JPH07285893A - New process for producing bicyclo(4,3,0) nonanes and its new synthetic intermediate - Google Patents

Abstract

PURPOSE:To provide a single-stage process for easily producing a bicyclo[4,3,0]nonane compound giving a CD ring of vitamin D or steroid by using a specific process for the radical cyclization of a specific chain compound easily synthesizable from easily available raw materials. CONSTITUTION:This bicyclo[4,3,0]nonane compound of formula II is produced by reacting a compound of formula I (R<1> to R<4> each is an alkyl, an aryl, etc.; X is a radical elimination group) with a hydrogenated trialkyltin or a hydrogenated triaryltin (preferably hydrogenated tributyltin) as a radical generator in the presence of a radical initiator (e.g. azobisisobutylonitile) usually at 60-100 deg.C, thereby radically cyclizing the starting compound. The compound of formula I wherein R<1> to R<3> each is methyl, R<4> is acetyl and X is I is a new substance and is producible e.g. by reacting a compound of formula III with a 2,2-dialkoxy- THF of formula IV (R is an alkyl), reacting the reaction product with methyllithium and substituting the terminal hydroxyl group of the product with the group X.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel method for producing bicyclo [4,3,0] nonane which can be used as a transindane skeleton constituting the CD ring of vitamin D and steroids, and a novel synthetic intermediate thereof. .

[0002]

2. Description of the Related Art Vitamin D derivatives and various steroids have been synthesized as physiologically active substances by various methods. One of the effective methods of this synthesis is to divide the target compound into several fragments, The convergent method of separately synthesizing and finally binding is widely adopted.

One of the major problems in synthesizing vitamin D derivatives and steroids by the convergent method is
The point is how to efficiently synthesize the CD ring.

[0006] The conventional methods of synthesizing a CD ring can be roughly classified into two. One is to cyclize a chain compound in one step to synthesize bicyclo [4,3,0] nonane having the same transindane skeleton as that of the CD ring (KA Parker et al.,
J. Org. Chem. , 4369 (1987);
Hatakeyama et al. J. Chem.
Soc. Chem. Commun. , 1893 (198
9) etc.). In this case, there is an advantage that various derivatives can be synthesized by synthesizing a linear compound having a polyfunctional group. On the other hand, first synthesize C ring or D ring,
Further, the remaining D ring or C ring is sequentially synthesized to produce bicyclo [4,4]
3,0] nonanes are synthesized (R.
A. Micheli et al. J. Org. Ch
em. 40 (6), 675 (1975); Suz
uki et al. J. Chem. Soc. Che
m. Commun. , 724 (1988); C.I. H. H
eastcock et al. J. Org. Che
m. , 4923 (1986)). In this case, there is an advantage that the stereoscopic arrangement of the condensed ring portion can be controlled at each stage.

[0005]

However, when the chain compound is closed in one step to synthesize the CD ring of a vitamin D derivative or steroid by the convergent method, the [4,3,0] -bicyclo ring is used. There is a problem that it is very difficult to synthesize a ring-closing precursor to obtain a compound having a unique structure, and the number of steps is long and the total yield is low. In addition, C ring or D ring is first synthesized,
Further, when the remaining D ring or C ring is sequentially synthesized to synthesize the CD ring, the number of steps becomes long and the total yield becomes low.

The present invention is intended to solve the above problems of the prior art, and bicyclo [4,3,0] nonanes which become the CD ring of vitamin D derivatives and steroids by the convergent method. In producing the compound, a chain compound that can be relatively easily synthesized from easily available raw materials is used as a ring-closing precursor, and this is subjected to ring-closing in one step to obtain the desired bicyclo [4,3,0] nonanes. The purpose is to make it easy to obtain.

[0007]

DISCLOSURE OF THE INVENTION The present inventor has prepared a compound of formula (2) which can be synthesized relatively easily from a citral derivative

[0008]

[Chemical 10] (In the formula, R ¹ , R ² , R ³ and R ⁴ are each independently an alkyl group such as methyl and ethyl; an aryl group such as a phenyl group; a hydroxyalkyl group such as 1-hydroxyethyl and hydroxymethyl; It is an alkylcarbonyl group such as an acetyl group and a propionyl group, and X is a radical leaving group that generates and leaves a halogen atom such as iodine and bromine, and a radical such as phenylselenium.)
In order to complete the present invention, it was found that the chain compound of (1) reacts with a trialkyltin hydride or a triaryltin hydride to perform a radical ring closure in one step to give a bicyclo [4,3,0] nonane. I arrived.

That is, the present invention uses the formula (1)

[0010]

[Chemical 11] (In the formula, R ¹ , R ² , R ³ and R ⁴ are as defined in the formula (2).) In the method for producing the compound of the formula (2), a radical initiator A process for producing a compound of the formula (1) is provided by reacting a trialkyltin hydride or a triaryltin hydride as a radical generator in the presence of the compound to carry out a radical ring closure reaction.

In the following, the compound of formula (3), which is easily obtained by reacting citral with a Grignard reagent such as methylmagnesium bromide, is used as a starting material, and the total synthesis of the compound of formula (1) is performed using R ¹ , R ² and R ³ are methyl groups, R ⁴ is an acetyl group, and X is iodine, and will be described according to the following reaction scheme.

[0012]

[Chemical 12] Step a First, the compound of formula (3) obtained in one step by reacting citral with a Grignard reagent such as methylmagnesium bromide is reacted with a cyclic orthoester body represented by formula (10) to undergo Claisen rearrangement. To form a compound of formula (6).

When carrying out this Claisen rearrangement reaction, the amount of the cyclic orthoester compound may be 1 mol times or more of the compound of the formula (3), particularly preferably about 5 mol times. As the acid catalyst, organic acids such as p-toluenesulfonic acid and heptanoic acid can be used, and heptanoic acid can be particularly preferably used.

As the solvent, halogenated hydrocarbons such as methylene chloride and dichloroethane, hydrocarbons such as hexane, aromatic hydrocarbons such as toluene and xylene,
Ethers such as diethyl ether can be used, and xylene can be particularly preferably used.

The reaction temperature is preferably 100 ° C. or higher, and particularly preferably around 160 ° C. The reaction time varies depending on the reaction temperature and the like, but is usually about 1 hour.

Step b The compound of formula (6) obtained in step a is reacted with methyllithium to form the compound of formula (7) with ring opening of the lactone ring moiety.

In this reaction, hydrocarbons such as hexane, aromatic hydrocarbons such as toluene and xylene, ethers such as diethyl ether and the like can be used as a solvent, and tetrahydrofuran is particularly preferably used. .

The amount of methyllithium used is preferably about 1 mol times that of the compound of formula (6). Reaction temperature is usually -10
The temperature is from 0 ° C to 30 ° C, preferably -78 ° C.
The reaction time varies depending on the reaction temperature and the like, but is usually about 10 minutes.

Step c The compound of formula (7) obtained in step b is reacted with phosphine and iodine to substitute the hydroxyl group with iodine to form the compound of formula (4) or formula (5).

In this substitution reaction, halogen-based hydrocarbons such as methylene chloride and dichloroethane, hydrocarbons such as hexane, aromatic hydrocarbons such as toluene and xylene can be used as a solvent, and it is particularly preferable. Can use benzene.

As the phosphine, an arylphosphine such as triphenylphosphine and an alkylphosphine such as tributylphosphine can be used, and preferably triphenylphosphine is used. The amount of the phosphine used may be 1 mol times or more of the compound of the formula (7), and usually 2 mol times to 3 mol times is preferable.

The amount of iodine used is 1 for the compound of formula (7).
The molar ratio is not less than 2 times and is preferably 3 times or more.

The reaction temperature varies depending on the phosphine used and the like, but is usually in the range of 0 ° C to 50 ° C, preferably 20 ° C to 30 ° C. The reaction time varies depending on the reaction temperature and the amount of iodine used, but is usually about 20 minutes.

Step d The compound of formula (4) or formula (5) obtained in step c, which is included in the compound of formula (2), is a trialkyl hydride as a radical generator in the presence of a radical initiator. Formula (8) included in the compound of formula (1) is obtained by reacting tin or triaryltin hydride to perform a radical ring closure reaction.
Alternatively, it forms a compound of formula (9).

The reaction route of this radical ring closure reaction is not clear, but it can be estimated as follows.

That is, first, a radical is generated from the radical initiator, and the radical reacts with the radical generator,
Trialkyltin radicals or triaryltin radicals are formed. Then, the tin radical abstracts iodine. An unpaired electron pair is formed in the part where iodine is extracted, and this unpaired electron pair attacks a spatially close double bond in the molecule to form a 5-membered ring, and at the same time, the double bond becomes It is considered that the unpaired electron pair moves, and the unpaired electron pair attacks the remaining double bond to form a 6-membered ring.

In this radical ring closure reaction, hydrocarbons such as hexane and aromatic hydrocarbons such as toluene and xylene can be used as a reaction solvent, and preferably benzene can be used.

As the radical generator, trialkyltin hydride such as tributyltin hydride or triaryltin hydride such as triphenyltin hydride is used. Preferably tributyltin hydride can be used.

The amount of the radical generator used may be 1 mol times or more of the compound of the formula (4) or (5), and usually 2 mol times to 3 mol times is preferable. Azobisisobutylnitrile or the like is used as a radical initiator.

The amount of the radical initiator may be a catalytic amount, but it is usually used in an amount of about 0.5 mol. Reaction temperature is from 50 ℃ to 20
It is preferably carried out in the range of 0 ° C, usually 60 ° C to 1
Perform at 00 ° C.

As a specific operation example of the radical cyclization reaction, a solution prepared by dissolving 1 mmol of a substrate in a solvent of about 60 ml is added to a mixture of about 50 ml of a solvent containing a radical generator and a radical initiator at a predetermined temperature. It can be illustrated that the solution is gradually dropped. The reaction time varies depending on the reaction temperature, the concentration of the substrate, the concentration of the radical generator, the concentration of the radical initiator, the type of the substrate, etc., but is usually about 1 hour.

Compounds of the formula (2) and compounds of the formula (1) other than when R ¹ , R ² and R ³ are methyl groups, R ⁴ is an acetyl group and X is iodine Can be obtained by introducing a desired substituent into any of the compounds of formula (3) to formula (9) by a known method.

The present invention has been described above by taking the compound of the formula (3) as a starting material and taking the total synthesis of the compound of the formula (1) as an example. The compounds of the formulas (4) to (7) mentioned therein are mentioned above. Are novel, and both are bicyclo [4,3, which form the CD ring of vitamin D derivatives and steroids.
[0] It is very useful as a synthetic intermediate for nonanes. The compounds of formulas (8) and (9) are vitamin D
It is a novel bicyclo [4,3,0] nonane which becomes the CD ring of derivatives and steroids.

[0034]

In the present invention, the chain compound of formula (2) is
Used as a ring closure precursor. Therefore, by reacting with a trialkyl tin hydride or a triaryl tin hydride to carry out a radical ring closure reaction, bicyclo [4,3,1]
[0] Nonanes can be converted. Further, the compound of formula (2) can be easily obtained from citral in a relatively short step. Therefore, when a CD ring of a vitamin D derivative or a steroid is produced by the convergent method, a chain compound as a ring-closing precursor is ring-closed in one step to synthesize a desired bicyclo [4,3,0] nonane. In this case, the present invention can be applied particularly advantageously.

[0035]

The present invention will be described in more detail below with reference to examples.

Example 1 (Step a) 653.7 mg of the compound of the formula (3) and 10 ml of xylene were charged into a reactor and dissolved. 747 mg of the compound of formula (10) and a catalytic amount of heptanoic acid were added to this solution, and the mixture was stirred at 160 ° C. for 30 minutes. Then, ethanol generated in the reaction system was distilled off together with xylene. To this solution was again added 747 mg of the compound of formula (10), catalytic amounts of heptanoic acid and 2 ml of xylene, and the mixture was heated to 160 ° C
And stirred for 30 minutes.

After completion of the reaction, the reaction solution was returned to room temperature, poured into saturated multistory water, and extracted with diethyl ether. The obtained diethyl ether layer was washed with saturated saline and then dried over anhydrous magnesium sulfate. After separating the solid matter by filtration, the solvent was distilled off from the filtrate under reduced pressure to obtain an oily crude product. This is subjected to silica gel column chromatography (5%
Ethyl acetate-hexane solution) to give an oily compound 59
6 mg was obtained.

The oily compound was identified as the compound of the formula (6) by the following identification data (yield: 65).
%).

Identification data IR (cm ^-1 ): 3422, 2926, 1703,
1450, 1378, 1355, 1160, 1055
979; ¹ H-NMR (270 MHz, CDCl ₃ , ppm):
5.34-5.49 (m, 2H), 5.00-5.2
1 (m, 1H), 4.05-4.26 (m, 1H),
2.42-2.48 (m, 1H), 1.70-2.42
(M, 6H), 1.68 (s, 3H), 1.59 (s,
3H), 1.08 (s, 3H).

Example 2 (Step b) Compound 17 of formula (6) obtained in Example 1
Charge 6.8 mg and tetrahydrofuran into the reactor,
Dissolved. This solution was cooled to −78 ° C., 1.19N methyllithium-diethyl ether solution was added dropwise, and 1
Stir for 0 minutes.

After completion of the reaction, the reaction solution was returned to room temperature, poured into a saturated aqueous solution of ammonium chloride and extracted with diethyl ether. The obtained diethyl ether layer was washed with saturated saline and then dried over anhydrous magnesium sulfate. After filtering off the solid matter, the solvent was distilled off from the filtrate under reduced pressure to obtain an oily crude product. This was purified by silica gel column chromatography (10% ethyl acetate-hexane solution),
141.6 mg of an oily compound was obtained. The oily compound was identified by the following identification data to be the compound of formula (7) (yield 75%).

Identification data IR (cm ^-1 ): 2916, 1765, 1451, ¹
975, 1196, 1034, 978; ¹ H-NMR (270 MHz, CDCl ₃ , ppm):
5.44 (d, 1H, J = 15.7 Hz), 5.31
(Dq, 1H, J = 6.0 Hz, J = 15.7 Hz),
4.95-5.10 (m, 1H), 3.40-3.60
(M, 2H), 2.67 (dd, 1H, J = 2.3H
z, J = 11.5 Hz), 2.14 (s, 3H), 1.
81-1.98 (m, 2H), 1.67-1.71.
(M, 6H), 1.58 (s, 3H), 1.21-1.
52 (m, 4H), 0.98 (s, 3H); ¹³ C-NMR (67.8 Hz, CDCl ₃ , pp.
m): 213.9, 136.82, 131.32, 1
24.17, 123.76, 62.01, 58.13,
41.28, 39.75, 34.04, 30.89, 2
5.64, 22.63, 18.92, 17.54.

Example 3 (Step c) Compound 39 of formula (7) obtained in Example 2
1 mg and 1.5 ml of benzene were charged into the reactor and dissolved. To this solution, 26.4 mg of imidazole and 101.6 mg of triphenylphosphine were added. 78.6 mg of iodine was added to this reaction mixture, and the mixture was stirred at room temperature for 20 minutes.

After completion of the reaction, the reaction solution was poured into a saturated sodium thiosulfate aqueous solution and extracted with diethyl ether.
The obtained diethyl ether layer was washed successively with saturated multilayer water and saturated saline. This was dried over anhydrous magnesium sulfate. After filtering off the solid matter, the solvent was distilled off from the filtrate under reduced pressure to obtain an oily crude product. This was purified by silica gel column chromatography (1% ethyl acetate-hexane),
27.5 mg of an oily compound was obtained. The following identification data revealed that this compound was a mixture of the compounds of formulas (4) and (5) (yield 66%).

Identification data IR (cm _-1 ): 2960, 2916, 1706
1451, 1381, 1356, 1166, 1121,
979; ¹ H-NMR (270 MHz, CDCl ₃ , ppm):
5.21-5.50 (m, 2H), 5.00-5.2
0 (m, 1H), 3.14-3.23 (m, 1H),
2.70-2.93 (m, 2H), 2.17 and 2.2
4 (each s, total 3H), 1.67-1.71
(M, 6H), 1.58 (m, 3H), 1.01 and 0.97 (each s, total 3H).

Example 4 (Step d) 0.04 ml of tributyltin hydride, 3.7 mg of azobisisobutylnitrile and 5 ml of benzene were charged into a reactor and dissolved. While heating and refluxing this mixture, 27.5 mg of a mixture of the compound of formula (4) and the compound of formula (5) obtained in Example 3 was added to benzene 4
What was melt | dissolved in ml was dripped over 1 hour.

After completion of the reaction, the reaction was returned to room temperature and the solvent was distilled off from the reaction solution under reduced pressure. The obtained residue was purified by silica gel column chromatography (1% acetic acid-hexane) to give 16.1 mg of white crystals. When this crystal was further separated and purified by HPLC, it was found to be a mixture of two types of white crystals. The following identification data revealed that these white crystals were compounds of formula (8) and formula (9) (yield 90%).

Identification data (compound of formula (8)) ¹ H-NMR (270 MHz, CDCl ₃ , ppm):
2.75-2.85 (m, 1H), 2.21 (s, 3
H), 1.05-2.05 (m, 12H) 0.91
(S, 3H), 0.83-0.88 (m, 6H), 0.
75 (d, J = 7.1 Hz, 3 H); (Compound of formula (9)) ¹ H-NMR (270 MHz, CDCl ₃ , ppm):
2.55 (dd, J = 9.3 Hz, J = 9.3 Hz,
1H), 2.21 (s, 3H), 1.21-2.10
(M, 12H), 0.91 (d, J = 7.3 Hz, 3
H), 0.83 (d, J = 6.5 Hz, 3H), 0.7
6 (d, J = 7.0 Hz, 3 H), 0.61 (s, 3
H).

[0049]

INDUSTRIAL APPLICABILITY According to the present invention, when the bicyclo [4,3,0] nonane to be the CD ring of vitamin D derivatives and steroids is produced by the convergent method, it can be obtained from relatively easily available raw materials. A chain compound that can be easily synthesized is used as a ring-closing precursor, and this can be ring-closed in one step to easily obtain the target bicyclo [4,3,0] nonanes.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification number Office reference number FI technical display location C07C 31/27 9155-4H 45/67 49/115 49/227 49/24 49/323 49/563 C07D 307/33

Claims (11)

[Claims] 1. Formula (1): (In the formula, R ¹ , R ² , R ³ and R ⁴ are each independently an alkyl group, an aryl group, a hydroxyalkyl group or an alkylcarbonyl group.) Chemical 2] (In the formula, R ¹ , R ² , R ³ and R ⁴ are as defined in formula (1), and X is a radical leaving group.)
The compound of formula (1) is obtained by reacting a compound of formula (1) with a trialkyltin hydride or a triaryltin hydride as a radical generator in the presence of a radical initiator to perform a radical ring closure reaction. Production method. 2. The method according to claim 1, wherein tributyltin hydride is used as the radical generator. 3. The method according to claim 1, wherein azobisisobutylnitrile is used as the radical initiator. 4. R ¹ , R ² and R ³ in the formula (2) are all methyl groups, and R ⁴ is an acetyl group.
The manufacturing method according to any one of to 3. 5. The following reaction scheme: As shown in, the compound of formula (3) is reacted with 2,2-dialkoxytetrahydrofuran to undergo Claisen rearrangement to form a compound of formula (6),
Forming a compound of formula (7) with ring-opening of the lactone moiety by reacting the compound of formula (1) with methyllithium, and substituting the radical leaving group X for the terminal hydroxyl group of the resulting compound of formula (7). To form a compound of the formula (4) or (5) as a compound of the formula (2), and further from the compound of the formula (4) or (5), a compound of the formula (8) or ( The production method according to claim 4, wherein the compound of 9) is obtained. 6. A formula (4): Compound of. 7. Formula (5): Compound of. 8. A formula (6): Compound of. 9. Formula (7): Compound of. 10. The formula (8): Compound of. 11. Formula (9): Compound of.