JP2896946B2 - Production method of neocardilines - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for producing neocardilines useful as pharmaceuticals.

[0002]

2. Description of the Related Art It has been known that various physiologically active substances are present in cultures of actinomycetes. Neocarzinostatin, a culture of bacteria belonging to Streptomyces carcinostasis, Neocardilines and the like have been isolated (JP-A-1-224341).

Neocardilines isolated from the microorganism culture are compounds represented by the following formula (11):
It is known that it has an excellent anticancer effect.

Embedded image [Wherein, R ⁵ represents a hydrogen atom or a methyl group, and R ⁶ represents a hydrogen atom or a chlorine atom]

[0004]

However, these neocardilines are produced by a small amount of bacteria belonging to Streptomyces cartinostasis, and the isolation operation is extremely complicated and the yield is low. Therefore, it was impossible at all as an industrial production method. It is also important to synthesize derivatives of neocardilines to develop even better drugs. Accordingly, an object of the present invention is to provide a method for chemically synthesizing neocardilines.

[0005]

Means for Solving the Problems The inventors of the present invention have made intensive studies on the total synthesis of neocardilines from inexpensive raw materials, and have found that neocardilines can be synthesized by simple operations using inexpensive alcohols as raw materials. It has been found that various neocardiline derivatives can be synthesized by various means, and the present invention has been completed.

The method of the present invention is represented by the following reaction formula.

[0007]

Embedded image

[Wherein, R¹Is a lower alkyl group, tetrahi
Dropranyloxyethyl group or N-tert-butyl
-N-methyl-aminomethyl group, wherein n is 1 or 2
And R^TwoMay be substituted by 1 to 3 halogen atoms
A good lower alkyl group; ^FourRepresents a lower alkyl group
You]

That is, the process of the present invention comprises reacting an alcohol (7) with triphenylphosphonylidene-2-propanone, and then reacting the resulting ketone (8) in the presence of a carboxylic acid (9) or A method for producing neocardilines (10), characterized by reacting the reactive derivative.

In the process of the present invention, the alcohol (7) is reacted with triphenylphosphonylidene-2-propanone, and the resulting ketone (8) is reacted with a carboxylic acid (9) or a carboxylic acid (9) in the presence of a strong base. A process for producing alkoxyneocardilines (1), which comprises reacting a reactive derivative and then reacting the resulting neocardilines (10) with an alkylating agent.

[0011]

[0012]

[0013]

In the present invention, a lower alkyl group usually means a linear or branched alkyl group having 1 to 5 carbon atoms,
Examples include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a sec-butyl group and an isobutyl group.

The reaction between alcohols (7) and triphenylphosphoranylidene-2-propanone is performed by first reacting an alcohol (7) with an oxidizing agent such as manganese dioxide and then triphenylphosphoranylidene-2-propanone. And stirring. As the reaction solvent,
Methylene chloride, chloroform or the like is used, and the reaction temperature is preferably from 0 to 80 ° C.

The reactive derivative of the carboxylic acid (9) to be reacted with the ketone compound (8) thus obtained includes an acid anhydride, an acid halide and the like. Specifically, monochloroacetic acid chloride, dichloroacetic anhydride,
Trichloroacetic anhydride, trifluoroacetic chloride,
α-chloropropionic acid chloride and the like. Examples of the strong base used in this reaction include lithium hexamethyldisilazane, sodium hexamethyldisilazane, potassium hexamethyldisilazane, and the like. The reaction between the ketone (8) and the carboxylic acid (9) or a reactive derivative thereof is performed by adding a strong base to the ketone (8) and gradually adding the carboxylic acid (9) or the reactive derivative thereto. It is performed by stirring at 78 to 20 ° C.

In the obtained neocardilines (10), when R ¹ is a tetrahydropyranyloxyethyl group, pyridinium paratoluenesulfonium,
Hydroxyneocardilines (10-B) can be obtained by reacting mineral acids, Lewis acids and the like.

The neocardilines (1) thus obtained
As the alkylating agent of 0), alkylating agents for alcohols such as diazomethane and trimethylsilyldiazomethane are preferable. The reaction between the neocardilines (10) and the alkylating agent is carried out, for example, when diazomethane is used as the alkylating agent, by stirring at a temperature of −5 to 60 ° C. for about 30 minutes to 5 hours. Thus, the alkoxy neocardilines (1) are obtained.

The neocardilines (10) and the alkoxyneocardilines (1) of the present invention have geometrical isomers and stereoisomers. In the present invention, both of these isomers are included.

In the method of the present invention, the product is isolated from the reaction mixture by a conventional method, for example, solvent extraction, recrystallization, column chromatography and the like.

The alcohol (7) used as a raw material in the method of the present invention is produced, for example, as follows.

[0022]

Embedded image

Wherein R ⁴ represents a benzyl group or an ethyl group, and R ¹ is the same as defined above.

[0024]

According to the present invention, neocardilines useful as anticancer agents can be efficiently produced from inexpensive raw materials by an easy operation.

[0025]

Next, the present invention will be described in detail with reference to examples, but the present invention is not limited to these examples.

Example 1 (1) L-isoleucine (6.53 g, 49.9 mmol) of (2S, 3S) -2-hydroxy-3-methylpentanoic acid was added to 1N.
After dissolving in H ₂ SO ₄ (50 ml), the mixture was stirred with 20% N
An aNO ₂ aqueous solution (70 ml, 202 mmol) was added dropwise over 1 hour, and the mixture was stirred for 5 hours. The reaction solution was neutralized with sodium carbonate and washed three times with ethyl acetate. After the aqueous layer was acidified with citric acid, it was extracted three times with ethyl acetate, and the organic layer was washed with water, half-saturated brine and saturated brine, and dried over anhydrous MgSO ₄ . After evaporating the solvent under reduced pressure, the residue was subjected to chromatography on 65 g of silica gel, and the fraction eluted with n-hexane-ethyl acetate (5: 1) from the fraction eluted with 5.84 g of the title compound (8
9%) as a colorless powder. mp 49-51 ° C. [α] _D ²² + 32.04 ° (c = 0.78, CHCl ₃ ) .IR ν _max (CHCl ₃ ) cm ^-1 : 3600-2400, 3150, 2980, 294
^{5, 2880, 1720. 1 H-} NMR (CDCl 3, 100MHz): δ 0.93 (3H, t, J = 7Hz), 1.02 (3H, d, J = 7Hz), 1.12~1.58 (2H,
m), 1.64 to 2.05 (1H, m), 4.17 (1H, d, J = 4 Hz), 4.60 to 5.10 (2
H, br s) .EIMS m / z : 132 [M ⁺ ] (Calcd forC ₆ H ₁₂ O ₃ : 132.0786, Foun
d: 132.0779).

(2) (2E, 4S) -4-methyl-2-
Benzyl hexenoate (2S, 3S) -2-hydroxy-3-methylpentanoic acid (1.06 g, 8.00 mmol) and (nC ₄ H ₉ ) ₄ N
IO ₄ (3.63 g, 8.38 mmol) was dissolved in methylene chloride (30 ml) and heated under reflux for 5 hours. Reaction solution is 10
2% aqueous sodium thiosulfate solution and dried over anhydrous MgSO
Dried at ₄ . The solvent was concentrated to 20ml position under reduced pressure benzyl (triphenylphosphoranylidene) acetate (3.61 g, 8.79 mmol) was added, 4 under a stream of N ₂
Stirred for 0 hours. After concentration of the reaction mixture, the residue was chromatographed on 80 g of silica gel to give 1.34 g (77%) of the title compound as a colorless oil from the fraction eluted with n-hexane-ethyl acetate (20: 1). Was. [α] _D ²⁵ + 26.60 ° (c = 1.29, CHCl ₃ ). IR ν _max (neat) cm ^-1 : 2960, 2925, 2870, 1720, 165
0, 1155, 980. ¹ H-NMR (CDCl ₃ , 100 MHz): δ 0.87 (3H, t, J = 7 Hz), 1.02 (3H, d, J = 7 Hz), 1.16 to 1.60 (2H,
m), 1.96 ~ 2.44 (1H, m), 5.16 (2H, s), 5.82 (1H, dd, J = 1,16H
z), 6.90 (1H, dd, J = 8,16Hz), 7.35 (5H, s) .EIMS m / z : 218 [M ⁺ ] (Calcd forC ₁₄ H ₁₈ O ₂ : 218.1307, Foun
d: 218.1307).

(3) (2E, 4S) -4-methyl-2-
Hexen-1-ol LiAlH ₄ (27.5 mg, 0.724 mmol) and A while cooling to −10 ° C. in an ice-methanol bath under a stream of N _2.
1Cl ₃ (33.7 mg, 0.252 mmol) was suspended in diethyl ether (4 ml) and stirred for 25 minutes. To this (2
E, 4S) -4-Methyl-2-benzylhexenoate (1
02.5 mg, 0.47 mmol) of diethyl ether (1 m
l) The solution was added dropwise over 5 minutes and stirred for 15 minutes. Water-containing diethyl ether was slowly dropped, and then water was slowly dropped. After washing the reaction solution with 1N hydrochloric acid, the aqueous layer was extracted three times with diethyl ether. Organic layer is saturated with NaHC
The extract was washed with O ₃ water, water and saturated saline, and dried over anhydrous MgSO ₄ . After evaporating the solvent under reduced pressure, the residue was subjected to chromatography using 20 g of silica gel, and the title compound (40.6) was eluted from a fraction eluted with n-hexane-ethyl acetate (10: 1).
mg (76%) was obtained as a colorless oil. ^{_{[α] D 25 + 21.75 °}} (c = 0.42, CHCl 3) IR ν max (neat) cm -1:.. 3320, 2960, 2925,2965,965 1 H-NMR (CDCl 3, 500MHz): δ 0.86 (3H, t, J = 7Hz), 0.99 (3H, d, J = 7Hz), 1.30 (1H, brs), 1.
32 (2H, dq, J = 7, 7 Hz), 2.01 to 2.09 (1H, m), 4.10 (2H, br d, J =
5Hz), 5.56 (1H, dd , J = 6,15Hz), 5.61 (1H, dd, J = 5,15Hz) EIMS m / z:. 114 [M +] (Calcd forC 7 H 14 O: 114.1045, Found :
114.1031).

(4) Ethyl (2E, 4E, 6S) -6-methyl-2,4-octadienoate (2E, 4S) -4-methyl-2-hexen-1-ol (349 mg, 3.06 mmol) n-hexane (20m
l) and added with MnO ₂ (3.66 g) and stirred for 3 hours. Further, MnO ₂ (0.54 g, 4.20 in total)
g, 48.2 mmol) and stirred for 2 hours. The reaction solution was filtered through celite, washed with n-hexane, and the filtrate was concentrated under reduced pressure until a small amount of solvent remained. Ethyl (triphenylphosphoranylidene) acetate (1.08
g, 3.10 mmol) and dissolved in methylene chloride (2 ml), followed by stirring overnight under a stream of N ₂ . After concentrating the reaction solution under reduced pressure, the residue was subjected to chromatography using 30 g of silica gel, and 305 mg (55%) of the title compound was obtained as a colorless oil from the fraction eluted with n-hexane-ethyl acetate (20: 1). Obtained. [α] _D ²⁵ + 50.87 ° (c = 1.49, CHCl ₃ ) .IR ν _max (neat) cm ^-1 : 2980, 2945, 2880, 1720, 165
0, 1145, 975. ¹ H-NMR (CDCl ₃ , 500 MHz): δ 0.87 (3H, t, J = 7 Hz), 1.03 (3H, d, J = 7 Hz), 1.29 (3H, t, J = 7H
z), 1.32 to 1.42 (2H, m), 2.12 to 2.22 (1H, m), 4.19 (2H, q, J = 7
Hz), 5.79 (1H, d, J = 15 Hz), 6.01 (1H, dd, J = 7, 15 Hz), 6.14 (1
H, dd, J = 11,15Hz), 7.26 (1H, dd, J = 11,15Hz) EIMS m / z : 182 [M ⁺ ] (Calcd forC ₁₁ H ₁₈ O ₂ : 182.1307, Foun
d: 182.1300).

(5) (2E, 4E, 6S) -6-methyl-2,4-octadien-1-ol LiAlH ₄ (108 mg, 2.7) according to Example 1 (3)
7 mmol) and AlCl ₃ (130mg, 0.97mmol) using (2E, 4E, 6S) -6- methyl-2,4-octadiene ethyl (334 mg, 1.84 mmol) was reduced. The reaction extract was chromatographed on 4 g of silica gel, n-hexane-ethyl acetate (5: 1).
From the eluted fraction, 236 mg (92%) of the title compound was obtained as a colorless oily substance. [α] _D ²⁴ + 44.19 ° (c = 0.72, CHCl ₃ ). IR ν _max (neat) cm ^-1 : 3340, 2980, 2940, 2880, 109
^{5, 995. 1 H-NMR (} CDCl 3, 100MHz): δ 0.85 (3H, t, J = 7Hz), 0.99 (3H, d, J = 7Hz), 1.12~1.50 (2H,
m), 1.52 (1H, br s), 1.90 ~ 2.22 (1H, m), 4.15 (2H, br d, J = 5
Hz), 5.40 to 6.35 (4H, m) .EIMS m / z : 140 [M ⁺ ] (Calcd for C ₉ H ₁₆ O: 140.1202, Foun
d: 140.1205).

(6) (3E, 5E, 7E, 9S) -9-
Methyl-3,5,7-undecatrien-2-one (2E, 4E, 6S) -6-methyl-2,4-octadien-1-ol (37.6 mg, 0.269 mmol) was added to n
-Dissolved in hexane (4 ml) and MnO ₂ (330 mg, 3.
79 mmol) and stirred for 2 hours. The reaction solution was filtered through celite, washed with n-hexane, and the filtrate was concentrated under reduced pressure until a small amount of solvent remained. This is chloroform (2
ml), triphenylphosphoranylidene-2-propanone (94.6 mg, 0.297 mmol) was added, and the mixture was heated and refluxed overnight under a stream of N ₂ . The reaction solution was concentrated under reduced pressure, and the residue was subjected to chromatography using 4 g of silica gel. From the fraction eluted with n-hexane-ethyl acetate (20: 1), 41.0 mg (86%) of the title compound was pale yellow. Obtained as an oil. [α] _D ²⁴ + 48.72 ° (c = 0.43, CHCl ₃ ). IR ν _max (neat) cm ^-1 : 2970, 2945, 2880, 1673, 161
^{5, 1585. 1 H-NMR (} CDCl 3, 500MHz): δ 0.88 (3H, t, J = 7Hz), 1.03 (3H, d, J = 7Hz), 1.33~1.40 (2H,
m), 2.12 to 2.19 (1H, m), 2.27 (3H, s), 5.85 (1H, dd, J = 7, 15H
z), 6.12 (1H, d, J = 15 Hz), 6.13 (1H, dd, J = 11, 15 Hz), 6.24 (1
H, dd, J = 11,15Hz), 6.58 (1H, dd, J = 11,15Hz), 7.15 (1H, dd, J
= 11,15Hz) .EIMS m / z : 178 [M ⁺ ] (Calcd forC ₁₂ H ₁₈ 0: 178.1358, Foun
d: 178.1368).

(7) (5E, 7E, 9E, 11S)-
1,1,1-trichloro-11-methyl-5,7,9-
Hexamethyldisilazane (HMDS) (1) under a stream of tridecatriene-2,4-dione N ₂
08 μl, 0.515 mmol) of tetrahydrofuran (T
A solution of HF (1 ml) was ice-cooled, 15% n-butyllithium (n-BuLi) (330 μl, 0.515 mmol) was slowly added dropwise, and the mixture was stirred for 30 minutes. This LHMDS solution was cooled to −78 ° C. under a stream of N ₂ (3E, 5E, 7).
E, 9S) -9-Methyl-3,5,7-undecatrien-2-one (60.9 mg, 0.342 mmol) in THF
(5ml) After slowly dripping into the solution and stirring for 30 minutes,
Trichloroacetic anhydride (125 μl, 0.676 mmol) was added dropwise and stirred for 15 minutes. The reaction was diluted with diethyl ether and saturated aqueous NaHCO ₃ (2 ml) was added. After slowly raising the temperature to room temperature, an aqueous layer and an organic layer were separated, and the aqueous layer was extracted three times with diethyl ether. The organic layer was washed with water and saturated saline and dried over anhydrous MgSO ₄ . After evaporating the solvent under reduced pressure, the residue was subjected to chromatography using 12 g of 10% water-containing silica gel, and 80.2 mg (7: 1) of a fraction eluted with n-hexane-ethyl acetate (50: 1).
3%) as a yellow oil. [α] _D ²⁹ + 45.65 ° (c = 0.09, CHCl ₃ ) .UV λ _max (MeOH) nm (logε): 383.4 (4.73), 269.0 (4.14),
231.6 (4.24) .IR ν _max (neat) cm ^-1 : 2970, 2940, 2870, 1735, 1590,
_{^{1550. 1 H-NMR (CDCl 3}} , 500MHz): δ 0.88 (3H, t, J = 7Hz), 1.03 (3H, d, J = 7Hz), 1.38 (2H, dq, J = 7,7
Hz), 2.17 (1H, dddq, J = 7,7,7,7Hz), 5.89 (1H, dd, J = 7,15H
z), 6.00 (1H, d, J = 15Hz), 6.15 (1H, s), 6.16 (1H, dd, J = 11,15
Hz), 6.28 (1H, dd, J = 11,15Hz), 6.62 (1H, dd, J = 11,15Hz), 7.
37 (1H, dd, J = 11,15Hz), 13.40 (1H, br s) .EIMS m / z : 322 [M ⁺ ] (Calcd forC ₁₄ H ₁₇ O ₂ ³⁵ Cl ₃ : 322.029
4, Found: 322.0292), 324 [M ⁺ '] (Calcd for C ₁₄ H ₁₇ O ₂ ³⁵ Cl
₂ ³⁷ Cl: 324.0265, Found: 324.0266), 326 [M ⁺ ''] (Calcd for
C ₁₄ H ₁₇ O ₂ ³⁵ Cl ³⁷ Cl ₂ : 326.0235, Found: 326.0211), 328
[M ⁺ '''] (Calcd for C ₁₄ H ₁₇ O ₂ ³⁷ Cl ₃ : 328.0206, Found: 32
8.0179),

(8) (3E, 5E, 7E, 9E, 11
S) -1,1,1-Trichloro-4-methoxy-11-
Methyl-3,5,7,9-tridecatetraen-2-one (5E, 7E, 9E, 11S) -1,1,1-trichloro-11-methyl-5,7,9-tridecatriene-
2,4-dione (12.4 mg, 0.039 mmol) was dissolved in diethyl ether (3 ml), and a solution of CH ₂ N ₂ in diethyl ether (3 ml) was added under ice-cooling, followed by stirring for 2 hours. After evaporating the solvent under reduced pressure, the residue was subjected to chromatography using 6 g of 10% water-containing silica gel, and 9.5 mg of the title compound was obtained from a fraction eluted with n-hexane-ethyl acetate (100: 1).
(73%) as a yellow oil. [α] _D ²² + 42.67 ° (c = 0.40, CHCl ₃ ) .UV λ _max (MeOH) nm (logε): 373.0 (4.68), 265.8 (4.3
5), 218.6 (4.16). IR ν _max (neat) cm ^-1 : 2975, 2930, 2880, 1695, 1590,
_{^{1535. 1 H-NMR (CDCl 3}} , 500MHz): δ 0.87 (3H, t, J = 7Hz), 1.02 (3H, d, J = 7Hz), 1.36 (2H, dq, J = 7,7
Hz), 2.15 (1H, dddq, J = 7, 7, 7, 7 Hz), 3.86 (3H, s), 5.80 (1H, d
d, J = 7,15Hz), 6.01 (1H, s), 6.15 (1Hz, dd, J = 11, 15Hz), 6.33
(1H, dd, J = 11,15Hz), 6.51 (1H, dd, J = 11,15Hz), 7.17 (1H, d
d, J = 11,15 Hz), 7.46 (1H, d, J = 15 Hz) .EIMS m / z : 336 [M ⁺ ] (Calcd for C ₁₅ H ₁₉ O ₂ ³⁵ Cl ₃ : 336.054
1, Found: 336.0426), 338 [M ⁺ '] (Calcd for C ₁₅ H ₁₉ O ₂ ³⁵ Cl ₂
³⁷ Cl: 338.0421, Found: 338.0433), 340 [M ⁺ ''] (Calcd for
C ₁₅ H ₁₉ O ₂ ³⁵ Cl ³⁷ Cl ₂ : 340.0391, Found: 340.0383), 342 [M
⁺ '''] (Calcd for C ₁₅ H ₁₉ O ₂ ³⁷ Cl ₃ : 342.0362, Found: 34
2.0374).

Example 2 (5E, 7E, 9E, 11S) -1,1-dichloro-1
1-methyl-5,7,9-tridecatriene-2,4-
Zeon According to Example 1- (7) (3E, 5E, 7E, 9S)
-9-Methyl-3,5,7-undecatrien-2-one (36.1 mg, 0.203 mmol) was enolized and alkylated with dichloroacetyl chloride (39 μl, 0.405 mmol). The reaction product was purified by silica gel chromatography, and n-hexane-ethyl acetate (1
00: 1) From the eluted fraction, 32.5 mg (55
%) As a yellow oil. ^{_{[α] D 24 + 57.52 °}} (c = 0.84, CHCl 3) IR ν max (neat) cm -1:.. 2970, 2930, 2880,1580,1550 1 H-NMR (CDCl 3, 500MHz): δ 0.87 (3H, t, J = 7Hz), 1.03 (3H, d, J = 7Hz), 1.37 (2H, dq, J = 7,7
Hz), 2.16 (1H, dddq, J = 7, 7, 7, 7 Hz), 5.88 (1H, dd, J = 7, 15H
z), 5.89 (1H, s), 5.96 (1H, s), 5.97 (1H, d, J = 15 Hz), 6.15 (1
H, dd, J = 11,15Hz), 6.27 (1H, dd, J = 11,15Hz), 6.60 (1H, dd, J
= 11,15Hz), 7.34 (1H, dd, J = 11,15Hz), 13.93 (1H, br s) .EIMS m / z : 288 [M ⁺ ] (Calcd for C ₁₄ H ₁₈ O ₂ ³⁵ Cl ₂ : 288.068
4, Found: 288.0684), 290 [M ⁺ '] (Calcd for C ₁₄ H ₁₈ O ₂ ³⁵ Cl
³⁷ Cl: 290.0654, Found: 290.0657), 292 [M ⁺ ''] (Calcd for
(C ₁₄ H ₁₈ O ₂ ³⁷ Cl ₂ : 292.0625, Found: 292.0632).

Example 3 (5E, 7E, 9E, 11S) -1-chloro-11-methyl-5,7,9-tridecatriene-2,4-dione According to Example 1- (7), (3E, 5E, 7E, 9S)
-9-Methyl-3,5,7-undecatrien-2-one (33.7 mg, 0.189 mmol) and chloroacetyl chloride (30 μl, 0.377 mmol) were treated, and the reaction product was subjected to silica gel chromatography. The title compound 2 was obtained from the fraction eluted with n-hexane-ethyl acetate (100: 1).
7.1 mg (56%) were obtained as a yellow powder. mp 50-52 ° C. [α] _D ²¹ + 52.59 ° (c = 0.48, CHCl ₃ ). IR ν _max (CHCl ₃ ) cm ^-1 : 2980, 2950, 2890, 1610, 15
60. ¹ H-NMR (CDCl ₃ , 500 MHz): δ 0.87 (3H, t, J = 7 Hz), 1.02 (3H, d, J = 7 Hz), 1.37 (2H, dq, J = 7,7
Hz), 2.15 (1H, dddq, J = 7, 7, 7, 7 Hz), 4.06 (2H, s), 5.85 (1H, d
d, J = 7, 15Hz), 5.87 (1H, s), 5.93 (1H, d, J = 15Hz), 6.13 (1H, d
d, J = 11,15Hz), 6.26 (1H, dd, J = 11,15Hz), 6.57 (1H, dd, J = 1)
EIMS m / z : 254 [M ⁺ ] (Calcd for C ₁₄ H ₁₉ O ₂ ³⁵ Cl: 254.1074, 1,15 Hz), 7.31 (1H, dd, J = 11,15 Hz).
Found: 254.1075), 256 [M ⁺ '] (Calcd for C ₁₄ H ₁₉ O ₂ ³⁷ Cl: 25
6.1044, Found: 256.1047).

Example 4 (5E, 7E, 9E, 11S) -1,1,1-trifluoro-11-methyl-5,7,9-tridecatriene
2,4-dione (3E, 5E, 7E, 9S) according to Example 1- (7)
-9-Methyl-3,5,7-undecatrien-2-one (31.4 mg, 0.176 mmol) and trifluoroacetic anhydride (50 μl, 0.360 mmol) were treated, and the reaction product was subjected to silica gel chromatography. The title compound 3 was obtained from the fraction eluted with n-hexane-ethyl acetate (50: 1).
1.6 mg (54%) were obtained as a yellow oil. ^{_{[α] D 21 + 65.75 °}} (c = 0.65, CHCl 3) IR ν max (neat) cm -1:.. 2980, 2940, 2880,1595,1560 1 H-NMR (CDCl 3, 500MHz): δ 0.88 (3H, t, J = 7Hz), 1.03 (3H, d, J = 7Hz), 1.38 (2H, dq, J = 7,7
Hz), 2.17 (1H, dddq, J = 7, 7, 7, 7 Hz), 5.89 (1H, s), 5.92 (1H, d
d, J = 7, 15Hz), 5.98 (1H, d, J = 15Hz), 6.16 (1H, dd, J = 11, 15H
z), 6.29 (1H, dd, J = 11,15Hz), 6.65 (1H, dd, J = 11,15Hz), 7.4
2 (1H, dd, J = 11,15Hz) .EIMS m / z : 274 [M ⁺ ] (Calcd forC ₁₄ H ₁₇ O ₂ F ₃ : 274.1180, Fo
(und: 274.1177).

Example 5 (2RS, 6E, 8E, 10E, 12S) -2-chloro-12-methyl-6,8,10-tetradecatriene-
3,5-dione According to Example 1- (7) (3E, 5E, 7E, 9S)
-9-Methyl-3,5,7-undecatrien-2-one (56.3 mg, 0.316 mmol) and chloropropionyl chloride (60 μl, 0.624 mmol) were treated, and the reaction product was subjected to silica gel chromatography. Then, 40.2 mg (47%) of the title compound was obtained as a yellow oily substance from the fraction eluted with n-hexane-ethyl acetate (50: 1). [α] _D ²⁵ + 57.30 ° (c = 1.49, CHCl ₃ ) .IR ν _max (neat) cm ^-1 : 2970, 2925, 2870, 1600, 1550. ¹ H-NMR (CDCl ₃ , 500 MHz): δ 0.87 (3H, t, J = 7Hz), 1.02 (3H, d, J = 7Hz), 1.38 (2H, dq, J = 7,7
Hz), 1.68 (3H, d, J = 7Hz), 2.15 (1H, dddq, J = 7, 7, 7, 7Hz), 4.3
8 (1H, q, J = 7Hz), 5.84 (1H, dd, J = 7,15Hz), 5.86 (1H, s), 5.94
(1H, d, J = 15Hz), 6.13 (1H, dd, J = 11,15Hz), 6.25 (1H, dd, J = 1
1,15Hz), 6.56 (1H, dd, J = 11,15Hz), 7.29 (1H, dd, J = 11,15H
z), 14.72 (1H, br s) .EIMS m / z : 268 [M ⁺ ] (Calcd for C ₁₅ H ₂₁ O ₂ ³⁵ Cl: 268.123
0, Found: 268.1225), 270 [M ⁺ '] (Calcd for C ₁₅ H ₂₁ O ₂ ³⁷ C
l: 270.1200, Found: 270.1189).

Example 6 (1) (3E, 5E, 7S) -7-methyl-3,5-nonadien-2-one (2E, 4S) -4-methyl-2-one according to Example 1- (6) Hexen-1-ol (48.0 mg, 0.42 mm
ol), and the reaction product was purified by silica gel chromatography (n-hexane: ethyl acetate = 20: 1) to give 22.0 mg (34%) of the title compound as a colorless oil. [α] _D ²⁵ + 52.86 ° (c = 0.23, CHCl ₃ ). IR ν _max (neat) cm ^-1 : 2925, 2880, 2830, 1650, 1615,
157. ¹ H-NMR (CDCl ₃ , 90 MHz): δ 0.88 (3H, t, J = 7 Hz), 1.03 (3H, d, J = 7 Hz), 1.35 (2H, dq, J = 7, 7
Hz), 2.05 to 2.35 (1H, m), 2.29 (3H, s), 5.90 to 6.35 (2H, m),
6.09 (1H, d, J = 15 Hz), 7.12 (1 H, dd, J = 11, 15 Hz) .EIMS m / z : 152 [M ⁺ ] (Calcd for C ₁₀ H ₁₆ O: 152.1201, Foun
d: 152.1200).

(2) (5E, 7E, 9S) -1, 1, 1
-Trichloro-9-methyl-5,7-undecadiene-
2,4-dione (3E, 5E, 7S) -7- according to Example 1- (7)
Methyl-3,5-nonadien-2-one (15.5 mg,
0.102 mmol) and trichloroacetic anhydride (38 μl,
0.206 mmol), and the reaction product was subjected to silica gel chromatography. From the fraction eluted with n-hexane-ethyl acetate (50: 1), 21.5 mg (71%) of the title compound was obtained.
%) As a pale yellow oil. ^{_{[α] D 22 + 49.45 °}} (c = 0.81, CHCl 3) IR ν max (neat) cm -1:.. 2975, 2940, 2880,1610,1560 1 H-NMR (CDCl 3, 500MHz): δ 0.87 (3H, t, J = 7Hz), 1.03 (3H, d, J = 7Hz), 1.40 (2H, dq, J = 7,7
Hz), 2.21 (1H, dddq, J = 7, 7, 7, 7 Hz), 5.96 (3H, d, J = 15 Hz), 6.
11 (1H, dd, J = 7,15Hz), 6.15 (1H, s), 6.20 (1H, dd, J = 11,15H
z), 7.32 (1H, dd , J = 11,15Hz), 13.41 (1H, br s) EIMS m / z:. 296 [M +] (Calcd for C 12 H 15 O 2 35 Cl 3: 296.013
7, Found: 296.0121), 298 [M ⁺ '] (Calcd for C ₁₂ H ₁₅ O ₂ ³⁵ Cl ₂
³⁷ Cl: 298.0108, Found: 298.0109), 300 [M ⁺ ''] (Calcd for
C ₁₂ H ₁₅ O ₂ ³⁵ Cl ³⁷ Cl ₂ : 300.0079, Found: 300.0078), 302
[M ⁺ '''] (Calcd for C ₁₂ H ₁₅ O ₂ ³⁷ Cl ₃ : 302.0049, Found: 30
2.0030).

(1) (3E, 5E, 7E) -3, 5, 7
-Nonatrien-2-one As in Example 1- (6), 2,4-hexadiene-1-
All (485 mg, 4.95 mmol) was treated, and the reaction product was purified by silica gel chromatography (n-hexane: ethyl acetate = 30: 1) to give the title compound 472.
mg (70%) was obtained as a pale yellow oil. ^{_{IR ν max (neat) cm -1}} :. 3030, 2930, 1675,1620,1585 1 H-NMR (CDCl 3, 90MHz): δ 1.84 (3H, br d, J = 7Hz), 2.23 (3H, s) , 5.80 ~ 6.34 (3H, m), 6.
24 (1H, d, J = 15Hz), 6.59 (1H, dd, J = 11,15Hz), 7.15 (1H, dd, J
EIMS m / z : 136 [M ⁺ ] (Calcd for C ₉ H ₁₂ O: 136.0888, Foun
d: 136.0876).

(2) (5E, 7E, 9E) -1, 1, 1
-Trichloro-5,7,9-undecatriene-2,4
-Dione (3E, 5E, 7E) -3 according to Example 1- (7),
5,7-Nonatrien-2-one (6.2 mg, 0.41
3 mmol) and trichloroacetic anhydride (160 μl, 0.86
(5 mmol), and the resulting product was subjected to silica gel chromatography to obtain 70.7 mg (58%) of the title compound as a yellow powder from a fraction eluted with n-hexane-ethyl acetate (50: 1). mp 79-81 ° C. IR ν _max (CHCl ₃ ) cm ^-1 : 3020, 2910, 2850, 1590, 155
_{^{0. 1 H-NMR (CDCl 3}} , 500MHz): δ 1.86 (3H, d, J = 7Hz), 6.00 (1H, d, J = 15Hz), 6.01 (1H, dq, J = 7,
15Hz), 6.15 (1H, s), 6.21 (1H, dd, J = 11,15Hz), 6.25 (1H, dd,
J = 11,15Hz), 6.61 (1H, dd, J = 11,15Hz), 7.36 (1H, dd, J = 11,1
EIMS m / z : 280 [M ⁺ ] (Calcd for C ₁₁ H ₁₁ O ₂ ³⁵ Cl ₃ : 279.982
4, Found: 279.9816), 282 [M ⁺ '] (Calcd for C ₁₁ H ₁₁ O ₂ ³⁵ Cl ₂
³⁷ Cl: 281.9795, Found: 281.9797), 284 [M ⁺ ''] (Calcd for
C ₁₁ H ₁₁ O ₂ ³⁵ Cl ³⁷ Cl ₂ : 283.9804, Found: 283.9785), 286
[M ⁺ '''].

Example 8 (1) (E) -5-tetrahydropyranyloxy-2-
Oxalyl chloride (250 μl, 2.87 mm) in a stream of ethyl pentenoate N ₂
ol) was dissolved in methylene chloride (5 ml) and cooled to -60 ° C, and then dimethylsulfoxide (DMSO) (430 µl,
6.06 mmol) in methylene chloride (1 ml) was added dropwise.
Stirred for 0 minutes. To this was added dropwise a solution of 3-tetrahydropyranyloxypropan-1-ol (300 mg, 1.87 mmol) in methylene chloride (1 ml), and the mixture was stirred for 30 minutes. Then, triethylamine (1.8 ml, 12.9 mmol) was slowly added dropwise. Then, the mixture was returned to room temperature and stirred for 15 minutes. After adding water to the reaction solution and stirring for 10 minutes, the organic layer and the aqueous layer were separated, and the aqueous layer was extracted twice with methylene chloride. Organic layer 1N H
It was washed with Cl, saturated aqueous NaHCO ₃ , water and saturated saline, and dried over anhydrous MgSO ₄ . After evaporating the solvent under reduced pressure, a crude aldehyde was obtained, which was purified without purification using methylene chloride (2.
ml) and dissolved in ethyl (triphenylphosphoranylidene)
Acetate (729 mg, 2.094 mmol) was added and N ₂
The mixture was stirred overnight in an air stream. After evaporating the solvent under reduced pressure, the residue was 6 g.
Chromatography on silica gel of n-
From the fraction eluted with hexane-ethyl acetate (20: 1), 324 mg (76%) of the title compound was obtained as a colorless oily substance. ^{_{IR ν max (neat) cm -1}} :. 2945, 2870, 1720,1035 1 H-NMR (CDCl 3, 90MHz): δ 1.30 (3H, t, J = 7Hz), 1.38~1.90 (6H, m), 2.51 (2H, ddt, J = 2,
7,7Hz), 3.40 ~ 3.62 (2H, m), 3.70 ~ 4.00 (2H, m), 4.20 (2H, m
q, J = 7Hz), 4.52 to 4.68 (1H, m), 5.90 (1H, dt, J = 2, 15Hz), 7.0
0 (1H, dt, J = 7,15Hz) .EIMS m / z : 228 [M ⁺ ], 128 [(M ⁺⁺ 1) -THPO] (Calcd for C ₇ H
₁₂ O ₂ : 128.0837, Found: 128.0838).

[0043] (2) (E) -5- tetrahydropyranyloxy-2-penten-1-ol N ₂ under a stream, (E) -5- tetrahydropyranyloxy-2-pentenoic acid ethyl (5.86 g, 25.7 mmol)
Of methylene chloride (200 ml) was cooled to -78 DEG C. and 1.0 ml of diisobutylaluminum hydride (DIBAH) was added.
An M n-hexane solution (78 ml, 78 mmol) was added dropwise. After stirring for 45 minutes, ethyl acetate and methanol were slowly and sequentially added dropwise. After washing the reaction solution with 1N HCl, the aqueous layer was extracted three times with methylene chloride. The organic layer was washed with a saturated aqueous solution of NaHCO ₃ , water and a saturated saline solution and dried over anhydrous MgSO 4.
Dried over O ₄ . After evaporating the solvent under reduced pressure, the residue was subjected to chromatography using 60 g of silica gel, and 4.59 g (96%) of the title compound was obtained as a colorless oil from the fraction eluted with n-hexane-ethyl acetate (2: 1). Obtained. ^{_{IR ν max (neat) cm -1}} :. 3400, 2950, 2875,1038 1 H-NMR (CDCl 3, 90MHz): δ 1.30~1.78 (6H, m), 1.79~1.90 (1H, m), 2.22~ 2.50 (2H,
m), 3.32 to 3.62 (2H, m), 3.64 to 3.98 (2H, m), 3.99 to 4.18 (2
H, m), 4.51-4.65 (1H, m), 5.64-5.81 (2H, m) .EIMS m / z : 186 [M ⁺ ], 101 [(M ⁺⁺ 1) -THP] (Calcd for C ₅ H ₉ O
₂ : 101.0603, Found: 101.0608).

(3) Ethyl (2E, 4E) -7-tetrahydropyranyloxy-2,4-heptadienoate (E) -5-tetrahydropyranyloxy-2-penten-1-ol (35.4 mg, 0 .190 mmol) was treated in the same manner as in Example 1- (4), and the reaction product was subjected to silica gel chromatography (n-hexane: ethyl acetate = 1).
0: 1) to give 33.7 mg (70
%) As a colorless oil. ^{_{IR ν max (neat) cm -1}} :. 2945, 2860, 1710,1035 1 H-NMR (CDCl 3, 500MHz): δ 1.29 (3H, t, J = 7Hz), 1.51~1.59 (4H, m), 1.68 to 1.75 (1H,
m), 1.78-1.85 (1H, m), 2.47 (2H, dt, J = 7,7Hz), 3.48-3.51
(2H, m), 3.80-3.84 (2H, m), 4.20 (2H, q, J = 7Hz), 4.60 (1H, d
d, J = 4,4Hz), 5.80 (1H, d, J = 15Hz), 6.16 (1H, dd, J = 7,15Hz),
6.25 (1H, dd, J = 11,15Hz), 7.26 (1H, dd, J = 11,15Hz), EIMS m / z: 255 [M + +1] (Calcd for C 14 H 23 O 4: 255.1596,
Found: 255.1604).

(4) (2E, 4E) -7-tetrahydropyranyloxy-2,4-heptadien-1-ol (2E, 4E) -7-tetrahydropyranyloxy-
Ethyl 2,4-heptadienoate (759 mg, 2.99 mm
ol) was treated in the same manner as in the above (2), and the reduced product was subjected to silica gel chromatography (n-hexane: ethyl acetate =
2: 1) to give 637 mg (96 mg) of the title compound.
%) As a colorless oil. ^{_{IR ν max (neat) cm -1}} :. 3290, 2945, 2870,1030 1 H-NMR (CDCl 3, 100MHz): δ 1.30~2.00 (6H, m), 2.38 (2H, dt, J = 7,7Hz ), 3.30-3.60 (2
H, m), 3.62-3.98 (2H, m), 4.15 (2H, d, J = 6Hz), 4.48-4.64
(1H, m), 5.50-6.46 (4H, m) .EIMS m / z : 212 [M ⁺ ] (Calcd for C ₁₂ H ₂₀ O ₃ : 212.1412, Fo
und: 212.1404).

(5) (3E, 5E, 7E) -10-tetrahydropyranyloxy-3,5,7-decatriene-
2-one (2E, 4E) -7-tetrahydropyranyloxy-
2,4-heptadien-1-ol (505 mg, 2.3
8 mmol) was treated in the same manner as in Example 1- (6), the reaction product was subjected to silica gel chromatography, and the title compound 4 was obtained from a fraction eluted with n-hexane-ethyl acetate (10: 1).
19 mg (70%) were obtained as a pale yellow oil. IR ν _max (neat) cm ^-1 : 2940, 2860, 1660, 1610, 1580,
_{^{1030. 1 H-NMR (CDCl 3}} , 500MHz): δ 1.51~1.60 (4H, m), 1.69~1.76 (1H, m), 1.79~1.87 (1H,
m), 2.27 (3H, s), 2.46 (2H, dt, J = 7, 7 Hz), 3.46 to 3.52 (2H,
m), 3.79 to 3.86 (2H, m), 4.60 (1H, dd, J = 4, 4Hz), 5.99 (1H, d
d, J = 7, 15Hz), 6.13 (1H, d, J = 15Hz), 6.24 (1H, dd, J = 11, 15H)
z), 6.25 (1H, dd, J = 11,15Hz), 6.59 (1H, dd, J = 11,15Hz), 7.1
4 (1H, dd, J = 11,15Hz) .EIMS m / z : 250 [M ⁺ ] (Calcd forC ₁₅ H ₂₂ O ₃ : 250.1569, Foun
d: 250.1560).

(6) (5E, 7E, 9E) -1, 1, 1
-Trichloro-12-tetrahydropyranyloxy-
5,7,9-Dodecatriene-2,4-dione By the same operation as in Example 1- (7), (3E, 5E,
7E) -10-Tetrahydropyranyloxy-3,5
7-decatrien-2-one (46.8 mg, 0.187
mmol) and trichloroacetic anhydride, and the reaction product was purified to give 34.9 mg (47%) of the title compound as a yellow oily substance. ^{_{IR ν max (neat) cm -1}} : 2970, 2890, 1610,1560, 1040. 1 H-NMR (CDCl 3, 500MHz): δ 1.45~1.65 (4H, m), 1.68~1.76 (1H, m), 1.77 to 1.88 (1H,
m), 2.48 (2H, dt, J = 7, 7 Hz), 3.47 to 3.54 (2H, m), 3.79 to 3.89
(2H, m), 4.60 (1H, dd, J = 3,4Hz), 6.02 (1H, d, J = 15Hz), 6.03
(1H, dt, J = 7,15Hz), 6.15 (1H, s), 6.26 (1H, dd, J = 11,15Hz),
6.28 (1H, dd, J = 11,15Hz), 6.62 (1H, dd, J = 11,15Hz), 7.36 (1
H, dd, J = 11,15Hz), 13.36 (1H, br s) .EIMS m / z : 394 [M ⁺ ] (Calcd for C ₁₇ H ₂₁ O ₄ ³⁵ Cl ₃ : 394.050
5, Found: 394.0498) 396 [M ⁺ '], 398 [M ⁺ ']], 400 [M ⁺ '''].

(7) (5E, 7E, 9E) -1, 1, 1
-Trichloro-12-hydroxy-5,7,9-dodecatriene-2,4-dione (5E, 7E, 9E) -1,1,1-trichloro-12
-Tetrahydropyranyloxy-5,7,9-dodecatriene-2,4-dione (32.0 mg, 0.081 mmol
l) was dissolved in ethanol (4 ml) and pyridinium paratoluenesulfonium (PPTS) (10.1 mg, 0.0
40 mmol), and the mixture was heated to 50 ° C. and stirred for 5 hours. After concentrating the reaction solution under reduced pressure, the residue was dissolved in methylene chloride and washed with water. The aqueous layer was extracted three times with methylene chloride, and the organic layer was washed with saturated saline and dried over anhydrous MgSO ₄ . After evaporating the solvent under reduced pressure, the residue was subjected to chromatography using 2 g of silica gel to obtain n-hexane-ethyl acetate (1:
1) From the eluted fraction, 22.0 mg (87%) of the title compound was obtained as a yellow oily substance. ^{_{IR ν max (neat) cm -1}} : 3350, 2940, 2880,1600, 1550. 1 H-NMR (CDCl 3, 500MHz): δ 2.45 (2H, dt, J = 6,7Hz), 3.74 (2H, t , J = 6Hz), 5.97 (1H, dt, J =
7,15Hz), 6.03 (1H, d, J = 15Hz), 6.16 (1H, s), 6.30 (1H, dd, J =
11,15Hz), 6.31 (1H, dd, J = 11,15Hz), 6.62 (1H, dd, J = 11,15H
z), 7.35 (1H, dd, J = 11,15Hz), 13.35 (1H, br s) .EIMS m / z : 310 [M ⁺ ] (Calcd for C ₁₂ H ₁₃ O ₃ ³⁵ Cl ₃ : 309.993
0, Found: 309.9893), 312 [M ⁺ '] (Calcd for C ₁₂ H ₁₃ O ₂ ³⁵ Cl
₂ ³⁷ Cl: 311.9901, Found: 311.9852), 314 [M ⁺ ''] (Calcd for
C ₁₂ H ₁₃ O ₃ ³⁵ Cl ³⁷ Cl ₂ : 313.9871, Found: 313.9886), 316
[M ⁺ '''] (Calcd for C ₁₂ H ₁₃ O ₃ ³⁷ Cl ₃ : 315.9842, Found: 31
5.9828).

Example 9 (1) Ethyl (E) -4- (N-tert-butoxycarbonyl-N-methyl) amino-2-butenoate According to Example 8- (1), 2- (N-tert-butoxy) Carbonyl-N-methyl) aminoethanol (3.5
8g, 20.4mmol), purified and treated with (Z) -4-
712 mg (14%) of ethyl (N-tert-butoxycarbonyl-N-methyl) amino-2-butenoate were obtained as a colorless oil. ^{_{IR ν max (neat) cm -1}} :. 2975, 2940, 1720,1705 1 H-NMR (CDCl 3, 90MHz): δ 1.30 (3H, t, J = 7Hz), 1.45 (9H, s), 2.86 ( 3H, s), 4.19 (2H, q, J
= 7Hz), 4.43 (2H, br d, J = 6Hz), 5.84 (1H, dt, J = 2,11Hz), 6.2
0 (1H, dt, J = 6,11Hz) .EIMS m / z : 243 [M ⁺ ] (Calcd for C ₁₂ H ₂₁ NO ₄ : 243.1470, F
ound: 243.1480). Then, 3.12 g (63%) of the title compound was obtained as a colorless oily substance. ^{_{IR ν max (neat) cm -1}} :. 2975, 2930, 1720,1700 1 H-NMR (CDCl 3, 100MHz): δ 1.30 (3H, t, J = 7Hz), 1.45 (9H, s), 2.85 ( 3H, s), 3.90 ~ 4.03
(2H, m), 4.20 (2H, q, J = 7Hz), 5.84 (1H, dt, J = 2,15Hz), 6.84
(1H, dt, J = 5,15Hz). FABMS m / z : 244 [M ⁺ +1]. EIMS m / z : 187 [(M ⁺ +1) ^-t Bu] (Calcd for C ₈ H ₁₃ NO ₄ : 18
7.0844, Found: 187.0833).

(2) (E) -4- (N-tert-butoxycarbonyl-N-methyl) amino-2-butene-1
-All (E) -4- (N-tert) according to Example 8- (2)
Ethyl-butoxycarbonyl-N-methyl) amino-2-butenoate (1.71 g, 7.03 mmol) was reduced and purified to give 1.25 g (88%) of the title compound as a colorless oil. IR ν _max (neat) cm ^-1 : 3410, 2975, 2930, 2870, 1680. ¹ H-NMR (CDCl ₃ , 100 MHz): δ 1.46 (9H, s), 1.64 to 1.80 (1 H, m), 2.81 ( 3H, s), 3.78-3.86
(2H, m), 4.04 ~ 4.18 (2H, m), 5.58 ~ 5.74 (2H, m) .EIMS m / z : 201 [M ⁺ ], 145 [(M ⁺⁺ 1) ^-t Bu] (Calcd for C ₆ H ₁₁
NO ₃ : 145.0739, Found: 145.0730).

(3) (2E, 4E) -6- (N-ter
(t-butoxycarbonyl-N-methyl) amino-2,4
-Ethyl hexadienoate (E) -4- (N-tert) according to Example 1- (4)
-Butoxycarbonyl-N-methyl) amino-2-buten-1-ol (1.01 g, 5.02 mmol),
Purification provided 825 mg (61%) of the title compound as a colorless oil. ^{_{IR ν max (neat) cm -1}} :. 2980, 2930, 1710,1690 1 H-NMR (CDCl 3, 500MHz): δ 1.30 (3H, t, J = 7Hz), 1.46 (9H, s), 2.84 ( 3H, s), 3.92 (2H, br
s), 4.20 (2H, q, J = 7 Hz), 5.86 (1H, d, J = 15 Hz), 6.00 to 6.06 (1
H, m), 6.19-6.28 (1H, m), 7.28 (1H, dd, J = 11,15Hz). FABMS m / z : 270 [M ⁺⁺ 1] .EIMS m / z : 213 [(M ⁺ +1) ^-t Bu] (Calcd for C ₁₀ H ₁₅ NO ₄ : 21
3.1001, Found: 213.0988).

(4) (2E, 4E) -6- (N-ter
(t-butoxycarbonyl-N-methyl) amino-2,4
-Hexadiene-1-ol (2E, 4E) -6- (N-
tert-butoxycarbonyl-N-methyl) amino-
Ethyl 2,4-hexadienoate (739 mg, 2.75 mm
ol) was reduced and purified to give 610 mg (98%) of the title compound as a colorless oil. ^{_{IR ν max (neat) cm -1}} : 3410, 2975, 2930,2860, 1690. 1 H-NMR (CDCl 3, 100MHz): δ 1.46 (9H, s), 1.51~1.76 (1H, m), 2.79 ( 3H, s), 3.83 (2H, br
d, J = 6Hz), 4.16 (2H, br d, J = 5Hz), 5.40~6.40 (4H, m) FABMS m / z:. 228 [M +] EIMS m / z:. 171 [(M + + 1) ^-t Bu] (Calcd for C ₈ H ₁₃ NO ₃ : 17
1.0895, Found: 171.0892).

(5) (3E, 5E, 7E) -9- (N-
tert-butoxycarbonyl-N-methyl) amino-
3,5,7-Nonatrien-2-one According to Example 1- (2), (2E, 4E) -6- (N-
tert-butoxycarbonyl-N-methyl) amino-
2,4-hexadien-1-ol (509 mg, 2.2
4 mmol) were treated and purified to give 422 mg (71 mg) of the title compound.
%) As a pale yellow oil. IR ν _max (neat) cm ^-1 : 2975, 2930, 1690, 1665, 1615,
_{^{1580. 1 H-NMR (CDCl 3}} , 500MHz): δ 1.46 (9H, s), 2.28 (3H, s), 2.84 (3H, s), 3.91 (2H, br s), 5.8
4 ~ 5.93 (1H, m), 6.15 (1H, d, J = 15Hz), 6.14 ~ 6.27 (1H, m),
6.30 (1H, dd, J = 11,15Hz), 6.60 (1H, dd, J = 11,15Hz), 7.14 (1
. H, dd, J = 11,15Hz ) FDMS m / z: 265 [M +] EIMS m / z:. 209 [(M + +1) - t Bu] (Calcd for C 11 H 15 NO 3: 20
9.1051, Found: 209.1042).

(6) (5E, 7E, 9E) -1, 1, 1
-Trichloro-11- (N-tert-butoxycarbonyl-N-methyl) amino-5,7,9-undecatriene-2,4-dione (3E, 5E, 7E)-according to Example 1- (7) 9-
(N-tert-butoxycarbonyl-N-methyl) amino-3,5,7-nonatrien-2-one (31.9
mg, 0.120 mmol) and trichloroacetic anhydride (45μ).
l, 0.243 mmol) was purified and purified to give the title compound 3
9.0 mg (79%) were obtained as a yellow oil. IR ν _max (neat) cm ^-1 : 2990, 2950, 1700, 1610, 1560. ¹ H-NMR (CDCl ₃ , 500 MHz): δ 1.46 (9H, s), 2.84 (3H, s), 3.93 (2H, br s), 5.86-5.95 (1H,
m), 6.04 (1H, d, J = 15Hz), 6.16 (1H, s), 6.17-6.29 (1H, m),
6.33 (1H, dd, J = 11,15Hz), 6.62 (1H, dd, J = 11,15Hz), 7.35 (1
H, dd, J = 11,15Hz) .EIMS m / z : 409 [M ⁺ ] (Calcd for C ₁₇ H ₂₂ NO ₄ ³⁵ Cl ₃ : 409.0
615, Found: 409.0626).

Test Example 1 Neocardilines were added to human leukemia cell K562 cells, and the number of viable cells after 96 hours of culture was measured. From the number of living cells, a 50% inhibitory concentration (IC ₅₀ ) was calculated to examine the anticancer effect. Table 1 shows the obtained results.

[0056]

[Table 1]

────────────────────────────────────────────────── ─── Continued on the front page (51) Int.Cl. ⁶ Identification symbol FI C07C 211/21 C07C 211/21 221/00 221/00 225/14 225/14 C07D 309/32 C07D 309/32 (58) Survey ⁶ (Int.Cl. ⁶ , DB name) L (QUESTEL)

Claims (2)

(57) [Claims] 1. A compound of the general formula (7) [Wherein R ¹ represents a lower alkyl group, a tetrahydropyranyloxyethyl group or an N-tert-butyl-N-methyl-aminomethyl group, and n represents 1 or 2]. Phosphoranylidene-
2-propanone is reacted, and then the obtained general formula (8) is obtained. [Wherein R ¹ and n are the same as those described above] in the presence of a strong base in the ketone represented by the general formula (9) R ² COOH (9) [wherein R ² represents 1 to 3 halogen atoms Represents a lower alkyl group which may be substituted]] or a reactive derivative thereof represented by the following general formula (10): [Wherein, R ¹ , R ² and n are the same as those described above]. 2. A compound of the general formula (7) [Wherein R ¹ represents a lower alkyl group, a tetrahydropyranyloxyethyl group or an N-tert-butyl-N-methyl-aminomethyl group, and n represents 1 or 2]. Phosphoranylidene-
Reaction with 2-propanone resulted in the general formula (8): [Wherein R ¹ and n are the same as those described above] in the presence of a strong base in the ketone represented by the general formula (9) R ² COOH (9) [wherein R ² represents 1 to 3 halogen atoms Represents a lower alkyl group which may be substituted], or a reactive derivative thereof, and then the resulting general formula (10) Wherein R ¹ , R ² and n are the same as defined above, wherein an alkylating agent is reacted with the neocardilines represented by the general formula (1): Wherein R ⁴ represents lower alkyl, R ¹ , R ² and n
Is the same as described above].