JPH09249611A - Production of substituted cyclopentenone and substituted cyclohexenone derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a substituted cyclopentenone and substituted cyclohexenone derivative useful as a synthetic intermediate for prostandines. SOLUTION: A compound represented by formula I [X is (α-OZ or '-H), etc.; Y is (α-OZ' or β-H), etc.; Z and Z' are each mutually independently H, methyl, etc.; R<1> is H, a 1-10C alkyl, etc.; (n) is 1 or 2] is reacted with a nucleophilic reagent represented by the formula R<2> M<1> (R<2> is a 1-10C alkyl, etc.; M<1> is Li, Na, etc.) to provide the objective substituted cyclopentenone derivative represented by formula II, e.g. a compound of formula III.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an intermediate of a medicinal and agricultural chemical,
In particular, the present invention relates to a method for producing a substituted cyclopentenone and a substituted cyclohexenone derivative useful as a synthetic intermediate for prostaglandins.

[0002]

2. Description of the Related Art Substituted cyclopentanone derivatives and α-substituted cyclopentenone derivatives have attracted attention as intermediates for medicinal and agricultural chemicals, and in particular, prostaglandins having strong physiological activity. Useful as an intermediate for

Conventionally, as one of the reactions for producing prostaglandins, a prostaglandin E type is synthesized from a cyclopentenone derivative having no substituent at the β-position by a so-called two-component reaction represented by the following formula. Is known [M
Jay Weiss (MJ Wiess), Journal Organic Chemistry (Journal Or)
Gan. Chemistry) 44, 1439 (1979)].

[0004]

Embedded image (In the formula, THP represents a tetrahydropyranyl group, Me represents a methyl group, and Ph represents a phenyl group.)

There are several known methods for producing intermediates derived from cyclopentenone derivatives having no substituent at the β-position (Terashima, Sakai, Yamamoto, "Prostaglandins and Related Physiological Activities"). Materials, 89-92, 1989.
Years), but there are various problems as an industrial production method.

Further, as a method for producing prostaglandins, a method of synthesizing prostaglandin F2α by a conjugate addition reaction represented by the following formula has been conventionally known [G Stark et al., Journal American Chemical. Sosayati (J. Am. Chem. Soc.),
97, 4745, 6260 (1975)].

[0007]

[Chemical 6]

The method for synthesizing the prostaglandin F2α has a feature that the yield from the compound IVa 'is high and that the α chain portion can be freely changed by selecting a conjugate addition reagent.

However, the previously known compound I
The Va ′ synthesis method has the drawback that the yield is low, the reagent used is expensive, and the compound IVa ′ obtained is often a racemic form, and it is difficult to obtain an optically active compound. [Ibid .; D. R. Morton et al., Journal Organic Chemistry (J. Org. Ch.)
em. ), 43, 2102 (1978);
J. Org. Chem., Vol. 49, Bee Kozhkovsky, et al.
2301 (1984)].

Therefore, it is desired to produce prostaglandins industrially advantageously.

The present invention has been made in view of the above circumstances,
It is an object of the present invention to provide a method for producing substituted cyclopentenone and substituted cyclohexenone derivatives capable of industrially producing prostaglandins.

[0012]

Means for Solving the Problems and Embodiments of the Invention The present inventors have made intensive studies in order to achieve the above object, and as a result, each compound represented by the following formula was used as a synthetic intermediate of prostaglandin. It was found to be useful.

[0013]

Embedded image

In the above formula, R ¹ is a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, an alkynyl group having 2 to 10 carbon atoms, a phenyl group,

[0015]

Embedded image Is shown.

R ² is an alkyl group having 1 to 10 carbon atoms, an alkylthio group having 1 to 10 carbon atoms, an alkylamino group having 1 to 10 carbon atoms, an alkylsilyl group having 1 to 10 carbon atoms, or an alkyl group having 1 to 10 carbon atoms. An alkyltin, a C2-C10 alkenyl group, a C2-C10 alkynyl group, or a cyano group is shown.

R ³ and R ⁴ each represent an alkyl group having 1 to 10 carbon atoms, phenyl group, p-chlorophenyl group, benzyl group or p-chlorobenzyl group, and R ³ and R ⁴ are the same as each other. Or different.

R ⁵ is an alkyl group having 1 to 15 carbon atoms, an alkenyl group having 2 to 15 carbon atoms, an alkynyl group having 2 to 15 carbon atoms, 4-phenoxybutyl group, 3- (t-butyldimethylsilyloxy) Octyl group, 3- (ethoxyethyloxy) -1-octen-1-yl group, 3- (2-tetrahydropyranyloxy) -1-octen-1-yl group, 3- (t-butylmethylsilyloxy) -5-methyl-1-nonen-1-yl group, 3- (benzyloxymethyloxy) -1-octen-1-yl group, or

[0019]

Embedded image (Wherein, Z ″ represents a trialkylsilyl group, an alkoxyalkyl group, an aralkyloxyalkyl group, a trityl group or a tetrahydropyranyl group,

[0020]

Embedded image Represents a single bond, a double bond or a triple bond, and R ⁷ represents an alkyl group having 1 to 10 carbon atoms, a hexa-4-yn-2-yl group, a hepta-4-yn-2-yl group, and 2,6. -Dimethyl-hepta-5-en-1-yl group, penta-1-ene-
1-yl group, penta-2-en-1-yl group, hexa-
1-en-2-yl group, 3-ethoxy-2-methyl-propan-2-yl group, ethoxyethyl group, 5-methoxyhexyl group, 6-methoxy-2-hexyl group, methyl halide group, halogenated n-butyl group, halogenated n-
Pentyl group, nonyl halide group, phenyl group, benzyl group, phenyl halide group, n-pentyloxymethyl group, 1-ethoxy-2-methyl-propan-2-yl group, phenoxymethyl group, benzyloxymethyl group, p-
Chlorophenoxymethyl group, 2-phenylethyl group, benzyloxyethyl group, p-fluorophenoxymethyl group, phenylacetylenyl group, m-chlorophenoxymethyl group, m-trifluoromethyl-phenoxymethyl group, benzothiophene-5 -Represents an yl group, a 2-octenyl group, a 3-methoxycarbonylpropyl group or a vinyl group. )

M ¹ and M ² are Li, Na, K, and
Mg, Ca, Ti, Zr, Ni, Cu, Zn, Al, S
A metal selected from n or a group containing the metal is shown.

X is (α-OZ, β-H) or (α-
H, β-OZ).

Y represents (α-OZ ′, β-H) or (α-
H, β-OZ ′).

Z and Z 'each represent a hydrogen atom, a methyl group, a trialkylsilyl group (for example, trimethylsilyl group, t-butyldimethylsilyl group), an alkoxyalkyl group (for example, methoxymethyl group), an aralkyloxyalkyl group (for example, benzyl group). Oxymethyl group), trityl group or tetrahydropyranyl (THP) group.
And Z ′ may be the same or different from each other.

W is CHR ¹ , (α-CHR ¹ OH, β-
H) or (α-H, β-CHR ¹ OH).

V represents (α-CHR ¹ OH, β-H) or (α-H, β-CHR ¹ OH).

U is expressed as (α) when X is (α-OZ, β-H).
-H, β-R ⁵ ) and (α-R ⁵ , β-H) when X is (α-H, β-OZ).

N is 1 or 2.

That is, by cyclizing the compound represented by the general formula [V] using a hypohalite or a base and a halogen gas, a novel compound [I] is obtained,
Using this new compound [I] as a starting material, a new compound [I
I] ([IIa] and [IIb]), and more specifically, the novel compound [II] by hydrogenating and hydrolyzing the novel compound [I] in the presence of a hydrogenation catalyst.
a] was synthesized, and it was found that a novel compound [IIb] was synthesized by sulfonylation of the new compound [IIa] in the presence of a base, followed by desulfonation.
Further, the novel compound [IIb] is reacted with the compound represented by the general formula [VI] to give the novel compound [III]
a) and the novel compound [IIIa] can be obtained by reacting the novel compound [IIb] with the compound [VII]. [IIIa]
Is sulfonylation of the above novel compound [IIa] in the presence of a base, followed by desulfonation, followed by the general formula [VII]
By reacting the compound represented by the general formula [VIII] with the novel compound [IIIa].
V] was obtained.

The formula [II] ([IIa],
[IIb]), [III], [IIIa], and [IV] have been found to be useful as intermediates for synthesizing prostaglandins, and have led to the present invention.

That is, the present invention provides a compound represented by the general formula [IIb]:

[0032]

Embedded image [Where X is (α-OZ, β-H) or (α-H,
β-OZ), Y is (α-OZ ′, β-H) or (α-
H, β-OZ ′), and Z and Z ′ each represent a hydrogen atom, a methyl group, a trialkylsilyl group, an alkoxyalkyl group, an aralkyloxyalkyl group, a trityl group, or a tetrahydropyranyl group. 'May be the same or different from each other. R ¹ is a hydrogen atom, carbon number 1
An alkyl group having 10 to 10, an alkenyl group having 2 to 10 carbon atoms,
An alkynyl group having 2 to 10 carbon atoms, a phenyl group,

[0033]

Embedded image (In the above formula, THP is a tetrahydropyranyl group, ^t Bu
Represents a tertiary butyl group, and EE represents an ethoxyethyl group. ). n is 1 or 2. The compound represented by the general formula [VI]

[0034]

Embedded image (In the formula, R ² is an alkyl group having 1 to 10 carbon atoms, an alkylthio group having 1 to 10 carbon atoms, an alkylamino group having 1 to 10 carbon atoms, an alkylsilyl group having 1 to 10 carbon atoms, and 1 to 1 carbon atoms. A group selected from 10 alkyl tin, an alkenyl group having 2 to 10 carbon atoms, an alkynyl group having 2 to 10 carbon atoms, and a cyano group; M ¹ is Li, Na, K, Mg, Ca, Ti,
A metal selected from Zr, Ni, Cu, Zn, Al and Sn or a group containing the metal is shown. ) A general formula [III] characterized by reacting a nucleophile represented by

[0035]

Embedded image (Wherein, X, R ¹ , R ² and n each have the same meaning as described above). A process for producing a substituted cyclopentenone and a substituted cyclohexenone derivative represented by the formula:

Hereinafter, the present invention will be described in more detail.
The production method of the compound [III] of the present invention comprises the above-mentioned general formula [I] and the general formula [II]
a) which is produced via the compound of the general formula [II]
The compound of formula [I] is produced from the compound of formula [V].

[0037]

Embedded image

Here, in the novel compound of the general formula [I], X represents (α-OZ, β-H) or (α-H, β
—OZ), Y is (α-OZ ′, β-H) or (α-H,
β-OZ ′), Z and Z ′ each represent a hydrogen atom or a hydroxyl-protecting group shown below, and Z and Z ′ may be the same or different from each other. R ¹ represents a hydrogen atom or the following group, and n represents an integer of 1 or 2.

The protective groups for the hydroxyl groups of Z and Z'include trialkylsilyl groups (eg trimethylsilyl group, t-butyldimethylsilyl group), alkoxyalkyl groups (eg methoxymethyl group), aralkyloxyalkyl groups (eg benzyloxymethyl group). Group), a trityl group or a tetrahydropyranyl (THP) group.

Further, specifically as R ¹ , a hydrogen atom,
C1-C1 such as methyl group, ethyl group and n-pentyl group
An alkyl group of 0,

[0041]

Embedded image An alkenyl group having 2 to 10 carbon atoms, such as 3-nonene, an alkynyl group having 2 to 10 carbon atoms, a phenyl group,

[0042]

Embedded image (In the above formula, THP is a tetrahydropyranyl group, ^t Bu
Represents a tertiary butyl group, and EE represents an ethoxyethyl group. )

The compound of the above general formula [I] is obtained by converting the oxime -CH = N-OH of the compound [V] to cyanate -C ネ ー ト N
⁺ -O ^- it may be prepared by cyclizing with a mild oxidizing agent, for example aqueous hypohalous acid or base and a halogen gas turned into. Examples of the hypohalite include sodium hypochlorite, sodium hypobromite, sodium hypoiodite and the like, and sodium hypochlorite is particularly preferably used. The amount of hypohalite is
It is usually used in an equivalent amount or more with respect to the compound [V]. Examples of the halogen gas include chlorine and bromine, and examples of the base include tertiary amines such as triethylamine, pyridine, and 4-dimethylaminopyridine. For the reaction, a solvent can be used, and as the solvent, halogenated hydrocarbons such as dichloromethane and hydrocarbons such as hexane, benzene, and toluene are used. The reaction temperature and the reaction time are appropriately selected. The reaction temperature is preferably from -20 ° C to the reflux temperature of the solvent, particularly preferably from 0 to 50 ° C.
~ 100 hours are employed.

Next, the compound represented by the general formula [II] ([IIa], [I
The method for producing the novel compound represented by Ib]) will be described.

[0045]

Embedded image

Where W is CHR ¹ , (α-CHR ¹ O
H, β-H) or (α-H, β-CHR ¹ OH), and V is (α-CHR ¹ OH, β-H) or (α-H,
β-CHR ¹ OH). X, Y, Z, Z′R ¹
And n each have the same meaning as described above.

Among the novel compounds represented by the general formula [II], a novel compound represented by the general formula [IIa] is produced by hydrolyzing the novel compound [I] in the presence of a hydrogenation catalyst. can do.

[0048]

Embedded image

In this hydrogenation hydrolysis reaction, a hydrogenation cleavage reaction and a hydrolysis reaction are simultaneously carried out under a weakly acidic condition using a hydrogenation catalyst in a hydrogen atmosphere.

As the hydrogenation catalyst used in this reaction, known hydrogenation catalysts can be used. For example, Raney cobalt, Raney nickel, palladium, platinum, palladium /
Examples thereof include carbon, palladium / alumina, platinum / carbon, platinum / alumina and the like.

It is preferable that the above-mentioned hydrogenolysis reaction is carried out under weak acidity, particularly at pH 5 to 6. Therefore, it is desirable to add a weak acid. In this case, the weak acid may be boric acid, phosphoric acid or the like. Is mentioned. The amount used is 1-10
It is desirable to make the equivalent, particularly 1 to 5 equivalent.

Further, it is preferable to use a solvent in the above reaction. As the solvent, water, tetrahydrofuran, dioxane, methanol, and a mixed solvent of ethanol and water can be used, but of course, the solvent is not limited thereto.

In the above reaction, the hydrogen pressure is from normal pressure to 100 kg / cm ² (gauge).
The reaction temperature is preferably -50 ° C to the boiling point of the solvent, and the reaction time is usually 20 minutes to 15 hours.

Further, among the novel compounds represented by the general formula [II], the novel compounds of the general formula [IIb] are sulfonylated in the presence of a base,
Then, it can be produced by desulfonylation.

[0055]

Embedded image

Here, a tertiary amine (for example, triethylamine), pyridine, 4-dimethylaminepyridine or the like can be used as a base, and an alkylsulfonyl chloride (for example, methylsulfonyl chloride) or an arylsulfonyl chloride (for example, as a sulfonylating agent) can be used. For example, p
-Toluenesulfonyl chloride) and the like. The amounts used are each equivalent or more, but usually the base is used in excess of the sulfonylation.

In the above sulfonylation reaction and desulfonation reaction, a solvent can be used. Examples of the solvent include chloroform, methylene chloride, carbon tetrachloride, and the like.
One or more mixed solvents such as diethyl ether can be used.

The sulfonylation reaction and desulfonation reaction can be carried out in accordance with known conditions for sulfonylation reaction and desulfonation reaction. In this case, the sulfonylation reaction and the desulfonation reaction may be carried out simultaneously, that is, the desulfonation reaction may be carried out without removing the reaction product of the sulfonylation reaction, or separately, that is, the reaction product of the sulfonylation reaction. The product may be taken out and subjected to a desulfonation reaction, but the reaction temperature is -1.
Desirably, the temperature is from 100 to 100 ° C. The reaction time is usually from 20 minutes to 6 hours.

In the present invention, the compound [III] is synthesized by reacting the above-mentioned novel compound [IIb] obtained as described above with a nucleophile represented by the general formula [VI].

[0060]

[Chemical 21]

Here, in the formula, each R ² has 1 to 1 carbon atoms.
0 alkyl group, alkylthio group, alkylamino group,
Alkylsilyl group, alkyltin, each having 2 to 1 carbon atoms
A group selected from an alkenyl group, an alkynyl group and a cyano group of 0, M ¹ is Li, Na, K, Mg, Ca, Ti, Z
A metal selected from r, Ni, Cu, Zn, Al and Sn or a group containing the metal is shown. R ¹ , X, Y, Z, Z ', n
Each have the same meaning as above.

In this case, the nucleophile [VI] is
Physically R^TwoLi, R^TwoMgBr, R^TwoMgI, R^TwoR⁶Cu
QLi_Two, R^TwoCuQLi , R^Two(R⁶)_TwoAlQLi , R^Two
(R¹)_TwoAl, R^TwoR⁶CuQLi MgBr, R^TwoCuQ
MgBr etc. are mentioned. Where R⁶Has 1 to 10 carbon atoms
Substituted or unsubstituted alkyl group, alkenyl group,
Lucinyl group, alkylthio group, alkylamino group, ar
Killsilyl group, alkyloxy group, alkylcarbonyl
A group selected from a group and a cyano group, R^TwoAnd R⁶Are
May be the same or different, and Q is halo
Gen atom, cyano group, alkylthio group, arylthio group
Alternatively, it represents a thiocyano group.

The above nucleophile [VI] is converted to a compound [IIb]
Upon reaction with the nucleophile [VI],
It is preferable to use 0.5 to 4 equivalents, particularly 0.8 to 1.2 equivalents, with respect to b).

A solvent can be used in the reaction, but any solvent may be used as long as it does not hinder the reaction, and examples thereof include tetrahydrofuran, hexane, pentane and diethyl ether.

The reaction temperature is usually -100 to 50 ° C,
Preferably it is -80 to 0 ° C, and the reaction time is usually 5 minutes to
50 hours.

Here, prostaglandin type E can be produced by the following reaction using the compound of the above formula [III]. [Kurozumi et al., Chemical Farmers Bulletin of Japan (Chemical
Pharmaceutical Bulletine
of Japan), 30, 1102, 1982.
Year〕.

[0067]

Embedded image (In the formula, Me is a methyl group, ^t Bu is a tertiary butyl group, and Ph is a phenyl group.)

Accordingly, the above compound [IIb] can be effectively used as a prostaglandin E type synthetic intermediate via the compound [III].

[0069]

According to the present invention, a compound [III] including a novel compound [IIIa] useful as a synthetic intermediate for prostaglandins can be easily produced.

[0070]

EXAMPLES The present invention will be described in detail below with reference to Reference Examples and Examples, but the present invention is not limited to these Examples. In the following formula, Me is a methyl group,
Et represents an ethyl group, ⁿ Bu represents an n-butyl group, and ^t Bu represents a t-butyl group.

[0071]

Embedded image

Compound 100 of Compound (VA) and (VB)
6 ml of a dichloromethane solution of mg (0.33 mmol)
Was cooled to 0 ° C., and 0.67 ml (0.4 mmol) of an aqueous solution of sodium hypochlorite was added dropwise with stirring. After stirring at room temperature for 10 hours, 5 ml of water was added, and the mixture was extracted three times with 5 ml of diethyl ether. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained crude product is purified by silica gel column chromatography,
90 mg (0.3 mmol) of a mixture of compounds (IA) and (IB) was obtained. Yield 91%. Analytical value of mixture of (VA) and (VB) ¹ H NMR (CDCl ₃ , internal standard tetramethylsilane) δ 0.78 (9H, S), 2.24 and 2.42 (2H,
t × 2, J = 6 Hz), 3.17 (3H, S), 3.8
0 (2H, br, d, J = 6 Hz), 4.2 to 4.7
(2H, m), 4.9-6.1 (3H, m), 6.60
And 7.18 (1H, t × 2, J = 6 Hz), 8.9 and 9.4 (1H, brs × 2) Analytical value of a mixture of (IA) and (IB) ¹ HNMR (CCl ₄ , internal standard) Benzene) δ 0.06 (S, 6H), 0.86 (S, 9H), 2.
10 to 2.95 (m, 3H), 3.24 (S, 3H),
3.45 to 4.95 (m, 6H) IR: 1740, 1630, 1460, 1360, 12
48, 1130, 1035, 820 cm ^-1 MS (m / e): 301 (5, M ⁺ ), 269 (7),
244 (18), 182 (15), 101 (11), 8
9 (42), 75 (13), 73 (45), 45 (10
0) Rf value (silica gel thin layer chromatography, n-hexane / ethyl acetate = 1/1) = 0.65 and 0.7

[0073]

Embedded image

The compounds (IA) obtained in Reference Example 1 and (I)
30.3 mg of boric acid was added to 5 ml of a water-methanol (1: 5) solution of 73 mg (0.243 mmol) of the mixture of B).
(0.49 mmol), 5% palladium on carbon catalyst 10
The mixture was stirred at 20 ° C. for 3 hours under a hydrogen atmosphere (normal pressure).

The reaction solution was filtered using silica gel, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography to give compound (IIa).
70 mg (0.231 mmol) of a mixture of A) and (IIaB) was obtained. 95% yield. Analytical value of a mixture of (IIaA) and (IIaB) ¹ HNMR (CCl ₄ , internal standard benzene) δ 0.10 (S, 6H), 0.85 (S, 9H), 1.
93-2.82 (m, 4H), 3.33 (S, 3H),
3.45 to 4.83 (m, 6H) IR: 3425, 1740, 1250, 1040, 83
0,775 cm ^-1 MS (m / e): 273 (2, M ⁺ ), 243 (4,
M ⁺ ), 186 (17), 185 (100), 157
(13), 143 (17), 89 (11), 75 (2
0), 73 (14), 45 (69) Rf value (silica gel thin layer chromatography, hexane /
(Ethyl acetate = 1/1) = 0.4

[0076]

Embedded image

To a solution of 165 mg (0.545 mmol) of a mixture of the compounds (IIaA) and (IIaB) obtained in Reference Example 2 in 2 ml of dichloromethane was added 0.23 ml (1.64 mmol) of triethylamine and cooled to 0 ° C. . With stirring, methylsulfonyl chloride 0.0
After dropwise adding 64 ml (0.82 mmol), the mixture was added at 0 ° C for 3 hours.
Stirred for 0 minutes. 5 ml of saturated saline was added, and extraction was performed with 10 ml of n-hexane. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained crude product is purified by silica gel column chromatography,
152 mg (0.53 mmol) of the compound of (IIbA)
I got 97% yield. Analytical value of compound of (IIbA) ¹ H NMR (CCl ₄ , internal standard benzene) δ 0.10 (S, 6H), 0.84 (S, 9H), 2.
34 (dd, J = 1.2, 5 Hz, 2H), 3.32
(S, 3H), 4.20-4.51 (m, 2H), 4.
63 (dd, J = 7.2, 12 Hz, 2H), 5.38
And 6.01 (2dd, J = 1.7, 2.3 Hz, 2H) IR: 1715, 1645, 1460, 1390, 12
40,1045,817,775 cm ^-1 Rf value (silica gel thin layer chromatography, n-hexane / diethyl ether = 1/1) = 0.65 ¹³ C NMR (CDCl ₃ ) δ 200.9, 144.2, 119.8, 94.5,7
7.0, 69.0, 55.2, 45.3, 25.4, 1
7.8, 5.0

[0078]

Embedded image

A mixture of compounds (VC) and (VD) was reacted in the same manner as in Reference Examples 1 and 2, and (IC) and (I
A mixture of (IIaC) and (IIaD) was obtained via the mixture of D). Next, the mixture of (IIaC) and (IIaD) was reacted in the same manner as in Reference Example 3 to give compound (IIbB)
I got Analytical value of mixture of (VC) and (VD) ¹ H NMR (CDCl ₃ , internal standard tetramethylsilane) δ 0.07 (6H, S), 0.87 (9H, S), 2.
0 to 2.9 (2H, m), 3.2 (3H, S), 4.9
-6.0 (3H, m), 6.4-7.7 (2H, m),
8.4 (1H, brs) analysis ¹ HNMR (CCl _4, internal standard benzene) of the compound of (IIbB) δ0.18 (s, 6H ), 0.94 (s, 9H), 2.
34 (d, J = 4.8 Hz, 2H), 3.48 (s, 3
H), 4.05-4.25 (m, 1H), 4.51.
(Q, J = 5.1 Hz, 1H), 5.47 and 6.11
(2brs, 2H) ¹³ C NMR (CDCl ₃ ) δ201.3, 144.1, 119.8, 82.5, 6
8.5, 56.6, 45.5, 25.6, 17.9,-
4.9 Rf value (silica gel thin layer chromatography, n-hexane / diethyl ether = 1/1) = 0.58 [α] ²⁵ _D- 35.4 ° (C = 2.30, CHCl ₃ ) (IC) Analytical value of mixture of (ID) ¹ H NMR (CDCl ₃ , internal standard tetramethylsilane) δ 0.09, 0.11 (6H, S × 2), 0.88 (9
H, S), 2.0-2.8 (3H, m), 3.47,
3.56 (3H, S × 2), 3.6 to 4.2 (3H,
m), 4.60 (1H, dt, J = 5 Hz, 2 Hz) IR: 2940, 1470, 1370, 1250, 11
40, 1070, 980 cm ^-1 MS (m / e): 271 (M ⁺ , 0.5%), 214
( 7 %), 89 (100%) Analytical value of a mixture of (IIaC) and (IIaD) ¹ HNMR (CDCl ₃ , internal standard tetramethylsilane) δ0.07 (6H, S), 0.89 (9H, S) ), 1.
6-1.9 (3H, m), 3.31 (3H, S), 3.
4-4.0 (4H, m) IR (KBr tablet = disk): 3600-3000,
2900, 1740 cm ^-1 MS (m / e): 274 (M ⁺ , 3%), 217 (7
%), 73 (100%)

[0080]

Embedded image

81.7 mg (0.43 mmol) of copper iodide
Of tetrahydrofuran / dimethyl sulfide (5/1) 3
The mixture was cooled to −70 ° C. and 0.56 ml (0.858 mmol; use of a 1.53 mol solution in n-hexane) of n-butyllithium was slowly added dropwise to the solution. −70
After stirring at 20 ° C. for 20 minutes, 3 ml of a tetrahydrofuran solution of 113 mg (0.395 mmol) of the compound (IIbA) obtained in Reference Example 3 was slowly added dropwise. −70
Stir at 20 ° C for 20 min.
1 was added. After returning to room temperature, the mixture was extracted with 7 ml of n-hexane. After drying the organic layer over anhydrous magnesium sulfate,
Concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography to obtain 110 mg (0.390 mmol) of the compound (IIIA). Yield 99
%. Analytical value of compound (IIIA) ¹ H NMR (CCl ₄ , internal standard benzene) δ 0.14 (s, 6H), 0.74 to 1.10 (m, 1
2H), 1.13 to 1.71 (m, 6H), 2.00
2.30 (m, 2H), 2.13 and 2.59 (2dd,
3. J = 2.6, 18 Hz and J = 6.0, 18 Hz);
72-4.94 (m, 1H), 6.82-6.98
(M, 1H) ¹³ C NMR (CDCl ₃ ) δ 205.8, 156.3, 147.2, 69.0, 4
5.5, 31.5, 27.1, 25.8, 24.3, 2
2.3, 18.0, 13.8, -4.7 Rf value (silica gel thin layer chromatography, n-hexane / diethyl ether = 8/1) = 0.63

[Examples 2 to 21] Various nucleophilic reagents were reacted in the same manner as in Example 1. The reaction conditions and results are shown in Tables 1-6.

In the table, Me is a methyl group, E
t represents an ethyl group, ⁿ Bu represents an n-butyl group, ^t Bu represents a t-butyl group, EE represents an ethoxyethyl group, THP represents a tetrahydropyranyl group, and THF represents tetrahydrofuran. In the column of the solvent, the weight ratio of the mixed solvent is shown in parentheses.

[0084]

[Table 1]

[0085]

[Table 2]

[0086]

[Table 3]

[0087]

[Table 4]

[0088]

[Table 5]

[0089]

[Table 6]

[0090]

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Cuprous cyanide 627 under an argon atmosphere
mg (7 mmol) in a mixture of 15 ml of tetrahydrofuran at −78 ° C. EEO (CH ₂ ) ₆ MgCl 0.34 m
1 (6 mmol, using a 0.58 mol solution in tetrahydrofuran) was added dropwise and stirred for 20 minutes. At −78 ° C., a solution of 1.28 g (5 mmol) of (IIaB) in 15 ml of tetrahydrofuran was added dropwise to the mixture, and the temperature was raised to room temperature over 1 hour. 30 ml of saturated ammonium chloride water
And 30 ml of hexane were added, and the mixture was stirred at room temperature for 1 hour. The organic layer was separated, the aqueous layer was extracted with 15 ml of hexane, and the obtained organic layer was dried over magnesium sulfate and filtered. The crude product obtained by evaporating the solvent of the filtrate under reduced pressure was purified by silica gel column chromatography, and (IIIB)
1.71 g (4.3 mmol) were obtained. 86% yield.

[0092]

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[0093]

Embedded image 269 mg (9.0 mmol) of diethyl ether 10
to ml solution, at -78 ℃ ⁿ BuLi10.6ml (18
Mmol, a 1.70 mol solution in pentane) was added dropwise and stirred at -78 ° C for 1 hour. To a separately prepared mixture of 967 mg (10.8 mmol) of cuprous cyanide and 20 ml of tetrahydrofuran, the above solvent was added dropwise at -78 ° C. After stirring for 15 minutes, a solution of 1.53 g (6 mmol) of (IIbB) in 18 ml of tetrahydrofuran was added at -70 ° C.
And the temperature was raised to room temperature over 1 hour. 50 ml of a saturated aqueous ammonium chloride solution and 50 ml of hexane were added, and the mixture was stirred at room temperature for 1 hour and extracted with 20 ml of hexane. The crude product obtained by drying over magnesium sulfate and concentrating was purified by a silica gel column, and 2.09 g of (IIIE) (5.
28 mmol). Yield 88%.

Compounds (IIIB), (III
C), (IIID), (IIIE), (IIIF),
The analytical values of (IIIH) and (IIII) are shown below. Analytical value of compound (IIIB)¹ HNMR (CCl_Four, Internal standard benzene) δ 0.15 (s, 6H, 2SiCH_Three), 0.93
(S, 9H, 3SiCCH_Three), 1.03 to 1.80.
(M, 16H), 2.01 to 2.30 (m, 2H, C =
CCH_Two), 2.14 (dd, J = 2.4, 19.2H)
z, 1H), 2.59 (dd, J = 6.0, 19.2H
z, 1H), 3.05 to 3.67 (m, 5H), 4.5
5 (q, J = 5.4Hz, 1H OCH(CH_Three)
O), 4.72 to 4.95 (m, 1H, SiOCH),
6.88 (brs, 1H, C = CH) IR: 2920, 1710, 1250, 1080, 83
5cm^-1 Rf value (silica gel thin layer chromatography, n-hexa
/ Diethyl ether = 2/1) = 0.33 Analytical value of compound (IIIC)¹ HNMR (CCl_Four, Internal standard benzene) δ 0.14 (S, 6H), 0.89 (s, 9H), 0.
80-1.85 (m, 5H), 1.98-2.32.
(M, 3H), 2.58 (dd, J = 5.7, 18.3)
Hz, 1H), 4.70 to 4.93 (m, 1H), 6.
86 (brs, 1H) Analytical value of compound (IIID)¹ HNMR (CCl_Four, Internal standard benzene) δ 0.09 (S, 6H), 0.90 (s, 9H), 1.
01-1.90 (m, 10H), 2.00-2.48
(M, 3H), 2.65 (dd, J = 6.1, 18H
z, 1H), 2.94 (brs, 2H), 3.15-
3.68 (m, 4H), 4.53 (q, J = 5.1H
z, 1H), 4.70-4.95 (m, 1H), 7.1
3 (brs, 1H) Analytical value of compound (IIIE)¹ HNMR (CDCl_Three, TMS) δ 0.80 (6H, S), 0.81 (9H, S), 1.
07 (3H, d, J = 7 Hz), 1.18 (3H, t,
J = 6 Hz), 1.3 to 1.6 (4H, m), 1.7 to
2.2 (2H, m), 2.19 (1H, dd, J = 18
Hz, 3 Hz), 2.68 (1H, dd, J = 18H)
z, 5 Hz), 2.8 (2H, m), 3.1-3.8
(4H, m), 4.58 (1H, q, J = 6 Hz),
4.78 (1H, m), 5.2 to 5.6 (2H, m),
6.93 (1H, d, J = 3 Hz) Analytical value of compound (IIIF)¹ HNMR (CCl_Four, Internal standard benzene) δ 0.13 (S, 6H), 0.89 (S, 9H), 1.
10 to 2.31 (m, 20H), 2.15 (dd, J =
2.4, 18 Hz, 1 H), 2.59 (dd, J = 1)
8, 6.0 Hz, 1H), 2.66 to 2.91 (m, 2
H), 3.05 to 3.88 (m, 4H), 4.45 (b
rs, 1H), 4.68-4.92 (m, 1H), 5.
15 to 5.65 (m, 2H), 6.84 (brs, 1
H) Analytical value of compound (IIIH)¹ HNMR (CCl_Four, Internal standard benzene) δ 0.18 (s, 6H, 2SiCH_Three), 0.94
(S, 9H, 3SiCCH_Three), 2.20 (dd, J =
3.18 Hz), 2.64 (dd, J = 6,18H)
z), 2.79-3.03 (m, 2H, C = CC
H_Two), 4.73-5.35 (m, 3H, SiOCH and
And C = CCH_Two), 5.58 to 6.08 (m, 1H,H
C = CH_Two), 6.93 (brs, 1H, (O =) CC
= CH) [α]^{twenty five} _D + 21.5 ° (C = 2.74, CHCl_ThreeThe optical purity was determined by Daicel's Chiral Cell OD (hexane 1.
0ml / min, 230nm)> 99% ee
And confirmed. Analytical value of compound (III I)¹ HNMR (CCl_Four, Internal standard benzene) δ 0.10 (s, 6H), 0.8 to 1.5 (m, 18
H), 2.4 (d, J = 2 Hz, 1H), 2.8 (2
H, dd, J = 17 Hz, J = 6 Hz), 4.7 (m,
1H), 7.1 (brd, 1H) MS (m / e): [M-CH_Three]⁺= 267 (2%),
[M-^tBu] = 225 (11%), 169 (base
)

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location C07C 69/738 C07C 69/738 A 323/52 7419-4H 323/52 C07F 7/18 C07F 7 / 18 A // B01J 23/44 B01J 23/44 X C07D 261/20 C07D 261/20 C07M 7:00 (31) Priority claim number Japanese patent application 63-43045 (32) Priority date Sho 63 (1988) February 25th (33) Japan (JP) claiming priority (72) Inventor Katsuaki Miyaji 722-1, Tsuboi-cho, Funabashi-shi, Chiba Nissan Chemical Industry Co., Ltd. Central Research Laboratory

Claims (1)

[Claims] 1. A compound of the general formula [IIb] [Where X is (α-OZ, β-H) or (α-H,
β-OZ), Y is (α-OZ ′, β-H) or (α-
H, β-OZ ′), and Z and Z ′ each represent a hydrogen atom, a methyl group, a trialkylsilyl group, an alkoxyalkyl group, an aralkyloxyalkyl group, a trityl group, or a tetrahydropyranyl group. 'May be the same or different from each other. R ¹ is a hydrogen atom, carbon number 1
An alkyl group having 10 to 10, an alkenyl group having 2 to 10 carbon atoms,
Alkynyl group having 2 to 10 carbon atoms, phenyl group, (In the above formula, THP is a tetrahydropyranyl group, ^t Bu
Represents a tertiary butyl group, and EE represents an ethoxyethyl group. ). n is 1 or 2. ] The compound represented by the general formula [VI] (In the formula, R ² is an alkyl group having 1 to 10 carbon atoms, an alkylthio group having 1 to 10 carbon atoms, an alkylamino group having 1 to 10 carbon atoms, an alkylsilyl group having 1 to 10 carbon atoms, and 1 to 1 carbon atoms. A group selected from 10 alkyl tin, an alkenyl group having 2 to 10 carbon atoms, an alkynyl group having 2 to 10 carbon atoms, and a cyano group, M ¹ is Li, Na, K, Mg, Ca, Ti,
A metal selected from Zr, Ni, Cu, Zn, Al and Sn or a group containing the metal is shown. ) A nucleophile represented by the general formula [III] (In the formula, X, R ¹ , R ² and n have the same meanings as described above.) A method for producing a substituted cyclopentenone or a substituted cyclohexenone derivative.