 8.1Hz). Elemental analysis: C ₁₅ H ₁₉ NO ₂ Calculated: C, 73.44; H, 7.81; N, 5.71. Found: C, 72.91; H, 7.81; N, 5.58.

Reference Example 29 (S) -N- [2- (6-Methoxyindan-1-yl) ethyl] propionamide (E) -N- [2- (6-methoxyindan-1-ylidene) ethyl] Propionamide (3.5 g, 14.26
mmol) and Ru (OCOCH ₃ ) ₂ [(S) -BINA
P] (120 mg, 142 μmol) was added to degassed anhydrous methanol (70 mL), and the obtained solution was heated and stirred at 70 ° C. for 3 hours in an autoclave (hydrogen pressure: 90 atm). The reaction liquid was analyzed by high performance liquid chromatography using a chiral column, and as a result, (S) -N- [2-
(6-Methoxyindan-1-yl) ethyl] propionamide has an asymmetric yield of 95% ee and a chemical yield of 99%.
Met. The reaction solution was concentrated to dryness under reduced pressure, and the obtained oily residue was purified by short column chromatography (silica gel 7 g), and further recrystallized from ethyl acetate / hexane to give an optical purity of 99% ee or more. Chemical purity 99%
The above title compound (2.92 g, 83% yield) was obtained. [α] _D ²⁰ = -7.0 ° (c 1.000, ethanol). Melting point: 76-77 ° C (recrystallized from ethyl acetate / hexane). NMR (CDCl ₃ ) δ: 1.15 (3H, t, J = 8 Hz), 1.56-
1.64 (1H, m), 1.72 (1H, qd, J = 8Hz, 13Hz), 2.04 (1H, d
td, J = 4Hz, 8Hz, 13Hz), 2.19 (2H, q, J = 8Hz), 2.32 (1H,
dtd, J = 4Hz, 8Hz, 13Hz), 2.77 (1H, td, J = 8Hz, 16Hz), 2.
85 (1H, dtd, J = 4Hz, 8Hz, 16Hz), 3.11 (1H, ddt, J = 4Hz, 8H
z, 14Hz), 3.34 (3H, s), 3.37-3.41 (2H, m), 5.53 (1
H, brs), 6.71 (1H, dd, J = 2Hz, 8Hz), 6.75 (1H, d, J = 2
Hz), 7.10 (1H, d, J = 8Hz). Elemental analysis: as C ₁₅ H ₂₁ NO ₂ Calculated: C, 72.84; H, 8.56; N, 5.66. Found: C, 72.59; H, 8.50; N, 5.84.

Reference Example 30 (S) -N- [2- (5-bromo-6-methoxyindan-1-yl) ethyl] propionamide In the same manner as in Reference Example 4, (S) -N- [2 -(6
-Methoxyindan-1-yl) ethyl] propionamide and bromine afforded the title compound (86% yield). [α] _D ²⁰ = + 5.2 ゜ (c 1.000, ethanol). Melting point: 105-107 ° C (recrystallized from ethyl acetate / hexane). NMR (CDCl ₃ ) δ: 1.16 (3H, t, J = 7.7 Hz), 1.49
-1.81 (2H, m), 1.98-2.41 (2H, m), 2.21 (2H, q, J = 7.7
Hz), 2.69-2.98 (2H, m), 3.00-3.20 (1H, m), 3.39
(2H, q, J = 7.3Hz), 3.88 (3H, s), 5.48 (1H, brs),
6.78 (1H, s), 7.37 (1H, s). Elemental analysis: as C ₁₅ H ₂₀ BrNO ₂ Calculated: C, 55.23; H, 6.18; N, 4.29. Found: C, 55.15; H, 6.18; N, 4.25.

Reference Example 31 (S) -N- [2- (5-bromo-6-hydroxyindan-1-yl) ethyl] propionamide (S) -N- [2- (5-bromo-6-methoxy) Indan-1-yl) ethyl] propionamide (56.7
g, 174 mmol) of dichloromethane (400 mL)
The solution was cooled to −30 ° C. and boron tribromide (95.8 g,
382 mmol) was slowly added dropwise. The reaction solution is -20 ° C
After stirring at −15 ° C. for 30 minutes, the reaction solution was poured into ice water, further stirred at room temperature for 10 minutes, and the organic matter was extracted with ethyl acetate. The extract was washed with brine and water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate) to obtain the title compound (51.12 g, 94%). [α] _D ²⁰ = + 2.7 ° (c 1.001, ethanol). 146-148 ° C (recrystallized from ethyl acetate). NMR (CDCl ₃ ) δ: 1.16 (3H, t, J = 7.5 Hz), 1.50
-1.80 (2H, m), 1.90-2.40 (1H, m), 2.20-2.40 (1H, m),
2.24 (2H, q, J = 7.5Hz), 2.65-2.95 (2H, m), 3.00-3.1
8 (1H, m), 3.38 (2H, q, J = 7.1Hz), 5.82 (1H, brs),
6.86 (1H, s), 7.27 (1H, s), 1H are hidden and invisible. Elemental analysis: as C ₁₄ H ₁₈ BrNO ₂ Calculated: C, 53.86; H, 5.81; N, 4.49. Found: C, 53.85; H, 5.78; N, 4.52.

Reference Example 32 (S) -N- [2- (6-allyloxy-5-bromoindan-1-yl) ethyl]
Propionamide (S) -N- [2- (5-bromo-6-hydroxyindan-1-yl) ethyl] propionamide (48.8
g, 156 mmol) in N, N-dimethylformamide (110 mL) was cooled with ice, and sodium hydride (6.35 g, 172 mmol, content 65%) was gradually added. When stirring for about 15 minutes and the bubbling of hydrogen gas stopped, allyl bromide (22.7 g, 188 mmol) was added, and the mixture was stirred for 30 minutes under ice-cooling. The reaction solution was poured into ice water, neutralized with dilute hydrochloric acid, and the organic matter was extracted with ethyl acetate. The extract was washed with brine and water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate) to obtain the title compound (yield: 52.97 g, 96%). [α] _D ²⁰ = + 3.7 ° (c 1.003, ethanol). 86-87 ° C (recrystallized from ethyl acetate / hexane). NMR (CDCl ₃ ) δ: 1.16 (3H, t, J = 7.5 Hz), 1.48
-1.80 (2H, m), 1.90-2.40 (2H, m), 2.20 (2H, q, J = 7.5
Hz), 2.70-2.91 (2H, m), 3.00-3.20 (1H, m), 3.37
(2H, q, J = 7.4Hz), 4.59 (2H, m), 5.25-5.60 (3H,
m), 5.97-6.20 (1H, m), 6.76 (1H, s), 7.37 (1H,
s). Elemental analysis: C ₁₇ H ₂₂ BrNO ₂ Calculated: C, 57.96; H, 6.29; N, 3.98. Found: C, 57.91; H, 6.28; N, 4.04.

Reference Example 33 (S) -N- [2- (7-allyl-5-bromo-6-hydroxyindan-1-yl) ethyl] propionamide (S) -N- [2- (6-allyloxy -5-bromoindan-1-yl) ethyl] propionamide (50.
A suspension of N, N-diethylaniline (75 mL, 144 mmol) in 150 mL was replaced with argon to give 200-2.
The mixture was heated and stirred at 05 ° C for 2.5 hours. After cooling the reaction solution, N, N-diethylaniline was distilled off under reduced pressure. Water (50 mL), 2N hydrochloric acid (50 mL) and ethyl acetate (100 mL) were added to the oily residue, and the organic matter was extracted twice. The extract was washed with brine and water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane = 7: 3) to give the title compound (40.6 g, 80% yield). [α] _D ²⁰ = −51.3 ° (c 1.003, ethanol). 85-87 ° C (recrystallized from ethyl acetate / hexane). NMR (CDCl ₃ ) δ: 1.14 (3H, t, J = 7.6 Hz), 1.45
-2.13 (4H, m), 2.18 (2H, q, J = 7.6Hz), 2.68-3.65 (7
H, m), 4.93-5.13 (2H, m), 5.41 (1H, brs), 5.49 (1
H, s), 5.89-6.10 (1H, m), 7.20 (1H, s). Elemental analysis: C ₁₇ H ₂₂ BrNO ₂ Calculated: C, 57.96; H, 6.29; N, 3.98; Br, 22.6
8. Found: C, 57.95; H, 6.22; N, 4.00; Br, 22.5.
2.

Reference Example 34 (S) -N- [2- (5-bromo-6-hydroxy-7- (2-hydroxyethyl)
Indan-1-yl) ethyl] propionamide Methanol of (S) -N- [2- (7-allyl-5-bromo-6-hydroxyindan-1-yl) ethyl] propionamide (588 mg, 1.67 mmol) (3
0 mL) The solution was cooled to around -70 ° C and ozone was injected for 5 minutes. After confirming the disappearance of the raw materials, an excess of sodium borohydride (510 mg, 13.4 mmol) powder was added to the reaction solution at about -70 ° C to decompose ozonide. After the temperature was raised to room temperature and neutralized with diluted hydrochloric acid, the organic matter was extracted with a mixed solvent of ethyl acetate: butanol = 1: 1. The extract was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was washed with diethyl ether to obtain the title compound (0.59 g, yield 99%). [α] _D ²⁰ = -43.7 ° (c 1.002, ethanol). 85-87 ° C (recrystallized from ethyl acetate / methanol). NMR (CDCl ₃ ) δ: 1.13 (3H, t, J = 7.5 Hz), 1.40
-2.10 (4H, m), 2.17 (2H, q, J = 7.5Hz), 2.62-3.01 (4
H, m), 3.07-3.22 (1H, m), 3.28 (2H, q, J = 6.8Hz), 3.
89 (2H, brs), 5.47 (1H, t, J = 3.7Hz), 6.31 (1H, br
s), 7.20 (1H, s), 9.07 (1H, s). Elemental analysis: C ₁₆ H ₂₂ BrNO ₃ Calculated: C, 53.94; H, 6.22; N, 3.93; Br, 22.4
3. Found: C, 53.97; H, 6.09; N, 3.97; Br, 22.4.
0.

Reference Example 35 (S) -N- [2- (6-hydroxy-7- (2-hydroxyethyl) indane-1
-Yl) ethyl] propionamide (S) -N- [2- (5-bromo-6-hydroxy-7
-(2-hydroxyethyl) indan-1-yl) ethyl] propionamide (590 mg, 1.66 mmol)
l), triethylamine (184 mg, 1.82 mmol)
l) and 5% palladium on carbon (100 mg) in methanol were catalytically reduced under a hydrogen atmosphere. When the calculated amount of hydrogen was absorbed, the catalyst was removed by filtration, and weakly acidified with dilute hydrochloric acid.
Was extracted with a mixed solvent. The extract was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was washed with diethyl ether to give the title compound (0.42 g, yield 91%). [α] _D ²⁰ = −69.7 ° (c 1.002, ethanol). 144-146 ° C (recrystallized from ethyl acetate / methanol). NMR (CDCl ₃ ) δ: 1.12 (3H, t, J = 7.7 Hz), 1.45
-2.10 (4H, m), 2.16 (2H, q, J = 7.7Hz), 2.60-3.00 (4
H, m), 3.10-3.23 (1H, m), 3.29 (2H, q, J = 6.8Hz), 3.
86 (2H, q, J = 5.5Hz), 5.00 (1H, t, J = 4.4Hz), 6.41 (1
H, brs), 6.69 (1H, d, J = 7.9Hz), 6.91 (1H, d, J = 7.9H)
z), 8.86 (1H, s). Elemental analysis: C ₁₆ H ₂₃ NO ₃ Calculated: C, 69.29; H, 8.36; N, 5.05. Found: C, 69.46; H, 8.28; N, 5.11.

Reference Example 36 6,7-Dimethoxy-1-indanone In the same manner as in Reference Example 18, 4-bromo-6,7-
The title compound was obtained from dimethoxy-1-indanone (84% yield). Oily. NMR (CDCl ₃ ) δ: 2.69 (2H, t, J = 6.0 Hz), 3.04
(2H, t, J = 6.0Hz), 3.89 (3H, s), 4.00 (3H, s), 7.10
(1H, d, J = 8.4Hz), 7.19 (1H, d, J = 8.4Hz).

Reference Example 37 (E)-(6,7-Dimethoxyindane-1-ylidene) acetonitrile In the same manner as in Reference Example 7, 6,7-dimethoxy-1
-The title compound was obtained from indanone and diethyl cyanomethylphosphonate (81% yield). 111-113 ° C (recrystallized from ethyl acetate). NMR (CDCl ₃ ) δ: 2.95-3.15 (4H, m), 3.87 (3
H, s), 3.91 (3H, s), 6.24 (1H, t, J = 2.4Hz), 6.95 (1
H, d, J = 8.6Hz), 7.00 (1H, d, J = 8.6Hz). Elemental analysis: as C ₁₃ H ₁₃ NO ₂ Calculated: C, 72.54; H, 6.09; N, 6.51. Found: C, 72.38; H, 6.11; N, 6.53.

Reference Example 38 2- (6,7-Dimethoxyindan-1-yl) ethylamine hydrochloride (E)-(6,7-Dimethoxyindan-1-ylidene) acetonitrile (1.8 g, 8.36 mmol) Raney nickel (2.
5 g, W2) and a 4 M ammonia / ethanol solution (20 mL) were added, and the mixture was heated with stirring at 60 ° C. for 6 hours under a hydrogen atmosphere (4 to 5 atm). After filtering the reaction solution, the filtrate was concentrated under reduced pressure. The residue was ethanol (50
5% palladium on carbon (0.2 g,
(50% water-containing product) and stirred at room temperature for 4 hours under a hydrogen atmosphere (normal pressure). After filtering the reaction solution, the filtrate was concentrated under reduced pressure to obtain (E) -2- (6,7-dimethoxyindan-1-yl) ethylamine. This was further dissolved in ethanol (2 mL), a saturated hydrogen chloride / ethanol solution was added, and the precipitated crystals were collected by filtration to give the title compound (1.68 g, yield 78%). 141-143 ° C (recrystallized from ethanol). _{NMR (d 6 -DMSO) δ:} 1.59-1.83 (2H, m), 1.95
-2.26 (2H, m), 2.60-2.94 (4H, m), 3.21-3.41 (1H,
m), 3.75 (3H, s), 3.76 (3H, s), 6.83 (1H, d, J = 8.4H)
z), 6.89 (1H, d, J = 8.4 Hz), 7.99 (2H, brs). Elemental analysis: C ₁₃ H ₁₉ NO ₂ .HCl Calculated: C, 60.58; H, 7.82; N, 5.43; Cl, 13.7
Five. Found: C, 60.03; H, 7.55; N, 5.66; Cl, 14.1.
1.

Reference Example 39 N- [2- (6,7-Dimethoxyindan-1-yl) ethyl] acetamide In the same manner as in Reference Example 12, 2- (6,7-dimethoxyindan-1-yl) ethylamine And the title compound was obtained from acetyl chloride (83% yield). 79-81 ° C (recrystallized from ethyl acetate / hexane). NMR (CDCl ₃ ) δ: 1.70-1.93 (3H, m), 1.95 (3
H, s), 2.15-2.36 (1H, m), 2.67-3.21 (3H, m), 3.25-3.
53 (2H, m), 3.85 (3H, s), 3.87 (3H, s), 5.90 (1H, b
rs), 6.75 (1H, d, J = 8.1Hz), 6.91 (1H, d, J = 8.1H)
z). Elemental analysis: C ₁₅ H ₂₁ NO ₃ Calculated: C, 68.42; H, 8.94; N, 5.32. Found: C, 68.16; H, 7.78; N, 5.35.

Reference Example 40 N- [2- (6,7-Dimethoxyindan-1-yl) ethyl] propionamide In the same manner as in Reference Example 12, 2- (6,7-dimethoxyindan-1-yl) The title compound was obtained from ethylamine and propionyl chloride (86% yield). 90-92 ° C (recrystallized from ethyl acetate / hexane). NMR (CDCl ₃ ) δ: 1.14 (3H, t, J = 7.7 Hz), 1.70
-1.94 (3H, m), 2.10-2.36 (1H, m), 2.18 (2H, q, J = 7.7
Hz), 2.65-3.20 (3H, m), 3.25-3.55 (2H, m), 3.85
(3H, s), 3.87 (3H, s), 5.90 (1H, brs), 6.75 (1H,
d, J = 8.0Hz), 6.90 (1H, d, J = 8.0Hz). Elemental analysis: C ₁₆ H ₂₃ NO ₃ Calculated: C, 69.29; H, 8.36; N, 5.05. Found: C, 69.23; H, 8.09; N, 5.14.

Reference Example 41 N- [2- (6,7-Dimethoxyindan-1-yl) ethyl] butylamide In the same manner as in Reference Example 12, 2- (6,7-dimethoxyindan-1-yl) ethylamine And butyryl chloride gave the title compound (84% yield). 66-68 ° C (recrystallized from ethyl acetate / hexane). NMR (CDCl ₃ ) δ: 0.94 (3H, t, J = 7.3 Hz), 1.57
-1.95 (5H, m), 2.10-2.35 (1H, m), 2.13 (2H, t, J = 7.3
Hz), 2.66-3.20 (3H, m), 3.26-3.55 (2H, m), 3.85
(3H, s), 3.87 (3H, s), 5.87 (1H, brs), 6.75 (1H,
d, J = 8.1Hz), 6.90 (1H, d, J = 8.1Hz). Elemental analysis: C ₁₇ H ₂₅ NO ₃ Calculated: C, 70.07; H, 8.65; N, 4.81. Found: C, 69.84; H, 8.43; N, 4.80.

Reference Example 42 N- [2- (6,7-dihydroxyindan-1-yl) ethyl] propionamide In the same manner as in Reference Example 31, N- [2- (6,7-
The title compound was obtained from dimethoxyindan-1-yl) ethyl] propionamide (yield 73%). 98-101 ° C (recrystallized from ethyl acetate / hexane). NMR (CDCl ₃ ) δ: 1.21 (3H, t, J = 7.5 Hz), 1.60
-1.98 (3H, m), 2.10-2.30 (1H, m), 2.31 (2H, q, J = 7.5
Hz), 2.60-3.15 (3H, m), 3.22-3.40 (1H, m), 3.52-
3.75 (1H, m), 5.95 (1H, s), 6.01 (1H, brs), 6.63
(1H, d, J = 7.9Hz), 6.74 (1H, d, J = 7.9Hz), 9.62 (1H,
s). Elemental analysis: C ₁₄ H ₁₉ NO ₃ Calculated: C, 67.45; H, 7.68; N, 5.62. Found: C, 67.35; H, 7.60; N, 5.66.

Reference Example 43 N- [2- (6,7-dihydroxyindan-1-yl) ethyl] butylamide In the same manner as in Reference Example 31, N- [2- (6,7-
The title compound was obtained from dimethoxyindan-1-yl) ethyl] butylamide (yield 92%). Oily. NMR (CDCl ₃ ) δ: 0.96 (3H, t, J = 7.5 Hz), 1.60
-2.00 (5H, m), 2.10-2.30 (1H, m), 2.23 (2H, t, J = 7.5
Hz), 2.60-2.78 (1H, m), 2.80-3.00 (1H, m), 3.03-
3.21 (1H, m), 3.22-3.40 (1H, m), 3.42-3.61 (1H,
m), 6.20 (1H, br s), 6.38 (1H, br s), 6.62 (1H, d,
J = 7.7Hz), 6.74 (1H, d, J = 7.7Hz), 9.13 (1H, brs).

Reference Example 44 6-methoxy-7-nitro-
1-Indanone 6-methoxy-1-indanone (30.0 g, 185 m
mol) in a concentrated sulfuric acid solution (130 mL) and a concentrated sulfuric acid solution of potassium nitrate (24.3 g, 0.24 mol) (100 mL).
mL) while maintaining the internal temperature at 0 ° C. or lower. 2 at the same temperature
After stirring for 0 minutes, the reaction solution was poured into ice water and extracted with ethyl acetate. The extract was washed with water and an aqueous solution of sodium hydrogen carbonate, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from ethyl acetate / hexane to give the title compound (yield 21.7 g, 58%). 155-158 ° C. NMR (CDCl ₃ ) δ: 2.78 (2H, t, J = 5.6 Hz), 3.13
(2H, t, J = 5.6Hz), 3.94 (3H, s), 7.34 (1H, d, J = 8.4H)
z), 7.56 (1H, d, J = 8.4Hz).

Reference Example 45 (E)-(6-Methoxy-7)
-Nitroindane-1-ylidene) acetonitrile In the same manner as in Reference Example 7, the title compound was obtained from 6-methoxy-7-nitro-1-indanone and diethyl cyanomethylphosphonate (84% yield). 138-141 ° C (ethyl acetate / isopropyl ether
Recrystallized from tell). NMR (CDCl ₃ ) δ: 3.00-3.20 (4H, m), 3.92 (3
H, s), 5.42 (1H, t, J = 2.6Hz), 7.14 (1H, d, J = 8.6H)
z), 7.43 (1H, d, J = 8.6Hz).

Reference Example 46 (E)-(7-amino-6-
Methoxyindane-1-ylidene) acetonitrile In the same manner as in Reference Example 3, the title compound was obtained from (E)-(6-methoxy-7-nitroindan-1-ylidene) acetonitrile (79% yield). 119-121 ° C (recrystallized from hexane / ethyl acetate). NMR (CDCl ₃ ) δ: 2.90-3.20 (4H, m), 3.87 (3
H, s), 4.23 (2H, brs), 5.60 (1H, t, J = 2.2Hz), 6.69
(1H, d, J = 8.0Hz), 6.84 (1H, d, J = 8.0Hz).

Reference Example 47 N- [2- (7-amino-6)
-Methoxyindan-1-yl) ethyl] acetamide In the same manner as in Reference Example 38, (E)-(7-amino-6-methoxyindan-1-ylidene) acetonitrile was converted to 2- (7-amino-6 Methoxyindane-1
-Yl) ethylamine was obtained. The obtained crude product was used for the reaction described below without further purification. 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (3.3 g, 17.2 mmol) and 1
-Hydroxybenzotriazole monohydrate (2.2 g,
14.4 mmol) was suspended in N, N-dimethylformamide (30 mL), and acetic acid (0.65 m
L) was added. After stirring the reaction solution at room temperature for 1 hour,
The mixture was ice-cooled again, and the above-mentioned solution of crude 2- (7-amino-6-methoxyindan-1-yl) ethylamine in N, N-dimethylformamide (10 mL) was added dropwise. 30
After stirring for minutes, the reaction solution was poured into water, and the organic matter was extracted with ethyl acetate. The hydrochloride was extracted from the organic layer with 2N hydrochloric acid.
= 10. The organic matter was extracted from the aqueous layer with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: ethanol = 10: 1) to give the title compound (1.6 g, yield 66%). 94-97 ° C (recrystallized from ethyl acetate / isopropyl ether). NMR (CDCl ₃ ) δ: 1.60-2.10 (6H, m), 2.20 (1
H, m), 2.74 (1H, m), 2.92 (1H, m), 3.18 (1H, m),
3.32 (2H, q, J = 5.0Hz), 3.78 (2H, brs), 3.83 (3H,
s), 5.70 (1H, br s), 6.59 (1H, d, J = 8.0Hz), 6.60
(1H, d, J = 8.0Hz).

Reference Example 48 N- [2- (7-amino-6)
-Methoxyindan-1-yl) ethyl] propionamide In the same manner as in Reference Example 47, the title compound was obtained from (E)-(7-amino-6-methoxyindan-1-ylidene) acetonitrile and propionic acid ( Yield 40
%). 71-73 ° C (recrystallized from ethyl acetate / isopropyl ether). NMR (CDCl ₃ ) δ: 1.09 (3H, t, J = 7.5 Hz), 1.6-
2.0 (3H, m), 2.12 (2H, q, J = 7.5Hz), 2.25 (1H, m),
2.7-3.2 (3H, m), 3.34 (2H, q, J = 5.0Hz), 3.80 (2H, br
s), 3.83 (3H, s), 5.67 (1H, br s), 6.59 (1H, d, J =
8.0Hz), 6.66 (1H, d, J = 8.0Hz).

Reference Example 49 N- [2- (7-amino-6)
-Methoxyindan-1-yl) ethyl] butylamide The title compound was obtained from (E)-(7-amino-6-methoxyindan-1-ylidene) acetonitrile and butyric acid in the same manner as in Reference Example 47 (yield). 71%). 65-68 ° C (recrystallized from ethyl acetate / isopropyl ether). NMR (CDCl ₃ ) δ: 0.91 (3H, t, J = 7.3 Hz), 1.50-
2.40 (8H, m), 2.60-3.20 (3H, m), 3.34 (2H, q, J = 5.1H
z), 3.80 (2H, br s), 3.83 (3H, s), 5.67 (1H, br)
s), 6.59 (1H, d, J = 8.2Hz), 6.66 (1H, d, J = 8.2Hz).

Reference Example 50 N- [2- (7-amino-6)
-Hydroxyindan-1-yl) ethyl] acetamide hydrochloride N- [2- (7-amino-6-methoxyindan-1-)
Yl) ethyl] acetamide (1.1 g, 4.4 mmol
Boron tribromide (2.1 mL, 22.1 mmol) was slowly added dropwise to a solution of 1) in dichloromethane (20 mL) at room temperature. After stirring at the same temperature for 30 minutes, the reaction solution was poured into ice water and extracted with 10% methanol / chloroform. After the extract was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 10: 1) to give N- [2- (7-amino-6-hydroxyindan-1-yl) ethyl] acetamide (yield 630 m).
g, 61% yield). After dissolving part in ethanol,
A saturated hydrogen chloride / ethanol solution was added. After evaporating the solvent under reduced pressure, the precipitated crystals were recrystallized from ethanol to obtain the title compound. 225-228 ° C (recrystallized from ethanol). NMR (d ₆ -DMSO) δ: 1.30-1.80 (2H, m), 1.83
(3H, s), 1.90-2.20 (2H, m), 2.60-3.50 (5H, m), 6.
79 (1H, d, J = 8.2Hz), 6.99 (1H, d, J = 8.2Hz), 7.96 (1
H, br s), 10.32 (1H, br s), 2H are hidden and invisible.

Reference Example 51 N- [2- (7-amino-6)
-Hydroxyindan-1-yl) ethyl] propionamide The title compound was obtained from N- [2- (7-amino-6-methoxyindan-1-yl) ethyl] propionamide in the same manner as in Reference Example 50. (Yield 88%). Oily. NMR (CDCl ₃ ) δ: 1.11 (3H, t, J = 7.5Hz), 1.60-
2.00 (3H, m), 2.14 (2H, q, J = 7.5Hz), 2.23 (1H, m),
2.70-2.90 (2H, m), 3.19 (1H, m), 3.34 (2H, q, J = 5.1H
z), 4.10 (2H, br s), 5.69 (1H, br s), 6.52 (1H, d,
J = 7.6Hz), 6.60 (1H, d, J = 7.6Hz), 1H are hidden and invisible.

Reference Example 52 N- [2- (7-amino-6)
-Hydroxyindan-1-yl) ethyl] butylamide In the same manner as in Reference Example 50, the title compound was obtained from N- [2- (7-amino-6-methoxyindan-1-yl) ethyl] butylamide (yield). Rate 89%). Oily. NMR (CDCl ₃ ) δ: 0.90 (3H, t, J = 7.2 Hz), 1.50-
1.90 (6H, m), 2.04 (2H, t, J = 7.2Hz), 2.23 (1H, m),
2.60-2.90 (2H, m), 3.10-3.40 (3H, m), 4.40 (2H, br
s), 5.86 (1H, br s), 6.50 (1H, d, J = 8.0Hz), 6.62
(1H, d, J = 8.0Hz).

Reference Example 53 N- [2- (5-bromo-6)
-(2-propynyl) oxyindan-1-yl) ethyl] propionamide In the same manner as in Reference Example 32, N- [2- (5-bromo-6-hydroxyindan-1-yl) ethyl] propionamide and The title compound was obtained from propargyl bromide (99% yield). 104-107 ° C (recrystallized from ethyl acetate / hexane). NMR (CDCl ₃ ) δ: 1.16 (3H, t, J = 7.6Hz), 1.50-
2.40 (6H, m), 2.55 (1H, t, J = 2.3Hz), 2.7-3.2 (3H,
m), 3.38 (2H, q, J = 7.6Hz), 4.76 (2H, d, J = 2.3Hz), 5.
48 (1H, br s), 6.93 (1H, s), 7.38 (1H, s).

Reference Example 54 N- [2- (6-allyloxy-5-bromoindan-1-yl) ethyl] propionamide In the same manner as in Reference Example 32, N- [2- (5-bromo-6- Hydroxyindan-1-yl) ethyl] propionamide and allyl bromide gave the title compound (93% yield). This compound was used for the next reaction without purification. NMR (CDCl ₃ ) δ: 1.16 (3H, t, J = 7.5Hz), 1.60-
2.20 (4H, m), 2.32 (2H, q, J = 7.5Hz), 2.6-3.2 (3H,
m), 3.32 (2H, q, J = 5.3Hz), 4.60 (2H, d, J = 4.6Hz), 5.2
8 (1H, d, J = 10.6Hz), 5.43 (1H, s), 5.52 (1H, br s),
6.05 (1H, m), 6.78 (1H, s), 7.35 (1H, s).

Reference Example 55 N- [2- (5-bromo-6)
-(2-methyl-2-propenyl) oxyindane-1
-Yl) ethyl] propionamide In the same manner as in Reference Example 32, the title compound was obtained from N- [2- (5-bromo-6-hydroxyindan-1-yl) ethyl] propionamide and methallyl chloride. Rate 84%). 105-108 ° C (recrystallized from ethyl acetate / hexane). NMR (CDCl ₃ ) δ: 1.16 (3H, t, J = 7.6 Hz), 1.86
(3H, s), 1.9-2.4 (6H, m), 2.80 (2H, m), 3.08 (1H,
m), 3.38 (2H, q, J = 7.6Hz), 4.47 (2H, s), 5.00 (1H,
s), 5.17 (1H, s), 5.40 (1H, br s), 6.76 (1H, s),
7.37 (1H, s).

Reference Example 56 N- [2- (7-allyl-5)
-Bromo-6-hydroxyindan-1-yl) ethyl] propionamide In the same manner as in Reference Example 33, N- [2- (5-bromo-6-allyloxyindan-1-yl) ethyl] propionamide was prepared. The title compound was obtained (87% yield). Oily. NMR (CDCl ₃ ) δ: 1.14 (3H, t, J = 7.6Hz), 1.50-
2.10 (4H, m), 2.18 (2H, q, J = 7.6Hz), 2.70-3.70 (7H,
m), 4.90-5.20 (2H, m), 5.41 (1H, br s), 5.49 (1H,
s), 5.90-6.20 (1H, m), 7.20 (1H, s).

Reference Example 57 N- [2- (5-bromo-6)
-Hydroxy-7- (2-methyl-2-propenyl) indan-1-yl) ethyl] propionamide In the same manner as in Reference Example 33, N- [2- (5-bromo-6- (2-methyl- The title compound was obtained from 2-propenyl) oxindan-1-yl) ethyl] propionamide (yield 91%). 89-91 ° C (recrystallized from ethyl acetate / hexane). NMR (CDCl ₃ ) δ: 1.14 (3H, t, J = 7.6Hz), 1.40
-1.80 (2H, m), 1.80 (3H, s), 1.90-2.10 (2H, m), 2.1
7 (2H, q, J = 7.6Hz), 2.60-3.50 (7H, m), 4.49 (1H,
s), 4.79 (1H, s), 5.32 (1H, br s), 5.47 (1H, s),
7.21 (1H, s).

Reference Example 58 (R) -N- [2- (6-Methoxyindan-1-yl) ethyl] acetamide (E) -N- [2- (6-methoxyindan-1-ylidene) ethyl] acetamide (119.0 mg, 0.5
15 mmol) and Ru (OCOCH ₃ ) ₂ [(R) -BIN
[AP] (40 mg, 50 μmol) and a solution obtained by adding degassed anhydrous methanol (70 mL) were transferred to an autoclave, and heated and stirred at 50 atm and a hydrogen pressure of 100 atm for 6 hours. As a result of analysis by high performance liquid chromatography using a chiral column, the asymmetric yield of (R) -N- [2- (6-methoxyindan-1-yl) ethyl] acetamide was 81% ee, and the chemical yield was 81% ee. 82%.

Reference Example 59 (S) -N- [2- (6-ethoxyindan-1-yl) ethyl] propionamide (E) -N- [2- (6-ethoxyindan-1-ylidene) ethyl] Propionamide (239.5 mg, 0.
924 mmol) and Ru (OCOCH ₃ ) ₂ [(S) -BI
[NAP] (78 mg, 93 μmol) and a solution obtained by adding degassed anhydrous methanol (70 mL) were transferred to an autoclave, and the mixture was heated with stirring under a hydrogen pressure of 100 atm and 50 ° C. for 6 hours. As a result of analysis by high performance liquid chromatography using a chiral column, the asymmetric yield of (S) -N- [2- (6-ethoxyindan-1-yl) ethyl] propionamide was 95% ee, and the chemical yield was 95%. Was 88%.

Reference Example 60 (R) -N- [2- (6-methoxyindan-1-yl) ethyl] propionamide (Z) -N- [2- (6-methoxyindan-1-ylidene) ethyl] Propionamide (258.5 mg, 1.
05 mmol) and Ru (OCOCH ₃ ) ₂ [(S) -BIN
[AP] (84 mg, 100 μmol) and a solution obtained by adding degassed anhydrous methanol (70 mL) were transferred to an autoclave, and heated and stirred at 70 atm and a hydrogen pressure of 100 atm for 3 hours. As a result of analysis by high performance liquid chromatography using a chiral column, the asymmetric yield of (R) -N- [2- (6-methoxyindan-1-yl) ethyl] propionamide was 80% ee, and the chemical yield was 80% ee. Was 95%.

Reference Example 61 (R) -N- [2- (6-methoxyindan-1-yl) ethyl] propionamide (Z) -N- [2- (6-methoxyindan-1-ylidene) ethyl] Propionamide (245.5 mg, 1.
0 mmol) and Ru ₂ Cl ₄ [(S) -BINAP] ₂ NEt
A solution obtained by adding degassed anhydrous methanol (70 mL) to ₃ (169 mg, 100 μmol) was transferred to an autoclave, and the mixture was heated and stirred at 70 atm and a hydrogen pressure of 100 atm for 6 hours. As a result of analysis by high performance liquid chromatography using a chiral column, the asymmetric yield of (R) -N- [2- (6-methoxyindan-1-yl) ethyl] propionamide was 86% ee, and the chemical yield was 86%. Was 82%.

Reference Example 62 6-Hydroxy-7-nitro-1-indanone In the same manner as in Reference Example 44, 6-hydroxy-1-
The title compound was obtained from indanone (61% yield). 218-220 ° C (recrystallized from ethanol / hexane). NMR (CDCl ₃ ) δ: 2.37 (2H, t, J = 5.5 Hz), 2.74
(2H, t, J = 5.5Hz), 2.95 (1H, s), 6.95 (1H, d, J = 8.4H
z), 7.15 (1H, d, J = 8.4Hz).

Reference Example 63 [(4-Nitro-3-oxoindan-5-yl) oxy] ethyl acetate 6-hydroxy-7-nitro-1-indanone (8.0)
g, 41 mmol) in N, N-dimethylformamide (50 mL) solution.
mmol) and stirred under ice-cooling. Ethyl bromoacetate (5.5 mL, 50 mmol) was added dropwise thereto, and after completion of the addition, the reaction solution was stirred at room temperature for 1 hour. The reaction solution was poured into ice water, and the organic matter was extracted with ethyl acetate. The extract was washed with brine and water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The precipitated crystals were collected by filtration and washed with hexane to give the title compound (10.8 g, 94% yield). 137-139 ° C (recrystallized from ethyl acetate / hexane). NMR (CDCl ₃ ) δ: 1.29 (3H, t, J = 7.1 Hz), 2.79
(2H, t, J = 6.0Hz), 3.14 (2H, t, J = 6.0Hz), 4.25 (2H,
q, J = 7.1Hz), 4.74 (2H, s), 7.25 (1H, d, J = 8.4Hz),
7.55 (1H, d, J = 8.4Hz).

Reference Example 64 Ethyl [(4-amino-3-oxoindan-5-yl) oxy] acetate In the same manner as in Reference Example 3, [(4-nitro-3-oxoindan-5-yl) oxy] acetic acid The title compound was obtained from ethyl (yield 98%). NMR (CDCl ₃ ) δ: 1.29 (3H, t, J = 7.1 Hz), 2.3-
3.0 (4H, m), 4.28 (2H, q, J = 7.1Hz), 4.61 (2H, s),
5.89 (2H, brs), 6.53 (1H, d, J = 8.2Hz), 6.87 (1H, d,
J = 8.2Hz).

Reference Example 65 7,8-Dihydroindeno [5,4-b] [1,4] oxazine-2,9 (1H,
3H) -dione [(4-Amino-3-oxoindan-5-yl) oxy] To a solution of ethyl acetate (8.7 g, 34.9 mmol) in toluene (200 mL) was added potassium tert-butoxide (400 mg, 3.6 mmol). Was added and the mixture was refluxed for 12 hours under an argon atmosphere. After cooling, the reaction solution was poured into water, neutralized with dilute hydrochloric acid, and the organic matter was extracted with ethyl acetate. The extract was washed with brine and water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to obtain the title compound (4.8 g, yield 66%). 136-139 ° C (recrystallized from ethyl acetate / hexane). NMR (CDCl ₃ ) δ: 2.74 (2H, t, J = 5.8 Hz), 3.10
(2H, t, J = 5.8Hz), 4.68 (2H, s), 7.01 (1H, d, J = 7.2H)
z), 7.17 (1H, d, J = 7.2Hz), 9.52 (1H, brs).

Reference Example 66 (E)-(1, 2, 3, 7,
8,9-Hexahydro-2-oxoindeno [5,4-
b] [1,4] oxazine-9-ylidene) acetonitrile In the same manner as in Reference Example 7, 7,8-dihydroindeno [5,4-b] [1,4] oxazine-2,9
The title compound was obtained from (1H, 3H) -dione and diethyl cyanomethylphosphonate (86% yield). 158-161 ° C (recrystallized from chloroform). NMR (CDCl ₃ ) δ: 3.00-3.20 (4H, m), 4.62 (2
H, s), 5.62 (1H, t, J = 2.3Hz), 6.97 (1H, d, J = 8.2Hz),
7.06 (1H, d, J = 8.2Hz), 8.07 (1H, brs).

Reference Example 67 N- [2- (5-Hydroxyindol-3-yl) ethyl] propionamide Serotonin hydrochloride (10 g, 47.5 mmol) in water (50 mL) under an argon atmosphere was added tetrahydrofuran (20 mL). And a solution of sodium carbonate (5.3 g) in water (20 mL) was added, and the mixture was cooled to 0 ° C. To this solution was added propionic anhydride (6.2 g, 49.9 mmol) and stirred at room temperature for 2 hours. The product was extracted with ethyl acetate, and the extract was washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and water, dried and concentrated to give the title compound as an oil (10.0 g, 98.0% yield). Was. This compound was used for the next reaction without further purification. NMR (d ₆ -DMSO) δ: 1.01 (3H, t, J = 7.6 Hz),
2.09 (2H, q, J = 7.6Hz), 2.73 (2H, t, J = 7.2Hz), 3.30
(2H, q, J = 7.2Hz), 3.72 (1H, brs), 6.61 (1H, dd, J =
8.8Hz, 2.2Hz), 6.85 (1H, d, J = 2.2Hz), 7.04 (1H,
s), 7.15 (1H, d, J = 8.8Hz), 7.91 (1H, t, J = 7.2Hz), 1
0.45 (1H, s).

Reference Example 68 N- [2- (5-allyloxyindol-3-yl) ethyl] propionamide N- [2- (5-hydroxyindol-3-yl) ethyl] propionamide (20.0 g, 92.5mmo
l), Allyl bromide (11 g, 90.8 mmol) was added to a mixture of cesium carbonate (31.6 g, 97 mmol) and N, N-dimethylformamide (150 mL) at 0 ° C. under an argon atmosphere. The reaction was stirred at 50 ° C. for 1 hour, water was added and the product was extracted with ethyl acetate. After the extract was washed with water and dried, the solvent was distilled off to obtain the title compound as an oil (yield: 20.0 g, 79.4%). This compound was used for the next reaction without further purification. NMR (CDCl ₃ ) δ: 1.11 (3H, t, J = 7.6 Hz), 2.14
(2H, q, J = 7.6Hz), 2.92 (2H, t, J = 7.0Hz), 3.58 (2H,
q, J = 7.0Hz), 4.57 (2H, dt, J = 5.6Hz, 1.6Hz), 5.28 (1
H, dq, J = 10.6Hz, 1.4Hz), 5.35 (1H, dq, J = 17.2Hz, 1.4H
z), 5.61 (1H, t, J = 7.0Hz), 6.10 (1H, m), 6.89 (1H,
dd, J = 8.8Hz, 2.2Hz), 6.99 (1H, d, J = 2.2Hz), 7.05 (1
H, d, J = 2.6Hz), 7.25 (1H, d, J = 8.8Hz), 8.33 (1H, br
s).

Reference Example 69 N- [2- (4-allyl-5)
-Hydroxyindol-3-yl) ethyl] propionamide N- [2- (5-allyloxyindol-3-yl)
Ethyl] propionamide (20.0 g, 73.4 mm
ol) was dissolved in N, N-diethylaniline (100 mL) and heated to 200 ° C. for 6 hours under an argon atmosphere.
After cooling, the separated solvent was removed and the residue was dissolved in ethyl acetate. This solution was washed with 1N hydrochloric acid and a saturated aqueous solution of sodium hydrogen carbonate, dried, concentrated and purified by silica gel column chromatography (hexane: ethyl acetate = 8: 2) to give the title compound (14.1 g, 71% yield). I got NMR (d ₆ -DMSO) δ: 1.03 (3H, t, J = 7.2 Hz),
2.11 (2H, q, J = 7.2Hz), 2.91 (2H, t, J = 7.4Hz), 3.31
(2H, q, J = 7.4Hz), 3.67 (2H, d, J = 5.2Hz), 4.86 (1H,
d, J = 9.2Hz), 4.90 (1H, d, J = 8.0Hz), 6.00 (1H, m),
6.68 (1H, d, J = 8.4Hz), 7.02 (1H, d, J = 8.4Hz), 7.87
(1H, t, J = 5.0Hz), 8.35 (1H, s), 10.49 (1H, s), 1H
Is hidden and invisible.

Reference Example 70 N- [2- (4-allyl-
2,3-dihydro-5-hydroxyindol-3-yl) ethyl] propionamide N- [2- (4-allyl-5-hydroxyindole-
3-yl) ethyl] propionamide (3.73 g, 1
4.3 mmol) was dissolved in acetic acid (20 mL), and sodium cyanoborohydride (2.7 g, 43.0 mmol) was gradually added while maintaining the internal temperature at 15 ° C. After stirring the reaction mixture for 1 hour while maintaining the temperature at 15 to 20 ° C, the reaction solution was poured into water, and the organic matter was extracted with ethyl acetate. The extract was washed with aqueous sodium hydrogen carbonate, saturated saline and water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting oily residue was purified without further purification.
Used for the next reaction.

Reference Example 71 N- [2- (4-allyl-1)
-Formyl-2,3-dihydro-5-hydroxyindol-3-yl) ethyl] propionamide Acetic anhydride (7.32 g, 71.7 mmol) was added to formic acid (3.3 g, 71.7 mmol) under ice cooling. The mixture was added dropwise, and the mixture was stirred for 10 minutes under ice cooling. This is formic acid (10m
L) dissolved in the above crude N- [2- (4-allyl-2,
3-dihydro-5-hydroxyindol-3-yl)
[Ethyl] propionamide solution was added dropwise under ice-cooling.
After the reaction mixture was further stirred for 1 hour under ice cooling, the reaction solution was poured into water, and the organic matter was extracted with 10% methanol / ethyl acetate. The extract was washed with aqueous sodium hydrogen carbonate, saturated saline and water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: methanol = 9: 1) to give the title compound (2.0 g, yield 46%, total yield from Reference Example 70). 173-175 [deg.] C (recrystallized from methanol / ethyl acetate). NMR (d ₆ -DMSO) δ: 1.01 (3H, dt, J = 1.6 Hz, 7.6
Hz), 1.30-1.50 (1H, m), 1.60-1.87 (1H, m), 2.08
(2H, dq, J = 1.6Hz, 7.6Hz), 3.00-3.50 (5H, m), 3.60-4.
10 (2H, m), 4.90-5.10 (2H, m), 5.80-6.04 (1H, m),
6.65 (1H, d, J = 8.4Hz), 7.08, 7.59 (1H, d × 2, J = 8.4H
z), 7.86 (1H, br s), 8.36, 8.85 (1H, s × 2), 9.1
7, 9.23 (1H, s × 2). Elemental analysis: C ₁₇ H ₂₂ N ₂ O ₃ Calculated: C, 67.53; H, 7.33; N, 9.26. Found: C, 67.25; H, 7.26; N, 9.25.

Reference Example 72 N- [2- [1-formyl-
2,3-Dihydro-5-hydroxy-4- (2-hydroxyethyl) indol-3-yl] ethyl] propionamide In the same manner as in Reference Example 34, N- [2- (4-allyl-1-formyl) -2,3-Dihydro-5-hydroxyindol-3-yl) ethyl] propionamide to give the title compound (66% yield). Oily. NMR (d ₆ -DMSO) δ: 1.00 (3H, dt, J = 2.2 Hz, 7.4)
Hz), 1.30-1.55 (1H, m), 1.58-2.02 (1H, m), 2.06
(2H, dq, J = 2.2Hz, 7.4Hz), 2.50-2.80 (2H, m), 2.95-3.
20 (2H, m), 3.22-4.00 (5H, m), 4.70-4.80 (1H, m),
6.62 (1H, d, J = 8.4Hz), 7.05,7.57 (1H, d × 2, J = 8.4H
z), 7.81 (1H, br s), 8.36, 8.84 (1H, s × 2), 9.1
6, 9.21 (1H, s × 2).

Reference Example 73 N- [2- (5-hydroxyindol-3-yl) ethyl] butyramide The title compound was obtained from serotonin hydrochloride and butyryl chloride in the same manner as in Reference Example 67 (yield: 39%). ). Oily. NMR (d ₆ -DMSO) δ: 0.86 (3H, t, J = 7.4 Hz),
1.49 (2H, sextet, J = 7.4Hz), 2.05 (2H, q, J = 7.4Hz), 2.7
2 (2H, t, J = 7.4Hz), 3.29 (2H, q, J = 6.8Hz), 6.59 (1H,
dd, J = 8.4Hz, 1.8Hz), 6.83 (1H, d, J = 1.8Hz), 7.03 (1
H, s), 7.12 (1H, d, J = 8.4Hz), 7.87 (1H, t, J = 7.4H)
z), 8.59 (1H, s), 10.47 (1H, s).

Reference Example 74 N- [2- (5-allylinoxyindol-3-yl) ethyl] butylamide In the same manner as in Reference Example 68, N- [2- (5-hydroxyindol-3-yl) ethyl The title compound was obtained from butyramide and allyl bromide (yield 91%). Oily. NMR (CDCl ₃ ) δ: 0.90 (3H, t, J = 7.4 Hz) 1.62 (2
H, sextet, J = 7.4Hz), 2.09 (2H, t, J = 7.4Hz), 2.92 (2
H, t, J = 7.0Hz), 3.61 (2H, q, J = 7.0Hz), 4.57 (2H, d, J =
5.6Hz), 5.27 (1H, dq, J = 10.2Hz, 1.4Hz), 5.43 (1H, d
q, J = 17.2Hz, 1.4Hz), 5.63 (1H, t, J = 7.0Hz), 5.80-6.2
0 (1H, m), 6.89 (1H, dd, J = 8.8Hz, 2.2Hz), 6.98 (1H,
d, J = 1.8Hz), 7.05 (1H, d, J = 2.2Hz), 7.25 (1H, d, J = 8.
8Hz), 8.37 (1H, brs).

Reference Example 75 N- [2- (4-allyl-5)
-Hydroxyindol-3-yl) ethyl] butylamide The title compound was obtained from N- [2- (5-allyloxyindol-3-yl) ethyl] butylamide in the same manner as in Reference Example 69 (yield 90%). ). Oily. NMR (d ₆ -DMSO) δ: 0.88 (3H, t, J = 7.4 Hz),
1.54 (2H, sextet, J = 7.4Hz), 2.07 (2H, t, J = 7.4Hz), 2.9
0 (2H, t, J = 7.4Hz), 3.31 (2H, q, J = 7.4Hz), 3.67 (2H,
d, J = 5.2Hz), 4.86 (1H, dd, J = 9.2Hz, 1.8Hz), 4.93 (1
H, d, J = 1.4Hz), 5.80-6.20 (1H, m), 6.68 (1H, d, J = 8.4
Hz), 6.99 (1H, s), 7.02 (1H, d, J = 8.4Hz), 7.90 (1H,
t, J = 5.0Hz), 8.36 (1H, s), 10.49 (1H, s).

Reference Example 76 N- [2- (4-allyl-
2,3-Dihydro-5-hydroxyindol-3-yl) ethyl] butylamide In the same manner as in Reference Example 70, N- [2- (4-allyl-5-hydroxyindol-3-yl) ethyl] butylamide and The title compound (84% yield) was obtained from sodium cyanoborohydride. NMR (d ₆ -DMSO) δ: 0.86 (3H, t, J = 7.3 Hz),
1.40-1.80 (4H, m), 2.06 (2H, t, J = 7.3Hz), 3.00-3.70
(8H, m), 4.91-5.07 (2H, m), 5.80-6.01 (1H, m), 6.6
3 (1H, d, J = 8.3Hz), 6.71 (1H, d, J = 8.3Hz), 7.88 (1H,
t, J = 5.5Hz), 9.13 (1H, s).

Reference Example 77 N- [2- (4-allyl-1)
-Formyl-2,3-dihydro-5-hydroxyindol-3-yl) ethyl] butylamide N- [2- (4-allyl-2,3-dihydro-5-hydroxyindole) was prepared in the same manner as in Reference Example 71. -3
-Yl) ethyl] butyramide to give the title compound (yield 7
5%). 172-174 ° C (recrystallized from methanol / ethyl acetate / hexane). NMR (d ₆ -DMSO) δ: 0.86 (3H, t, J = 7.3 Hz),
1.25-1.83 (4H, m), 2.04 (2H, t, J = 7.3Hz), 3.00-3.40
(5H, m), 3.60-4.03 (2H, m), 4.90-5.10 (2H, m), 5.8
0-6.01 (1H, m), 6.64 (1H, d, J = 8.4Hz), 7.08, 7.59
(1H, d × 2, J = 8.4Hz), 7.88 (1H, brs), 8.36,8.85
(1H, s × 2), 9.17, 9.22 (1H, s × 2). Elemental analysis: C ₁₈ H ₂₄ N ₂ O ₃ Calculated: C, 68.33; H, 7.65; N, 8.85. Found: C, 68.17; H, 7.65; N, 8.99.

Reference Example 78 N- [2- [1-formyl-
2,3-Dihydro-5-hydroxy-4- (2-hydroxyethyl) indol-3-yl] ethyl] butyramide N- [2- (4-
Allyl-1-formyl-2,3-dihydro-5-hydroxyindol-3-yl) ethyl] butylamide gave the title compound (69% yield). Oily. NMR (d ₆ -DMSO) δ: 0.85 (3H, t, J = 7.3 Hz),
1.38-1.81 (4H, m), 2.03 (2H, t, J = 7.3Hz), 2.50-2.82
(2H, m), 2.98-4.00 (7H, m), 4.74-4.83 (1H, m), 6.6
2 (1H, d, J = 8.1Hz), 7.06, 7.57 (1H, d × 2, J = 8.1Hz),
7.83 (1H, br s), 8.35, 8.83 (1H, s × 2), 9.17, 9.22
(1H, s × 2). Reference Example 79 (2,3-dihydrobenzofuran-5-yl) methanol 2,3-dihydrobenzofuran-5-carbaldehyde (30.0 g, 0.202 mol) in methanol (15
0 mL) solution, sodium borohydride (3.83 g, 0.101 mol) was added thereto under ice cooling. After the mixture was stirred for 15 minutes, water was added and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give the title compound (yield 27.6).
g, yield 91%). Oily. NMR (CDCl ₃ ) δ: 1.67 (1H, s), 3.20 (2H, t, J =
8.6Hz), 4.57 (2H, t, J = 8.6Hz), 4.58 (2H, s), 6.76
(1H, d, J = 8.0Hz), 7.10 (1H, d, J = 8.0Hz), 7.22 (1H,
s).

Reference Example 80 5-bromomethyl-2,3-
Dihydrobenzofuran A solution of (2,3-dihydrobenzofuran-5-yl) methanol (29.0 g, 0.193 mol) in tetrahydrofuran (150 mL) was cooled with iced brine, and then phosphorus tribromide (34.8 g, 0.129 mol). ) Was added dropwise and the mixture was stirred for 20 minutes. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous magnesium sulfate. Concentration under reduced pressure gave 5-bromomethyl-2,3-dihydrobenzofuran (yield 4).
1.0 g, 100% yield). This compound was used for the next reaction without further purification. Melting point 57-60 [deg.] C. NMR (CDCl ₃ ) δ: 3.20 (2H, t, J = 8.8 Hz), 4.51
(2H, s), 4.59 (2H, t, J = 8.8Hz), 6.73 (1H, d, J = 8.2H
z), 7.14 (1H, d, J = 8.2 Hz), 7.24 (1H, s). Reference Example 81 3- (2,3-dihydrobenzofuran-5)
-Yl) -ethyl 2-phenylpropionate 1,1,1,3,3,3 at -78 ° C under an argon atmosphere
-Hexamethyldisilazane (37.4 g, 0.232 m
ol) in tetrahydrofuran (150 mL) solution.
6M butyl lithium hexane solution (127 mL, 0.2
03 mol) was added dropwise and stirred for 15 minutes. To this was added dropwise a solution of ethyl phenylacetate (33.3 g, 0.203 mol) in tetrahydrofuran (20 mL).
Stir for 5 minutes. Further, 5-bromomethyl-2,3-dihydrobenzofuran (41.0 g, 0.193 mol)
Of tetrahydrofuran (50 mL) was added dropwise, and 20
Stirred for minutes. After adding water to the reaction solution and raising the temperature to room temperature,
Extracted with ethyl acetate. The extract was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1) to obtain the title compound (yield 54.5 g, 95%). Oily. NMR (CDCl ₃ ) δ: 1.13 (3H, t, J = 6.8 Hz), 2.93
(1H, dd, J = 6.2Hz, 13.8Hz), 3.14 (2H, t, J = 8.8Hz), 3.
32 (1H, dd, J = 9.0Hz, 13.8Hz), 3.78 (1H, dd, J = 6.2Hz, 9.
0Hz), 4.00-4.15 (2H, m), 4.52 (2H, t, J = 8.8Hz), 6.
64 (1H, d, J = 8.2Hz), 6.87 (1H, d, J = 8.2Hz), 6.96 (1
H, s), 7.21-7.38 (5H, m).

Reference Example 82 3- (7-Bromo-2,3-
Ethyl dihydrobenzofuran-5-yl) -2-phenylpropionate In the same manner as in Reference Example 4, the title compound was obtained from ethyl 3- (2,3-dihydrobenzofuran-5-yl) -2-phenylpropionate. (Yield 97%). Oily. NMR (CDCl ₃ ) δ: 1.15 (3H, t, J = 7.2 Hz), 2.89
(1H, dd, J = 6.2Hz, 13.8Hz), 3.23 (2H, t, J = 8.6Hz), 3.
29 (1H, dd, J = 8.8Hz, 13.8Hz), 3.75 (1H, dd, J = 6.2Hz, 8.
8Hz), 4.12 (2H, q, J = 7.2Hz), 4.62 (2H, t, J = 8.6H)
z), 6.87 (1H, s), 7.04 (1H, s), 7.30-7.32 (5H,
m).

Reference Example 83 3- (6,7-dibromo-
Ethyl 2,3-dihydrobenzofuran-5-yl) -2-phenylpropionate By a method similar to that in Reference Example 15, 3- (7-bromo-
The title compound was obtained from ethyl 2,3-dihydrobenzofuran-5-yl) -2-phenylpropionate (yield 3).
5%). Oily. NMR (CDCl ₃ ) δ: 1.14 (3H, t, J = 7.0 Hz), 3.11
(1H, dd, J = 5.4Hz, 14.0Hz), 3.19 (2H, t, J = 8.8Hz), 3.
50 (1H, dd, J = 9.4Hz, 14.0Hz), 3.96 (1H, dd, J = 5.4Hz, 9.
4Hz), 4.08 (2H, q, J = 7.0Hz), 4.64 (2H, t, J = 8.8H)
z), 6.92 (1H, s), 7.28-7.32 (5H, m).

Reference Example 84 3- (6,7-dibromo-
2,3-Dihydrobenzofuran-5-yl) -2-phenylpropionic acid In the same manner as in Reference Example 5, 3- (6,7-dibromo-2,3-dihydrobenzofuran-5-yl) -2-phenylpropionic acid was obtained. The title compound was obtained from ethyl onate (56% yield). 188-189 ° C (recrystallized from ethyl acetate / hexane). NMR (CDCl ₃ ) δ: 3.06-3.21 (3H, m), 3.50 (1
H, dd, J = 8.8Hz, 14.0Hz), 4.01 (1H, dd, J = 5.8Hz, 8.8H
z), 4.63 (2H, t, J = 8.8Hz), 6.85 (1H, s), 7.32 (5H,
s), 1H is hidden and invisible. Reference Example 85 4,5-Dibromo-1,2,6,7-tetrahydro-7-phenyl-8H-indeno [5,4-
b] Furan-8-one The title compound was obtained from 3- (6,7-dibromo-2,3-dihydrobenzofuran-5-yl) -2-phenylpropionic acid in the same manner as in Reference Example 6. Rate 81
%). 208-211 ° C. NMR (CDCl ₃ ) δ: 3.19 (1H, dd, J = 3.9Hz, 17.7H)
z), 3.55 (2H, t, J = 9.0Hz), 3.61 (1H, dd, J = 8.3Hz, 17.
7Hz), 3.92 (1H, dd, J = 3.9Hz, 8.3Hz), 4.81 (2H, t, J =
9.0Hz), 7.15-7.45 (5H, m).

Reference Example 86 1,2,6,7-Tetrahydro-7-phenyl-8H-indeno [5,4-b] furan-8-one In the same manner as in Reference Example 18, 4,5-dibromo-
1,2,6,7-tetrahydro-7-phenyl-8H-
The title compound was obtained from indeno [5,4-b] furan-8-one (70% yield). Melting point 108-110 ° C NMR (CDCl ₃ ) δ: 3.12 (1H, dd, J = 4.0Hz, 16.8H)
z), 3.38 (2H, t, J = 8.8Hz), 3.53 (1H, dd, J = 8.1Hz, 16.
8Hz), 3.79 (1H, dd, J = 4.0Hz, 8.1Hz), 4.57 (2H, t, J =
8.8Hz), 6.98 (1H, d, J = 8.4Hz), 7.07-7.29 (6H, m).

Reference Example 87 (E)-(1,6,7,8-
Tetrahydro-7-phenyl-2H-indeno [5,4
-B] furan-8-ylidene) acetonitrile and (1,6-dihydro-7-phenyl-2H-indeno [5,4-b] furan-8-yl) acetonitrile 1,2,6,7 at reflux To a solution of -tetrahydro-7-phenyl-8H-indeno [5,4-b] furan-8-one (4.4 g, 17.6 mmol) in tetrahydrofuran (100 mL), diethyl cyanomethylphosphonate (3.27 g, 18.1 g). 5 mmol), a phosphonate ylide solution prepared from 60% sodium hydride (0.73 g, 18.5 mmol) and tetrahydrofuran (80 mL) was added dropwise. After heating and refluxing the reaction solution for 1.5 hours, the same amount of phosphonate ylide solution was further added dropwise.
After heating the reaction solution to reflux for 30 minutes, it was cooled to room temperature and water was added. The product was extracted with ethyl acetate, and the extract was washed with water, dried and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1), and subsequently crystallized from ethyl acetate / isopropyl ether to give (E)-(1,6,7,8-tetrahydro-7-phenyl). -2H-indeno [5,4-b] furan-8-ylidene) acetonitrile (abbreviated as A) and (1,6-dihydro-7-phenyl-2H-indeno [5,4-b] furan-8-yl ) A mixture of acetonitrile (abbreviated as B) (A: B = 1: 2) was obtained. 123-126 ° C (recrystallized from ethyl acetate / isopropyl ether). NMR (CDCl ₃ ) δ: (A) 3.03 (1H, dd, J = 17.2 Hz,
1.8Hz), 3.32 (2H, dt, J = 11.4Hz, 2.2Hz), 3.59 (1H, d
d, J = 17.2Hz, 8.4Hz), 4.48 (1H, dt, J = 8.4Hz, 1.8Hz),
4.68 (2H, t, J = 11.4Hz), 5.53 (1H, d, J = 1.8Hz), 6.91
(1H, d, J = 8.0Hz), 7.10-7.60 (6H, m). (B) 3.61 (2H, t, J = 8.8Hz), 3.68 (2H, s), 3.75 (2
H, s), 4.68 (2H, t, J = 8.8Hz), 6.73 (1H, d, J = 8.0H
z), 7.10-7.60 (6H, m).

Example 1 N- [2- (1,6,7,8-
Tetrahydro-2H-indeno [5,4-b] furan-
8-yl) ethyl] acetamide 2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethylamine hydrobromide (0.10 g, 0.352 mmol ) In tetrahydrofuran (1.5 mL) and 1N aqueous sodium hydroxide solution (1.5 mL) and acetic anhydride (0.050 m
L, 0.528 mmol) was added and the mixture was allowed to stand at room temperature for 30 minutes.
Stirred for minutes. Water was added to the reaction solution, which was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from isopropyl ether / hexane to give the title compound (0.057 g, 66% yield). 78-79 ° C. NMR (CDCl ₃ ) δ: 1.53-2.12 (3H, m), 1.96 (3
H, s), 2.20-2.38 (1H, m), 2.70-2.96 (2H, m), 3.02-
3.40 (5H, m), 4.45-4.68 (2H, m), 5.46 (1H, brs),
6.62 (1H, d, J = 8.0Hz), 6.96 (1H, d, J = 8.0Hz). Elemental analysis: C ₁₅ H ₁₉ NO ₂ Calculated: C, 73.44; H, 7.81; N, 5.71. Found: C, 73.55; H, 7.90; N, 5.60.

Example 2 N- [2- (1,6,7,8-
Tetrahydro-2H-indeno [5,4-b] furan-
8-yl) ethyl] propionamide In the same manner as in Example 1, 2- (1,6,7,8-
Tetrahydro-2H-indeno [5,4-b] furan-
The title compound was obtained from 8-yl) ethylamine hydrobromide and propionyl chloride (78% yield). 102-104 ° C (recrystallized from isopropyl ether / hexane). NMR (CDCl ₃ ) δ: 1.14 (3H, t, J = 7.6 Hz), 1.55
-2.38 (4H, m), 2.18 (2H, q, J = 7.6Hz), 2.69-2.99 (2
H, m), 3.02-3.40 (5H, m), 4.42-4.63 (2H, m), 5.61
(1H, brs), 6.62 (1H, d, J = 7.8Hz), 6.95 (1H, d, J = 7.
8Hz). Elemental analysis: C ₁₆ H ₂₁ NO ₂ Calculated: C, 74.10; H, 8.16; N, 5.40. Found: C, 74.20; H, 8.37; N, 5.25.

Example 3 N- [2- (3,7,8,9-
Tetrahydropyrano [3,2-e] indol-1-yl) ethyl] acetamide In the same manner as in Example 1, 2- (3,7,8,9-
The title compound was obtained from tetrahydropyrano [3,2-e] indol-1-yl) ethylamine and acetic anhydride (54% yield). 185-186 ° C (recrystallized from methanol / isopropyl ether). NMR (CDCl ₃ ) δ: 1.96 (3H, s), 2.03-2.15 (2
H, m), 3.09 (2H, t, J = 6.8Hz), 3.20 (2H, t, J = 6.8H
z), 3.56 (2H, q, J = 6.4Hz), 4.18 (2H, t, J = 7.0Hz),
5.60 (1H, brs), 6.73 (1H, d, J = 8.8Hz), 6.96 (1H, d,
J = 2.2Hz), 7.09 (1H, d, J = 8.8Hz), 7.98 (1H, brs). Elemental analysis: C ₁₅ H ₁₈ N ₂ O ₂ Calculated: C, 69.74; H, 7.02; N, 10.84. Found: C, 69.69; H, 7.09; N, 10.79.

Example 4 N- [2- (3,7,8,9-
Tetrahydropyrano [3,2-e] indol-1-yl) ethyl] propionamide In the same manner as in Example 1, 2- (3,7,8,9-
The title compound was obtained from tetrahydropyrano [3,2-e] indol-1-yl) ethylamine and propionyl chloride (67% yield). 147-148 ° C (recrystallized from methanol / isopropyl ether). NMR (CDCl ₃ ) δ: 1.14 (3H, t, J = 7.6 Hz), 2.02-
2.16 (2H, m), 2.17 (2H, q, J = 7.6Hz), 3.08 (2H, t, J =
7.0Hz), 3.19 (2H, t, J = 7.0Hz), 3.57 (2H, q, J = 6.2H)
z), 4.18 (2H, t, J = 5.0Hz), 5.60 (1H, brs), 6.72
(1H, d, J = 8.4Hz), 6.94 (1H, d, J = 2.2Hz), 7.09 (1H,
d, J = 8.4 Hz), 8.11 (1H, br s). Elemental analysis: C ₁₆ H ₂₀ N ₂ O ₂ Calculated: C, 70.56; H, 7.40; N, 10.29. Found: C, 70.69; H, 7.54; N, 10.27.

Example 5 N- [2- (3,7,8,9-
Tetrahydropyrano [3,2-e] indol-1-yl) ethyl] butylamide In the same manner as in Example 1, 2- (3,7,8,9-
The title compound was obtained from tetrahydropyrano [3,2-e] indol-1-yl) ethylamine and butyryl chloride (yield 62%). 154-155 ° C (recrystallized from methanol / isopropyl ether). NMR (CDCl ₃ ) δ: 0.93 (3H, t, J = 7.2 Hz), 1.57
-1.73 (2H, m), 2.06-2.16 (4H, m), 3.08 (2H, t, J = 6.8
Hz), 3.19 (2H, t, J = 6.4Hz), 3.52-3.63 (2H, m), 4.1
8 (2H, t, J = 5.2Hz), 5.58 (1H, brs), 6.72 (1H, d, J =
8.4Hz), 6.94 (1H, d, J = 2.6Hz), 7.09 (1H, d, J = 8.4H)
z), 8.05 (1H, br s). Elemental analysis: C ₁₇ H ₂₂ N ₂ O ₂ Calculated: C, 71.30; H, 7.74; N, 9.78. Found: C, 71.45; H, 7.86; N, 9.78.

Example 6 N- [2- (1,2,3,7,
8,9-Hexahydropyrano [3,2-e] indole-1-yl) ethyl] acetamide N- [2- (3,7,8,9-tetrahydropyrano [3,2-e] indole- To a suspension of 1-yl) ethyl] acetamide (0.90 g, 3.48 mmol) in ethanol (40 mL) was added platinum oxide (45 mg) and hydrochloric acid (2 mL), and the mixture was placed under a hydrogen atmosphere (4 to 5 atmospheres). Stirred at 50 ° C. for 6 hours. After the reaction solution was filtered, the solution was concentrated under reduced pressure. The residue was neutralized with saturated aqueous sodium hydrogen carbonate, and then saturated with sodium chloride, and extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate / isopropyl ether to give the title compound (0.53 g, 59% yield). 137-138 ° C. NMR (CDCl ₃ ) δ: 1.78-2.05 (4H, m), 1.90 (3
H, s), 2.68 (2H, t, J = 6.6Hz), 2.96-3.14 (1H, m), 3.
31-3.50 (3H, m), 3.65 (1H, t, J = 9.4Hz), 3.98-4.10
(1H, m), 4.15-4.26 (1H, m), 6.13 (1H, brs), 6.49
(1H, d, J = 8.4Hz), 6.57 (1H, d, J = 8.4Hz), 1H are hidden and invisible. Elemental analysis: C ₁₅ H ₂₀ N ₂ O ₂ Calculated: C, 69.20; H, 7.74; N, 10.76. Found: C, 69.05; H, 7.74; N, 10.61.

Example 7 N- [2- (1,2,3,7,
8,9-Hexahydropyrano [3,2-e] indol-1-yl) ethyl] propionamide In the same manner as in Example 6, N- [2- (3,7,
The title compound was obtained from 8,9-tetrahydropyrano [3,2-e] indol-1-yl) ethyl] propionamide (42% yield). 106-107 ° C (recrystallized from ethyl acetate / isopropyl ether). NMR (CDCl ₃ ) δ: 1.11 (3H, t, J = 7.6 Hz), 1.76
-2.08 (4H, m), 2.13 (2H, q, J = 7.6Hz), 2.68 (2H, t, J =
6.4Hz), 2.99-3.16 (1H, m), 3.31-3.51 (3H, m), 3.6
5 (1H, t, J = 9.4Hz), 3.98-4.10 (1H, m), 4.15-4.24 (1
H, m), 6.10 (1H, brs), 6.48 (1H, d, J = 8.4Hz), 6.56
(1H, d, J = 8.4Hz), 1H is hidden and invisible. Elemental analysis: C ₁₆ H ₂₂ N ₂ O ₂ Calculated: C, 70.04; H, 8.08; N, 10.21. Found: C, 70.18; H, 8.34; N, 10.13.

Example 8 N- [2- (1,2,3,7,
8,9-Hexahydropyrano [3,2-e] indol-1-yl) ethyl] butylamide In the same manner as in Example 6, N- [2- (3,7,
The title compound was obtained from 8,9-tetrahydropyrano [3,2-e] indol-1-yl) ethyl] butyramide (55% yield). 91-93 ° C (recrystallized from ethyl acetate / isopropyl ether). NMR (CDCl ₃ ) δ: 0.92 (3H, t, J = 7.2 Hz), 1.53
-1.71 (2H, m), 1.76-1.88 (2H, m), 1.91-2.10 (2H, m
m), 2.05 (2H, q, J = 8.2Hz), 2.68 (2H, t, J = 6.6Hz),
2.99-3.16 (1H, m), 3.30-3.50 (3H, m), 3.64 (1H, t, J
= 9.2Hz), 3.98-4.09 (1H, m), 4.15-4.23 (1H, m), 6.
11 (1H, brs), 6.48 (1H, d, J = 8.4Hz), 6.56 (1H, d, J =
8.4Hz), 1H is hidden and invisible. Elemental analysis: C ₁₇ H ₂₄ N ₂ O ₂ Calculated: C, 70.80; H, 8.39; N, 9.71. Found: C, 70.55; H, 8.45; N, 9.68.

Example 9 N- [2- (5-fluoro-
3,7,8,9-tetrahydrocyclopenta [f]
[1] Benzopyran-9-yl) ethyl] propionamide N- [2- (5-fluoro-6- (2-propynyloxy) indan-1-yl) ethyl] propionamide (0.55 g, 1.90 mmol) Of bromobenzene (15 mL) was stirred in a sealed tube at 250 ° C. for 8 hours. After cooling the reaction solution, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate) to obtain the title compound (yield 0.27 g, 49%). 108-110 ° C (recrystallized from ethyl acetate / hexane). NMR (CDCl ₃ ) δ: 1.14 (3H, t, J = 7.5 Hz), 1.50
-1.81 (2H, m), 1.89-2.30 (2H, m), 2.18 (2H, q, J = 7.5
Hz), 2.55-3.00 (2H, m), 3.16-3.40 (3H, m), 4.66
4.92 (2H, m), 5.40 (1H, brs), 5.88 (1H, dt, J = 9.9H
z, 3.7Hz), 6.43-6.53 (1H, m), 6.80 (1H, d, J = 10.6H
z).

Example 10 N- [2- (5-fluoro-
1,2,3,7,8,9-Hexahydrocyclopenta [f] [1] benzopyran-9-yl) ethyl] propionamide In the same manner as in Reference Example 3, N- [2- (5-fluoro -3,7,8,9-tetrahydrocyclopenta [f]
[1] Benzopyran-9-yl) ethyl] propionamide gave the title compound (80% yield). 106-108 ° C (recrystallized from ethyl acetate / hexane). NMR (CDCl ₃ ) δ: 1.14 (3H, t, J = 7.7 Hz), 1.47
-1.84 (2H, m), 1.84-2.27 (4H, m), 2.17 (2H, q, J = 7.7
Hz), 2.60-3.01 (4H, m), 3.05-3.20 (1H, m), 3.21-
3.41 (2H, m), 4.05-4.20 (1H, m), 4.27-4.39 (1H,
m), 5.40 (1H, br s), 6.77 (1H, d, J = 10.6 Hz).

Example 11 (S) -N- [2- (1,
6,7,8-tetrahydro-2H-indeno [5,4-
b] furan-8-yl) ethyl] propionamide N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide was converted at a high speed. Liquid chromatography (Equipment: L
C Module 1 (manufactured by Nippon Millipore Limited),
Column: Ceramospher RU-1 (10
(Id) × 250 mm manufactured by Shiseido), mobile phase: methanol, flow rate: 4.4 mL / min, column temperature: 50
° C, sample concentration: 17% (w / v), injection amount: 8.5 m
Separation was performed using g) to obtain the title compound. [Α] _D ²⁰ = -57.8 ° (c 1.004, chloroform). 113-115 ° C (recrystallized from ethyl acetate). NMR (CDCl ₃ ) δ: 1.14 (3H, t, J = 7.7 Hz), 1.52-2.
40 (4H, m), 2.17 (2H, q, J = 7.7Hz), 2.69-3.00 (2H, m), 3.01-
3.40 (5H, m), 4.42-4.64 (2H, m), 5.40 (1H, br s), 6.62 (1H,
d, J = 7.7 Hz), 6.95 (1H, d, J = 7.7 Hz). Elemental analysis: C ₁₆ H ₂₁ NO ₂ Calculated: C, 74.10; H, 8.16; N, 5.40. Found: C, 73.86; H, 7.97; N, 5.47.

Example 12 (R) -N- [2- (1,
6,7,8-tetrahydro-2H-indeno [5,4-
b] Furan-8-yl) ethyl] propionamide In the same manner as in Example 11, N- [2- (1,6,
7,8-tetrahydro-2H-indeno [5,4-b]
Furan-8-yl) ethyl] propionamide was fractionated using high performance liquid chromatography to give the title compound. [Α] _D ²⁰ = + 57.8 ° (c 1.005, chloroform). 113-115 ° C (recrystallized from ethyl acetate). NMR (CDCl ₃ ) δ: 1.14 (3H, t, J = 7.7 Hz), 1.52-2.
40 (4H, m), 2.17 (2H, q, J = 7.7Hz), 2.69-3.00 (2H, m), 3.01-
3.40 (5H, m), 4.42-4.64 (2H, m), 5.40 (1H, br s), 6.62 (1H,
d, J = 7.7 Hz), 6.95 (1H, d, J = 7.7 Hz). Elemental analysis: C ₁₆ H ₂₁ NO ₂ Calculated: C, 74.10; H, 8.16; N, 5.40. Found: C, 73.97; H, 7.97; N, 5.47.

Example 13 N- [2- (1,6,7,8
-Tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] butylamide In the same manner as in Example 1, 2- (1,6,7,8-
Tetrahydro-2H-indeno [5,4-b] furan-
The title compound was obtained from 8-yl) ethylamine hydrochloride and butyryl chloride (67% yield). 55-57 ° C (recrystallized from ethyl acetate) NMR (CDCl ₃ ) δ: 0.94 (3H, t, J = 7.3 Hz), 1.51-1.
90 (4H, m), 1.92-2.08 (1H, m), 2.12 (2H, t, J = 7.3Hz), 2.17-
2.38 (1H, m), 2.68-2.98 (2H, m), 3.00-3.40 (5H, m), 4.41-4.
68 (2H, m), 5.43 (1H, br s), 6.62 (1H, d, J = 8.0Hz), 6.96 (1H,
d, J = 8.0Hz). Elemental analysis: C ₁₇ H ₂₃ NO ₂ Calculated: C, 74.69; H, 8.48; N, 5.12. Found: C, 74.59; H, 8.33; N, 5.36.

Example 14 N- [2- (1,6-dihydro-2H-indeno [5,4-b] furan-8-yl)
Ethyl] acetamide 2- (1,6-dihydro-2H-indeno [5,4-
b] Furan-8-yl) ethylamine hydrochloride (0.6
g, 2.52 mmol) and triethylamine (0.
Acetyl chloride (0.2 g) was added to a solution of N, N-dimethylformamide (64 mL, 64 g, 6.31 mmol) in 60 mL of N, N-dimethylformamide.
(4 g, 3.03 mmol) was gradually added dropwise under ice cooling.
After stirring at room temperature overnight, the reaction solution was concentrated, poured into water, and the organic matter was extracted with ethyl acetate. The extract was washed with brine and water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: methanol = 98: 2), and further recrystallized from ethyl acetate to obtain the title compound (425 mg, yield 70%). 153-155 ° C (recrystallized from ethyl acetate). NMR (CDCl ₃ ) δ: 1.98 (3H, s), 2.80 (2H, m), 3.31
(2H, brs), 3.43 (2H, t, J = 8.6Hz), 3.57 (2H, q, J = 7.0Hz), 4.
60 (2H, d, J = 8.6Hz), 5.62 (1H, br s), 6.30 (1H, s), 6.67 (1H,
d, J = 7.9 Hz), 7.18 (1H, d, J = 7.9 Hz). Elemental analysis: C ₁₅ H ₁₇ NO ₂ Calculated: C, 74.05; H, 7.04; N, 5.76. Found: C, 73.98; H, 7.06; N, 5.92.

Example 15 N- [2- (1,6-dihydro-2H-indeno [5,4-b] furan-8-yl)
Ethyl] propionamide By a method similar to that in Example 14, 2- (1,6-dihydro-2H-indeno [5,4-b] furan-8-yl)
The title compound was obtained from ethylamine hydrochloride and propionyl chloride (90% yield). 131-133 ° C (recrystallized from ethyl acetate / hexane). NMR (CDCl ₃ ) δ: 1.15 (3H, t, J = 7.7 Hz), 2.20 (2
H, q, J = 7.7Hz), 2.80 (2H, m), 3.31 (2H, br s), 3.44 (2H, t, J =
8.6Hz), 3.58 (2H, q, J = 7.0Hz), 4.60 (2H, d, J = 8.6Hz), 5.60
(1H, br s), 6.29 (1H, s), 6.68 (1H, d, J = 7.9Hz), 7.19 (1H, d,
J = 7.9Hz). Elemental analysis: C ₁₆ H ₁₉ NO ₂ Calculated: C, 74.68; H, 7.44; N, 5.44. Found: C, 74.59; H, 7.34; N, 5.71.

Example 16 N- [2- (1,6-dihydro-2H-indeno [5,4-b] furan-8-yl)
Ethyl] butylamide By a method similar to that in Example 14, 2- (1,6-dihydro-2H-indeno [5,4-b] furan-8-yl)
The title compound was obtained from ethylamine hydrochloride and butyryl chloride (95% yield). 131-133 ° C (recrystallized from ethyl acetate / hexane). NMR (CDCl ₃ ) δ: 0.94 (3H, t, J = 7.3 Hz), 1.58-1.
76 (2H, m), 2.14 (2H, q, J = 7.5Hz), 2.80 (2H, m), 3.31 (2H, br
s), 3.44 (2H, t, J = 8.6Hz), 3.58 (2H, q, J = 6.8Hz), 4.60 (2H,
d, J = 8.6Hz), 5.60 (1H, br s), 6.29 (1H, s), 6.67 (1H, d, J = 7.
9Hz), 7.18 (1H, d, J = 7.9Hz). Elemental analysis: C ₁₇ H ₂₁ NO ₂ Calculated: C, 75.25; H, 7.80; N, 5.16. Found: C, 75.25; H, 7.73; N, 5.23.

Table 1 shows the structural formulas of the compounds obtained in Examples 1 to 16.

[Table 1]

Example 17 2- (1,6-dihydro-2)
H-indeno [5,4-b] furan-8-yl) ethylamine hydrochloride

Embedded image (E)-(1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-ylidene) acetonitrile (2.6 g, 13.2 mmol) in ethanol (1
50 mL) solution, a saturated ammonia / ethanol solution (150 mL) and Raney cobalt (8.4 g) were added, and the reaction mixture was placed under a hydrogen atmosphere (5 kgf / cm ² ).
Stir at room temperature for 3 hours. After removing Raney cobalt,
The solvent was distilled off under reduced pressure to give 2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-
Ylidene) ethylamine was obtained. A saturated hydrogen chloride / ethanol solution (100 mL) was added to the residue, and the mixture was heated under reflux for 1 hour. The residue obtained by concentrating the reaction solution was recrystallized from ethanol to obtain the title compound (yield 2.75 g,
Yield 88%). 243-245 ° C (recrystallized from ethanol). _{NMR (d 6 -DMSO, D 2} O) δ: 2.90 (2H, t, J = 7.7H
z), 3.13 (2H, t, J = 7.7Hz), 3.28 (2H, s), 3.40 (2H, t, J = 8.7H
z), 4.56 (2H, t, J = 8.7Hz), 6.41 (1H, s), 6.62 (1H, d, J = 7.9H
z), 7.19 (1H, d, J = 7.9Hz). Elemental analysis: C ₁₃ H ₁₅ NO · HCl Calculated: C, 65.68; H, 6.78; N, 5.89; Cl, 14.9
1. Found: C, 65.81; H, 6.83; N, 5.90; Cl, 14.8.
9.

Example 18 2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-
Yl) ethylamine hydrobromide

Embedded image (E)-(4-Bromo-1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-ylidene) acetonitrile (0.44 g, 1.59 mmol)
To a suspension of ethanol (30 mL) was added Raney nickel (0.4 g, W2) and a 4 M ammonia / ethanol solution (10 mL), and the mixture was stirred at room temperature under a hydrogen atmosphere (4 to 5 atm) for 5 hours. After filtering the reaction solution, the filtrate was concentrated under reduced pressure. Residue is ethanol (50 mL)
Then, 5% palladium carbon (1 g, 50% water-containing product) was added, and the mixture was stirred at room temperature for 4 hours under a hydrogen atmosphere (normal pressure). After the reaction solution was filtered, the solution was concentrated under reduced pressure.
The title compound (0.42 g, 93% yield) was obtained. Amorphous. NMR (CDCl ₃ ) δ: 1.58-1.83 (2H, m), 1.97-2.
36 (2H, m), 2.70-2.96 (6H, m), 3.03-3.36 (3H, m),
4.42-4.64 (2H, m), 6.61 (1H, d, J = 8.2Hz), 6.95 (1H, m
d, J = 8.2Hz).

Example 19 (S) -N- [2- (1,
6,7,8-tetrahydro-2H-indeno [5,4-
b] furan-8-yl) ethyl] propionamide (S) -2- (1,6,7,8-tetrahydro-2H-
N, N of indeno [5,4-b] furan-8-yl) ethylamine hydrochloride (5.55 g, 23.1 mmol) and triethylamine (4.7 g, 46.3 mmol)
-Propionyl chloride (2.57 g, 27.8 mmol) was gradually added dropwise to a solution of dimethylformamide (100 mL) under ice-cooling. After stirring at room temperature for 1 hour, the reaction solution was poured into water, and the organic matter was extracted with ethyl acetate. The extract was washed with brine and water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: methanol = 98: 2) to give the title compound (5.25 g, 88% yield). 113-115 ° C (recrystallized from ethyl acetate). NMR (CDCl ₃ ) δ: 1.14 (3H, t, J = 7.7 Hz), 1.52
-2.40 (4H, m), 2.17 (2H, q, J = 7.7Hz), 2.69-3.00 (2
H, m), 3.01-3.40 (5H, m), 4.42-4.64 (2H, m), 5.40
(1H, brs), 6.62 (1H, d, J = 7.7Hz), 6.95 (1H, d, J = 7.
7Hz). Elemental analysis: C ₁₆ H ₂₁ NO ₂ Calculated: C, 74.10; H, 8.16; N, 5.40. Found: C, 73.83; H, 8.12; N, 5.23.

Example 20 (S) -N- [2- (1,
6,7,8-tetrahydro-2H-indeno [5,4-
b] Furan-8-yl) ethyl] propionamide (S) -N- [2- (6-hydroxy-7- (2-hydroxyethyl) indan-1-yl) ethyl] propionamide (5 g, 18 mmol) Pyridine (14.6
Methanesulfonyl chloride (1.4 mL, 18 mmol) was added dropwise while the solution was cooled on ice and kept at about −10 ° C. The reaction solution was stirred in a range of -10 ° C to -5 ° C for 25 minutes. Furthermore, methanesulfonyl chloride (0.7m
L, 9 mmol) was added dropwise to the reaction solution to give a temperature of -10C to -5C.
Stirred for another 25 minutes in the range of ° C. Ethyl acetate (10 mL) and saturated aqueous sodium hydrogen carbonate (10 mL) were gradually added to the reaction solution, and the mixture was returned to room temperature and stirred for 30 minutes. The organic matter was extracted with ethyl acetate, which was washed with 2N hydrochloric acid and water.
After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was dissolved in ethyl acetate (20 mL),
Triethylamine (4.6 g, 45.1 mmol) was added, and the mixture was heated under reflux for 40 minutes. The reaction mixture was added with 2N hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate and water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate) to obtain the title compound (4.04 g, 86% yield). ^{_{[Α] D 20 = -57.8 °}} (c 1.004, chloroform). 113-115 ° C (recrystallized from ethyl acetate). NMR (CDCl ₃ ) δ: 1.14 (3H, t, J = 7.7 Hz), 1.52-
2.40 (4H, m), 2.17 (2H, q, J = 7.7Hz), 2.69-3.00 (2H, m
m), 3.01-3.40 (5H, m), 4.42-4.64 (2H, m), 5.40 (1
H, brs), 6.62 (1H, d, J = 7.7Hz), 6.95 (1H, d, J = 7.7H)
z). Elemental analysis: C ₁₆ H ₂₁ NO ₂ Calculated: C, 74.10; H, 8.16; N, 5.40. Found: C, 73.86; H, 7.97; N, 5.47.

Example 21 N- [2- (7,8-dihydro-6H-indeno [4,5-d] -1,3-dioxol-8-yl) ethyl] propionamide hexamethylphosphoramide (5 mL) ) Was cooled on ice to give sodium hydride (0.28 g, 7.5 mmol, content 6).
5%) was added slowly. A solution of N- [2- (6,7-dihydroxyindan-1-yl) ethyl] propionamide (0.85 g, 3.41 mmol) in hexamethylphosphoramide (5 mL) was added thereto over 6 minutes at room temperature. It was dropped. When the bubbling of the hydrogen gas stopped, diiodomethane (1.1 g, 4.1 mmol) was added dropwise, and the mixture was stirred at room temperature for 2 hours. Pour the reaction mixture into water and neutralize with dilute hydrochloric acid.
Organics were extracted with ethyl acetate. After the extract was washed with saturated saline and water, dried over anhydrous magnesium sulfate,
The solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate) to give the title compound (280 mg, 31%). 102-104 ° C (recrystallized from ethyl acetate / hexane). NMR (CDCl ₃ ) δ: 1.16 (3H, t, J = 7.7 Hz), 1.70
-1.89 (2H, m), 1.90-2.10 (1H, m), 2.15-2.40 (1H,
m), 2.20 (2H, q, J = 7.7Hz), 2.68-3.00 (2H, m), 3.13
-3.36 (2H, m), 3.40-3.59 (1H, m), 3.68 (1H, br
s), 5.92 (2H, dd, J = 1.5Hz, 9.9Hz), 6.67 (2H, s). Elemental analysis: C ₁₅ H ₁₉ NO ₃ Calculated: C, 68.94; H, 7.33; N, 5.36. Found: C, 68.89; H, 7.28; N, 5.42.

Example 22 N- [2- (7,8-dihydro-6H-indeno [4,5-d] -1,3-dioxol-8-yl) ethyl] butylamide N- [2- (6 7-dihydroxyindan-1-yl) ethyl] butyramide (1.13 g, 4.29 mm)
ol), dibromomethane (2.98 g, 17.2 mmol)
l), potassium carbonate (1.78 g, 12.9 mmol)
And copper (II) oxide (34 mg, 0.43 mmol)
Of N, N-dimethylformamide (15 mL)
The mixture was heated and stirred at 10 ° C. for 3 hours. The reaction solution was cooled, poured into water, neutralized with dilute hydrochloric acid, and extracted with ethyl acetate.
The extract was washed with brine and water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate) to obtain the title compound (785 mg, yield 67%). 71-73 ° C (recrystallized from ethyl acetate / hexane). NMR (CDCl ₃ ) δ: 0.95 (3H, t, J = 7.3 Hz), 1.57
-2.40 (6H, m), 2.15 (2H, t, J = 7.5Hz), 2.67-3.00 (2
H, m), 3.15-3.34 (2H, m), 3.39-3.58 (1H, m), 5.67
(1H, s), 5.91 (2H, dd, J = 1.5Hz, 9.5Hz), 6.67 (2H,
s). Elemental analysis: C ₁₆ H ₂₁ NO ₃ Calculated: C, 69.79; H, 7.69; N, 5.09. Found: C, 69.75; H, 7.40; N, 5.28.

Example 23 N- [2- (2,3,8,9
-Tetrahydro-7H-indeno [4,5-b] -1,
4-Dioxin-9-yl) ethyl] propionamide By a method similar to that in Example 22, N- [2- (6,7-
The title compound was obtained from dihydroxyindan-1-yl) ethyl] propionamide and 1,2-dibromoethane (yield 90%). 120-122 ° C (recrystallized from ethyl acetate / hexane). NMR (CDCl ₃ ) δ: 1.15 (3H, t, J = 7.5 Hz), 1.60
-2.00 (3H, m), 2.10-2.32 (1H, m), 2.19 (2H, q, J = 7.5
Hz), 2.61-3.01 (2H, m), 3.08-3.53 (3H, m), 4.25
(4H, br s), 5.67 (1H, br s), 6.69 (2H, s). Elemental analysis: C ₁₆ H ₂₁ NO ₃ Calculated: C, 69.79; H, 7.69; N, 5.09. Found: C, 69.90; H, 7.61; N, 5.20.

Example 24 N- [2- (2,3,8,9
-Tetrahydro-7H-indeno [4,5-b] -1,
4-Dioxin-9-yl) ethyl] butyramide In the same manner as in Example 22, N- [2- (6,7-
The title compound was obtained from dihydroxyindan-1-yl) ethyl] butylamide and 1,2-dibromoethane (yield 90%). 84-87 ° C (recrystallized from ethyl acetate / diethyl ether / petroleum ether). NMR (CDCl ₃ ) δ: 0.95 (3H, t, J = 7.7 Hz), 1.57
-2.00 (5H, m), 2.14 (2H, t, J = 7.3Hz), 2.18-2.34 (1
H, m), 2.61-3.01 (2H, m), 3.10-3.55 (3H, m), 4.25
(4H, s), 5.65 (1H, brs), 6.60 (2H, s). Elemental analysis: C ₁₇ H ₂₃ NO ₃ Calculated: C, 70.56; H, 8.01; N, 4.84. Found: C, 70.45; H, 7.85; N, 4.98.

Example 25 N- [2- (7,8-dihydro-6H-indeno [4,5-d] oxazole-8-
Yl) ethyl] acetamide N- [2- (7-amino-6-hydroxyindane-1
-Yl) ethyl] acetamide (630 mg, 2.7 m
mol) in methanol (5 mL), a solution of methyl orthoformate (7.4 mL, 67.3 mmol) and a saturated hydrogen chloride / methanol (1.4 mL) solution were added under ice-cooling. The reaction solution was heated and stirred at room temperature for 30 minutes and further at 60 ° C. for 1 hour. After cooling, the reaction solution was poured into ice water, and the organic matter was extracted with chloroform. The extract was washed with brine and water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 20: 1) to give the title compound (520 mg, yield 79%). 89-92 ° C (recrystallized from ethyl acetate / isopropyl ether). NMR (CDCl ₃ ) δ: 1.88-2.02 (3H, m), 2.04 (3
H, s), 2.34-2.53 (1H, m), 2.86-3.19 (3H, m), 3.59-
3.72 (2H, m), 6.94 (1H, brs), 7.25 (1H, d, J = 8.4H
z), 7.40 (1H, d, J = 8.4 Hz), 8.09 (1H, s). Elemental analysis: C ₁₄ H ₁₆ N ₂ O ₂ Calculated: C, 68.83; H, 6.60; N, 11.47. Found: C, 68.64; H, 6.43; N, 11.50.

Example 26 N- [2- (7,8-dihydro-6H-indeno [4,5-d] oxazole-8-
Yl) ethyl] propionamide The title compound was obtained from N- [2- (7-amino-6-hydroxyindan-1-yl) ethyl] propionamide and methyl orthoformate in the same manner as in Example 25. Rate 79%). 81-84 ° C (recrystallized from ethyl acetate / isopropyl ether). NMR (CDCl ₃ ) δ: 1.20 (3H, t, J = 7.5Hz), 1.80-
2.10 (3H, m), 2.27 (2H, q, J = 7.5Hz), 2.37-2.53 (1H,
m), 2.80-3.20 (3H, m), 3.55-3.80 (2H, m), 6.93 (1
H, brs), 7.25 (1H, d, J = 8.8Hz), 7.40 (1H, d, J = 8.8H)
z), 8.09 (1H, s). Elemental analysis: C ₁₅ H ₁₈ N ₂ O ₂ Calculated: C, 69.75; H, 7.02; N, 10.84. Found: C, 69.76; H, 6.90; N, 10.76.

Example 27 N- [2- (7,8-dihydro-6H-indeno [4,5-d] oxazole-8-
Yl) ethyl] butylamide The title compound was obtained from N- [2- (7-amino-6-hydroxyindan-1-yl) ethyl] butylamide and methyl orthoformate in the same manner as in Example 25 (yield 90). %). 65-68 ° C (recrystallized from ethyl acetate / isopropyl ether). NMR (CDCl ₃ ) δ: 0.97 (3H, t, J = 7.4Hz), 1.67-
1.80 (2H, m), 1.80-2.12 (3H, m), 2.22 (2H, q, J = 7.5H
z), 2.33-2.53 (1H, m), 2.80-3.20 (3H, m), 3.50-3.
73 (2H, m), 6.90 (1H, brs), 7.25 (1H, d, J = 8.0H
z), 7.40 (1H, d, J = 8.0 Hz), 8.08 (1H, s). Elemental analysis: C ₁₆ H ₂₀ N ₂ O ₂ Calculated: C, 70.56; H, 7.40; N, 10.29. Found: C, 70.48; H, 7.30; N, 10.45.

Example 28 N- [2- (5-bromo-
3,7,8,9-tetrahydrocyclopenta [f]
[1] Benzopyran-9-yl) ethyl] propionamide N- [2- (5-bromo-6- (2-propynyl) oxyindan-1-yl) ethyl] propionamide (2.9 g, 8.4 mmol) Bromobenzene (30
mL) solution in a sealed tube at 200 ° C under argon atmosphere for 1 hour.
The mixture was heated and stirred for 8 hours. After cooling, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate) to obtain the title compound (yield 2.5 g, 85%). 110-111 ° C (recrystallized from ethyl acetate / hexane). NMR (CDCl ₃ ) δ: 1.14 (3H, t, J = 7.5Hz), 1.50
-2.50 (5H, m), 2.60-3.10 (3H, m), 3.15-3.25 (1H,
m), 3.32 (2H, q, J = 7.5Hz), 4.80-4.90 (2H, m), 5.40
(1H, brs), 5.88 (1H, dt, J = 10.0Hz, 3.8Hz), 6.45 (1
H, dd, J = 1.6Hz, 9.8Hz), 7.18 (1H, s). Elemental analysis: C ₁₇ H ₂₀ BrNO ₂ Calculated: C, 58.30; H, 5.76; N, 4.00; Br, 22.8
1. Found: C, 58.17; H, 5.54; N, 3.98; Br, 22.6.
Five.

Example 29 N- [2- (5-bromo-
1,2,3,7,8,9-Hexahydrocyclopenta [f] [1] benzopyran-9-yl) ethyl] propionamide N- [2- (5-bromo-3,7,8,9- Tetrahydrocyclopenta [f] [1] benzopyran-9-yl)
Ethyl] propionamide (1.2 g, 3.4 mmol
To a solution of 1) in ethanol (10 mL) was added 5% palladium on carbon (120 mg, 50% water-containing product), and the mixture was stirred under a hydrogen atmosphere at room temperature for 1 hour. After filtering the reaction solution, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate) to obtain the title compound (327 mg, 27%). 114-116 ° C (recrystallized from ethyl acetate / hexane). NMR (CDCl ₃ ) δ: 1.14 (3H, t, J = 7.6Hz), 1.50
-2.30 (7H, m), 2.60-3.20 (6H, m), 3.30 (2H, q, J = 7.6
Hz), 4.10-4.22 (1H, m), 4.30-4.42 (1H, m), 5.40 (1H
H, brs), 7.22 (1H, s). Elemental analysis: C ₁₇ H ₂₂ BrNO ₂ Calculated: C, 57.96; H, 6.29; N, 3.98; Br, 22.6
8. Found: C, 57.84; H, 6.20; N, 4.01; Br, 22.4.
2.

Example 30 N- [2- (1,2,3,3)
7,8,9-hexahydrocyclopenta [f] [1] benzopyran-9-yl) ethyl] propionamide N- [2- (5-bromo-1,2,3,7,8,9-hexahydro Cyclopenta [f] [1] benzopyran-9
-Yl) ethyl] propionamide (200 mg, 0.
To a solution of 6 mmol) in ethanol (5 mL) was added 5% palladium on carbon (200 mg, 50% hydrated), and the mixture was stirred under a hydrogen atmosphere at room temperature for 3 hours. After the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give the title compound (yield 130
mg, 85% yield). 85-88 ° C (recrystallized from ethyl acetate / isopropyl ether). NMR (CDCl ₃ ) δ: 1.16 (3H, t, J = 7.6 Hz), 1.80
-2.10 (6H, m), 2.15 (2H, q, J = 7.6Hz), 2.60-3.50 (7
H, m), 4.00-4.30 (2H, m), 5.35 (1H, brs), 6.63 (1
H, d, J = 8.2Hz), 6.94 (1H, d, J = 8.2Hz). Elemental analysis: C ₁₇ H ₂₃ NO ₂ Calculated: C, 74.69; H, 8.48; N, 5.12. Found: C, 74.56; H, 8.25; N, 5.16.

Example 31 N- [2- (4-bromo-
2,2-dimethyl-1,6,7,8-tetrahydro-2
H-indeno [5,4-b] furan-8-yl) ethyl] propionamide N- [2- (5-bromo-6-hydroxy-7- (2-
A solution of methyl-2-propenyl) indan-1-yl) ethyl] propionamide (2.4 g, 6.5 mmol) in methylene chloride (40 mL) was ice-cooled, and boron trifluoride diethyl ether complex (4.0 mL, 32. 5mmo
l) was slowly added dropwise. After stirring the reaction solution under ice cooling for 3 hours, the reaction solution was poured into ice water, and the organic matter was extracted with ethyl acetate. After washing the extract with water and a saturated aqueous solution of sodium bicarbonate,
After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was recrystallized from ethyl acetate / isopropyl ether to give the title compound (2.1 g, yield 89).
%). 98-101 ° C (recrystallized from ethyl acetate / isopropyl ether). NMR (CDCl ₃ ) δ: 1.15 (3H, t, J = 7.5Hz), 1.48
(3H, s), 1.54 (3H, s), 1.76-2.02 (2H, m), 2.19 (2
H, q, J = 7.5Hz), 2.25-2.38 (1H, m), 2.62-3.16 (6H,
m), 3.32 (2H, q, J = 5.3Hz), 5.41 (1H, br s), 7.11
(1H, s). Elemental analysis: as C ₁₈ H ₂₄ BrNO ₂ Calculated: C, 59.02; H, 6.60; N, 3.82; Br, 21.8
1. Found: C, 58.94; H, 6.48; N, 3.98; Br, 21.9.
7.

Example 32 N- [2- (2,2-Dimethyl-1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide Reference Example N- [2- (4
The title compound was obtained from -bromo-2,2-dimethyl-1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide (76% yield). ). 69-72 ° C (recrystallized from ethyl acetate / isopropyl ether). NMR (CDCl ₃ ) δ: 1.14 (3H, s), 1.43 (3H,
s), 1.50 (3H, s), 1.60-2.10 (2H, m), 2.13 (2H, q, J
= 7.5Hz), 2.24-2.40 (1H, m), 2.60-3.20 (6H, s), 3.3
5 (2H, q, J = 5.3Hz), 5.39 (1H, brs), 6.55 (1H, d, J =
7.6Hz), 6.95 (1H, d, J = 7.6Hz). Elemental analysis: C ₁₈ H ₂₅ NO ₂ Calculated: C, 75.22; H, 8.77; N, 4.87. Found: C, 74.98; H, 8.74; N, 4.96.

Example 33 N- [2- (4-bromo-2)
-Methyl-1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide In the same manner as in Example 31, N- [2- (5- Bromo-6-hydroxy-7-allylindan-1-yl)
The title compound was obtained from ethyl] propionamide (65% yield). 131-133 ° C (recrystallized from ethyl acetate / isopropyl ether). NMR (CDCl ₃ ) δ: 1.15 (3H, t, J = 7.6Hz), 1.46
-2.40 (9H, m), 2.60-3.40 (7H, m), 4.90-5.03 (1H, m),
5.42 (1H, brs), 7.11 (1H, s). Elemental analysis: C ₁₇ H ₂₂ BrNO ₂ Calculated: C, 57.96; H, 6.29; N, 3.98; Br, 22.6
8. Found: C, 58.08; H, 6.28; N, 4.07; Br, 22.8.
0.

Example 34 N- [2- (4-bromo-2)
-Hydroxymethyl-2-methyl-1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8
-Yl) ethyl] propionamide N- [2- (5-bromo-6-hydroxy-7- (2-
Methyl-2-propenyl) indan-1-yl) ethyl] propionamide (550 mg, 1.5 mmol)
Was cooled in ice (5 mL), and triethylamine (0.2 mL, 1.5 mmol) and m-chloroperbenzoic acid (1.0 g, 4.1 mmol) were added.
The reaction was stirred at room temperature for 2 hours. The reaction solution was poured into an aqueous solution of sodium thiosulfate, and the organic matter was extracted with ethyl acetate. The extract was washed with 1N hydrochloric acid and a saturated aqueous solution of sodium bicarbonate, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in dichloromethane (5 mL), and triethylamine (1 mL) was added thereto.
Stirred for hours. The solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (chloroform:
Purification with methanol (10: 1) gave the title compound (420 mg, 73% yield). Oil. NMR (CDCl ₃ ) δ: 1.00-1.20 (3H, m), 1.50-2.
40 (10H, m), 2.60-3.81 (9H, m), 5.50 (1H, br s),
7.11 (1H, s). Elemental analysis: C ₁₈ H ₂₄ BrNO ₃ .0.5H ₂ O Calculated: C, 55.25; H, 6.44; N, 3.58; Br, 20.4
2. Found: C, 55.58; H, 6.46; N, 3.58; Br, 20.2.
8.

Example 35 N- [2- (2-methyl-
1,6,7,8-tetrahydro-2H-indeno [5,
4-b] furan-8-yl) ethyl] propionamide In the same manner as in Reference Example 35, N- [2- (4-bromo-2-methyl-1,6,7,8-tetrahydro-2H) was obtained.
-Indeno [5,4-b] furan-8-yl) ethyl]
The title compound was obtained from propionamide (yield 76
%). 68-72 ° C (recrystallized from ethyl acetate / isopropyl ether). NMR (CDCl ₃ ) δ: 1.14 (3H, t, J = 7.2 Hz), 1.43
(1.2H, d, J = 6.2Hz), 1.50 (1.8H, d, J = 6.2Hz), 1.60-2.
40 (6H, m), 2.60-3.40 (7H, m), 4.80-5.00 (1H, m),
5.30-5.45 (1H, m), 6.58 (1H, d, J = 8.0Hz), 6.95 (1H, m
d, J = 8.0Hz). Elemental analysis: C ₁₇ H ₂₃ NO ₂ Calculated: C, 74.69; H, 8.48; N, 5.12. Found: C, 74.62; H, 8.55; N, 5.24. Example 36 N- [2- (1,2,3,7,8,9-hexahydro-2-oxoindeno [5,4-b] [1,
4] Oxazin-9-yl) ethyl] propionamide 1-ethyl-3- (3-dimethylaminopropyl) hydrochloride
Carbodiimide (372.0 mg, 1.9 mmol) and 1-hydroxybenzotriazole monohydrate (25
7 mg, 1.7 mmol) was suspended in a N, N-dimethylformamide (2.5 mL) solution, and propionic acid (0.11 mL, 1.4 mmol) was added under ice-cooling. The reaction mixture was stirred at room temperature for 1 hour, and then cooled again with ice and 9-
(2-Aminoethyl) -1,7,8,9-tetrahydroindeno [5,4-b] [1,4] oxazine-2 (3
H) -one (300 mg, 1.3 mmol) of N, N-
A solution of dimethylformamide (1.5 mL) was added dropwise.
After stirring under ice cooling for 1 hour, the reaction solution was poured into water, and the organic matter was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 10: 1) to give the title compound (yield 25
3.0 mg, yield 88%). 216-219 ° C (recrystallized from ethyl acetate / methanol). NMR (CDCl ₃ ) δ: 1.18 (3H, d, J = 7.5 Hz), 1.50-
2.00 (3H, m), 2.10-2.30 (3H, m), 2.70-3.10 (2H,
m), 3.30-3.50 (3H, m), 4.59 (2H, s), 5.97 (1H, br
s), 6.81 (2H, s), 9.77 (1H, br s).

Example 37 N- [2- (1,2,3,3)
7,8,9-Hexahydro-2-oxoindeno [5,
4-b] [1,4] oxazin-9-yl) ethyl] butylamide By a method similar to that in Example 36, 9- (2-aminoethyl) -1,7,8,9-tetrahydroindeno [5, 4
-B] The title compound was obtained from [1,4] oxazin-2 (3H) -one and butyric acid (yield 64%). 209-212 ° C (recrystallized from ethyl acetate / hexane). NMR (CDCl ₃ ) δ: 0.95 (3H, t, J = 7.3 Hz), 1.50
−2.00 (5H, m), 2.10−2.30 (3H, m), 2.70−3.10 (2
H, m), 3.20-3.50 (3H, m), 4.58 (2H, s), 5.93 (1H,
br s), 6.80 (2H, s), 9.72 (1H, br s). Example 38 N- [2- (1,2,3,7,8,9-hexahydroindeno [5,4-b] [1,4] oxazin-9-yl) ethyl] propionamide 9- ( 2-aminoethyl) -1,7,8,9-tetrahydroindeno [5,4-b] [1,4] oxazine-2
A solution of (3H) -one (1.2 g, 5.3 mmol) in tetrahydrofuran (30 mL) was ice-cooled, lithium aluminum hydride (0.8 g, 21.4 mmol) was added, and the mixture was heated and refluxed for 18 hours under an argon atmosphere. did. After cooling, water (0.8 mL), a 15% aqueous sodium hydroxide solution (0.8 mL) and water (2.4 mL) were sequentially added, and the mixture was stirred at room temperature for 30 minutes. The insolubles were removed by filtration, and the filtrate was concentrated under reduced pressure. Thereafter, the obtained 2- (1,2,3,7,8,9-hexahydroindeno [5,4-b] [1,4] oxazin-9-yl was obtained in the same manner as in Example 36. )
The title compound was obtained from ethylamine and propionic acid (yield 250 mg, 51%). 80-83 ° C (recrystallized from ethyl acetate / hexane). NMR (CDCl ₃ ) δ: 1.11 (3H, t, J = 7.5Hz), 1.50-
2.30 (6H, m), 2.60-3.20 (3H, m), 3.32 (2H, q, J = 6.7H
z), 3.43 (2H, t, J = 4.4Hz), 3.85 (1H, brs), 4.20 (2
H, t, J = 4.4Hz), 5.84 (1H, brs), 6.50 (1H, d, J = 8.0H)
z), 6.62 (1H, d, J = 8.0Hz).

Example 39 N- [2- (1,2,3,3)
7,8,9-hexahydroindeno [5,4-b]
[1,4] oxazin-9-yl) ethyl] butylamide In the same manner as in Example 38, 9- (2-aminoethyl) -1,7,8,9-tetrahydroindeno [5,4
-B] The title compound was obtained from [1,4] oxazin-2 (3H) -one and butyric acid (yield 61%). 115-118 ° C (recrystallized from ethyl acetate / hexane). NMR (CDCl ₃ ) δ: 0.93 (3H, t, J = 7.3 Hz), 1.50-
2.30 (8H, m), 2.60-3.20 (3H, m), 3.32 (2H, q, J = 6.7
Hz), 3.45 (2H, t, J = 4.4Hz), 3.80 (1H, brs), 4.22 (2
H, t, J = 4.4Hz), 5.54 (1H, brs), 6.52 (1H, d, J = 8.0H
z), 6.63 (1H, d, J = 8.0Hz). Example 40 N- [2- (6-formyl-1,6,7,
8-tetrahydro-2H-furo [3,2-e] indol-8-yl) ethyl] propionamide N- [2- [1-formyl-2,3-dihydro-5-hydroxy-4- (2-hydroxy Ethyl) indole-
3-yl] ethyl] propionamide (0.8 g, 2.
Methanesulfonyl chloride (0.2 mL, 2.61 mmol) was added dropwise while keeping a solution of pyridine (10 mL) in pyridine (10 mL) cooled to about -10 ° C with ice. The reaction solution was stirred for 20 minutes in the range of -10C to -5C. Further, methanesulfonyl chloride (0.1 mL, 1.3 mmol
l) was added dropwise to the reaction solution, and the mixture was further stirred at -10 ° C to -5 ° C for 15 minutes. Ethyl acetate (10m
L) and saturated aqueous sodium hydrogen carbonate (10 mL) were gradually added, and the mixture was returned to room temperature and stirred for 30 minutes. The organic matter was extracted with ethyl acetate, washed with 2N hydrochloric acid and water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 9: 1) to give the title compound (0.25 g, 33% yield). 139-141 ° C (recrystallized from ethyl acetate). NMR (CDCl ₃ ) δ: 1.15 (3H, t, J = 7.6 Hz), 1.62
-2.11 (2H, m), 2.19 (2H, q, J = 7.6Hz), 3.01-3.50 (5
H, m), 3.70-3.95 (1H, m), 4.07-4.30 (1H, m), 4.48-
4.71 (2H, m), 5.70 (1H, brs), 6.63,6.65 (1H, d ×
2, J = 8.4Hz), 6.92,7.87 (1H, d × 2, J = 8.4Hz), 8.43,
8.80 (1H, s × 2). Elemental analysis: C ₁₆ H ₂₀ N ₂ O ₃ Calculated: C, 66.65; H, 6.99; N, 9.72. Found: C, 66.43; H, 7.01; N, 9.73.

Example 41 N- [2- (1,6,7,8
-Tetrahydro-2H-furo [3,2-e] indol-8-yl) ethyl] propionamide 1) N- [2- (6-formyl-1,6,7,8-tetrahydro-2H-furo [3] , 2-e] indole-8-
Yl) ethyl] propionamide (0.18 g, 0.6
To a solution of 2 mmol) in ethanol (5 mL) was added a saturated hydrogen chloride / ethanol solution (15 mL), and the mixture was heated with stirring at 80 ° C. for 1.5 hours. After cooling the reaction solution, the solvent was distilled off under reduced pressure to obtain the hydrochloride (amorphous) of the title compound. NMR (d ₆ -DMSO) δ: 1.01 (3H, t, J = 7.5 Hz),
1.54-1.76 (1H, m), 1.88-2.10 (1H, m), 2.08 (2H, q, J
= 7.5Hz), 3.00-3.95 (7H, m), 4.61 (2H, q, J = 8.1H)
z), 6.76 (1H, d, J = 8.4Hz), 7.16 (1H, d, J = 8.4Hz),
7.98 (1H, br s), 11.23 (1H, br s). 2) The obtained compound was added to a saturated aqueous sodium hydrogen carbonate solution to remove
Extracted with% methanol / chloroform. The extract was washed with saturated saline and water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 9: 1), and further recrystallized from ethyl acetate / hexane to give the title compound (97 mg, yield 60 mg).
%). 96-98 ° C (recrystallized from ethyl acetate / hexane). NMR (CDCl ₃ ) δ: 1.12 (3H, t, J = 7.6Hz), 1.70-
2.06 (2H, m), 2.15 (2H, q, J = 7.6Hz), 2.99-3.50 (6H,
m), 3.68 (1H, t, J = 8.3Hz), 4.40-4.63 (2H, m), 5.86
(1H, brs), 6.44 (1H, d, J = 8.2Hz), 6.52 (1H, d, J = 8.
2Hz) and 1H are hidden and invisible. Elemental analysis: C ₁₅ H ₂₀ N ₂ O ₂ Calculated: C, 69.20; H, 7.74; N, 10.76. Found: C, 68.80; H, 7.48; N, 10.73. Example 42 N- [2- (6-formyl-1,6,7,
8-Tetrahydro-2H-furo [3,2-e] indol-8-yl) ethyl] butyramide N- [2- [1-formyl-2,3-dihydro-5- Hydroxy-4- (2-
The title compound was obtained from (hydroxyethyl) indol-3-yl] ethyl] butylamide (55% yield). amorphous. NMR (CDCl ₃ ) δ: 0.94 (3H, t, J = 7.3Hz), 1.30-
1.80 (4H, m), 2.17 (2H, t, J = 7.3Hz), 2.82-3.60 (5H, m
m), 3.80-4.26 (2H, m), 4.40-4.60 (2H, m), 5.77 (1
H, brs), 6.61,6.63 (1H, d × 2, J = 8.3Hz), 6.92,7.9
6 (1H, d × 2, J = 8.3Hz), 8.40, 8.78 (1H, s × 2).

Example 43 N- [2- (1,6,7,8
-Tetrahydro-2H-furo [3,2-e] indol-8-yl) ethyl] butylamide N- [2- (6-formyl-1,6,7,8-tetrahydro-2 The title compound was obtained from -2H-furo [3,2-e] indol-8-yl) ethyl] butyramide (yield 64%). amorphous. NMR (CDCl ₃ ) δ: 0.93 (3H, t, J = 7.3 Hz), 1.50
-1.90 (4H, m), 2.13 (2H, t, J = 7.3Hz), 3.00-3.50 (6
H, m), 3.67 (1H, m), 4.40-4.60 (2H, m), 6.00 (1H, b
rs), 6.47 (1H, d, J = 8.2Hz), 6.55 (1H, d, J = 8.2H)
z), 1H is hidden and invisible. Example 44 N- [2- (7-phenyl-1,6-dihydro-2H-indeno [5,4-b] furan-8-yl) ethyl] acetamide By a method similar to that in Example 14, 2- ( 7-phenyl-
The title compound was obtained from 1,6-dihydro-2H-indeno [5,4-b] furan-8-yl) ethylamine hydrochloride and acetyl chloride (yield 69%). 150-153 ° C (recrystallized from ethyl acetate / hexane). NMR (CDCl ₃ ) δ: 1.78 (3H, s), 2.96 (2H, t, J =
7.2Hz), 3.42 (2H, q, J = 7.2Hz), 3.53 (2H, t, J = 8.6H)
z), 3.70 (2H, s), 4.63 (2H, t, J = 8.6Hz), 5.41 (1H,
br s), 6.70 (1H, d, J = 7.9Hz), 7.21 (1H, d, J = 7.9Hz),
7.26-7.50 (5H, m). Example 45 N- [2- (7-phenyl-1,6-dihydro-2H-indeno [5,4-b] furan-8-yl) ethyl] propionamide By a method similar to that in Example 1, 2- (7-phenyl-
The title compound was obtained from 1,6-dihydro-2H-indeno [5,4-b] furan-8-yl) ethylamine hydrochloride and propionic anhydride (yield 67%). 166-168 ° C (recrystallized from ethyl acetate / hexane). NMR (CDCl ₃ ) δ: 1.02 (3H, t, J = 7.7 Hz), 2.01
(2H, q, J = 7.7Hz), 2.96 (2H, t, J = 7.3Hz), 3.44 (2H,
q, J = 7.3Hz), 3.54 (2H, t, J = 8.6Hz), 3.70 (2H, s),
4.63 (2H, t, J = 8.6Hz), 5.40 (1H, brs), 6.70 (1H, d,
J = 8.1Hz), 7.21 (1H, d, J = 8.1Hz), 7.26-7.50 (5H, m). Example 46 N- [2- (7-phenyl-1,6-dihydro-2H-indeno [5,4-b] furan-8-yl) ethyl] butylamide By a method similar to that in Example 14, 2- ( 7-phenyl-
The title compound was obtained from 1,6-dihydro-2H-indeno [5,4-b] furan-8-yl) ethylamine hydrochloride and butyryl chloride (yield 71%). 172-175 ° C (recrystallized from ethyl acetate / hexane). NMR (CDCl ₃ ) δ: 0.86 (3H, t, J = 7.3 Hz), 1.40-
1.62 (2H, m), 1.95 (2H, t, J = 7.3Hz), 2.96 (2H, t, J =
7.1Hz), 3.44 (2H, q, J = 7.1Hz), 3.54 (2H, t, J = 8.8H)
z), 3.70 (2H, s), 4.63 (2H, t, J = 8.8Hz), 5.41 (1H,
br s), 6.70 (1H, d, J = 7.7Hz), 7.21 (1H, d, J = 7.7Hz),
7.26-7.50 (5H, m).

Table 2 shows the structural formulas of the compounds obtained in Examples 19 to 46.

[Table 2]

Example 47 (E) -2- (1,6,7,
8-tetrahydro-2H-indeno [5,4-b] furan-8-ylidene) ethylamine

Embedded image By the same method as in Reference Example 27, (E)-(1, 6,
7,8-tetrahydro-2H-indeno [5,4-b]
The title compound was obtained from (furan-8-ylidene) acetonitrile (65% yield). Oily. NMR (CDCl ₃ ) δ: 2.61-2.78 (2H, m), 2.80-2.
94 (2H, m), 3.20-3.38 (4H, m), 4.56 (2H, t, J = 8.8H
z), 5.83 (1H, m), 6.60 (1H, d, J = 8.1Hz), 6.99 (1H, m
d, J = 8.1Hz), 2H is hidden and invisible. Example 48 9- (2-aminoethyl) -1,7,8,
9-tetrahydroindeno [5,4-b] [1,4] oxazin-2 (3H) -one

Embedded image (E)-(1,2,3,7,8,9-hexahydro-2
-Oxoindeno [5,4-b] [1,4] oxazine-9-ylidene) acetonitrile (3.0 g, 13.3)
mmol) and Raney nickel (14.0 g) were suspended in a saturated ammonia / ethanol solution (300 mL), and heated and stirred at 40 ° C. for 6 hours under a hydrogen atmosphere (5 kgf / cm ² ). After cooling, the Raney nickel catalyst was removed by filtration, and the solvent was distilled off under reduced pressure. The oily residue was poured into 2N hydrochloric acid, washed with ethyl acetate, and the aqueous layer was adjusted to pH = 10 with a 4N aqueous sodium hydroxide solution. The organic matter was extracted from the aqueous layer with a mixed solvent of chloroform / methanol (10: 1), dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was recrystallized from ethyl acetate / isopropyl ether to give the title compound (yield 1.9).
g, yield 62%). 128-134 ° C (recrystallized from ethyl acetate / isopropyl ether). NMR (CDCl ₃ ) δ: 1.40-1.90 (6H, m), 2.20-2.5
0 (2H, m), 2.70 (1H, dd, J = 8.0,15.4Hz), 2.90-3.00
(2H, m), 3.40 (1H, q, J = 7.9Hz), 4.44 (1H, d, J = 15.0H
z), 4.58 (1H, d, J = 15.0Hz), 6.75 (1H, d, J = 8.0Hz),
6.79 (1H, d, J = 8.0Hz).

Example 49 2- (1,2,3,7,8,
9-hexahydroindeno [5,4-b] [1,4] oxazin-9-yl) ethylamine

Embedded image By a method similar to that in Example 38, 9- (2-aminoethyl) -1,7,8,9-tetrahydroindeno [5,4
-B] The title compound was obtained from [1,4] oxazin-2 (3H) -one (80% yield). Oily. NMR (CDCl ₃ ) δ: 1.10-3.20 (12H, m), 3.41 (2
H, m), 4.20 (2H, m), 6.49 (1H, d, J = 8.0Hz), 6.61 (1
H, d, J = 8.0Hz). Example 50 2- (1,6-dihydro-7-phenyl-)
2H-indeno [5,4-b] furan-8-yl) ethylamine hydrochloride

Embedded image (E)-(1,6,7,8-tetrahydro-7-phenyl-2H-indeno [5,4-b] furan-8-ylidene) acetonitrile and (1,6-dihydro-7-phenyl-2H- A mixture of indeno [5,4-b] furan-8-yl) acetonitrile (0.815 mg, 2.9
8 mmol) saturated ammonia / ethanol (250 m
L) The solution was stirred with Raney cobalt (2.8 g) under a hydrogen atmosphere at room temperature and 5 kgf / cm ² for 6 hours. The filtrate obtained by filtering the catalyst is concentrated, diluted with water,
Organics were extracted with 10% methanol / chloroform.
The extract was washed with water, dried and concentrated, and a saturated hydrogen chloride / ethanol solution (20 mL) was added to the obtained residue.
For 1 hour. After cooling the reaction mixture, the solvent was distilled off under reduced pressure, and the residue was recrystallized from ethanol to give the title compound (390 mg, yield 42%). 165-168 ° C (recrystallized from ethanol). _{NMR (d 6 -DMSO) δ:} 2.87-3.14 (4H, m), 3.51
(2H, t, J = 8.4Hz), 3.72 (2H, s), 4.58 (2H, t, J = 8.4H)
z), 6.63 (1H, d, J = 7.9Hz), 7.19 (1H, d, J = 7.9Hz),
7.30-7.58 (5H, m), 8.33 (2H, brs).

Formulation Example 1 (1) 10.0 g of the compound obtained in Example 1 (2) Lactose 60.0 g (3) Corn starch 35.0 g (4) Gelatin 3.0 g (5) Magnesium stearate 2.0 g Using a mixture of 10.0 g of the compound obtained in Example 1, 60.0 g of lactose and 35.0 g of corn starch in 30 ml of a 10% by weight aqueous gelatin solution (3.0 g as gelatin), 1 mm
After granulation through a mesh sieve, it was dried at 40 ° C. and sieved again. The granules obtained were mixed with 2.0 g of magnesium stearate and compressed. Sucrose,
Coated with sugar coating with an aqueous suspension of titanium dioxide, talc and acacia. The coated tablets were polished with beeswax to obtain 1000 coated tablets.

Formulation Example 2 (1) 10.0 g of the compound obtained in Example 1 (2) Lactose 70.0 g (3) Corn starch 50.0 g (4) Soluble starch 7.0 g (5) Magnesium stearate 0 g 10.0 g of the compound obtained in Example 1 and 3.0 g of magnesium stearate were granulated with 70 ml of an aqueous solution of soluble starch (7.0 g as soluble starch), dried, 70.0 g of lactose and 50.5 g of corn starch. 0 g.
The mixture was compressed to give 1000 tablets.

Formulation Example 3 (1) Compound obtained in Example 19 1.0 g (2) Lactose 60.0 g (3) Corn starch 35.0 g (4) Gelatin 3.0 g (5) Magnesium stearate 2.0 g Using a mixture of 1.0 g of the compound obtained in Example 19, 60.0 g of lactose and 35.0 g of corn starch in 30 ml of a 10% by weight aqueous gelatin solution (3.0 g as gelatin), 1 mm
After granulation through a mesh sieve, it was dried at 40 ° C. and sieved again. The granules obtained were mixed with 2.0 g of magnesium stearate and compressed. Sucrose,
Coated with sugar coating with an aqueous suspension of titanium dioxide, talc and acacia. The coated tablets were polished with beeswax to obtain 1000 coated tablets.

Experimental Example 1 Inhibition of 2- [ ¹²⁵ I] iodomelatonin binding The forebrain was excised from a 7-day-old chick (white leghorn).
Ice-cold assay buffer (50 mM Tris-HCl, p
H7.7, 25 ° C.) to prepare a homogenate
A precipitate was obtained by centrifugation at 0 × g for 10 minutes. This was washed once with the same buffer, and then 0.3-0.4 mg protein / mL.
Was homogenized with an assay buffer so as to obtain a membrane sample. Fill the test tube with the drug solution, membrane sample, and ligand (8
0 pM2- [ ¹²⁵ I] iodomelatonin, about 100,00
0dpm) in a total volume of 0.5 ml and incubated at 25 ° C for 90 minutes. 3 mL of ice-cold assay buffer was added, and the mixture was immediately suction-filtered over Whatman GF / B. The filter was further washed twice with 3 mL of ice-cold assay buffer, and then radioactivity was measured with a γ-counter.
The value obtained by subtracting the binding in the presence of 10 μM melatonin as a non-specific binding was defined as a specific binding. The 50% inhibitory concentration (IC ₅₀ ) was calculated by the log-probit method, and the results are shown in [Table 3].

[0271]

[Table 3] From the results shown in Table 3, it can be seen that the compound (I) of the present invention has excellent melatonin receptor agonist activity.

[0272]

The compound (I) of the present invention or a salt thereof is
Since it exhibits excellent affinity for melatonin receptors, it can provide a clinically useful preventive / therapeutic agent for diseases related to the action of melatonin in vivo. Further, the compound (I) or a salt thereof of the present invention has excellent pharmacokinetics,
Furthermore, the water solubility is excellent.

──────────────────────────────────────────────────続 き Continuation of the front page (56) References Table 9-5057057 (JP, A) Table 10-502336 (JP, A) (58) Fields surveyed (Int. Cl. ⁶ , DB name) C07D 307/77 A61K 31/34 AAB CAPLUS (STN) REGISTRY (STN)

Claims (1)

(57) [Claims] (1) (S) -N- [2- (1,6,7,8-tetrahydro-2H-indeno [5,4-b] furan-8
-Yl) ethyl] propionamide.