JPH03151376A - Acetylenic derivative - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I [R<1> is H or silyl of R<3> R<4>R<5>Si (R<3> to R<5> are 1-4C alkyl or aryl); R<2> is 1-6C alkyl or aryl]. EXAMPLE:(2S)-Hydroxy-(2S)-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-3-butynyl 2,2- dimethylpropionate. USE:A raw material for producing cyclopentane derivatives useful as a carcinostatic agent. PREPARATION:A compound expressed by formula II and lithiumtrimethylacetylide are subjected to addition reaction in an ethereal solvent at -100 to +30 deg.C and the trimethylsilyl group is then removed to afford the compound expressed by formula I.

Description

Detailed Description of the Invention [Industrial Application Field] The present invention is based on the following formula (■)] [In the formula, R1 is a hydrogen source, a hydrogen source, or R''R'R'S i (in the formula, R3, R4 and R% each independently represent a linear or branched alkyl group having 1 to 4 carbon atoms, or a substituted or unsubstituted aryl group, and R8 is a silyl group having 1 to 6 carbon atoms. represents a linear or branched alkyl group, or a substituted or unsubstituted aryl group, and the acetylene derivative of the present invention is represented by the formula (1) %formula% It is used as a raw material for the production of cyclopentane derivatives, which are cytotoxic and useful as 11116 agents.

[Conventional technology]

There is a strong demand from society for the development of excellent anticancer drugs.
The creation of new compounds with strong anticancer activity plays a very important role in the development of excellent anticancer drugs. In general, the anticancer activity and anticancer spectrum of a compound largely depend on its chemical structure. There is an extremely high possibility that an anticancer drug with these characteristics will be developed.

As a result of testing the cytotoxicity of the new compound from this viewpoint, it was found that the cyclopentane derivative represented by the above formula (1) has strong cytotoxicity and can be used as an anticancer agent.

[Problem to be solved by the invention]

The object of the present invention is to provide the above formula (
An object of the present invention is to provide an acetylene derivative represented by the formula -m (■), which is used as a raw material for producing a cyclopentane derivative represented by the formula -m.

(Means for Solving 1!mu) The present invention provides a method for solving the problem of - formula [wherein R1 is a hydrogen atom or a silyl group represented by R''R'R'S i (wherein R3, R4, and R5 are each independently represents a straight chain or branched alkyl group having 1 to 4 carbon atoms, or a substituted or unsubstituted aryl group, and R3 is a straight chain or branched alkyl group having 1 to 6 carbon atoms, or a substituted or unsubstituted aryl group], and relates to an acetylene derivative used as a raw material for producing a cyclopentane derivative having use as an anticancer agent.

The acetylene derivative represented by formula (II) of the present invention can be produced by the following synthetic steps.

(In the formula, R, R4, and R1 represent the same meanings as above, and R1 represents a straight chain or branched alkyl group having 1 to 5 carbon atoms.) [First step] This step is described in the literature. method (E., Abushanab, e.
tal, tJ, Org, Ches, , 53.259
8 (1988), (2R)-hydroxy-(2R)((4R)-
2,2-dimethyl-1,3-dioxolan-4-yl)
After protecting the 2-position hydroxyl group of the alkyl acetate derivative, the ester group is reduced, and the resulting primary alcohol is acylated, and the 2-position hydroxyl group is protected! By removing one group, carboxylic acid (2R)-hydroxy-(2R)- represented by -m formula (rV)
((4R)-2,2-dimethyl-1,3-dioxolan-4-yl)ethyl H, 1 body is produced.

As the protecting group to be introduced into the 2-position water 61 group, one is selected that exists stably during reduction of the ester group and acylation of l-alcohol and can be removed without damaging the 1,3-dioxolane ring and the acyloxy group. be done. Examples of hydroxyl-protecting groups that meet these requirements include 1-ethoxyethyl group, 1-ethreki-1-methylethyl group, and tetrahydropyranyl group, but preferably l
-ethoxyethyl group is used. Two of these protecting groups
The introduction into the hydroxyl group is carried out using known methods (T, jl, Green
ne.

Protectlve Groups ln Orga
nic 5ynthesis, “JohnWllsy
& 5ons, New York, 1980. GIP1
4-50. (see).

When a 1-ethoxyethyl group is used as the protecting group for the 2-position hydroxyl group, the protecting group is introduced by using ethyl vinyl ether in the presence of an acid catalyst such as p-toluenesulfonic acid or pyridinium p-)luenesulfonate. The 0-reaction is carried out in a solvent, and any solvent can be used as long as it does not participate in the reaction, but the 0-reaction, which uses a halogenated hydrocarbon solvent such as dichloromethane or chloroform, is preferably carried out from 0°C. Proceeds smoothly at 50°C.

Acylation of the generated primary alcohol is carried out using chlorides, bromides, and acids of aliphatic carboxylic acids having a linear or branched alkyl group having 1 to 6 carbon atoms, or aromatic carboxylic acids having a substituted or unsubstituted aryl group. It is carried out in a solvent in the presence of a base using an acylating agent such as an anhydride or a mixed acid anhydride with a carbonic acid monoester. As the acylating agent, acetic acid, propionic acid, butyric acid, 2-methylpropionic acid, pentanoic acid, 2-methylbutyric acid, 3-methylbutyric acid, 2,2-dimethylpropionic acid, hexanoic acid, 2,2-dimethylbutyric acid,
Mixed acid anhydrides with chlorides, bromides, acid anhydrides, and carbonic acid monoesters of aliphatic carboxylic acids such as heptanoic acid, 2,2-dimethylpentanoic acid, and 2-ethyl-2-methylbutyric acid;
Also, benzoic acid, p-chlorobenzoic acid, p-methoxybenzoic acid, p-methylbenzoic acid, m-chlorobenzoic acid, m-
Methoxybenzoic acid, m-methylbenzoic acid, 0-chlorobenzoic acid, 0-methoxybenzoic acid, 0-methylbenzoic acid,
3,4-dimethoxybenzoic acid, 2,4-dimethoxybenzoic acid, 2,6-dimethoxybenzoic acid, 3,4-dimethylbenzoic acid, 2,4-dimethylbenzoic acid, 2,6-dimethylbenzoic acid, 2, 4.6-trimethoxybenzoic acid, 2,
4.6-) Chlorides, bromides, acid anhydrides, and mixed acid anhydrides with carbonic acid monoesters of aromatic carboxylic acids such as dimethylbenzoic acid are used. As a base, pyridine,
4-dimethylaminopyridine, triethylamine, ethyldiisopropylamine, 1,4-diazabicyclo(2
,2,2) octane, 1,8-diazabicyclo(5,4
, 0) Any solvent can be used in the 0 reaction in which a tertiary amine such as undec-7-ene is used as long as it does not participate in the reaction, but preferably,
Ether solvents such as diethyl ether, tetrahydrofuran and dioxane, hydrocarbon solvents such as pentane, hexane and toluene, and halogen hydrocarbon solvents such as dichloromethane and chloroform are used. Moreover, when pyridine is used as a base, a large excess of pyridine can also be used as a solvent. The protective group for the 2-position hydroxyl group can be removed by a known method (T
, W. Greene.

”Protective Groups in Org
anic 5 synthesis.

John-Wiley &, 5oz, New Year
K, 1980. pp14-50. (see) can be applied. When a 1-ethoxyethyl group is used as a protecting group for the 2-position hydroxyl group, it is prepared using an acid catalyst such as p-toluenesulfonic acid or pyridinium p-1 luenesulfonate in a lower alcohol such as methanol, ethanol, or propatool. Protecting group removal can be carried out 1
The reaction was carried out at 0°C (-in E').
s.

[Second Step] In this step, carboxylic acid (2R)-hydroxy-(2R)-((4R)2.
The 2-hydroxyl group of the 2-dimethyl-1,3-dioxolan-4-yl)ethyl derivative is oxidized to form the carboxylic acid 2-((4R)2,2-dimethyl-
A 1,3-dioxolan-4-yl)-2-oxoethyl derivative is produced.

Oxidation includes chromic anhydride-pyridine adduct, pyridinium chlorochromate, pyridinium dichromate, sulfur pyridine complex-dimethylsulfoxide-triethylamine, oxalyl chloride-dimethylsulfoxide-triethylamine, N-chlorosuccinimide dimethylsulfide-triethylamine, etc. Normal 2
The oxidizing agent used to oxidize the alcohol to the corresponding ketone is carried out in a solvent, and any solvent that does not participate in the reaction can be used, but dichloromethane is preferred. , toluene, dimethyl sulfoxide, etc., proceed smoothly at -20°C to 30°C.

[Third Step] This step is carried out to prepare the carboxylic acid 2- represented by the above-mentioned formula (V).
((4R)-2,2-dimethyl-1,3-dioxolan-4-yl-2-oxoethyl derivative is added with trimethylsilylacetylene, and then the silyl group is removed to obtain the compound of the present invention with the formula (na ) [carboxylic acid (2S)-hydroxy-
(25)-((4R)-2,2-dimethyl-1,3-dioxolan-4-yl-3-butynyl derivative is produced.

Addition of trimethylsilylacetylene is methyllithium, n-butyllithium,
It can be prepared by reacting alkyllithium or aryllithium such as 5ee-butyllithium, t-butyllithium, and phenyllithium, or by using lithium trimethylacetylide. Preparation of lithium trimethylacetylide is carried out in a solvent, and any solvent can be used as long as it does not participate in the reaction, but preferably,
Ether solvents such as diethyl ether, tetrahydrofuran, and dioxane are used.

The reaction proceeds smoothly at a temperature of -100°C to -30°C.

Carvone 111 of lithium trimethylsilylacetylide
! The addition of 2-((4R)-2,2-dimethyl-1,3-dioxolan-4-yl-2-oxoethyl derivative ＼ can be used to prepare lithium trimethylsilylacetylide without taking out the prepared lithium trimethylsilylacetylide. The addition reaction also proceeds smoothly at temperatures ranging from -100°C to 30°C.

In this addition reaction, in addition to the desired (2S) monomer, 2R) monomer is produced without any need, but both are used for the subsequent removal of the trimethylsilyl group without being separated.

The removal of the trimethylsilyl group can be carried out using a fluoride such as hydrogen fluoride, sodium fluoride, potassium fluoride, or tetrabutylammonium fluoride in a solvent.The solvent used in the reaction may be one that does not participate in the reaction. Although any solvent can be used, preferably, the reaction using an ether solvent such as diethyl ether, tetrahydrofuran, dioxane, etc. proceeds smoothly at a temperature of -30°C to 30°C.

In this reaction, in addition to the desired (2S)-isomer, an unnecessary (2R)-isomer is obtained as a reaction product, but the desired (2S)-isomer can be easily obtained from a mixture of both by a separation method such as column chromatography. [Fourth Step] In this step, carboxylic acid (2S)-hydroxy-(2S)-((4R)-2,2
-dimethyl-1,3-dioxolan-4-yl2-3-
The hydroxyl group at the 2-position of the butynyl derivative is silylated to produce the compound of the present invention, the carboxylic acid (2S)-silyloxy-(2S)-((4R)-2
, 2-dimethyl-1,3-dioxolan-4-yl-3-butynyl derivative.

As the silylating agent, silyl halides such as trimethylsilyl chloride, trimethylsilyl bromide, trimethylsilyl iodide, isoprodimethylsilyl chloride, isopropyldimethylsilyl bromide, t-butyldimethylsilyl chloride, t-butyldiphenylsilyl chloride, or Silyl trifluorosulfonates such as trimethylsilyl trifluoromethanesulfonate, t-butyldimethylsilyl trifluoromethanesulfonate, and FJL-butyldiphenylsilyl trifluoromethanesulfonate are used.

The silylation is carried out in the presence of a base, and when a silyl halide is used as the silylating agent, imidazoles such as imidazole and 4-methylimidazole, or silyl trifluoromethanesulfonate are used as the silylating agent. Pyridines such as pyridine, 2-picoline, and 2,6-lutidine are used.

The silylation is carried out in a solvent, and any solvent can be used as long as it does not participate in the reaction, but preferably a halogenated hydrocarbon solvent such as dichloromethane or chloroform is used. Proceeds smoothly at ℃.

The general formula (II b
) Carvone M(23)-silyloxy-(2
S)-((4R)-2,2-dimethyl-1,3-dioxolane-4,-yl2-3-butynyl derivative has strong cytotoxicity and is used as an anticancer drug by the following synthesis process. It can be derived into a cyclopentane derivative represented by formula (1).

(In the formula, R1, R35Q4, Rs, M, and t; 11
144 table,,R6,R? , R1 each independently represents a straight chain or branched alkyl group having 1 to 4 carbon atoms, or a substituted or unsubstituted aryl group) [Step 5] This step is carried out in accordance with the formula (■b) above. carboxylic acid (
2S)-silyloxy-(2S)-((4R)-2,2
-dimethyl-1,3-dioxolan-4-yl2-3-
The butynyl derivative is converted into trifluoromethanesulfonic acid (3Z)-(3-silyl-2
-propynylidene) cyclopenten-2-yl derivative, and the carboxylic acid (
2S)-silyloxy-(23)-(<4A>-2
,2-dimethyl-1,3-dioxolan-4-yl)-
A 4-((3Z)-(3-silyl-2-propynylidene)cyclopenten-2-yl-3-butynyl derivative is produced.

The trifluoromethanesulfonic acid (3Z)-(3-silyl-2-propynylidene)cyclopenten-2-yl derivative represented by formula (Vl) is a known compound 1,4. -dioxaspiro(4,4)nonane-6-aldehyde (1?, Jones.

at al,,J,Ches,Soc,Perkin
Trans, I+ 1978+209. ) can be easily synthesized from (see reference side).

The reaction involves lower dialkylamines such as dimethylamine, diethylamine, diisopropylamine, and chloride*
(1) In the presence of monovalent copper salts such as w4 bromide (■), copper (I) iodide, copper cyanide (ri), tetrakistriphenylphosphinepalladium (O), tetrakistributylphosphinepalladium (O), It is carried out in a solvent using a palladium (o) catalyst such as bis-1,2-bisdiphenylphosphine ethane palladium (0).Any solvent can be used as long as it does not participate in the reaction, but preferred The reaction, in which an aprotic amide polar solvent such as N,N-dimethylformamide or N,N-dimethylacetamide is used, proceeds smoothly at 0°C to 50°C.

[Step 6] This step removes the linear or branched acyl group having 2 to 7 carbon atoms, or the substituted or unsubstituted aroyl group contained in the cyclopentane derivative represented by formula (■) above. death,
Cyclopentane derivative ((
23)-silyloxy-(23)-((4R)-2,2
-dimethyl-1,3-dioxolan-4-yl)-4-
=((3Z)-(3-silyl-2-propynylidene)
cyclopenten-2-yl-3-butaine-1-ol derivative].

Removal of acyl groups and aroyl groups is carried out reductively, and examples of reducing agents include aluminum hydride-based reducing agents such as lithium aluminum hydride, diisobutylaluminum hydride, and sodium bis-(2-methoxyethoxy)aluminum hydride. However, for reactions in which diisobutylaluminum hydride gives suitable results, a solvent is required.Any solvent can be used as long as it does not participate in the reaction, but dichloromethane, chloroform, etc. are preferably used. Halogenated hydrocarbon solvent, pentane,
The reaction using a hydrocarbon solvent such as hexane or toluene proceeds smoothly at a temperature of -100°C to 0°C.

[Step 7] This step removes two silyl groups contained in the cyclopentane derivative represented by the formula (■) above, and converts it into the cyclopentane derivative represented by the formula (1).
) is a cyclopenkune derivative ((23)-((4
R)-2,2-dimethyl-1,3-dioxolane-4-
yl]-4-((3Z)-(2-propynylidene)cyclopenten-2-yl-3-butaine-1,2-diol).

To remove the silyl group, a fluoride such as hydrogen fluoride, sodium fluoride, potassium fluoride, or tetrabutylammonium fluoride is used, and preferably tetrabutyla or ammonium fluoride is used.

The reaction is carried out in a solvent, and any solvent can be used as long as it does not participate in the reaction, but preferably,
The reaction using an ether solvent such as diethyl ether, tetrahydrofuran, dioxane, etc. proceeds smoothly at -30°C to 30°C.

A malignant tumor cell proliferation inhibition test was conducted on the cyclopentane derivative represented by the formula (1) obtained as above, and it was found that this compound has strong cytotoxicity and is useful as an anticancer agent. It was confirmed.

The test was conducted using mouse lymphocytic leukemia cells (P 388) according to a conventional method, and the cell proliferation inhibition rate was determined.

Hereinafter, the present invention will be explained in detail with reference to Reference Examples, Examples, and Test Examples, but the present invention is not limited thereto.

Reference example method described in literature (E, Abushanab at al
,,J,Org.

(2R)-Hydroxy-(2R)-((4R)-
2,2-dimethyl-1,3-dioxolan-4-yl]
To a solution of ethyl acetate (5.02 g, 25 mmol 1) in dichloromethane (80 ml) was added ethyl vinyl ether (14.7 g, 19.5 m 1.0.20 mo 1) at room temperature.
was processed. Pyridinium p-+-luenesulfonate (62+w, 0.25 mmol 1) was added under water cooling, and the mixture was stirred at room temperature for 3 hours, concentrated, and diluted with ether and hexane.

After washing with water and saturated brine, drying over anhydrous magnesium sulfate and concentrating the crude (2R)-(1-ethoxyethoxy)-(2R)-((4R)-2,2-dimethyl-1,3
-dioxolan-4-yl]ethyl acetate was obtained as the diastereomer yJL&.

After drying the crude product by azeotroping with toluene, ether (
50 ml). This ether solution was added dropwise to an ether solution (30 ml) of lithium aluminum hydride (2.05 g, 54 mmol) while cooling with water. 40 at room temperature
After stirring for a minute, water (2.1 ml), 15% sodium hydroxide aqueous solution (2.1 ml), and water (6.3 ml) were added to the reaction solution.
were sequentially added to stop the reaction, diluted with ether, and filtered.

The filtrate was concentrated to give crude (2R)-(1-ethoxyethoxy)-(2R)-((4R)-2,2-dimethyl-1
, 3-dioquinran-4-yl]ethanol was obtained as a mixture of diastereomers.

The crude product was dissolved in pyridine (10 ml) and 2,2-dimethylpropionyl chloride (4,45 g+
4.5 ml, 37 mmol I) was added dropwise. After stirring for 1 hour under water cooling, the mixture was allowed to react at room temperature for 1 hour. Dilute with ether and hexane, wash sequentially with water and saturated brine, and concentrate to obtain crude 2,2-dimethylpropionic acid (2R)-(1-ethoxyethoxy)-(2R)-((4R)-2, 2-Dimethyl-1,3-dioxolan-4-yl]ethyl was obtained as a mixture of diastereomers.

The crude product was dissolved in methanol (50 μl) and pyridinium p-)luenesulfonate (1.24 g) was added under water cooling.
, 4.9 mmol) and stirred for 1 hour, then stirred at room temperature for 2 hours.
The reaction mixture was stirred for 4 hours, concentrated, and diluted with ether and hexane. After sequentially washing with water and saturated saline, drying with anhydrous magnesium sulfate and concentrating the residue, column chromatography (silica gel: hexane-ethyl acetate-4:1)
2,2-dimethylpropionic acid (2R)
-Hydroxy-(2R)-((4R)-2,2-dimethyl-1,3-dioxolan-4-yl)ethyl(4,7
6 g, 79% (4 steps)). Recrystallization from pentane gave needle-shaped crystals. In addition, a small amount of 2,2-dimethylpropionic acid (2R)-(
1-ethoxyethoxy)-(2R)-((4R)-2,
2-dimethyl-1,3-dioxolan-4-yl)ethyl (1,47 g, 19%) was recovered.

Haze, 42-44℃.

[α] H-s, 2nd responsibility C-1.00. Chloroform)'H
-NMR (CDCIg): ζ1.23 (s, 911)
, 1.3B, 1.43 (s×2t3Hx2), 3.85
(Zen, 111), 4.13 (dd, IH, J-11, 8
, 6,0Hz), 4.33(dd, IH, J-11,8
,3,2Hz).

IR(neat): 3525.3010.172B,
1160.1070,850w-'MS:Il/Z(χ
):231 ((M-Me)”) (15), 10
1 (100), 73 (29), 57 (97
).

Elemental analysis (C+J*tOs): Calculated value: C, 58,54; [1,8,94K.

Analysis value: C, 58, 68; H, 9, 10χ.

Reference example 2.2-dimethylpropionic acid (2R)-hydroxy-
(2R)-((4R)-2,2-dimethyl-1,3-dioxolan-4-yl]ethyl (452 g, 1.8 mm
o +-) was dried by azeotroping with toluene and then dissolved in dichloromethane (16m+1). Activated powdered Molecular Sheeps 3A (0.9 g) and dry Florisil (2.7 g) were added to this and stirred. Pyridinium dichromate (1,73g, 4.5mmol) under water cooling
was added and stirred at room temperature for 16 hours. After diluting with ether, adding Florisil and further stirring, the mixture was filtered through Celite-Florisil and concentrated. The residue was purified by column chromatography (silica gel: hexane-ethyl acetate-8
: 2-oxoethyl 2-(4R)-2,2-dimethyl-1,3-dioxolan-4-yl-2-oxoethyl 2-dimethylpropionate (385■, 8
6%).

(α] Mo +70.3° (C-1,07, chloroform) dish H-NMR (CDC1*)! 6 1.26 (
s, 9H), 1.39, 1.51 (sX2゜3HX2)
, 4.13 (dd, IH, J-8, 9, 5, 4Hz),
4.22 (dd.

IH, J-8, 8, 7, 8Hz), 4.53 (d
d, IH, J-7, 8, 5, 4Hz).

4.89.4.99 (dx2.IHx2.J-17 each
．． 7Hz).

IR(neat): 2980.1?33.1140,
1065.845cm-'MS: m/z (χ): 229
((M-Me)”) (4,1), 101(100)
.

57(43).

Trimethylsilylacetylene (1.30g, 1.9ml
, 13 mmo 1) in tetrahydrofuran solution (1
A 1.6M n-butyllithium hexane solution (6,6@11.l 1 mmol) was added to the mixture (6,6@11.l 1 mmol) at -78°C and stirred for 50 minutes to prepare a tetrahydrofuran solution of lithium trimethylsilylacetylide. 2.
2-dimethylpropionic acid 2- ((4R)-2,2-
A solution of dimethyl-1,3-lyxolan-4-yl]-2-oxoethyl (2.15 g, 8.8 mm o 1 ) in tetrahydrofuran (10 ml) was added dropwise at −78° C., and the mixture was stirred at the same temperature for 1 hour. The reaction was stopped by adding a saturated aqueous solution of ammonium chloride, and extracted with a mixed solvent of ether-hexane. After drying with anhydrous magnesium sulfate and concentrating, crude 2,2-dimethylpropionic acid 2-
Hydroxy-2-((4R)-2,2-dimethyl-1,
3-Dioxolan-4-yl-3-butynyl was obtained as a mixture of two diastereomers.

Tetrahydrofuran (
30 ml) and 1.0M tetrabutylammonium fluoride tetrahydrofuran solution (9.4 ml,
9.4 mmol 1) was added and stirred for 1 hour. After tmm, the residue was diluted with a mixed solvent of ether-hexane and washed successively with water and saturated brine. After drying over anhydrous magnesium sulfate and concentrating, the residue was separated by column chromatography (silica gel: hexane-ethyl acetate-4:l) to obtain 2.2-
Dimethylpropionic acid (2S)-hydroxy-(2S)
-((4R)-2,2-dimethyl-1,3-dioxolan-4-yl-3-butynyl (0,65g, 27χ
) as a more polar product, and 2,2-dimethyl(2R)-hydroxy-(2R)-((4R)=2.
2-dimethyl-1,3-dioxolan-4yl]-3-
Butynyl (1.54 g, 64x) was obtained as a less polar product. The structure of the more polar product was determined by X-ray analysis. The two types of crystals were each recrystallized from a mixed solvent of hexane-ethyl acetate (lO: 1) to obtain needle-shaped crystals.

2.2-dimethylpropionic acid (2S)-hydroxy-
(2S)-((4R)-2,2-dimethyl-1,3-dioxolan-4-yl-3-butynyl; mpHo-112°C.

(α); “+18.0” (C.1.03.Chloroform).

'H-NMR (CDCIi): δ1.25 (s, 9
B), 1.37.1.48 (S X 2゜3HX2
), 2.50 (s, 1B), 2.90 (brs, 11)
, 4.11-4.17 (m, 3H), 4.19, 4.4
1 (dX2.IHx2.J - 11.6 Hz each).

IR(CIICI 2> :3325,3000.21
25.1?30.1150.1070゜850.645
alB-' MS: s/z (Xh 225 ((M-Me)')
(16), 101 (100), 57 (8B),
43 (51).

Elemental analysis (C+ 4! IzzOs): Calculated value: C, 6
2,20;H,8,20χ.

Analysis value: C, 62,04; l(, 8,29χ.

2.2-Dimethylpropionic acid (2R)-hydroxy-
(2R)-((4R)-2,2-dimethyl-1,3-dioxolan-4-yl-3-butynyl mp 56-58°C.

[α] Mo' +7.3C・0.90. chloroform).

'H-NMR (CDCIs): δ1.24 (s, 9H
), 1.38, 1.47 (SX2゜3HX2) +2.4
9 (s, IH), 2.85 (s, IH), 4.15 (m
, 2■).

4.11, 4.33 (dx2.IHx2.J = 11 each
．． 2Hz) 4.24 (dd, lH, J-7, 1, 6, 1
Hz).

I R (CHCI S) j 3575.3125.2
990.2125.1730.1150.1065°8
50.645011-' MS: s/z (χ): 255 ((M-Me)'') (5), 101 (50), 57 (100).

Elemental analysis (C+JtxOs): Calculated value: C, 62,20; H, 8,20χ.

Min Nfi1: C, 62, 24; fl, 8.21! .

Example 2.2-dimethylpropionic acid (2S)-hydroxy-
(2S)-((4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-3-butaniyl (54!1g
, 2.0 mmo 1) in Jig 00 methane solution (5 ml)
to 2,6-lutidine (653*, 0.71*I, 6.1
mmo I) and trif) Lt-olomethanesulfonic acid t-
Butyldimethylsilyl (1,07g, 0.93ml1,4
．． 1 mmol) was added thereto, and the mixture was reacted overnight at room temperature. After diluting with a mixed solvent of ether and hexane, the mixture was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated.

The residue was purified by column chromatography (silica gel: hexane-ethyl acetate-30:1) to give 2,2-dimethylpropion #(23)-t-butyldimethylsilyloxy-(23)-((4R)-2, 2-dimethyl-
1,3-dioxolan-4-yl]3-butynyl(4
58■, 59%) was obtained.

[α), 5”+4.6” (C-1,36, chloroform).

'II-NMR (CDCh) two δ0.22, 0.23 (
SX2, 3tlX2), 0.84 (s, 9H), 1.2
3 (s, 9M), 1.34.1.45 (SX2, 3HX
2).

2.55 (s, 18), 4.08 (dd, IH, J-8
,3,7,0Hz),4.11(dd,IH,J-8,
3,6,1Hz), 4.19(t, 11.J-6,5H
z).

4, 13.4.29 (d X 2. IHX 2.
Jm each 11.5Hz).

rR (neat): 3275, 2950, 2125.1
? 35,1150.1085°840.780cs-凰MS: m/z(χ): 369 ((M-Me)")
(3), 327(4), 269(5).

159 (30), 101 (61), 57
(100).

Trimethylsilylacetylene (5.44g, 7.8ml
．． 55 mmo +) in tetrahydrofuran solution (60
*I) with 1.6M n-butyllithium hexane solution (
17.3m1. 28 mmol 1) was added dropwise at -78°C and stirred for 30 minutes. In addition, the method described in the literature (R, L
,Jones,et al,+J,chem,soc,
, Perkin Trans.

1.19, 209. 1,4-dioxaspiro(4,4)nonane-6-aldehyde (2,16
After dropwise addition of a tetrahydrofuran solution (20+1) of g+14+nmol), the mixture was reacted for 40 minutes. A saturated aqueous ammonium chloride solution was added, the temperature was raised to room temperature, and then tetrahydrofuran was distilled off under reduced pressure. The residue was dissolved in a mixed solvent of ether-hexane, washed with saturated brine, and then dried over anhydrous magnesium sulfate.

After filtration and concentration, 6-(1-hydroxy-3-trimethylsilyl-2-propan-1-yl)-1,4-dioxaspiro(4,4)nonane was obtained as a mixture of diastereomers (3.24 g). Ta.

This product was dissolved in a mixture of acetone (60*I) and water (20+1), pyridinium p-)toluenesulfonate (about 100 ml) was added, and the mixture was heated under reflux for 7 hours. After cooling, acetone was distilled off under reduced pressure, and the resulting aqueous solution was saturated with common salt, and then extracted with a mixed solvent of ether-hexane.

Yes 89J! was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was separated by column chromatography (silica gel: hexane-ethyl acetate-15:1), and 2-(1-hydroxy-3-trimethylsilyl-2-propan-1-yl)cyclopentanone was separated from a mixture of diastereomers ( 2,61g.

91%).

Meng H-NMR (CDCIs): δ0.16. (S, 9
H), 1.7-2.7 (m, 7) 1).

3, 1-3.3 (m, IH), 4.6-4.8 (
a, 18).

Reference Example 4 Triethylamine ( 3.66g, 5.0■l.

36 mmol) and methanesulfonyl chloride (1.70 g,
1.1 ml 1.14 mmol 1) was added. After stirring at room temperature for 4 hours, the mixture was diluted with a mixed solvent of ether-hexane, and washed successively with saturated aqueous sodium bicarbonate and saturated brine while cooling with water. After drying over anhydrous magnesium sulfate and concentrating, the resulting residue was purified by column chromatography (silica gel: hexane-ethyl acetate-2081) to give (2E)-(3-trimethylsilyl-2-propynylidene)cyclopentanone (
1.46 g, 74%) was obtained.

mp51-52.5°C.

'H-NMR (CDCh): δ0.25 (s, 9H)
, 1.97 (quint, 2H, J-7, 6Hz), 2
．． 39 (t, 2H, J-7, 8Hz), 2.79 (dt
, 2H.

J-7, 3, 2, 9Hz), 6.35 (t, IH, J-
2.9Hz).

IR (CHCI s) +2980.2148r471
011610.1090.990.845m -'? '
lS:sb/zcχh 192 (M”) (5), 17?
((M-Me)”) (100).

12H4), 75(5), 43(5).

Elemental analysis (C11111&05l): Calculated value: C, 68
,69;H,8,38χ.

Analysis value: C, 68,62; H, 8,46χ.

Reference example Acetone (80) (2E)-(3-trimethylsilyl-2-propynylidene) cyclopentanone (1,4
6 g, 7.6 mmol 1) was dissolved and internally irradiated with a low pressure mercury lamp through a Vycor filter for 1 hour at room temperature. After concentration, the residue was separated and purified by column chromatography (silica gel: hexane-ethyl acetate-40:1) to obtain (2Z)-(3-trimethylsilyl-2-propynylidene)cyclopentanone (0.53 g, 3
6%). In addition, the raw material (E) integral (0,81
g, 55%) was recovered.

mp99-100.5℃.

'H-NMR (CDCIs): δ0.25 (s, 9
H), 1.92 (quint, 2H, J-7, 5H
z), 2.37(t, 20.J-7,8)1x),
2.72 (dt, 2H.

J-7,2,2,5Hz), 5.82(t, IH
, J-2,5Hz).

IR (CHC1): 2B? 5.2220.1?1
0.1603.1048.840(J-'MS:s/
z(χ): 192(M(29), 177((
M-Me)”) (100), 121(12),
75 (39), 43 (9).

Elemental analysis (C++H+*05i): Calculated value: C, 68,
69; H, 8, 38X.

Analysis value: C, 68,49; H, 8,40χ.

Reference Example 6 Diisoprobylamine (131■, 0.18s+1゜1
．． A tetrahydrofuran solution (4 mmol) of 3 mmol) was cooled to -78°C, and a 1.60 M n-butyllithium hexane solution (0.49 ml, 0.80 mmol) was added dropwise and stirred for 15 minutes to form a tetrahydrofuran solution of lithium diisopropylamide. was prepared.

This was followed by (2Z)-(3-)tumethylsilyl-2-propynylidene)cyclopentanone (99,4■).

0.50 mmol) in tetrahydrofuran ==(4
After stirring for 30 minutes, N-phenyltrifluoromethanesulfonimide (222μ, 0.60ml) was added dropwise and stirred for 30 minutes.
A solution (2 ml) of tetrahydrofuran (mmol) in tetrahydrofuran was added thereto, and the mixture was stirred for 4 hours while raising the temperature to -20°C. Diluted with hexane, removed inorganic salts by column chromatography (silica gel: hexane-ethyl acetate-40:1), and further purified by preparative thin layer chromatography (silica gel: hexane-ethyl acetate-20:1). Thus, trifluoromethanesulfonic acid (3Z)-(3-trimethylsilyl-2-propynylidene)cyclopentanon-2-yl (131 ml, 78%) was obtained.

mp37-38℃.

'H-NMR (CDCI M): δ-0,18(s
, 90), 2.53 (m, 2H), 2.73 (a, 2B
)+5.49(s+, 111), 6.23(m, 1[1
).

IR (CCI,): 2975.2130.160
2.142B, 1210.1140.848°600
c*” MS: Key/z (χ): 324 (M (5), 309
((M-Me)”) (5).

176 (100), 141 (5),? ? (5), 43(
3).

High resolution MS: M”: Calculated value (C+tH+5hOsSSt): 324,04
62° Measured value 324.0456° Reference example 7 2.2-dimethylpropionic acid (2S) 1-butyldimethylsilyloxy-(2S)-((4R) -2,2-dimethyl-1,3-dioxolane-4 -yl]-3-butynyl (33,5■, 0.087 mmol
) and trifluoromethanesulfonic acid (3Z)-(3-)
trimethylsilyl-2-propynylidene)cyclopenten-2-yl (15,4■,=;0.048mmo 1
) was dissolved in N,N-dimethylformamide (0.3 ml), and diethylamine (9.8 μM, 0.095 μM) was dissolved in N,N-dimethylformamide (0.3 ml).
After completely replacing the air in the sN+N-dimethylformamide solution containing mmol) with argon, iodination!
Ii! (1) (9,1■.

0.048 mmo 1) and tetrakistriphenylphosphine palladium (o) (27,5*, 0.024 mm
ol) was added and stirred at room temperature for 5 minutes. After diluting with a mixed solvent of ether and hexane, the mixture was washed successively with water and saturated brine, and dried over anhydrous magcinelum sulfate. After tmm, the residue was subjected to preparative thin layer chromatography (silica gel: hexane-
2,2-dimethylpropionic acid (23)-1-butyldimethylsilyloxy-(23)-((4R)-2,2-dimethyl-1)
゜3-Dioxolan-4-yl)-4-((3Z)-(
3-trimethylsilyl-2-probynylidene)cyclopenten-2-yl]-3-butynyl (19,3■,
73%).

[α] Snow/+1O06°C (C-0.66, hexane).

'H-NMR (CDC1s): δ-0,18 (a, 9
11) , 0.25 (s, 61) , 0.90 (s+9
11), 1.23 (s, 9H), 1.35.1.45 (
sX2.3HX2).

2.53 (a, 2B), 2.67 axis, 2H), 4.0
8-4.15 (m, 2H).

4.27 (t, IH, J-6,7Hz), 4.18,4
．． 48 (dx2.IHx2°J-each 11.6Hz),
5.57 (steel, l1l), 0.66 (-, LH).

IR(neat):2975,2180.2125.1
? 35,1140.840 >-'MS: m/z (χ)
7501(2), 457(3), 341(3), 159
(29).

101 (46), 5T (100), 43 (17).

Reference example 2.2-dimethylpropionic acid (2S)-t-butyldimethylsilyloxy-(2S) -((4R)-2,2
-dimethyl-1,3-dioxolan-4-yl)-4-
A dichloromethane solution (31) of ((3Z)-(3-1-dimethylsilyl-2-probynylidene)cyclopenten-2-yl-3-butynyl (33,6μ, 0.060 mmol) was cooled to -78°C, and 1 .0M diisobutylaluminum hydride hexane solution (0.7ml,
0.70 mm o 1 ) was added dropwise. After reacting for 1 hour, water was added to stop the reaction, and the mixture was stirred at room temperature. The produced white gel-like substance was filtered using Celite, and the filtrate was concentrated. The residue was purified by preparative thin layer chromatography (silica gel: hexane: ethyl acetate-10+1) to give (23)-t-butyldimethylsilyloxy-(2S
)-((4R)-2,2-dimethyl-1°3-dioxolan-4-yl) -4-((3Z)-(3-)dimethylsilyl-2-probynylidene)cyclopentene-2
-irku-3-butain-1-ol (19,4w, 6
8%).

[α)”+32.6° (C-1,05, hexane).

'H-NMR (CDCIs): δ-0,25(s
, 91), 0.27, 0.28 (SX2゜3HX2),
0.90 (s, 9H), 1.36.1.45 (sX2,
3HX2).

2.18 (t, IH, J-7, 2Hz), 2.53 (m
, 2■), 2.67 (m, 2H).

3.75 (s+, 2H), 4.10 (s, 2B), 4.
24 (t, IH, J-6,7Hz).

5.59 (-, IN), 6.68 (familiar, IH).

IR(CCI:2920,214011250.108
0,847 Bei-1M5: m/z (χ): 443
((M-clltoll)”) (1), 417((
M-MesC)”) (1), 373(4), 285(
2), 241(5), 195(3), 101(53
), 73 (100), 43 (20).

Reference example (23) -t-butyldimethylsilyloxy-(2S)
-((4R)-2,2-dimethyl-1゜3-diaxolan-4-yl)-4-((3Z)-(3-trimethylsilyl-2-propynylidene)cyclopenten-4-yl-3-butaine-1 -all (10,2w, 0.
022mmo +) in tetrahydrofuran solution (1ml
) was cooled to 0°C, and a 1.0M tetrabutylammonium fluoride tetrahydrofuran solution (0,043ml 1.0.
043 mmol) was added and stirred for 5 minutes. After diluting with a mixed solvent of ether and hexane, the mixture was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. After concentration, the residue was purified by preparative thin layer chromatography (silica gel: hesaquine-ethyl acetate-1=2) to obtain (23)-((
4R)-2,2-dimethyl-1゜3-dioxolane-4
-yl)((3Z)-(2-propynylidene)cyclopenten-2-yl-3-butaine-1,2-diol (5,5■.

89%) was obtained as a colorless solid.

(ff); @+16.2” (C-0,38, methanol).

'H-NMR (CDCIs): δ-1,37,1,4
8 (Sx2.3Hx2), 2.24 (dd, IIl, J
-9,0,5,311z), 2.54(m, 21ri, 2
．． 58 (g+, 21).

2.93 (s, IB), 3.15 (s, lH), 3.7
2 (dd, IH, J-11, 3°8.95Hz), 3.
86 (dd, IH, J-11, 4, 5, IHz), 4.
16 (dd.

IH, J-8, 4, 7, 1Hz), 4.19 (dd, 1
11. J-8, 5, 5, 7Hz).

4.23 (dd, IH, J-7, 1, 5, 711z),
5.45 (m, LH), 6.67 (■, 111).

IR (WBr): 3450, 3275.2940, 2
125, 1680, 1370° 1060, 1030.8
60cm -'hS; Audience/2 (χ>: 273 ((
M-Me)”) (3), 199(4), 12B(12
).

101 (100), 73 (13), 43 (51).

High-resolution MS: (M-Me) ”: Calculated value (C+, l1taOoh 273,1125° Measured value 273.1133° Test example (Cancer cell growth inhibition test) Mouse lymphocytic leukemia cells CP38B) by 10% In addition to the RPMI-1640 culture solution containing calf fat serum, the number of cultured cells was adjusted to 5 x 10' cells/1 ml.To this, the compound of the present invention, (23)-((
4R)-2,2-dimethyl-1,3-dioxolane-4
-yl)-4-((3Z)-(2-probynylidene)
cyclopenten-2-yl]-3-butaine-1,2-
Add diol to the specified concentration and incubate at 37℃ for 2 hours.
Cultured for 1 day. The number of floating cells was counted using a Coulter counter, and the concentration of 50% cell growth inhibition ICs was determined based on the growth inhibition rate relative to the control group. I asked for As a result, I C5o
= 3.1xlO-”mM (8,9,ug/ml
), a 50% cell growth inhibition concentration was obtained.

Claims (1)

[Claims] (1) Acetylene derivatives represented by the general formula ▲ Numerical formulas, chemical formulas, tables, etc. ,
R^5 each independently represents a straight chain or branched alkyl group having 1 to 4 carbon atoms, or a substituted or unsubstituted aryl group. ), where R^2 has 1 to 6 carbon atoms.
represents a straight-chain or branched alkyl group, or a substituted or unsubstituted aryl group. ]