JPH0637431B2 - Method for producing bicyclo (3.3.0) octanes - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION <Industrial field of application> The present invention relates to a novel method for producing bicyclo [3.3.0] octanes.

More specifically, the present invention relates to 2-alkoxycarbonyl-3-
By using a substituted cyclopentanone compound as a raw material and subjecting it to the conditions of an intramolecular cyclization reaction, bicyclo [3.3.
0] relates to a method for efficiently producing oct-6-en-2-ones.

<Prior art and its problems> Bicyclo [3.3.0] octanes are useful intermediates in the production of prostaglandins useful as pharmaceuticals [EJCorey et al., Journal of Organic Chemistry (J.Org.Che
m.), 40 , 2265 (1975)]. Conventionally, the following methods are known as methods for obtaining these compounds.

(i) A method in which a 3-substituted cyclopentanone compound is used as a starting material, a vinyl cyclopropane compound is passed through, and this is subjected to isomerization and cyclization by heat (see the above document). (ii) A diazoketone compound as a starting material Method of obtaining via cyclopropane body [T. Hudliskyi (T.Hu
dlicky) et al., Journal of Organic Chemistry (J.Org.Ckem.), 45 , 5020 (1980)].

(iii) A method of obtaining a vinylcyclopropane derivative which can be activated with a base [S. Danishefsk (S. Danishefsk
y) et al., Journal of the Chemical Society, Chemical Communication (JCSChem.Com)
m.), 7 (1975)].

(iv) A method for obtaining tricyclo [4.2.0.0 ² , ^4, ] octane by solvolysis [LA P-Weighty (L.
A.Paquette) et al., Journal of the American
Chemical Society (J.Amer.Chem.Soc.), 96 , 489
2 (1974)].

(v) A method of obtaining a bicyclo [3.2.0] heptane by a ring expansion reaction using diazomethane as a starting material [dia.
JDRoberts et al., Journal of the Organic Chemistry (J.Org.Chem.), 4
6 67 (1981), JK White Cell (JKWhite)
sell), Tetrahedron, 37 , 4451 (198
1)].

(vi) A method of obtaining a 2-methoxycarbonyl-3-substituted cyclopentanone body as a starting material by a rearrangement reaction via a vinylcyclopropane body [Ikegami et al., The Pharmaceutical Society of Japan No. 10]
5th Annual Meeting Abstracts P609 (1985)].

These methods have the following drawbacks as manufacturing methods.

That is, the first method requires a high vacuum of 0.2 mmHg and a high temperature of 600 ° C. in the rearrangement reaction of the vinylcyclopropane compound, and the second method requires the use of an unstable diazoketone compound as a starting material in the starting material. I won't. Further, in the third method, the starting material is a relatively complicated compound, and therefore, a multi-step process is required for producing the compound. In the fourth method, the starting material is unstable as a compound. Moreover, there is a drawback that it is difficult to obtain easily.
In the method of 1, the ring-expansion reaction using diazomethane has a drawback in that two structural isomer products, which are difficult to separate, are provided. Further, the sixth method is characterized by using a 2.3-disubstituted cyclopentanone compound as a starting material, but has a chemical structural restriction that the 3-position substituent must be a cis-double bond. There are difficulties.

<Purpose of the Invention> The present invention is based on the above technical background and is based on bicyclo [3.3.0].
Efficient method for producing octanes, using a readily available starting compound, efficiently, that is, in a short stage and without being affected by the double bond steric structure as in the sixth method The present inventors have conducted intensive studies on a method for producing bicyclo [3.3.0] octanes. As a result, by using a 2-alkoxycarbonyl-3-substituted cyclopentanone compound as a starting material compound and subjecting the compound to an intramolecular cyclization reaction, the stereostructure of the double bond of the substituent at the 3-position is affected. The present invention has been completed and found that bicyclo [3.3.0] octanes can be easily produced at once.

DISCLOSURE OF THE INVENTION That is, the present invention provides the following formula [Ia]. Characterized in that the cyclopentanone compound represented by the formula [II] is treated with an alkali metal hydride in an inert medium.
-A] [In the formula, R is the same as the above definition. ] It is a manufacturing method of the bicyclo [3.3.0] octane represented by. In the above formulas [I] and [II], in the above formulas [I], [II] and [III], R represents a lower alkyl group having 1 to 6 carbon atoms and a lower 2-alkenyl group having 3 to 6 carbon atoms. . As the lower alkyl group having 1 to 6 carbon atoms, methyl, ethyl, n-propyl, isopropyl, n-
Butyl, SEC-butyl, t-butyl, n-pentyl, n
-Hexyl and the like can be mentioned. Examples of the lower 2-alkenyl group having 3 to 6 carbon atoms include 2-propenyl, 2-butenyl, 2-, methyl-2-propenyl, 2-pentenyl, 2-hexenyl and the like. Of these, a lower methyl group is a special methyl or ethyl group,
A 2-propenyl group is particularly preferable as the lower 2-alkenyl group.

X is a halogen atom, and examples thereof include a chlorine atom, a bromine atom and an iodine atom, and a bromine atom is particularly preferable.

The 2-alkoxycarbonyl-3-substituted cyclopentanone compound of the above formula [I] used as a starting material can be easily obtained as follows. That is, the compound [I] was added to 2-alkoxycarbonyl-2-cyclopentenone, Ikegami et al.
J. Corey), an organoaluminum compound or an organocopper compound is conjugated and added, and if necessary, after reduction, deprotection, and then halogenation of the hydroxyl group in the substituent at the 3-position. [Ia] can be obtained. [Ikegami et al., Proceedings of the 105th Annual Meeting of the Pharmaceutical Society of Japan P609
(1985) and EJ Corey (EJCorey)
J. Org. Chemistry, 40 , 2265 (1975)].

The desired bicyclo [3.3.0] octanes [II-a] are produced by treating the cyclopentanone compound represented by the above formula [Ia] with an alkali metal hydride in an inert medium. The inert organic medium used is preferably an aprotic organic medium, for example, an ether organic medium such as ethyl ether, isopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diglyme, or a polar organic medium such as dimethylformamide or dimethylsulfoxide. Used. The cyclization reaction is initiated by the addition of alkali metal hydride. Alkali metals include lithium, sodium and potassium, any of which can be used to advantage in combination with the medium used. The amount of alkali metal hydride used is 0.1 to 20 times, preferably 1.5 to 5.0 times the mol of the raw material of the formula [Ia]. The reaction is -80 ℃ to 30 ℃
Done in.

The amount of the inert organic medium used is 1 part to 1 with respect to the raw material.
00 parts, preferably 3 to 10 parts are used. The reaction is usually completed in 1 to 10 hours. After the reaction, the reaction solution is neutralized with acidic water and then treated by a usual method, and the crude product can be purified by a purification means such as column chromatography, thin layer chromatography or liquid chromatography. . The product is a compound of the above formula [Ia] and the following formula [III] depending on the combination of the alkali metal hydride and the inert organic medium used. [In the formula, R is the same as the above definition. ] The compound represented by each is mainly obtained. For example, in the system of lithium hydride and tetrahydrofuran, the main product is the cyclopentanone body represented by the above formula [Ia], and in the system of potassium hydride and dimethylformamide, the main product is the above formula [III]. Bicyclo (3.
1.0] Hexane.

The product obtained by the above reaction can be further converted into the target bicyclo [3.3.0] octanes [II-b] by heating with lithium halide in a polar inert medium. Examples of the polar inert medium used at this time include dimethylformamide, dimethylsulfoxide, dimethylacetamide, sulfolane and the like, and dimethylformamide is particularly preferable. The lithium halide used is preferably lithium bromide or lithium iodide, and the amount thereof is 0.5 to 20 times molar equivalent, preferably 1.0 to 5 times molar equivalent, based on the raw material. The amount of the polar inert medium used is 1 part to 100 parts, preferably 3 parts to 10 parts, based on the raw material. The desired product differs depending on the nature of the ester residue and the heating time, and is, for example, a cyclopentanone of the formula [Ia] or a formula [III]
When R is a methyl group in the bicyclo [3.1.0] hexane body of the above, the product is the cyclopentanone body of the formula [II-b] and A is a hydrogen atom, Or a compound of the formula [III] in which R is an ethyl group or a 2-propenyl group, the product is a bicyclo [3.3.0] octane of the formula [II-b] and A is COOR.
The heating temperature is usually 80 ° C. or higher, and the higher the reaction temperature, the shorter the reaction time to reach the product.

Thus, the bicyclo [3.3.
[0] Octanes can be easily and efficiently produced from a starting material, a compound represented by the formula [Ia].
The feature of the present invention is that bicyclo [3.3.0] octanes can be obtained all at once from a cyclopentanone compound having a halogenated substituent at the 3-position, and its industrial significance is great.

Hereinafter, the present invention will be described with reference to examples, but the present invention is not limited thereto.

Example 1 Lithium hydride 200 mg (2
(5 mmole), THF1m1 is added, the atmosphere is replaced with argon, and the mixture is cooled to -10 ° C with stirring.

Starting material (1) 3.25g (12.5mmole) there THF15 there
It was dissolved in m1 and transferred to the reaction solution using a cannula. After 4 hours, add 100mg (12.5mmole) of lithium hydride and add 5 ℃.
Left for 18 hours.

To the reaction solution was added 100 ml of ether and 7.5 ml of 10% hydrochloric acid under ice cooling, extracted twice with an organic solvent (ether: pentane = 5: 1) (250 ml, 100 ml), washed twice with 50 ml of saturated saline solution, and dried with sodium sulfate. After that, concentrate (crude yield 6.7
g). Chromatographic purification using 200 g of silica gel BW-820 (elution solvent, ether: pentane = 1: 2), Rf
This gave 1.52 g (yield: 67.3%) of a yellow oily substance (2) showing a yellowish green color when treated with anise showing 0.67.

The spectral data are as follows.

IR (neat): 1745,1725,1255 cm ^{-1 1} HNMR (CDCl ₃ ): δ 1.88-2.58 (4H, m), 2.76,3.13 (2H, two ddd, J each = 18,4,
2H _Z , CH = CHCH H ₂ ), 3.74 (3H, s), 3.74 (1H, br s, CH ₂ C H C
=), 5.48-5.78 (2H, m, C H = C H ). MS m / z: 181 [(M + 1) ⁺ ], 180 (M ⁺ ), 152,149,124,93. Examples 2 to 9 Using the same formulation as in Example 1, various conditions for base, solvent and reaction time were used. The reaction was performed below and the results shown in the table below were obtained.

Reference example 1 2.3 g of 3-methoxy-3-methyl-1-butyne in a reaction tube
(23.4mmole) is taken and anhydrous THF1 is added under argon atmosphere.
It was dissolved in 0 ml. 15.0 ml (23.8 mmole) of a hexane solution of 1.59 Mn-butyllithium was added dropwise with stirring under ice cooling.
Stir for 0 minutes. 10 ml of anhydrous THF containing 4.5 g (23.4 mmole) of cuprous iodide was added to this solution under ice-cooling using a cannula.
The 3-methoxy-3-methyl-1-butynyl copper reagent was prepared by adding to the suspension solution with stirring.

5.7 g (21.2 mmole) of 3-tetrahydropyranyloxy-1-iodo-1-propene was placed in a reaction tube and dissolved in anhydrous THE 15 ml under an argon atmosphere. With stirring at -78 ° C, 18.4 ml of a 2.3 M t-butyllithium pentane solution (2
1.3 mmole) was added dropwise, and the mixture was stirred for 1 hour. A solution of 3-methoxy-3-methyl-1-butynylcopper reagent prepared in this reaction solution was added using a cannula, and then a starting material (6) 2.5 g (17.7 mmole) of anhydrous THF 10 ml solution was added. added. The temperature was raised to -35 ° C over 30 minutes, and at this temperature, 1
Stir for 5 minutes. The reaction mixture was stirred vigorously under ice cooling AcOEt
8 ml, hexane 4 ml, saturated ammonium chloride water 30 ml, and ammonia water 4 ml were poured into a two-layer solution and stirred for 30 minutes. 60 ml of an organic solvent (ethyl acetate: hexane = 10: 1) was added for extraction, and saturated aqueous ammonium chloride solution: aqueous ammonia = 5:
It was washed 4 times with 30 ml of an aqueous solution of 1 and then with 30 ml of saturated saline and dried over sodium sulfate.

After drying, the solvent was distilled off (crude yield 5.4 g), and silica gel B was used.
Chromatographic purification using 250 g of W-820 (elution solvent,
AcOEt: hexane = 1: 3). As a result, 2.2 g of a pale yellow oily substance (7) showing an Rf value of 0.45 by TLC (ethyl acetate: hexane = 1: 1) and showing a dark blue color when treated with anise.
(Yield 45%) was obtained.

The spectrum data of this product are as follows.

IR (neat): 1755,1725,1270,1200,1115,1025,905,870,815 cm ^-1 . ¹ H NMR (CDCl ₃ ): δ 1.38-2.00 (7H, m), 2.02-2.62 (3H, m) 2.96,3.02 (1H, two d,
_{J = 12Hz, COC H COOCH 3} , CiS / trans = 1/3), 3.32-
3.69 (1H, m, C H CH =), 3.76,3.79 (3H, two s, cis / tr
ans = 1/3), 3.69-4.42 (4H, m), 4.58-4.72 (1H, br s, OC H O),
5.58-5.94 (2H, m, C H = C H ).

MS m / z: 282 (M ⁺ ), 223,198,181,149,121 Reference Example 2 1.95 g (6.9 mmole) of starting material was placed in a 50 m1 eggplant flask equipped with a Dimroth condenser, and acetic acid: water: TH
F = 3: 1: 1 10 ml was dissolved and stirred at 50 ° C. for 2 days. After confirming the completion of the reaction, neutralize by adding 10 ml of 10% NaOH,
It was extracted 3 times with 70 ml of an organic solvent (ethyl acetate: hexane = 10: 1), washed with 10 ml of saturated saline and dried over sodium sulfate.

After drying, the solvent was distilled off (crude yield 1.3 g), and silica gel B was used.
Cutnato was purified using 50 g of W-820 (elution solvent, ethyl acetate: hexane = 1: 1.5). As a result, TL
A yellow oily substance (8) showing an Rf value of 0.15 with C (ethyl acetate: hexane = 1: 1) and showing a deep blue color when treated with anise was added to 0.
88 g (yield 64%) was obtained.

The spectrum data of this product are as follows.

IR (neat): 3425,1755,1725,1275,1010,983 cm ^-1 . ¹ H NMR (CDCl ₃ ): δ 1.44-1.96 (2H, m), 2.04-2.58 (3H, m), 2.99,302 (1H, two d,
J ＝ 12Hz each, COC H COOCH ₃ , cis / trans ＝ 1/3), 3.52-3.82
(1H, m, C H CH ＝), 3.76,3.78 (3H, two s, cis / trans ＝ 1 /
3), 4.06-4.36 (2H, m, C H ₂ O), 5.32-6.0 (2H, m, C H C H ).

MS m / z: 198 ( ⁺ ), 180,167,148,135,120.

Reference example 3 Starting material (8) 0.85 g (4.3 mm
ole), 20 ml of anhydrous benzene is added, the atmosphere is replaced with argon, and the mixture is cooled to 5 ° C. with stirring. There pyridine 0.
66 g (8.4 mmole), phenyl chlorocarbonate 0.99 g (6.
3mmole) is added and left for 10 minutes. After standing, the reaction mixture was ice-cooled, 1 piece of ice was added and stirred for 10 minutes, 8 ml of water was added and extracted with 20 ml of an organic solvent (ethyl acetate: hexane = 10: 1) 5% HCl 6 ml, saturated sodium bicarbonate water 6 ml, saturated Salt water 6m1
It was washed with and dried over sodium sulfate.

After drying, the solvent was distilled off (1.4 g of crude product), and chromatographic purification was performed using 70 g of silica gel BW-200 (elution solvent,
Ethyl acetate: hexane = 1: 5). As a result, TL
C. (Ethyl acetate: hexane = 1: 1) gave a yellow oily substance (3) which had an Rf value of 0.45 and exhibited a deep blue color when treated with anise.
2 g (yield 88%) was obtained.

The spectrum data of this product are as follows.

IR (neat): 1755,1725,1585,1240,1205,975,775 cm ^-1 . ¹ H NMR (CDCl ₃ ): δ 1.48-1.92 (1H, m), 2.02-2.59 (3H, m), 2.99,3.05 (1H, two
d, J ＝ 12Hz each, COC H COOCH ₃ , cis / trans ＝ 1/3), 3.45-3.7
7 (1H, m, C H CH ＝), 3.75,3.77 (3H, two s, cis / trans ＝ 1 /
3), 4.64-5.15 (2H, m, C H ₂ O), 5.47-6.07 (2H, m, C H C H ), 7.11-
7.55 (5H, m).

^{MS m / z: 181 (+} -OCOOC 6 H 5), 149,121.

Reference example 4 2.5 g of the starting material (8 ') (12.
5 mmole) and dissolve with 20 ml of methylene chloride. 3.67 g of triphenylphosphine (14.
0mmole) and 4.65 g (14.0mmole) of carbon tetrabromide are added.

After 30 minutes, 100 ml of pentane is added to the reaction solution to precipitate unnecessary components (mainly a pale yellow viscous oily substance), which is then filtered and concentrated. Concentrate the organic solvent (ether:
250 ml of pentane = 1: 5) was added, and unnecessary components (mainly white solid components) were precipitated to over-concentrate cotton thread, and this operation was repeated twice. However, as a result of an experiment carried out later, it was found that it was not necessary to repeat the procedure if white turbidity was not observed in the product after concentration.

As a result of the above, TLC (ethyl acetate: hexane = 1: 2)
Rf value of 0.7 and anise treatment gave a colorless transparent oily substance (1) of green color, having a crude weight of 6.0 g.

The spectral data are as follows.

^{_{IR (CHCl 3): 1750,1720,1200,720cm -1}} . ¹ H NMR (CDCl ₃ ): δ 1.54-2.02 (1H, m), 2.20-2.62 (3H, m), 2.97, (1H, d, J = 12H
z, COC H COOCH ₃ , 3.36-3.74 (1H, m, C H CH =), 3.75 (3H, s),
3.95 (1H, dd, J = 10,8Hz, CHC H HBr), 4.15 (1H, dd, J = 10,9H
z, CHC H HBr), 5.47 (1H, dd, J = 10,10Hz, C H = CHCH ₂ Br), 5.87
(1H, dt, J = 10,8Hz, CH = C H H ₂ Br).

MS m / z: 263,261 (M ⁺ ), 181,149,121.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (56) References Tetraheclron Letters, Vol. 27, No. 25, 2889-2892, published in 1986 Proceedings of the 105th Annual Meeting of the Pharmaceutical Society of Japan, 609, published in 1985

Claims (5)

[Claims] 1. The following formula [I-a]: Characterized in that the cyclopentanone compound represented by the formula [II] is treated with an alkali metal hydride in an inert medium.
-A] [In the formula, R is the same as the above definition. ] The manufacturing method of the bicyclo [3.3.0] octane represented by. 2. The method for producing bicyclo [3.3.0] octanes according to claim 1, wherein the alkali metal hydride is lithium hydride or sodium hydride. 3. The method for producing bicyclo [3.3.0] octanes according to claim 1 or 2, wherein the inert medium is dimethylformamide or dimethylsulfoxide. 4. The method for producing bicyclo [3.3.0] octane according to claim 1 or 2, wherein the inert medium is an ether. 5. The process for producing bicyclo [3.3.0] octanes according to any one of claims 1 to 4, wherein X is a bromine atom.