JPH0692886A - Production of 6,7-disubstituted-2-hydroxy-3-methylenebicyclo(3.3.0)octanes - Google Patents

Abstract

PURPOSE:To obtain the subject compound, an intermediate for synthesizing a carbacycline useful as a medicine by subjecting a propargylcyclopentane to ring formation reaction in the presence of a specific reducing agent and a specific compound and, as necessary, further to deprotecting reaction. CONSTITUTION:A propargylcyclopentane such as a compound of formula I [R<11> and R<21> are tri(1-7C) hydrocarbon silyl or group to form acetal bond with O of OH; R<3> is H, methyl or vinyl; R<4> is alkyl, alkenyl, etc., which may contain O; (n) is 0 or 1], its enantiomer or their mixture in an arbitrary ratio is subjected to ring formation reaction by using a metal (preferably sodium or lithium) and a compound having pKa >=5 (preferably pKa 8-14) (e.g. trifluoroethanol) preferably at -78 to 0 deg.C for <=1 hour and optionally deprotected to give the objective compound of formula II [R<1> and R<2> are H, tri(1-7C) hydrocarbon silyl, etc.].

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention uses 6,7-disubstituted-2-hydroxy-3-methylenebicyclo, which is useful as a synthetic intermediate for carbacyclins, which is expected to be applied as a drug, using propargylcyclopentanes. [3.3.
0] relates to a method for producing octanes.

[0002]

BACKGROUND OF THE INVENTION Carbacyclin is a prostaglandin in which the 6,9-position oxygen atom of prostaglandin (sometimes abbreviated as PG) I ₂ (PGI ₂ ) which is a physiologically active substance in vivo is substituted with a methylene group. It is a glandin I ₂ analog and is a compound useful as a drug such as an antithrombotic agent because it is chemically stable as compared with natural prostaglandin I ₂ having an enol ether partial structure in the molecule. . Recently, one of the double bond isomers of carbacycline, i.e., 9 (O) -methano-
Δ ^{6 (9} α ⁾ -It was discovered that prostaglandins I ₁ have the strongest inhibitory effect on platelet aggregation among the homologues, and it has been expected to be applied as a drug [Ikegami et al., Tetra. Tedrahedron Letters
s), 33 , 3493 and 3497 (1983))].

Such 9 (O) -methanol Δ ^{6 (9} α
⁾ ― Prostaglandin I ₁ (isocarbacycline)
JP-A-62-61937 discloses a method for producing 6,7-disubstituted-2-hydroxy-3-methylenebicyclo [3.3.0] octanes which are useful as a key intermediate of the above. The outline is as follows.

[0004]

[Chemical 3]

According to this process, allyl alcohol (C) (6,
7-disubstituted-2-hydroxy-3-methylenebicyclo [3.3.0] octane), but the yield during this period is 50%, and half of (A) is lost.

Further, 6,7-disubstituted-2-hydroxy-
The following formula (1) is used as a method for producing 3-methylenebicyclo [3.3.0] octanes.

[0007]

[Chemical 4]

[Wherein R ¹¹ , R ²¹ , R ³ , R ⁴ and n
Is the same as the above definition. ], A method of cyclizing propargylcyclopentane represented by the formula (I) by a reducing agent using an alkali metal or an alkaline earth metal (see JP-A-62-258330). Furthermore, JP-A-63-303962 discloses a method for coexisting an alcohol, particularly t-butanol, in order to further improve the efficiency of the cyclization reaction. These production methods are also useful methods, but there is room for further improvement in yield.

[0009]

The object of the present invention is 9
(O) -Methano-Δ ^{6 (9} α ⁾ -Prostaglandin I ₁
To provide an effective method for producing 6,7-disubstituted-2-hydroxy-3-methylenebicyclo [3.3.0] octanes, which are useful key intermediates of bisphenols (isocarbacyclines) is there.

The present inventors have found that 9 (O) -methano-Δ ^{6 (9} α
⁾ — 6,7-Disubstituted-2-, which is a useful synthetic key intermediate for prostaglandins I ₁ (isocarbacyclines)
As a result of diligent research to find an effective production method for further improving the yield of hydroxy-3-methylenebicyclo [3.3.0] octane, as a result, it was reduced using a specific propargylcyclopentane. Agent and specific pK
By cyclizing with a proton source having a,
The inventors have found that the desired 6,7-disubstituted-2-hydroxy-3-methylenebicyclo [3.3.0] octanes can be efficiently obtained in a high yield, and arrived at the present invention.

[0011]

Means for Solving the Problems That is, the present invention provides the following formula (1):

[0012]

[Chemical 5]

[Wherein R¹¹, R^{twenty one}Are the same or different
Ri (C₁~ C₇) Hydrocarbon silyl group or hydroxy
The group that forms an acetal bond with the oxygen atom of the group is displayed.
I, R ³Represents a hydrogen atom, a methyl group or a vinyl group
And R^FourIs a straight chain or a chain which may contain an oxygen atom.
Chain C₃~ C₈Alkyl group, alkenyl group or ar
Quinyl group; substituted or unsubstituted phenyl group; substituted if
Or unsubstituted phenoxy group; substituted or unsubstituted C₃
~ C_TenA cycloalkyl group; or C₁~ C₆Alkoxy
Group, optionally substituted phenyl group, optionally substituted
Optionally a phenoxy group, optionally substituted C₃~ C_Ten
Straight or branched chain substituted with a cycloalkyl group
C₁~ C_FiveRepresents an alkyl group, and n represents 0 or 1.
You ] And its enantiomers or
A mixture of propargylcyclopenes in any proportion
Tans as a reducing agent and proton source containing metal species
A compound having an active hydrogen of pKa 5 or more and less than 17
Use cyclization reaction and, if necessary, deprotection reaction
The following formula (2) characterized in that

[0014]

[Chemical 6]

[Wherein R ¹ and R ² are the same or different and each represents a hydrogen atom, a tri (C ₁ -C ₇ ) hydrocarbon silyl group,
Alternatively, it represents a group that forms an acetal bond together with an oxygen atom of a hydroxyl group, and R ³ , R ⁴ and n are the same as defined in the above formula (1). ] And the enantiomers thereof or a mixture thereof in an arbitrary ratio, 6,7-disubstituted-2-hydroxy-3-methylenebicyclo [3.3.
0] A method for producing octanes.

In the above formula (1), R¹¹And R^{twenty one}Is the same
One or different, the bird (C₁~ C ₇) Hydrocarbon silyl
Form an acetal bond with the oxygen atom of the group or hydroxyl group
Represents a group to be formed.

Examples of the tri (C ₁ -C ₇ ) hydrocarbon silyl group include tri (C ₁ -C ₄ ) alkylsilyl groups such as trimethylsilyl group, triethylsilyl group, triisopropylsilyl group and t-butyldimethyl group. Group, diphenyl such as t-butyldiphenylsilyl group (C ₁ -C
₄ ) Preferred examples include an alkylsilyl group, a di (C ₁ -C ₄ ) alkylphenyl group such as a dimethylphenyl group, and a tribenzylsilyl group. Tri (C ₁ -C ₄ ) alkylsilyl, diphenyl (C ₁ -C ₄ ) alkylsilyl, phenyldi (C ₁ -C)
₄ ) Alkylsilyl groups are preferable, and t-butyldimethylsilyl group and trimethylsilyl group are particularly preferable.

The group forming an acetal bond with the oxygen atom of the hydroxyl group is, for example, a methoxymethyl group, 1-
Ethoxyethyl group, 2-methoxy-2-propyl group, 2
-Ethoxy-2-propyl group, (2-methoxyethoxy) methyl group, benzyloxymethyl group, 2-tetrahydropyranyl group, 2-tetrahydrofuranyl group, or 6,6-dimethyl-3-oxa-2-oxobicyclo [3.1.0] hex-4-yl group may be mentioned. 2-tetrahydropyranyl group, 2-tetrahydrofuranyl, 1-ethoxyethyl, 2-ethoxy-2-propyl, (2-methoxyethoxy) methyl, 6,6-dimethyl-3-oxa-2-oxobicyclo [3. 1.0]
Hex-4-yl is particularly preferred. Of these, a 2-tetrahydropyranyl group is particularly preferable.

It is to be understood that these silyl groups and the groups forming an acetal bond are hydroxyl-protecting groups. These protecting groups can be easily removed in the final product stage to give free hydroxyl groups useful as drugs. Therefore, the hydroxyl-protecting group having such properties can be used in place of the silyl group or the group forming an acetal bond.

In the above formula (1), R ₃ represents a hydrogen atom, a methyl group or a vinyl group.

In the above formula (1), R^FourContains an oxygen atom
Straight or branched chain C which may be present₃~ C₈Alkyl
Groups, alkenyl groups or alkynyl groups; substituted or
Unsubstituted phenyl group; substituted or unsubstituted phenoxy
Group; substituted or unsubstituted C ₃~ C_TenCycloalkyl
Group; or C₁~ C₆Alkoxy group, even if substituted
Good phenyl group, optionally substituted phenoxy group
Or optionally substituted C₃~ C_TenCycloalkyl
A straight or branched chain C substituted with a group₁~ C _FiveAl
Represents a kill group.

The linear or branched C ₃ -C ₈ alkyl group which may contain an oxygen atom is 2-methoxyethyl group, 2-ethoxyethyl group, propyl group, butyl group,
Pentyl group, hexyl group, heptyl group, 2-hexyl group, 2-methyl-2-hexyl group, 2-methylbutyl group, 2-methylpentyl group, 2-methylhexyl group,
2,2-dimethylhexyl group and the like can be mentioned. Butyl group, pentyl group, hexyl group, heptyl group,
A 2-hexyl group, a 2-methyl-2-hexyl group, a 2-methylbutyl group, a 2-methylpentyl group and a 2-methylhexyl group are preferable. Examples of the linear or branched C ₃ -C ₈ alkenyl group which may contain an oxygen atom include 1-butylvinyl, 2-propylallyl, 2-pentenyl, 4-pentenyl, 2-methyl-3-pentenyl and 4
-Hexenyl, 1,4-dimethyl-3-pentenyl, 5
-Heptenyl, 1-methyl-5-hexenyl, 6-methyl-5-heptenyl, 2,6-dimethyl-5-heptenyl and the like are preferable.

Examples of the straight chain or branched chain C ₃ -C ₈ alkynyl group which may contain an oxygen atom include, for example, 2-
Butynyl, 2-pentynyl, 3-pentynyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl are preferred.

The substituent of the substituted phenyl group, the substituted phenoxy group, or the C ₃ -C ₁₀ substituted cycloalkyl group is, for example, a halogen atom or a protected hydroxyl group (eg, silyloxy group, C ₁ -C ₆ alkoxy group, etc.). , C ₁ ~
Such as C ₄ alkyl group. Examples of the C ₃ -C ₁₀ cycloalkyl group include a cyclopropyl group, a cyclopentyl group, a cyclohexyl group, a cyclohexenyl group,
Examples thereof include a cycloheptyl group, a cyclooctyl group and a cyclodecyl group. A cyclopentyl group and a cyclohexyl group are preferred.

A C ₁ -C ₆ alkoxy group, an optionally substituted phenyl group, an optionally substituted phenoxy group, or an optionally substituted C ₃ -C ₁₀ cycloalkyl group. Chain or branched chain C _{1 to} C
_{In the 5} alkyl group, examples of the C ₁ -C ₆ alkoxy group include a methoxy group, an ethoxy group, a propyloxy group, an isopropyloxy group, a butoxy group, a t-butoxy group and a hexyloxy group. As the optionally substituted phenyl group, optionally substituted phenoxy group, or optionally substituted C ₃ -C ₁₀ cycloalkyl group, the same ones as those mentioned above can be mentioned. Examples of the linear or branched C _{1 to} C ₅ alkyl group include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a t-butyl group, a pentyl group and the like. be able to. Examples of R ⁴ include butyl, pentyl, hexyl,
Heptyl, 2-hexyl, 2-methyl-2-hexyl,
2-Methylbutyl, 2-methylpentyl, cyclopentyl, cyclohexyl, phenyl, phenoxy, cyclopentylmethyl, cyclohexylmethyl groups and the like can be mentioned as preferable ones. In addition, the substituent may be bonded to any position thereof.

In the above (1), n represents 0 or 1.

In the above formula (2), R ¹ and R ²
Are the same or different and each is a hydrogen atom or tri (C ₁ -C ₇ ).
It represents a group that forms an acetal bond together with an oxygen atom of a hydrocarbon silyl group or a hydroxyl group. Here, the bird (C ₁ ~
Examples of the C ₇ ) hydrocarbon silyl group and the group forming an acetal bond together with the oxygen atom of the hydroxyl group include the same groups as those in the above formula (1).

As the metal species of the reducing agent containing the metal species used in the cyclization reaction using the propargylcyclopentane represented by the above formula (1) as a raw material, an alkali metal,
Examples thereof include alkaline earth metals and zinc. Examples of the alkali metal include lithium, sodium and potassium, with sodium and lithium being particularly preferred.

Among the alkaline earth metals, calcium, magnesium and the like can be mentioned as preferable ones. These may be used alone or in combination of two or more. The amount of the alkali metal and / or alkaline earth metal used is 1.0 to 1 mol with respect to 1 mol of the propargylcyclopentane represented by the formula (1).
40.0, preferably 1.2 to 20.0 times by mole.

The alkali metal and / or alkaline earth metal reducing agent is used as an anion radical solution in the cyclization reaction. As a solvent for the anion radical solution, liquid ammonia or naphthalene, 1- (N, N-
Dimethylamino) -naphthalene or 4,4'-di-t
-Ethyl solvents such as diethyl ether and tetrahydrofuran dimethoxyethane containing butyl biphenyl in an equimolar amount or more with the alkali metal or alkaline earth metal are preferred, and among them, naphthalene or 4,4'-di-
Most preferred is tetrahydrofuran containing t-butylbiphenyl. The amount used may be an amount sufficient for the reaction to proceed smoothly, and is usually 1 to 1 of the starting compound.
A volume of 000 times, preferably a volume of 2 to 50 times is used.

In order to effectively carry out this cyclization reaction, a proton source having a specific pKa for trapping the reactive species and leading to a product is required. A compound having active hydrogen is used as the proton source. Preferable compounds as the proton source include phenol, phenol derivatives such as p-methoxyphenol catechol, trifluoroethanol, succinimide, and the like. , Trifluoroethanol and succinimide are preferred. The amount used is 1.0 to 20. per 1 mol of propargyl cyclopentane represented by the formula (1).
It is carried out at 0, preferably 1.5 to 10 times the molar amount.
When the pKa of the proton source is outside this range, active hydrogen is not used in the reductive cyclization reaction, and the alkoxide generated as a result of the reaction acts as a base to abstract the methine hydrogen of the aldehyde substituent of the substrate. Is caused by isomerization and the yield of the compound represented by the formula (2) decreases, which is not preferable.

The reaction temperature is -100 ° C to + 100 ° C, preferably -78 ° C to + 50 ° C, and particularly preferably -78 ° C.
A temperature range of about 0 ° C is adopted. The reaction time varies depending on the reaction temperature, but usually the reaction is completed within 1 hour at -78 ° C to 0 ° C.

Zinc is also preferably used as the metal species used as the reducing agent. The cyclization reaction with zinc is usually carried out in the coexistence of trimethylchlorosilane and a base. The amount of zinc used is 1 to 50 times mol, preferably 10 to 30 times mol, relative to 1 mol of the propargyl cyclopentane represented by the formula (1). Further, zinc activated by hydrochloric acid, copper, silver, mercury or the like is used. Trimethylchlorosilane is used in an amount of 1 to 20 times, preferably 5 to 10 times the mol of the compound represented by the formula (1). As the base, 2,6-lutidine is preferably used. The base is used in an amount of 1 to 10 times, preferably 1 to 5 times the mol of the compound represented by the formula (1).

The product thus obtained is quenched with saturated aqueous ammonium chloride or previously quenched with ammonium chloride, alcohols and the like, and extracted with saturated aqueous ammonium chloride and the like to obtain a crude product. Can be taken out from the reaction system. The crude product can be purified by a purification means such as column chromatography, thin layer chromatography, liquid chromatography, recrystallization and the like, if desired.

The 6,7-disubstituted-2-hydroxy-3-methylenebicyclo [3.3.
[0] In the case where the 7'- and 6-position 3'-position (or 4'-position) of the [0] octane is protected, it can be converted into a free hydroxyl group by deprotecting it if necessary.

When the protecting group for the hydroxyl group is a group which forms an acetal bond with the oxygen atom of the hydroxyl group, for example, acetic acid, a pyridinium salt of p-toluenesulfonic acid or a cation exchange resin is used as a catalyst. , For example, water,
It is preferably carried out by using tetrahydrofuran, ethyl ether, dioxane, acetone, acetonitrile or the like as a reaction solvent. The reaction is usually performed in the temperature range of −78 ° C. to + 50 ° C. for about 10 minutes to 3 days. When the protecting group is a tri (C ₁ -C ₇ ) hydrocarbon silyl group, for example, in the presence of acetic acid, tetrabutylammonium fluoride, cesium fluoride, hydrogen fluoride, pyridine-hydrogen fluoride, It is carried out in a reaction solvent as described above at similar temperatures and for similar times.

In the compounds represented by the above formulas (1) and (2), a cyclopentane ring and a bicyclo [3.
3.0] Octane rings themselves and carbons to which the substituents bonded to those rings are bonded have stereoisomers due to asymmetric ring opening. In the present invention, any stereoisomers are present. Is also included, and a mixture of stereoisomers in any proportion thereof may be used. Further, the compound represented by the formula represents all of these stereoisomers and a mixture of these isomers at an arbitrary ratio, and a compound having a stereostructure represented by the formula is most preferred.

The propargylcyclopentanes represented by the above formula (1) used in this reaction are, for example,
It can be obtained based on the method described in JP-A-1-254635 and other known methods.

Thus, according to the method of the present invention, 6,7-disubstituted-2-hydroxy-3-methylenebicyclo [3.3.
[0] Octanes can be produced in an extremely high yield.

[0040]

The present invention will be described in more detail with reference to Examples and Comparative Examples, but the present invention is not limited thereto.

[0041]

[Example 1]

[0042]

[Chemical 7]

8.33 g (1.2 mol) of metallic lithium and 153.6 g (1.2 mol) of naphthalene were added to 1 liter of distilled tetrahydrofuran (THF), and the mixture was stirred for 2 hours under ice cooling to give a dark green anion radical suspension. A suspension was prepared and cooled to -35 ° C. Here [1a] 5
0.6 g (0.1 mol) and trifluoroethanol 2
A solution of 0 g (0.2 mol) of 1 liter of distilled tetrahydrofuran was cooled to -35 ° C. and added dropwise under pressure of argon gas for 10 minutes using a stainless tube. -35
The mixture was stirred at ℃ for 20 minutes, 50 g of ammonium chloride and 30 ml of ethanol were added to the reaction solution to terminate the reaction, and 1.5 liters of ice water and 1 liter of ethyl acetate were added.
Liquid separation extraction was performed. The aqueous layer was extracted again with 0.5 liter of ethyl acetate. The extract was washed twice with 1 liter of saturated saline, the extract was dried over magnesium sulfate, filtered and concentrated to obtain 200 g of a crude product. This was subjected to silica gel column chromatography to give hexane-ethyl acetate 20:
41.15 g (81 mmo) of [3a] was eluted with the mixed solution of 1.
l) got. Yield 81%.

[0044]

Comparative Example 1 Lithium metal 15 mg and naphthalene 266 mg
Was added to distilled THF (7 ml) and stirred at room temperature for 2 hours to prepare a dark green anion radical solution. This is -50 ℃
After cooling to 50 ° C., a solution of 50 mg of [1a] in 3 ml of THF was added. After 5 minutes, saturated ammonium chloride solution was added to terminate the reaction, extraction was performed with ethyl acetate, the aqueous layer was extracted again with ethyl acetate, the organic layer was washed with saturated brine, dehydrated and dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give crude product 3
46 mg was obtained. This was eluted with a mixed solvent of hexane-ethyl acetate 9: 1 by silica gel column chromatography to obtain 34 mg of [3a]. Yield 67%.

[0045]

[Comparative Example 2]

[0046]

[Chemical 8]

Mineral oil dispersion of lithium (content 25%; containing 1% sodium) 15.3G
550 ml of tetrahydrofuran was added to (552 mmol),
Naphthalene 70.3g (550mmo under ice cooling and nitrogen atmosphere)
l) was added. The mixture was stirred under ice cooling for 2 hours to prepare a dark green anion radical solution. Acetylene aldehyde (21)
25.1 g (50 mmol) and t-butanol 18.7
ml (320 mmol) was dissolved in 120 ml of tetrahydrofuran, cooled to -70 ° C, and then added to the above anion radical solution cooled to -70 ° C. After stirring at -70 ° C for 15 minutes, 50 g of ammonium chloride was added, and ethanol was added until the dark green anion radical disappeared. After adding 900 ml of a saturated aqueous ammonium chloride solution, the mixture was extracted with ethyl acetate (2 x 700 ml). The combined organic layers were washed twice with saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting crude product was separated and purified by silica gel column chromatography to give hexane-
Ethyl acetate = 19: 1 5.34 g (yield 21
%) [(20) α], and hexane-ethyl acetate =
12.95 g (51% yield) of [(2
9) β] was obtained.

[0048]

Example 2

[0049]

[Chemical 9]

Distilled TH of 8.33 g (1.2 mol) of metallic lithium and 153.6 g (1.2 mol) of naphthalene.
The mixture was added to 1 liter of F and stirred for 2 hours under ice cooling to prepare an anion radical suspension, which was cooled to -35 ° C. A solution of 53.4 g (0.1 mol) of [1b] and 20 g (0.2 mol) of trifluoroethanol in 1 liter of distilled THF was cooled to −35 ° C. and added dropwise over 10 minutes. Stir for 20 minutes at −35 ° C., then add ammonium chloride 50
g and 30 ml of ethanol were added to the reaction solution to terminate the reaction, and 1.5 liters of ice water and 1 liter of ethyl acetate were added for liquid separation and extraction. The aqueous layer was extracted again with 0.5 liter of ethyl acetate. The extract was washed twice with 1 liter of saturated saline, dehydrated and dried over magnesium sulfate, filtered and concentrated to obtain 230 g of a crude product. This was eluted with a mixed solvent of hexane-ethyl acetate 20: 1 by silica gel chromatography [3b] 42.35 g (79 mmol).
Got Yield 79%.

[0051]

Examples 3 to 7 and Comparative Examples 3 to 8 In Example 1, the proton source and the reaction temperature are the pKa values shown in Table 1, respectively.
In the same manner as above, except that the reaction is carried out for 20 minutes with metallic lithium / naphthalene (12 times mol used as 1a) as the anion radical solution. 3a] was obtained (Examples 3 to 7, Comparative Examples 3 to 8).

[0052]

[Table 1]

As is clear from Table 1, the use of a proton source having a pKa of 17 or higher or 4.70 or lower has a low yield as compared with the examples. In addition, in Comparative Examples 6 and 7, a large amount of a compound in which the substituent aldehyde was isomerized from α to β was produced.

Claims (10)

[Claims] 1. The following formula (1):[In the formula, R¹¹, R^{twenty one}Are the same or different, and₁
~ C₇) Hydrocarbon silyl group, or oxygen atom of hydroxyl group
R represents a group which together forms an acetal bond, ³Is water
Represents an elementary atom, a methyl group or a vinyl group, R^FourIs oxygen
A straight or branched chain C which may contain atoms₃~ C₈
Alkyl group, alkenyl group or alkynyl group; Substitution
Or an unsubstituted phenyl group; a substituted or unsubstituted phenyl group
Enoxy group; substituted or unsubstituted C₃~ C_TenCycloa
Rukyi group; or C₁~ C₆Alkoxy group, substituted
Optionally substituted phenyl group, optionally substituted phenoxy
Si group, optionally substituted C₃~ C_TenCycloalkyl
A straight or branched chain C substituted with a group₁~ C_FiveAl
Represents a kill group, and n represents 0 or 1. ]]
Compound and its enantiomer or any ratio thereof
Propargyl cyclopentanes, a mixture of
PKa5 or more as a reducing agent and a proton source containing
Cyclize using a compound having an active hydrogen of less than 17
It is characterized in that
The following formula (2)[In the formula, R¹, R²Are the same or different, a hydrogen atom,
Bird (C₁~ C₇) Hydrocarbon silyl group or hydroxyl group
Represents a group that forms an acetal bond with an oxygen atom.
And R³, R^FourAnd n are the same as defined in the above formula (1).
Same. ] And its enantiomers or
6,7-disubstituted-2-hi, which is a mixture of them in any proportion.
Droxy-3-methylenebicyclo [3.3.0] octa
Manufacturing method. 2. The method for producing 6,7-disubstituted-2-hydroxy-3-methylenebicyclo [3.3.0] octanes according to claim 1, wherein the metal species is an alkali metal. 3. The 6,7-disubstituted-2- according to claim 2, wherein the alkali metal is sodium and / or lithium.
Process for producing hydroxy-3-methylenebicyclo [3.3.0] octanes. 4. The method for producing 6,7-disubstituted-2-hydroxy-3-methylenebicyclo [3.3.0] octane according to claim 1, wherein the metal species is an alkaline earth metal. 5. The alkaline earth metal is calcium and / or
Or magnesium, 6,7-disubstituted-2-hydroxy-3-methylenebicyclo [3.3.
0] A method for producing octanes. 6. The method according to claim 1, wherein the metal species is zinc.
Process for producing 7-disubstituted-2-hydroxy-3-methylenebicyclo [3.3.0] octanes. 7. The p of a compound used as a proton source
6,7-disubstituted- according to claim 1, wherein Ka is 8-14.
2-hydroxy-3-methylenebicyclo [3.3.0]
Octane production method. 8. The 6,7-disubstituted-2-hydroxy-3-methylenebicyclo [3.3.7] according to claim 7, wherein the compound used as the proton source is trifluoroethanol.
0] A method for producing octanes. 9. The 6,7-disubstituted-2-hydroxy-3-methylenebicyclo [3] according to claim 7, wherein the compound used as the proton source is phenol and / or phenol optionally having a substituent. .3.0] Method for producing octanes. 10. The 6,7-disubstituted- according to claim 7, wherein the compound used as the proton source is succinimide.
2-hydroxy-3-methylenebicyclo [3.3.0]
Octane production method.