JPS62116559A - 4-acylmethylidene-4,5,6,7-tetrahydroindole derivative and production thereof - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I (R<1> is lower alkoxy, benzyloxy, lower alkyl, dialkylamino or phenyl; R<2> is H or lower alkyl; R<3> is H or a protecting group of amino group: X is H, Cl or Br). USE:Useful as a raw material for a synthetic key intermediate for indole derivatives of high utilization value as a synthetic intermediate for 4-substituted indole based medicines having isoprene chain at the 4-position. PREPARATION:A 4-oxo-4,5,6,7-tetrahydroindole, expressed by formula II and readily produced from cyclohexanedione is condensed with a carbonyl compound expressed by formula III in the presence of a base to give a compound expressed by formula IV, which is then dehydrated to afford the aimed compound expressed by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention is based on the general formula (wherein R is a lower alkoxy group, a benzyloxy group, a lower alkyl group, a dialkylamino group or a thunyl group,
R3 is hydrogen or a lower alkyl group, R3 is hydrogen or a holding group for an amino group, and X is hydrogen, chlorine or bromine. ) 7 4-acylmethylidene-4,5,6
, 7-titrahydroindole conductor and manufacturing method.

The indole derivative represented by the general formula (1) is, for example, 4-(2-oxopropyl)indole, which is highly useful as a 4-substituted indole pharmaceutical synthesis intermediate, or 4-(3-methyl-2- Indole derivatives having an isoprene chain at the 4-position such as oxobutyl)indole and 3-(4-indolyl)-butene-2-carboxylic acids [e.g. Ber, e 2783 (1956)
;Tetra, Letters.

26, 4043 (1985); J, Am, Chem.
,8oc,,to z.

4265 (1980); Ann, 743.95 (19
70); Tetrahedron, 39,3695 (1
This can lead to 4-(2-oxoethyl)indole derivatives, which are widely available as synthetic key intermediates (see References below).

[Conventional technology]

Conventionally, when synthesizing indole derivatives having, for example, an isoprene chain at the 4-position, a method has been adopted in which 4-formylindole or 4-indolyl acetaldehyde are used as starting materials and a carbon elongation reaction is performed on them. .

[Problem that the invention seeks to solve]

However, the synthesis of 4-formylindole requires multiple steps, and 4-indolyl acetaldehyde is also not easy to synthesize, and is an unstable metal compound that must be handled with care. . (Helv, Chim,
Acta, 37, 1826 (1954); Ber
,,96. ; 1618 (1963); JP-A-57-91
973; J, Org, Chem, 45.3350 (1
980); Chem Lett.

813 (1980); J, Org, Chem, 46,
1752 (1981), 743.95 (1970)
[Reference] As a result of intensive studies to overcome the conventional drawbacks, the present inventors found that the compound of the present invention is an extremely important intermediate for easily synthesizing indoles having a carbon chain of C5 or more at the 4-position. They discovered that this is the case and completed the present invention.

[Means for solving problems]

The present invention provides 4-oxo-4,5,6,7-titrahydroindole represented by the general formula (wherein n5 is hydrogen or a protecting group for an amino group, and X is hydrogen, chlorine, or bromine). is a general formula (wherein W is a lower alkoxy group, a benzyloxy group, a lower alkyl group, a dialkylamino group or a tunyl group,
i is hydrogen or a lower alkyl group. ) in the presence of a base to form a 4-hydroxy-4,5, 6,
By obtaining 7-titrahydroindole and then dehydrating it, the 4-acylmethylidene-4,5,6,7-tetrahydroindole derivative represented by the general formula (Ω) is produced.

The tetrahydroindole derivative represented by the general formula (ff), which is a raw material, is a compound that can be easily produced from cyclohexanedione (Heterocycles
.

Itsu, 2313 (1984) and Kashi, 165 (1985)
)reference〕. In addition, examples of protecting groups for the amine group represented by the general formula (3) include benzenesulfonyl group, toluenesulfonyl group, arylsulfonyl group, methanesulfonyl group, ethanesulfonyl group, alkanesulfonyl group, Examples include benzyl group.

The carbonyl compounds represented by the general formula (button), which is the other raw material, include methyl acetoacetate, ethyl acetoacetate, t-butyl acetoacetate, propyl acetoacetate,
Isopropyl acetoacetate, Butyl acetoacetate, Benzyl acetoacetate, N,N-dimethylacetoacetamide, N
, N-diethylacetamide, ethyl l-methyl-2-oxopropanecarboxylate, acetylacetone, 2.4
~hexanedione, 2.4-hebutanedione, 2.4-
Examples include octanedione and acetoacetophenone.

The synthesis of 4-hydroxyindole represented by the general formula is carried out by condensing the oxoindole represented by the general formula (fi) and the carbonyl compound represented by the general formula (Ml) in the presence of a base. In this reaction, it is preferable to prepare the dianion of the carbonyl compound represented by the general formula 1 in advance by a conventional method and react it with the oxoindole represented by the general formula (It).

In the preparation of the above dianion, in a solvent that does not directly participate in the reaction and under an inert gas atmosphere, the carbonyl compound represented by the general formula (1) is first hydrogenated in an amount of The most common method is to treat with an equivalent amount of butyl lithium, or alternatively, depending on the substrate instead of these bases, alkyl lithium such as potassium hydride, sodium amide, methyl lithium, 5eC-butyl lithium, phenyl lithium, diisopropylamino lithium, etc. There is no harm in using lithium amide, Grignard reagent, etc. as appropriate.

Examples of the solvent for the reaction include ether solvents such as diethyl ether, tetrahydrofuran, dimethoxyethane, dioxane, and diethylene glycol dimethyl ether, and hydrocarbons such as benzene and toluene.

The reaction proceeds at -78°C to room temperature.

In order to produce the indole derivative represented by the general formula (1), it is necessary to dehydrate the compound represented by the general formula (5). This dehydration step is accomplished by treating the compound represented by the above general formula with a catalytic amount of an acid, such as p-toluenesulfonic acid, sulfuric acid, hydrochloric acid, or phosphoric acid. As a solvent for the reaction, dichloromethane, dichloroethane, chloroform, benzene, toluene, etc. can be used. Although the reaction proceeds even below room temperature, it is preferably carried out at a temperature of about room temperature to 80°C.

In addition, when producing the indole derivative represented by the general formula (11) from the compound represented by the general formula (11) (1), it is necessary to isolate and purify the intermediately generated compound represented by the general formula (1). The present invention will be explained in more detail with reference to examples and diagnostic examples. Example 1 Ts About 60% sodium hydride 420■
l) in about 30 ml of THF at 0°C in an argon stream, and to this was added 1.37 g of ethyl acetoacetate (10.5 ml of ethyl acetoacetate).
Mo 1) was added dropwise and the sodium salt of ethyl acetoacetate Zheng! ll♀, and 6.7 ml of n-butyllithium (15% n-hexane solution) was added thereto to prepare a dianion of ethyl acetoacetate. To the solution of this dianion, 4-oxo-1-p-)luenesulfonyl-4
, 5,6,7-titrahydroindole 12.28g
(7.9 mmol 1) was added and stirred at 0° C. for 1 hour and 15 minutes. After the reaction was completed, THF was distilled off from the reaction mixture, the residue was poured into an aqueous ammonium chloride solution, and extracted with dichloromethane.

The extracted layer was washed with water, dried over magnesium sulfate, concentrated, applied to a silica gel column, and treated with dichloromethane and ethyl acetate.
When poured out with a mixed solvent of 0 to 1, 3.16 g of this was found.
Obtained with a yield of 95.5%.

Physical property value of L mp 72.5-74.0°C (from ether) white granular crystals'H-NMR (In CDCl,): δ1.25 (t
, 3H, J-7,0Hz), 1.48-2.30 (m
, 4H), 2.40 (s, 3H).

2.50-2.78 (m, 2H), 2.78 (d, I
H, J = 16.6 Hz), 3.07 (d, IH, J = 1
6.6Hz), 3.45 (s, 2H), 3.61 (
s, IH).

4.15 (q, 2H, J-7, 0H2).

6.23 (d, IH, J-3, 6H2).

7.15 (d, IH, J-3, 6Hz).

7.18-7.36 (m, 2H), 7.54-7.
64 (m, 2H) ppm.

IR (KBr): 3550,1732. ni'ltG
.

1597, 1367, 1179 country-1°Mas
sm/e (%): 419 (M”, t
race).

401 (12), 329 (39).

314 (40), 290 (31).

174 (4B), 134 (30).

130 (53), 91 (100), 65 (32
), 43 (52).

Elemental analysis value: C□H,, No, Calculated value as s: C,
60,13; H, 6,01; N, 3.34 i S,
7.64 (%) Actual value: C, 60, 18i H, 6
, 13; N, 3.34; S, 7.59 (%) Example 2 'rS 2 3 T 5 4-(3-ethoxycarbonyl-2-oxopropyl)
-4-hydroxy-1-p-)luenesulfonyl-4,
21.36 g of 5,6,7-titrahydroindole
(3,2mmo +) dissolved in 10ml of benzene, 70
% phosphoric acid was added thereto, and the mixture was stirred at room temperature for 1 hour and 30 minutes.

Subsequently, the mixture was stirred at about 60° C. for 5 to 6 minutes and then at room temperature for 1 hour. After the reaction was completed, the reaction mixture was poured into an aqueous sodium bicarbonate solution and extracted with ethyl acetate. After washing the extracted layer with water and drying magnesium sulfate, the solvent was distilled off, and the run rate was 1.1.
4 g, yield 87.5%.

Physical property value mp 123-124℃ (from ethyl acetate) Pale yellow ``Cinnamon'' crystal HNMR (In CDCl5): δ1.25
(t, 3H, J=7.0Hz), 1.62-1.9
8 < m, 2H), 2.40 (s,
3H).

2.64-3.10 (m, 4H), 3.4
7 (s, 2H), 4.16 (Q, 2H, J
-7,0H2), 6.30 (broad s.

IH), 6.4t (a, IH,J-3,6
Hz), 7.12-7.40 (m, 3H)
.

7.56-7.76 (m, 2H) I) pm.

IR(KBr):1742. 1683°1591,
1374. 1178cm-'.

Massm/e (%): 401 (M”, 4
7).

314 (100), 159 (31).

158 (38), 130 (92).

91(84).

Elemental analysis value: C! Calculated as I Ht s N Os S: C, 62, 83; H, 5, 77
;N, 3.49 ;S, 7.99 (%)
Actual measurement: C, 62, 79; H, 5, 9B
.

N, 3.48; S, 7.94 (%) Example 3 C) about 60% sodium hydride 1-0 g (25 m-mo
1) was suspended in THF at 0°C in an argon stream, and ethyl 1-methyl-2-oxopropanecarboxylate 3.
6 g (25 mmol) was added dropwise to the sodium salt prepared by v4, 16 ml of n-butyllithium (15% n-hexane solution) was added, and 5.8 g ( Add 20 mmol I) and incubate at 0°C.
After stirring for ~2 hours and stirring overnight at room temperature, after the reaction was completed, THF was distilled off from the reaction mixture, the residue was poured into an aqueous ammonium chloride solution, and extracted with dichloromethane. The extracted layer was washed with water, dried with magnesium sulfate, concentrated, applied to a silica gel column, and flushed out with a 40-1 mixed solvent of dichloromethane and ethyl acetate. 1 was recovered in a yield of 21.0%, followed by 4 and 3. .86 g, yield 44.4%.

Physical property value of 4 Colorless viscous substance 'HNMR (in CDCl5): δ1.21and
1.23 (two t, 3H, J-7,0Hz),
1.29 (d, 3H, J-7,0Hz), 1.46~
2.08 (m, 4H).

2.39 (a, 3H), 2.50-3.22 (m, 4
H), 3.49 and 3.52 (two q, IH,
J=7.0Hz).

3.92and3.97 (two s, '@'H
), +4.11and4.13 (two q
, 2H.

J-7,0Hz), 6.21 (d, IH,
J=3.6Hz), 7.15 (d, IH,
J-3,6Hz), 7.18-7.36 (m.

2H), 7.52-7.76 (m, 2H) ppm.

IR (liquid film): 3525°173
9, 1706. 1595°1366, 1174-1°Masam/e (%): M''' could not be confirmed.

415 (17), 314 (100).

130 (37), 91 (33).

Example 4 4.78 (1w (1,8mmo I) to benzene 7
After the reaction was completed, the reaction mixture was poured into an aqueous sodium hydrogen carbonate solution and extracted with dichloromethane. The extracted layer was washed with water, dried over magnesium sulfate, and then concentrated. When the concentrate was applied to a silica gel column and flushed with dichloromethane, 703 ml of 5 was obtained in a yield of 94.0%.

Physical property value of 5 mp 8o ~ 82℃ (fr Omzm Phthal) company white) 1-state 'H-NMR (in CDCl5): δ1.23 (
t, 3H, J=7.2Hz), 1.35(d,
3H, J=7.2Hz), 1.64-1.98
(m, 2H), 2.41 (s, 3H).

2.70-3.12 (m, 4H), 3.5
5 (q, IH, J-7, 2Hz), 4.15 (q,
2H, J 7.2Hz), 6.35 (broa
d s, IH), 6.43 (d.

LH, J=3.6Hz), 7.14~7.40(m
, 3H), 7.58-7.78 (m.

2H)ppm.

IR (KBr): 1720.1673°1582.13
66.1173cm-', .

Ma S sm/e (%): 415 (M
”, 15) 314 (100), 91 (28
).

Elemental analysis value: C**H□Calculated value as No5s: C,
63,60i H, 6,06; N, 3.37; S, 7
．． 72 (%) Actual value: C, 63, 66; H, 6,
12; N, 3.41; S, 7.65
(%) Example 5? Ta 50% sodium hydride 240w (s, o as 50%
x 10-'no l) was suspended in 20 ml of THF under a stream of alkylgon at 0°C, and ethyl acetoacetate 8
31m (6,4X 10-'no l) was added dropwise, stirred at room temperature, and the sodium salt of ethyl acetoacetate was added! Made by JI. The solution was cooled again to 0°C, and the solution of this dianion was cooled to -78°C, giving 61.62
g (5,OX 10-3 mo I) was added and heated to -78°C.
After stirring for 3 hours, the temperature was gradually lowered and the mixture was stirred overnight at room temperature. After one reaction, the reaction mixture was poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The extracted layer was washed with brine, dried with magum sulfate, concentrated, and the concentrate was applied to a silica gel column and flushed out with a 100:1 mixed solvent of dichloromethane and ethyl acetate.
．． 64 g was obtained in a yield of 72%.

Colorless viscous 'HNMR (In CDCl5): δ1.26 (t,
3H, J=7.0Hz), 2.00-3.30 (m,
5H), 2.40 (s, 3H).

3.10 (a, 2H), 3.48 (s, 2H).

4.15 (q, 2H, J=7.0Hz).

Hz, 3.6Hz), 6.23 (d, LH.

J-1,8Hz), 7.10-7.38 (m.

3H), 7.50-7.72 (m, 2H) ppm.

IR (liquid film): 3540°174
0.1720. 1600°1500cm-'.

Massm/e (%”): 437 (M”-18°3)
, 435 (M”-18,9).

130 (35), 91 (100).

Example 6 t) 50% sodium hydride 247■ (5.1 as 50%)
X10-" mol) was suspended in 20 ml of THF at 0°C in an argon stream, and 731 w of ethyl acetoacetate (5
,7X 10-"mo 1) was added dropwise and stirred at room temperature to prepare the sodium salt of ethyl acetoacetate.
The mixture was cooled to 0° C., and 3.6 ml of n-butyllithium (15% hexane solution) was added to prepare a dianion of ethyl acetoacetate. This dianion solution was cooled to -78°C,
8,1.5g (4,1X
1 (I”mol) was added dropwise over 20 minutes to -78
After the reaction was completed by stirring at °C for 2 hours, the reaction mixture was poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The extracted layer was washed with brine, dried over magnesium sulfate, and concentrated.
When this concentrate was applied to a silica gel column and flushed out with a 100:1 mixed solvent of dichloromethane and ethyl acetate, 1.92 g of 9 was obtained in a yield of 959A.

Example 7 7.1.017 g (2,24X10-"no I) was dissolved in about 10 ml of benzene, to which 1 ml of 70% phosphoric acid solution was added.
After the completion of the reaction, the reaction mixture was poured into water and extracted with ethyl acetate.The extracted layer was washed with an aqueous sodium bicarbonate solution, then with saturated brine, and dried over magnesium sulfate. It was then concentrated. When concentrated Y was applied to a silica gel column and flushed out with disololomethane, 933 ml of IO was obtained in a yield of 96%.

Colorless flaky crystals Melting point 120.0-121.5℃ (from n-hexane-carbon tetrachloride) 'HNMR (l n CDCl5) Partially enolized (
Keto type; enol type 75:25) Keto type δ1.25 (
t, 3H, J-7,0Hz).

1.50-2.56 (m, 2H), 2.40 (s, 3
H), 2.83-3.20 (m.

2H), 3.52 (S, 2H), 4.16 (q, 2H
, J-7,0Hz), 6.16(t, LH, J-3,0
Hz), 6.29 (s, IH), 6.41 (d, I
H, J-3,8Hz), 7.12-7.42 (m, 3
H).

7.56-7.80 (m, 2H) ppm.

Enol type δ1.28 (t, 3H, J-7,0Hz)
.

1.50-2.56 (m, 2H), 2.40 (s, 3
H), 2.83-3.20 (m.

2H), 4.18 (q, 2H, J-7,0Hz), 5
．． 14 (s, LH), 5.80 (broad s,
LH), 6.10 (t, IH, J-3,0Hz), 6.
37 (d, IH, J=3.6Hz), 7.12-7.4
2 (m, 3H), 7.56-7.80 (m, 2 old,
12.34 (d, IH.

J-1,6Hri ppm.

TR (KBr): 1739,1677°1587.1
500,1343°1 177 cm-'.

Massm/e (%): 437 (M”, 2.4
).

435 (M', 5.8), 399 (10).

350 (4), 348 (9), 155 (18)
, 130 (51), 91 (100), 65 (31), 45 (42).

36 (39), 31 (99), 29 (41)
.

Example 8: 2-1□ 9.910w (1,8
10-'mol) was added to 10 ml of chloroform and stirred at room temperature for 20 minutes and at 50°C for 40 minutes. After the reaction was completed, the reaction mixture was poured into water and extracted with dichloromethane. The extracted layer was washed with water, dried with magnesium sulfate, and then concentrated, and the t1 condensate was applied to a silica gel column and flushed out with a 1001 mixed solvent of dichloromethane and ethyl acetate to obtain 11 with a yield of 823 and 94%.

Pale yellow powder 'H-NMR (I n CDCl5) Partially enolized (keto form: enol form 7614) Keto form δ1.25 (t, 3H, J-7,0Hz)
.

1.72-2.50 (m, 2H), 2.40 (s, 3
H), 2.86-3.10 (m.

2H), 3.51 Cs, 2H), 4.16(q, 2
H, J=7.0Hz), 6.24(s, '4'H), 6
．． 30 (t, I H, J-3,0Hz), 6.41
(d, LH, J-3,6Hz), 7.14-7.44
(m, 3H).

7.56-7.80 (m, 2H) ppm.

Enol type (partially superimposed on keto type, characteristic shifts unknown, f1 only recognizable characteristic shifts are described) δ1.27 (t
, 2H, J-7, 0Hz).

4.18 (q, 2H, J-7,0Hz).

5.13 <s, IH), 5.73 (b
roads, IH), 12.35 (d, IH.

J-1,6Hz) ppm.

IR (KBr): 1740. 1675°15
84, 1500. 1343°1 1 7 B am-'.

Massm/e (%): 481 (M”, 1
．． 5).

479 (M', 1.7), 399 (3
6) Example 9 Yasushi.

50% sodium hydride 240■ (5.0% as 50%)
X 10-'no I) was suspended in 20 ml of THF at 0°C in an argon stream, and 780 μm of N,N-dimethylacetoacetamide (6,OXlo-3mo +) was added dropwise thereto, followed by stirring at room temperature. The sodium salt of N,N-dimethylacetoacetamide was prepared. Cool the solution again to 0°C, add n-butyllithium (15%, n-hexane solution) 3
．． 8 ml was added to prepare a dianion of N,N-dimethylacetoacetamide. A solution of this dianion is
After cooling to ℃, 61.5g (4,6xl O-'
Add rH01), gradually raise the temperature, and leave at room temperature for 3 hours.
After the reaction was completed after stirring for 0 minutes, the reaction mixture was poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate.

The extracted layer was washed with saturated brine, dried with magnesium sulfate, and concentrated. The concentrate was applied to a silica gel column and flushed out with a 4:1 mixed solvent of dichloromethane and ethyl acetate to obtain 1.89 g of 12 in a yield of 90%. It was done.

Physical properties of 12 White granular crystals Melting point 116-117℃ (from ethyl acetate)'H
NMR (in CDC11): δ2.00-2.50
(m, 2H), 2.42 Cs.

3H), 2.64-3.22 (m, 2H).

2.94 (s, 3H), 2.95 (s, 3H).

3.13 (s, 2H), 3.59 (s, 2H).

4.46-4.70 (m, IH), 6.26-6.
48 (m, IH), 7.14-7.42 (m, 3H)
, 7.56-7.80 (m.

2H)ppm.

IR (KBr): 3425,1717°1643.16
00.1497°1365.1179cm-'.

Massm/e (%): 398 (M'-)(
, 0°HCl, 27), 284 (30).

130 (36), 114 (43).

91 (86), 87 (50), 72 (100)
, 46 (40), 45 (51).

44 (65), 43 (32), 36<60).

Example 10 υ″゛50% sodium hydride 240μ (5.O as 50%)
X L (I"mo 1) was suspended in 2Qml of THF at 0°C in an argon stream, and 20% of N,N-dimethylacetoacetamide (5,6X l O-"mo I)
was added dropwise and stirred at room temperature to prepare a sodium salt of N,N-dimethylacetoacetamide. Bring the solution back to 0℃
was cooled, and 3.8 ml of n-butyl IJtium (15% H-hexane solution) was added to prepare the dianion of N,N-dimethylacetoacetamide. This dianion solution was cooled to -78°C, and 81.5 g (4, IX I O
After the completion of the reaction, saturated ammonium chloride aqueous solution was added to the reaction mixture, and the mixture was transferred to a separating funnel and extracted with ethyl acetate. The extracted layer was washed with saturated saline and dried over magnesium sulfate.
Shrunk. When this concentrate was applied to a silica gel column and flushed out with a 4:1 mixed solvent of dichloromethane and ethyl acetate, 8 was recovered in 184 μm, 12%, followed by 4-oxo-L-p-)luenesulfonyl-4. ,5,6,7-
Titrahydroindole was obtained in an amount of 103 cm in a yield of 9%, and 1.577 g of 13 in a yield of 78% (selective yield of 89%).

Example 11 12.452w (1,OX I O-'mo 1) was dissolved in 10ml of benzene, and 7094 phosphorus M solution 0
．． After 1 reaction of adding 3 ml and heating under reflux for 20 minutes,
The reaction mixture was poured into water and extracted with ethyl acetate. The extracted layer was washed with an aqueous sodium hydrogen carbonate solution and then with saturated brine, dried over magnesium sulfate, and concentrated. The product was applied to an llllll metal silica gel column and flushed out with a mixed solvent of dichloromethane, ethyl acetate and ethanol in a ratio of 100:10:1 to obtain 14 (390 μm) in a yield of 90%.

Physical properties of No. 14 White granular crystal Melting point 151.0-152.0°C (from ethyl acetate) ~2.48 (m, 2H), 2.42 (s.

3H), 2.80-3.16 (V, 2) ()
.

2.98 (s, 6H), 3.61 (broad
s.

IH), 5.33 (broad s.

0.5H), 5.83 (broad a.

0.5H), 6.17 (t, IH, 3.0Hz)
.

6.26~6.52 (m, 1.5H), 7.10~
7.40 (m, 3H), 7.55-7.76 (m,
2H) 9 ptu.

IR (KBr): 1636, 1597° 1560,
1504.1377°1180cm-'.

Massm/e (%): 436 (M”, 1.2
).

434 (M”, 1.9), 398
(47).

354 (63), 114 (38), 9
1 (67), 87 (43), 72 (9
3).

46 (31), 45 (46), 44 (
100), 36 (47).

Elemental analysis (II: Calculated value as Ct+HtsNmSO4Cl: C, 57,99; H, 5,33iN, 6.
44; S, 7.37; C1,8,15 (%) Actual value j C, 57,75i H, 5,26; N, 6.
29; S, 7.42; C1,8,03 (%) Example 12 Tsujiko.

Dissolve 13.75w (5,5x 10-'mol) in 5ml of benzene, and add 0.5ml of 70% phosphoric acid solution to this.
After the reaction was completed, the reaction mixture was poured into water and extracted with ethyl acetate. The extracted layer was washed with water, dried with magnesium sulfate, and then concentrated, and the JI product was applied to a silica gel column and washed off with a mixed solvent of dichloromethane, ethyl acetate, and ethanol in a ratio of 100:10:1. Obtained.

Physical properties of 15 Yellow granular crystals Melting point 116.0-117.5°C (from ethyl acetate-n-hexane) IR (KBr): 1637, 1597° 1502.1
380.1186 cm-'.

Massm/e (%): 398 (M”-HB
r.

13), 284 (56), 130 (30).

114 (31), 91 (62), 87 (37)
, 82 (97), 81 (39).

80 (100), 79 (43), 72 (38)
, 45 (52), 44 (78).

Example 13 587 μm of 50% sodium hydride (1,22×10-”m
ot) was suspended in 15 ml of THF at 0°C in an argon stream, and to this was added 1.42 g of methyl acetoacetate (1,22xlO
-''mo was added dropwise and stirred at room temperature to prepare sodium salt of methyl acetoacetate.

The solution was cooled again to 0 °C and diluted with n-butyllithium (15%
, hexane solution) was added to prepare a dianion of methyl acetoacetate. A solution of this dianion is
Cool to 8°C and weigh 83.008g (0.82X 10-”
No. 1) was added thereto, and the mixture was stirred at -78°C for 5 hours. In the meantime, add THF to help dissolve 8, which was added as a solid.
After the completion of the reaction, the reaction mixture was poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The extracted layer was washed with saturated saline, dried over magnesium sulfate, and then filtered to 1 mL solution. The concentrate was applied to a silica gel column and flushed with a mixed solvent of dichloromethane and ethyl acetate 50:1 to obtain an adduct of 8 and methyl acetoacetate. Since the adduct was partially dehydrated, the next dehydration reaction was performed. The obtained adduct was dissolved in 2Qml of dichloromethane, and 100mtr of p-toluenesulfonic acid (5,81X
10-'mo +) was added, stirred at room temperature for 25 minutes,
After the reaction was completed, the mixture was heated under reflux for 20 minutes, and the reaction mixture was poured into an aqueous sodium bicarbonate solution and extracted with dichloromethane. The extracted layer was washed with water, dried with magnesium sulfate, and then concentrated. The concentrate was applied to a silica gel column and flushed out with a 50-1 mixed solvent of dichloromethane and ethyl acetate. 3.068 g of 16 was obtained in a yield of 80.5%. Ta.

Colorless columnar crystals (from ethyl acetate-n-hexane) Melting point 115.0-117.0°C 'HNMR (ln CDCIs) Keto:E^-ru mixture 4:1, EM-390 measurement 61.77- 2.1
7 (m, 2H), 2.42 (s, 3H),
2.87-3.17 (m.

2H), 3.57 (s, 1.6Hs).

3.74 (s, 3H), 5.18 (3°0.2Hz
), 5.76 (broad s.

0.2Hs), 6.25 (s, 0.8Hs).

6.23-6.40 (m, IH), 6.46 (
d, IH, J-3, 6Hz), 7.1
7-7.43 (m, 3H), 7.57-7.82
J=1.6Hz) ppm.

IR (KBr-disk): 1750°1675.1
594,1500°1377,1175cm-'.

Massm/e (%): 467 (M”, 1).

465 (M', 1), 385 (40).

311 (17), 285 (22).

284 (100), 155 (1g).

130 (46), 129 (25).

91(73).

Elemental analysis value: Calculated value as CxaH*aNSOsBr: C, 51, 51i fertilizer 4.32°N, 3.00
, S, 6.8? .

X (Br), 17.13 (%) Actual value: C
,51,44i H,4,36iN,2.8B ,S,
6.85.

8r, 17.32 (%) Example I4 50% sodium hydride 589■ (1,23x10-'
mol) was suspended in 5 ml of THFI at 0°C in an argon stream. To this solution, add 2.550 g of benzyl acetoacetate (1,33
) was added dropwise and stirred at room temperature to prepare sodium salt of benzyl acetoacetate. The solution was cooled again to 0°C, and 8.5 ml of n-butyllithium (15%, hexane solution) was added (
After stirring for several minutes, the solution was cooled to -78°C, and 82.972 g (8,08X 10-"mol) dissolved in 35ml of THF was added.
was added dropwise and stirred for 40 minutes at -78°C. After completion of the reaction,
The reaction mixture was poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The extracted layer was washed with saturated brine, dried over magnesium sulfate, and concentrated. This concentrate was applied to a silica gel column and flushed out with a 1:2 mixed solvent of n-hexane and ethyl acetate to obtain an adduct of 8 and benzyl acetoacetate. This adduct was dehydrated in the effluent solvent and concentrated to obtain 1.77 g of 17 in a yield of 40.5%.

Colorless powder crystal (from ethyl acetate-n-hexane) Melting point 95.5-97.0°C 'HNMR (In CDC11): δ1.
74-2.52 Cm, 2H), 2.42
(s.

3H), 2.90-3.16 (m, 2H)
.

3.60 (s, 2H), 5.20 (s
, 2H).

6.26 (s, IH), 6.34 (t
, L.H.

J=3.0Hz), 6.40 (d, LH,
J=3.8Hz), 7.14~7.50 (m,
.

8H), 7.64-7.88 (m, 2H)
ppm.

IR (KBr): 1626. 1593°15
52, 1497. 1370°1177 country-direct.

Massm/6 (%): 543 (M”, 2
).

541 (M”, 2), 461 (44)
.

370 (30), 353 (56).

285 (53), 284 (100).

170 (32), 155 (61).

130 (85), 129 (54).

10B (56), 107 (43).

92 (30), 91 (100), 79 (77)
, 77 (66), 65 (65).

51 (41), 39 (41).

Example 15 B Ts 50% Sodium Hydride 637■ (1,33X1 (1”
2.05 g of acetoacetophenone (
1,26xl O-"no 1) was added and stirred at room temperature for 40 minutes. The solution was cooled again to 0°C and 8.09ml of n-butyllithium (15%, n-hexane solution) was added (
1,26×10 −1 mat) and stirred for 20 minutes. This prepared dianion solution was cooled to -78°C,
83.10 g (8,4
After the completion of the reaction, the reaction mixture was poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The extracted layer was washed with water, dried over magnesium sulfate, and concentrated. When the concentrate was applied to a silica gel column and flushed out with a 100:1 ffi mixed solvent of dichloromethane and ethyl acetate, raw material 8 was obtained with a yield of 497 cm and a yield of 16.
0% recovery followed by the adduct of 8 and acetoacetophenone. The adduct was partially dehydrated in the effluent solvent, and the next dehydration reaction was carried out.

In addition, some parts do not undergo dehydration and remain as adducts, forming 907■
, could be isolated with a yield of 20.3%. After the dehydration progressed in the effluent solvent, after concentrating it, dissolve it in dichloromethane,
After the completion of the reaction, p-toluenesulfonic acid was added and heated under reflux, and the reaction mixture was carbonated. The extracted layer was washed with water, dried over magnesium sulfate, and concentrated. Dissolve the concentrate in ethyl acetate,
When crystallized, 1.748 g of 18 was obtained, yield 40
．． Obtained at 5%. The filtrate was purified with 'tJH91, applied to a silica gel column, and dichloromethane and n-hexane 1=1
When washed out with γ-containing solvent, 18 was 281■, 6.
Obtained with a yield of 5%.

Next, the isolated adduct 19 was subjected to a dehydration reaction.

・19.907 g (1,71 x 10-3 mol) of i''s panicle was dissolved in 10 ml of dichloromethane, 40 at (2,3 x 10-' mol) of p-toluenesulfonic acid was added, and the mixture was heated under reflux for 1 hour. After the reaction was completed, the reaction mixture was poured into an aqueous solution of sodium hydrogen carbonate and extracted with dichloromethane.The extracted layer was washed with water, dried with magnesium sulfate, and concentrated for 9 hours.The concentrate was dissolved in ethyl acetate and crystallized. (2) was obtained in a yield of 60.9%.The crystal filtrate was concentrated, applied to a silica gel column, and flushed out with a mixed solvent of di-bromethane and n-hexane 1:1.
The total yield was 92.9%.

As described above, 18 was obtained in a yield of 65.9% by the addition reaction of 8 with the dianion of acetoacetophenone and the subsequent dehydration reaction.

Physical properties of 18 Yellow columnar crystals (from ethyl acetate) ~ 2.60 (
m, 2H), 2.42 (s3 old, 2.92-3.2
6 (m, 2H).

6.04 (s+IH), 6.32 (s, I
H).

6.50 (d, IH, J-3, 6Hz).

6.55 (t, IH, J=3.0Hz).

7.24-8.10 (m, 10H).

16.10-17.20 (m, IH) ppm.

T R (K B r ) Yumisaki 6 mock 4 Yin: l 620
.

1600.1375.11803-'.

Maasm/e (%): 431 (M”-HBr.

11), 311 (36), 285 (46).

284 (14), 148 (10).

147 (100), 131 (12).

130 (41), 129 (14).

105 (45), 91 (44),? ? (30)
, 69 (52).

19 Physical properties 'H-NMR (in CDCIsCDCl5)E measurement (-m/-/I/type): δ2.20-3.37 (
m, 5H), 2.38 (s, 3H).

2.99 (s, 2) (), 4.71 (doV
d.

LH, J=8.5Hz, J-4,5Hz).

6.18 (s, IH), 6.35 (d', IH
.

J=3.6Hz), 7.03-7.97 (m.

10H), 15.17-16.17 (m.

IH)ppm.

Reference example 1 3.600m (1.5mmo I) and carbonic power IJ
Add 621w (4.5 mmol) to 15 ml of a 9:1 mixed solvent of ethanol and water and heat under reflux for 69 hours. After the reaction, ethanol was distilled off from the reaction mixture.
The tM condensate was poured into an aqueous ammonium chloride solution and extracted with dichloromethane. The extracted layer was washed with water, dried over magnesium sulfate, concentrated, and this concentrate was applied to a silica gel column.
Elution with a 10:1 mixed solvent of dichloromethane and ethyl acetate gave 237 ml of 20 in a yield of 90.5%.

Physical properties of 20 Colorless plate crystals (from ethanol) Melting point 182.5
~183.0'c' H-NMR(InCDCls)
: δ1.77-2.08 (m, 2H), 2.23
(s.

3H), 2.61-2.80 (m, 2H).

3.05-3.26 (m, 2H), 6.35-6.4
8 (m, 2H), 6.64-6.76 (m, IH)
, 8.14-8.68 (m, LH) ppm-IR (KBr): 3231.1643cs*-'.

Massm/e (%): 175 (M”, 65).

160 (100), 132 (30).

Elemental analysis value calculated as C++H+xNO: C, 75,40; H, 7,48; N, 7.
99 C%) Actual value: C, 75,23; H, 7,54.

N, 7.90 C%) Reference Example 2 20-80w (4,57X 10-'mol) and 40cm of 5% palladium-carbon catalyst were added to 1.5ml of diethylene glycol diethyl ether, and argon was introduced into the reaction system. After the completion of the reaction, which was heated and stirred at 200° C. for 3 hours while direct blowing, dichloromethane was added to the reaction mixture, and the catalyst was removed by filtration. Remove the solvent from the filtrate (diethylene glycol diethyl ether is
The residue (removed by pulling with a vacuum pump while soaking in a 0°C water bath) was applied to a silica gel column and flushed out with a 1 j 100 mixed solvent of ethyl acetate and dichloromethane. 21 was 73 cm, yield 92.3%. Obtained with.

C Melting point 132.0-133. Literature value 127.5-128
,OCham,Bar-,89,2783゜'H-NM
R(in CDCIs): δ2.09(a, 3H)
, 3.95 (s, 2H).

6.47-6.60 (m, IH), 6.90-7.3
9 (m, 4H), 8.20-8.60 (m, LH)p
p.m.

IR (KBr): 3342,1713 cm-'.

Ma s sm/e (%): 173 (M”, 26)
.

130 (100).

Calculated value as elemental analysis value 'C++H++NO: C, 76,27, H, 6,40; N, 8.0
9 (%) Actual value: C, 76,26; H, 6,29; N, 8.
12C%) 3.15.0 g (37,5 mmo I), 15.0 g potassium carbonate (0,11 mmo +) and 10.6 g methyl iodide (74,6 mmo I) were added to 100 ml of acetone and with vigorous stirring The mixture was heated to reflux.

After 1 hour, 5.0 g of methyl iodide was added and the mixture was further heated under reflux for 2 hours. After completion of one reaction, the mixture was poured into the reaction mixture and extracted with ethyl acetate. The extracted layer was washed with water, dried over magnesium sulfate, and then the solvent was distilled off. When the operation of crystallizing the residue with ethanol was repeated, Σ was 14.1 g and the yield was 9.
Obtained at 1.0%.

Reference Example 3 5.600w (1,44mmol I) and potassium carbonate 60Cat (4,34mmol I) were added to 15ml of 9:Ljli@solvent of ethanol and water and heated under reflux for 45 hours. When treated in the same manner, 262 ml of 22 was obtained in a yield of 96.0%.

Physical properties of 22 Colorless columnar crystals (from ethanol) Melting point 173.5
~175.0℃'HNMR (in CDCl5): δ1.12(t,
3H, J=7.2Hz>, 1.74~2.08 (m,
2 old, 2.53 (q, 2H.

J-7, 2Hz), 2.69 (t, 2H.

J-6,0Hz>, 3.06-3.23 (m.

2H), 6.34-6.49 (m, 2H).

6.65-646 (m, LH), 8.24-8.94
(m,]H) pPm-IR(KBr):3279.16433-'.

Maasm/e (%): ts9 (M'', 2B).

160 (100), 132 (13).

Elemental analysis value: C1□HIs Calculated value as N O: C
,76,15i H,? , 99 iN, 7.40 (%
) Actual measurement value: C, 76,04, H, 8,08; N, 7.
35 (%) Reference Example 4 22.80 g (4,23xlO-'mol) and 40 µ of the 59 palladium-carbon catalyst were added to diethylene glycol diethyl ether and reacted and treated in the same manner as in Reference Example 2, resulting in 78 µ of 23, Obtained in a yield of 9B, 5%.

Physical properties of 23 Colorless needle crystals (from ethyl acetate-〇-hexane) Melting point 60.0-62.0℃ 'HNMR (in CDCl5): δ0.97 (t
, 3H, J=7.2Hz), 2.46(q, 2H, J-
7,2Hz), 3.95 (s, 2H), 6.46-6.
62 (m.

IH), 6.90-7.40 (m, 4H)
.

8.14-8.70 (m, IH) p pm.

IR (KBr): 3350.　1720cm-'.

Massm/e (%): 187 (M', 25
).

130 (1 (10).

Elemental analysis value: Calculated value as C+tH+sNO: C
,76,97;H,7,00;N,7.48 (
%) Actual measurement (II: C, 76,70i H, 6,98; N
, 7.40 (%) Reference Example 5 1 tert-butyl potassium was added to a solution of 3.2=Og (5.0 mmol) dissolved in THF at 0°C under a nitrogen stream.
．． After adding 21 g (10.5 mmo 2 ) and stirring for several minutes, 2.2 g (15.5 mmo 1) of methyl iodide was added and the mixture was stirred at room temperature for 1 hour. Tertiary butyl potassium 0.
5g (4,3mmo 1), and methyl iodide 1
．． After the completion of the reaction, the reaction mixture was poured into an aqueous ammonium chloride solution and extracted with dichloromethane. The extracted layer was washed with water, dried with magnesium sulfate, and then dried in a tall container. When this concentrate was applied to a silica gel column and flushed out with dichloromethane, 1.22 g of 24 was obtained, yield 57.1%.
Obtained with.

2J physical properties pale yellow viscous substance'HNMR (in CDC1x): δ1.19 (t,
3H, J-7,0Hz), 1.37(s, 6H),
1.62-1.98 (m.

2H), 2.39 (s, 3H), 1.66-3.10
(m, 4H), 4.14 (q, 2H.

J=7.0Hz), 6.27 (broad3.
LH), 6.39 (d, lH, J-3
, 6Hz), 7.14-7.38 (m, 3
H) 7.60-7.76 (m, 2 H) p p
m.

Massm/a (%>: 乎学￥<M゛, 5).

314 (100).

Reference example 6 2j, 293mg (6,83X 10-'no l)
and 100 μ (2.5 mmo+) of sodium hydroxide were added to 12 ml of 91 mixed solvent of ethanol and water and heated under reflux for 26 hours. After the reaction was completed, the same treatment as in Reference Example 1 was carried out, and 25 was 110 μ, yield. Obtained at 79.314.

Physical property value of 25 Colorless columnar crystals (from ethyl acetate), melting point 13
9.0-141.0℃'HNMR (In CDCl5): δ1.14 (d,
6H, J=7.0Hz), 1.77-2.10 (m,
2H), 2.55-2.88- (m, 3H), 3.
08-3.28 (m.

2H), 6.36-6.50 (m, 2H).

6.65-6.76 (m, IH), 8.26-8.7
6 (m, LH) ppm.

IR (KBr): 33QO, 1646c*-'.

Massm/e (%) 103 (M'', 22).

160 (100).

Elemental analysis 41: Calculated value as C+jH+yNO: C
, 76,81; H, 8,43; N, 6.89 C%) Actual value: C, 76,54; H, 8,42; N, 6.
80 (%) Reference Example 7 25.80 m (3,94X 10-'mo +) and 40 st of 5% palladium-carbon catalyst were added to 1.5 ml of diethylene glycol diethyl ether, and Reference Example 2
When the reaction and treatment were carried out in the same manner as above, 26 was obtained in 63 degrees and in a yield of 79.594.

Physical properties of 2G Colorless columnar crystals (from #ethyl acid) Melting point 106.5
~107.5°C'H-NMR (I n CDCIg)! 131
．． 05 (c, IH, J-6, 8Hz), 3.91 (s,
2H), 6.38-6.52 (m.

IH), 6.82-7.30 (m, 4 old.

8.08-8.54 (m, LH) I) pm.

IR(KBr):3360. 1708cs-'.

V(as sm/e (%): 201 (M”,
23).

130 (100).

Elemental analysis value: C1! Calculate as H,, No.Ill:
C, 77,58; H, 7,51; N, 5°96
(%) Actual value: C,? ? ,73,H,7,59iN,
6.93 (%) Reference example 8
After the reaction was completed, the reaction mixture was poured into water and extracted with dichloromethane. The extracted layer was washed with water, dried with magnesium sulfate, and then concentrated. The concentrate was applied to a silica gel column and flushed with dichloromethane to obtain 27 (178 μm) in a yield of 79%.

Physical properties of 27 Colorless columnar crystals Melting point 95.0-96.0t (from ethyl acetate)'HNMR (in CDCl5): δ2. o6
(s, 3H), 2.31 (s, 3H).

3.82 (s, 2H), 6.61 (d, 1) 1°J-3,6Hz), 6.96-7.36 (m.

4H), 7.53 (d, IH, J 3.6Hz), 7.64-8.00 (m, 3H).

ppm.

rR (KBr-di sk method): 1718°160
0.1490,1360°1 1 7 5c+m-'.

Massm/e (%): 327 (M”,
41).

284 (100), 130 (31).

91 (49), 43 (56).

Elemental analysis value: Calculated value as Ct*H+vN Os S: C, 66,04; H, 5,23iN, 4.
28, S, 9.79 (%) Actual value: C, 66
,01;H,5,19;N, 4.22;S,
9.95 (%) Reference Example 9 14.125+w (2,9x 10-'mo 1) and 75g of lithium bromide (8,5X 10-'mo
I) was added to 5 ml of DMF and stirred at 150° C. for 3 hours and 30 minutes in an argon stream. After the reaction was completed, the reaction mixture was poured into water and extracted with dichloromethane. The extracted layer was washed with water, dried over magnesium sulfate, and concentrated. lI]
When the substance was applied to a silica gel column and flushed out with a 50-1 mixed solvent of dichloromethane and ethyl acetate, 27 was changed to 75.
(2) Obtained with a yield of 80%.

Reference Example 10: 11.4 g (8,3 x 10-" mol) and 2.17 g (2,5 x 1 mol) of lithium bromide (anhydrous)
6. After the reaction, the reaction mixture was poured into water and extracted with ethyl acetate. The extracted layer was washed 4 times with water. , magnesium sulfate was dried and concentrated.This concentrate was applied to a silica gel column and flushed out with a mixed solvent of dichloromethane and ethyl acetate 100:1.28
3.289 g of the product was obtained in a yield of 99%.

Colorless columnar crystals (from ethyl acetate-n-hexane) Melting point 75.0-76.5℃ 'HNMR (l n CDCl5) Partial enolization (
Keto type: Enol type 89:11) Keto type: 61.18
(t, 3H, J-1,0Hz).

2.29 (s, 3H), 3.35 (s, 2H).

3.97 (s, 2H), 4.07 (Q, 2H.

J-7,0Hz), 6.63 (d, IH.

Enol type (characteristic shifts only): δ1.
20 (t, 3H, J=7.0Hz).

3.65 (s, 2H), 4.81 (s, L
H).

12.10 (s, IH) p pm.

IR (KBr): 1750. 1725°1600
, 1357. 1176cm-'.

Massm/e (%): 399 (M”, 57)
.

311 (31), 284 (100).

130 (52), 129 (30).

91 (75), 29 (34).

Elemental analysis value: Calculated value as Cz + Hz r N S Os: C, 63, 14; H, 5, 30; N, 3
．． 51; S, 8.03 (%) Actual value: C, 63,
09; H, 5,17iN, 3.37; S, 7.8
3 (%) Reference example 11 50% sodium hydride 150■ (3,13X10-3
mol) in a stream of argon.

Add cyclohexanol 400* to the solution suspended in ml.
(4,OX 10-" mol) was added and stirred at room temperature for 2 hours. To this solution, 28.500μ (1,25X
After the completion of the reaction, the reaction mixture was poured into an aqueous ammonium chloride solution and extracted with ethyl acetate. The extracted layer was washed with water, dried with magnesium sulfate, and concentrated. When the concentrate was applied to a silica gel column and flushed with dichloromethane, 28 was recovered in 12% yield, followed by 29 and 2.
It was obtained in a yield of 77.2%.

Colorless oil 'HNMR (in CDCl5): δ1.20
(t, 3H, J=7.2Hz), 3.41(s
, 2H), 4.09 (s, 2H).

4.15 (q, 2H, J=7.2Hz), 6.4
7-6.64 (m, LH), 6.90-7
．． 44 (m, 4H), 8.26-8.66
(m, IH) ppm.

IR (liquid film) i3430°17
43, 17170-1゜Mas sm/e (%): 245 (M'''
, 17).

Reference Example 12 1,'i'・15.120g (2,5X 10-'mo 1) and lithium bromide lOOs (1,2x 1-0-'n
o l) to 2.5 ml of 0MF and heated at 60°C in a nitrogen stream.
The mixture was heated and stirred at 80° C. for 1 hour and 30 minutes for 30 minutes.

After the reaction was completed, the reaction mixture was poured into water and extracted with ethyl acetate. The extracted layer was washed four times with water, dried over magnesium sulfate, and then concentrated. This concentrate was applied to a silica gel column with 100:1 of dichloromethane, ethyl acetate and ethanol.
When poured out with a 10:1 mixed solvent, 84g of 30 was obtained.
, with a yield of 84%.

Physical properties of 30 Colorless granular crystals (from ethyl acetate) Melting point 135-1
38.5℃ 'HNMR (I n CDCl5) Partial enolization (
Keto type: Enol type 78:22) Keto type: 62.31
(s. 3 old, 2.69 (s.

3H), 2.85 (s, 3H), 3.42
(s, 2H), 4.00 Cs, 2H).

6.71 (d, LH, J-3, 6Hz).

6.96-7.34 (m, 4H), 7.53 (d, I
H, J-3,6Hz), 7.60-7.96 (m,
3H)ppm.

Enol type (only characteristic shifts are listed): δ3.66
(s, 2H), 4.94 (s, IH).

12.88 (broad s, LH) p pm・IR (KBr): 1635.1606°1504.14
21.1373°1190 t*-'.

Ma s sm/e (%): 398 (M”, 4
7).

284 (34), 114 (88), 91 (63),
87 (100), 72 (97).

Reference example 13 14.351w (8,1x 10-'no 1) and lithium bromide 210w (2,4X 10-'no
1) was added to 5 ml of 0MF and heated and stirred at 80°C for 24 hours in a nitrogen stream. After the reaction, the reaction mixture was poured into water.
Extracted with ethyl acetate. The extracted layer was washed three times with water, dried over magnesium sulfate, and then concentrated. This concentrate was applied to a silica gel column and flushed out with a 10:1 mixed solvent of dichloromethane, ethyl acetate and ethanol, yielding 230 ml of 30 in a yield of 71%.

Reference example 14 16.201s+g (4,31X 10-'mo 1
) and 112 ml of lithium bromide (1,29X l
O-'mol) was added to 2.5 ml of 0MF and stirred at 85° C. for 2 hours in an argon stream. After completion of the reaction, the reaction mixture was poured into water and extracted with ethyl acetate. After washing the extracted layer with water and drying with magnesium sulfate? I shrink, this tl$1! The product was applied to a silica gel column and flushed out with a mixed solvent of too:t of dichloromethane and ethyl acetate to obtain 156 g of 31 in a yield of 93.9%.

Physical properties of colorless oil 'HNMR (in CDCl5): δ2.35 (s,
3H), 3.42 (s, 2H).

3.66 (s, 3H), 4.03 (s
, 2H).

6.71 (d, IH, J-3, 8Hz).

7.04-7.44 (m, 4H), 7.6
4 (d, LH, J-3,8Hz), 7.72~
8.08 (m, 3H) ppm.

IR (llquld film): 1750°1?
24. 1599. 1370°1 177cm-'.

Massm/e (%) 8385 (M”, 3
8).

311 (18), 285 (23).

284 (100), 156 (10).

155 (18), 130 (43).

129 (28), 102 (13).

(C**H+*NOs S) Reference example 15 32M 50% sodium hydride 164■ (3,42X10-''
mol) in 5 ml of THF under a stream of argon.
29 was suspended at ℃ and dissolved in 4 ml of THF.
．． 399 g (1,63 x 10-' mol) was added and stirred until hydrogen evolution disappeared. 1.1 ml of n-butyllithium (15%, n-hexane solution) was added to the solution to prepare 29 trianions.

(Yellow-red solid precipitation) A solution of this trianion was added to
2-methyl-2- cooled to ℃ and dissolved in 4 ml of THF.
Propenyl iodide 350■ (1,92X 10-
”mol) was added. After 30 minutes, more THFl was added.
350 µm (1,92 x 10-” m
After the reaction was completed, the reaction mixture was poured into dilute hydrochloric acid and extracted with ethyl acetate. The extracted layer was washed with saturated brine, dried with magnesium sulfate, and concentrated. The concentrate was applied to a silica gel column and flushed out with a 100:1 mixed solvent of dichloromethane and ethyl acetate. Subsequently, the raw material 29 was recovered in 178 cm, a yield of 45%.

Physical properties of colorless oil 'HNMR (In CDC1x): δ1.16 (t,
3H, J=7.0Hz), 1.68 (s, 3H), 2.
58 (dd, IH.

J-14,6Hz, J-7,0Hz).

3.05 (dd, IH, J=14.6Hz.

J-7,0Hz), 3.23 (d, IH.

J-15,6Hz>, 3.52 (d, LH.

J-15,6Hz), 4.10 (q, 2H
.

J-7,0Hz), 4.47 (t, IH.

J-7,0Hz), 4.68 (broads,
2H), 6.56-6.72 (m.

IH), 6.88-7.46 (m, 4H)
.

8.32-8.84 (m, LH) ppm.

IR (liquid film): 3430°17
40, 1715. 1650clI-'.

Massm/ec%): 299 (M+,
11).

ゝ, ↑ ) Reference Example 16 48T゛50% Sodium Hydrogen 128■ (2,67X10-'m
ol) in 15ffll of THF in an argon stream at 0°C.
Suspend 28.1.0g (2,50X 10-
'no l) and stirred for 10 times, then stirred for another 1 time at room temperature.
Stir for 0 minutes to prepare the sodium salt of 28. The solution was cooled again to 0 °C and diluted with n-butyllithium (15%, n-
Add 1.75ml of hexane solution, stir for 20 minutes,
28 dianions were prepared. To this dianion solution, 623m (2,76X 10-"mol) of 2-methyl-2-propenyl-p-toluenesulfonate was added and stirred at 0°C for 20 minutes. After the reaction was completed, the reaction mixture was diluted with saturated ammonium chloride. It was poured into an aqueous solution and extracted with ethyl acetate.The extracted layer was washed with saturated brine, dried with magnesium sulfate, concentrated, and this ?111 substance was applied to a silica gel column and flushed out with dichloromethane.
1, with a yield of 84.8%.

Physical property value of υ Colorless viscous substance 'H-NMR (in CDCIs): δ1.10 (
t, 3H, J-7,0Hz), 1.61(s, 3H),
2.32 (s, 3H).

2.43 (dd, IH, J=14.4Hz.

J-7, 2Hz>, 2.95 (dd, IH.

J=14.4Hz, J-7.2Hz).

3.27 (dd, J-20,5H3J-15,6H
z), 4.02 (q, 2H, J-7,0Hz), 4.
39 (t, 1M, J-7, 21(z), 4.57 (
broad s.

IH), 4.64 (broads, LH).

6.80 (d, 11 (, J-3, 6Hz).

7.02-7.42 (m, 4H), 7.65 (d, L
H, J=3.6Hz), 7.70-8.06 (m,
3H)ppm.

IR (liquid film): 1745°17
20, 1650 countries-1°Massm/e (%): 453 (M′″, 19).

338 (74), 183 (42).

182 (100), 168 (33).

167 (44), 155 (45), 91 Reference Example 17 υ 34 Ketoester 33 (906*, 2 mm and LICI
(300q) was added to dimethylformamide (3 ml) and heated to about 150° C. for 3 hours under an argon atmosphere. After cooling, the reaction mixture was diluted with CH*C1* and washed with water. The CH, C1 layer was dried and concentrated with Mg5o4, and the residue was applied to a silica gel column and flushed out with CHICI□, and the acetonyl compound 347 was obtained as a pale yellow viscous oil.
I got 20 tatami.

NMR (in CDC1*): δ1.16 (broa
d s, IH), 1.98 (s, 3H), 1.33
(s, 3H).

2.20-3.00 (m, 2H), 4. LO(t, J
-6,5Hz, LH), 4.52and4.51 (
two m, VH).

6.74 (d, J=4Hz, LH).

6.98-7.50 <m, 8H) ppm.

IR (liquldfilm): 1715°1650,
1600. 1370°1 177 cs-'.

Ma s sm/e (%), : 381 (M'
, 13).

338 (100), 183 (42).

182 (100), 168 (34).

167 (46), 155 (44), 9
1 (89).

Reference example 18 50% sodium hydride 203■ (4,23X10-'
To a solution of 423 mol of cyclohexanol (4,23 x 10
-"m o + ) was added and stirred for about 1 hour and 30 minutes.

In this solution, 33,606■ (
1,34×10-' mol) was added thereto, and the mixture was stirred at room temperature.

After 2 hours, add 37+qr of 50% sodium hydride.
(0.77X 10-" mol) was added and stirred for 1 hour. After completion of the reaction, the reaction mixture was poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The extracted layer was washed with saturated brine and dried with magnesium sulfate. , concentrated.This?
When the 1SlI product was applied to a silica gel column and flushed out with a too:1 mixed solvent of dichloromethane and ethyl acetate, 363 ml of 32 was obtained in a yield of 90.8%.

Reference example 19 Ts Ts 17.280w (5,17X 10-'mol) and lithium bromide 135■ (1,55X10 bow no l
) was added to 5 ml of DMF and incubated at 85°C in an argon stream for 30 minutes.
After the reaction was completed after stirring for 30 minutes, the reaction mixture was poured into water and extracted with ethyl acetate. The extracted layer was washed with water, dried over magnesium sulfate, and concentrated. When this concentrate was applied to a silica gel column and flushed out with a 1:1 mixed solvent of ethyl acetate and n-hexane, 217 μm of 35 was obtained in a yield of 91.2%.

Colorless oil 'HNMR (in CDCl5): δ2.27 (s,
3H), 3.43 (s, 2H).

3.97 (s, 2H), 5.10 (s, 2H).

6.62 (d, IH, J-3, 8Hz).

6.94-7.46 (m, 9H), 7.57 (d, I
H, J-3,8Hz), 7.68-8.04 (m, 3
H)ppm.

IR (liquid film): 1745°1
725, 1600. 1373°1 180 am-'.

Massm/s (%): 461 (M”, 13)
.

284 (39), 155 (16).

130 (26), 91 (100), 7
9(45), 77(35).

Reference example 20 Ts H 50% sodium hydride 362■ (7,54X10-"
mol) in THFloml in an argon stream at 0°C.
5 ml of THF was dissolved in the suspended solution. 3JJ, 1
6g (2,52X10-'no 1) was added and stirred until no hydrogen was generated. Add THF2 to this solution
223 g of 2-propatool dissolved in ml (3,7
2x 10-"mo 1 ) for 30 minutes at 0°C.
Subsequently, the mixture was stirred at room temperature for 1 hour and 30 minutes.

After the reaction was completed, the reaction mixture was poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. After washing the extracted layer with water and drying with magnesium sulfate, i! It was m. This concentrate was applied to a silica gel column and dichloromethane and ethyl acetate were added.
When washed out with a mixed solvent, 571 ml of 36 was obtained in a yield of 74.0%.

Physical properties of L6 Colorless oil 'HNMR (In CDCIx): δ3.45 (s,
2H), 4.06 Cs, 2H).

5.12 (s, 2H), 6.45-6.58 (m, I
H), 6.87-7.46 (m.

9H), 8.06-8.58 (m, IH) ppm.

IR (liquid film): 3440
゜1740, 1716+:II-'.

Massm/e (%): 307 (M″″, 14
).

216 (13), 130 (100).

Reference example 21 35.87w (1,89XIG-'mol) and 5%
Five parts of the palladium-carbon catalyst were added to 2.5 ml of a 4=1 mixed solvent of ethanol and ethyl acetate, and the mixture was stirred at room temperature under -atmosphere hydrogen pressure. After 2 hours, 5 palladium-carbon catalyst 911I was added, and the mixture was further stirred at room temperature for 17 hours. After that, the reaction mixture was heated under reflux for 1 hour. After the reaction was completed, the reaction mixture was concentrated, and the concentrate was applied to a silica gel column and flushed out with a 3:2 mixed solvent of n-hexane and ethyl acetate.
7 was obtained in 42 cm and yield 68.1%.

Colorless columnar crystals Melting point 95.0-96.0°C (from ethyl acetate) HNMR (in CDCIs): δ2.06 (s,
3H), 2.31 <s, 3H).

3.82 (s, 2H), 6.61 (d, IH.

J-3,6Hz), 6.96-7.36 (m.

4H), 7.53 (d, IH, J- 3,6Hz), 7.64-8.00 (m, 3H)pp
m.

IR (KBr-disk method): 1718°1600,
1490. 1360°Massm/e (%): 327 (M″″, 41).

284 (100), 130 (31).

91 (49), 43 (56).

Elemental analysis value: Calculated value as C+s H1,NOs S: C,66,04; H,5,23iN, 4
゜28 i S, 9.79 (%) Actual value: C,
66,01; H, 5,19; N, 4.22; s
, 9.95 (%) Reference Example 22 18.2.81 g (5,49X10-'no 1)
and lithium bromide 1.43g (1,65X10-”
Mo+) was added to 20 ml of DMF, and in an argon stream,
After the reaction was completed by stirring at 5° C. for 1 hour and 15 minutes, the reaction mixture was poured into water and extracted with ethyl acetate. After washing the extracted layer with water and drying with magnesium sulfate, 7! Shrunk. When this concentrate was dissolved in ethyl acetate and crystallized, 37 was 1.87
5g was obtained with a yield of 79.3%.

The crystal filtrate was concentrated, applied to a silica gel column, and flushed out with dichloromethane.
．． The total yield was 89.4%.

Physical properties of 37 Colorless columnar crystals (from ethyl acetate) Melting point 142.5
~143.5°C'H-NMR (in CDCl, ) (z-norm type); δ2.32 (s, 3H), 3.92 (s.

2H), 6.09 (s, IH), 6.79 (d, I
H, J=3.6Hz), 7.05~8.09 (
m, 13H), 15.99-16.29 (
m, IH) pI) m.

IR (KBr): 1600. 1373°1
190clI-'.

Massm/eC%): 431 (M”, 9).

311 (38), 285 (49).

147 (100), 130 (37).

105 (41), 91 (37), 77 (24)
, 69 (52).

Elemental analysis value: Calculated value as CzsH□, N SO,
C, 69,59, H, 4,91.

N, 3.25; S, 7.43 (%) Actual values: C, 69,49; H, 4,89.

N, 3.20 i S, 7.39 (%) Reference example 23 50% sodium hydride 340■ (7,08X10-"
37.1. OOg(2,32X 10
-'mo 1) was added, and the mixture was stirred until no hydrogen was generated. Add 360 mg of cyclohexanol to this solution.
After the completion of the reaction, the reaction mixture was poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The extracted layer was washed with water, dried with magnesium sulfate, and then stirred for 5 hours at room temperature. When the concentrate was applied to a silica gel column and extracted with dichloromethane, 586 μm of 38 was obtained in a yield of 91.3%.

Physical properties of 38 Colorless columnar crystals (from ethyl acetate) Melting point 137.2
~138.5℃ 'HNMR (In CDCIz) (enol form)
;64.03 (s, 2H), 6.17 (s.

IH), 6.56-6.73 (m, IH).

6.93-7.91 (m, 9H), 8.05-8.
53 (m, LH), 15.88-16.36 (m,
IH)I)pm.

IR (KBr): 3350, 1600 cm-'.

Massm/e (%): 27.7 (M”, 22)
.

157 (45), 141 (51).

131 (100), 130 (76).

77 (28), 69 (46).

Elemental analysis value: Calculated as C+aH+sN○ (,l:
C, 77, 96; old 5.45; N, 5.05
(%) Actual value: C, 77,76; H, 5,44; N,
4.99 (%) Reference Example 24 Ta31 3g Ta2-(3-methoxycarbonyl-2-oxtubulov-1-yl)-1
-p-toluenesulfonylindole 31 (2,17
g, 5.63 mmol) in ethyl acetate (25 ml)
, dissolved in water (1 ml), anhydrous potassium carbonate (930 r
z, 6.74 mmol), and further methyl iodide (53
Anhydrous magnesium sulfate was added to the reaction mixture, which was stirred for 12 hours at room temperature under an argon atmosphere. After stirring for a while, the inorganic salts were filtered off, and the filtrate was condensed. . The residue was subjected to column chromatography and eluted with methylene chloride to obtain 4-
(3-methoxycarbonyl-2-oxobut-1-yl)-1-p-toluenesulfonylindole 39 (2
, 06g, 91.7%) was obtained.

Physical property value of 39 NMR (in CD CI s): δ1.25
(d.

J-7, 4Hz, 3H), 2.33 (s.

3H), 3.60 (s, VH), 3.61
(q, J-1, 4H31H), 4.03 (s, 2H),
6.67 (d, J-4H31H), 7.04-7.36 (m.

4H), 7.60 (d, J-4Hz, IH).

7.78 (d,,l-8,5Hz, 2H).

7.95 (d, J-8Hz, IH) ppm.

IR (KBr) ν: I 750.172G.

1595.1358.1185゜ 1125.755,680.575 cm-'.

Ma s sm/e (%): 400 (M”+1°10
．． 7), 399 (M″″, 41.7).

311 (18,7), 285 (21,5)
.

284 (100), 165 (18,2).

155 (14,5), 130 (30,2).

129 (27,8), 91 (59,6).

mp, 6 7.5-6 8.5℃ (from
5ther).

Reference example 25 4-(3-methoxycarbonyl-2-oxobuta-1-
yl)-1-p-) luenesulfonylindole 39
(1.6 g, 4.0 mmo +) in methylene chloride (15
m1) and diluted with sodium borohydride (1 m1) under water cooling.
Add 78W, 4.7 mmo 1). Methanol (2 ml) was added to this suspension and stirred for 30 minutes under an argon atmosphere. After the reaction was completed, the reaction mixture was poured into an aqueous ammonium chloride solution and extracted with methylene chloride. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. By removing the solvent, 4-(2-hydroxy-3-
methoxycarbonylbut-1-yl)-1-p-toluenesulfonylindole 40 (1,54 g.

96.3%) was obtained, and this compound was used in the next reaction without purification.

Physical property value of 40 NMR (CDCI3): δ1.25 (d, J 7Hz
, 3H), 2.27 (s, 3H).

2.36~3.03 (m, 4H), 3.63°3.6
5 (each s, 3H), 3.75-4.33
(m, IH), 6.63-6.77 (m, IH), 6
．． 97-7.33 (m.

4H), 1.53 (d, J-4Hz, IH).

7.66-7.93 (m, 3H) ppm.

Massm/e (%): 401 (M”, 2.
7).

285 (27,2), 284 (16,8)
.

130 (100), 129 (30,3>.

91 (38,8).

IR(l lq, film)j'=3550
゜1730, 1600cm-'.

Reference example 26 4-(2-hydroxy-3-methoxycarbonylbuta-
1-yl)-1-p-)luenesulfonylindole 4
0 (1,149 g, 2.86 mmol) was dissolved in methylene chloride (10 ml), methanesulfonyl chloride (0.8 ml) and pyridine (1 ml) were added under water cooling,
Stirred for 5 hours. The solvent was removed using an aspirator and a vacuum pump, and the residue was subjected to silica gel column chromatography and eluted with methylene chloride to obtain 4-(2-methanesulfonyloxy-3-methoxycarbonylbutylene).
1-yl)-1-p-toluenesulfonylindole 4
,1 (1.13g, 83%) was obtained.

(Physical property value NMR (CDCIs) of (1): δ1.33 (d, J-7,5
Hz, 3H), 1.82 (s.

0.43H), 2.19 (s, 0.57H
).

2.30 (s, 3Ff), 2.52-3.
33 (m, 3H), 3.62 (s),
3.67 (s), 4.92~5.23 (m,
IH).

6.81-6.90 (m, IH), 6.9
9-7.34 (m, 4H), 7.60
(d, J-4Hz, IH), 7.73
(d, J-8,5Hz, 2H), 7.9
0 (d, J-8,5Hz, IH) 9pm-Massm/e (%): 479 (M″″, 14.8)
.

384 (20,3), 383 (74,5).

324 (40,5), 284 (32,7).

196 (20,0), 169 (63,4).

168 (100), 155 (30,8).

154 (21,6), 129 (23,3).

9 L (96,0).

IR(llq, film)y:1740°1600.1
435,1360°1170.1130.910,760°670cm-'
.

Reference Example 27 4-(2-hydroxy-3-methoxycarbonylbuta-
1-yl)-1-p-toluenesulfonylindole, dimethylformamide (0.3 ml) and thionyl chloride (0.4 ml) were added, and the mixture was stirred at room temperature for 10 hours. The reaction mixture was diluted with methylene chloride, washed successively with an aqueous sodium bicarbonate solution and saturated brine, and dried over magnesium sulfate. After concentration, the residue was subjected to silica gel column chromatography and eluted with methylene chloride.
3-methoxycarbonyl-2-buten-l-yl)-1
-p-toluenesulfonylindole 42 (56*.

51%).

Physical property value NMR (CDC1z) of 42: δ1.98 (d, J-1,
5Hz, 3H), 2.34 (s.3H).

3, 68 (d.J=7.5Hz, 2H).

3, 70 (s, 3H), 6.64 (d, d.

J-3.8, 0.9Hz, IH), 6.88(t,
q+ J=7.5, 1.5Hz, LH).

7, 02 (d, J-7.4Hz, IH).

7, 22 (d, d, J=8.0. 0.9H
z.

2H), 7.23 (d, d, J-8.3.

7.4Hz, LH), 7.58 (d.
J-3, 8Hz. IH), 7.77 (d
, J-8, 0Hz. 2H), 7.87
(d. J-8, 3Hz. IH) ppm.

"C-NMR (CDC Is): δ12.63.

2m56. 32.25. 51.80.

-Eyes. qd 10 6, 84. Hanari Hanzo 1 2 2.90.

1 2 4, 80, 1 2 6.14, 1 2 6
．． 88.

128, 38, 129.93, 131.72.

134, 83, 135.32, 139.61.

1 4 4, 99, 1 6 8.38 1) pm.

Reference Example 28 4-(2-methanesulfonyloxy-3-methoxycarbonylbut-1-yl)-1-p-)luenesulfonylindole 41 (1321IIr.

0.28 mmol) was dissolved in anhydrous benzene, diazabicycloundecene (5Qw, 0.33 mmol) was added, and the mixture was heated under reflux for 1 hour under an argon atmosphere.

The solvent was concentrated under reduced pressure, and the residue was eluted by silica gel column chromatography to obtain a mixture of 42 and 43 (75%, 78%).

〜 〜 N of compound Rino
The MR spectrum matched that of a separate V product. Further, the NMR spectrum of compound (3) was measured as a mixture, and was determined to be 42:43-5:2 from the integral ratio of methyl groups.

Physical property value of 43 NMR (CDC13): δ1.37 (d, J-5
Hz, 3H), 2.23 (s, 3H).

3.37 (quint J=5Hz.

IH), 3.67 (s, 3H), 6.33 (d, d
, J-16,5,5Hz, IH).

Massm/e (%): 383 (M”, 57.8
).

324 (28,3), 196 (23,9).

169 (47,1), 16B (100).

167 (22,1), 155 (16,1).

154 (18,6), 141 (18,1).

91 (55,7).

IR (liq, flm) 71715°1650.16
00.1375°1265, 1180. 1130°815, 760ct-'.

patent originator Sagami Central Chemical Research Institute

Claims (3)

[Claims] (1) 4-acylmethylidene-4,5,6,7- represented by the general formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼
Tetrahydroindole derivatives (wherein R^1 is a lower alkoxy group, benzyloxy group, lower alkyl group, dialkylamino group, or phenyl group, R^2 is hydrogen or a lower alkyl group, R^3 is hydrogen or an amino group) is a protecting group and X is hydrogen, chlorine or bromine). (2) 4-hydroxy-4,5,6,7-tetrahydroindole derivative represented by the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (wherein R^1 is a lower alkoxy group, benzyloxy group, lower alkyl group) group, dialkylamino group or phenyl group, R^2 is hydrogen or a lower alkyl group, R^3 is hydrogen or a protecting group for the amino group, and X is hydrogen, chlorine or bromine). 4-acylmethylidene-4,5,6,7-, which is represented by the general formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼
Tetrahydroindole derivatives (wherein R^1 is a lower alkoxy group, benzyloxy group, lower alkyl group, dialkylamino group, or phenyl group, R^2 is hydrogen or a lower alkyl group, R^3 is hydrogen or an amino group) a protecting group, and X is hydrogen, chlorine or bromine). (3) 4-oxo-4,5,6,7-tetrahydroindole represented by the general formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (wherein R^3 is hydrogen or a protecting group for the amino group, X is hydrogen, chlorine, or bromine) and carbonyl compounds represented by the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (wherein R^1 is a lower alkoxy group, benzyloxy group, lower alkyl group, dialkylamino or phenyl group, R^2 is hydrogen or a lower alkyl group) in the presence of a base, 4-hydroxy-4, 5,6,7-tetrahydroindole derivative (in the formula, R^1, R^2, R^
3 and X have the same meanings as above. ), and then by dehydrating this 4-hydroxy-4,5,6,7-tetrahydroindole derivative, 4-acylmethylidene-4 represented by the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ ,5,6,7-
Tetrahydroindole derivative (in the formula, R^1, R^2
R^3 and X represent the same meanings as above. ).