JPH05194468A - Method for reducing allyl alcohol - Google Patents

Abstract

PURPOSE:To selectively reduce the 5-hydroxy group of an allyl alcoholic type compound and provide a compound useful as a therapeutic agent for glaucoma by treating the allyl alcoholic type compound with a trialkylsilane in the presence of an aluminum halide. CONSTITUTION:An allyl alcoholic type compound expressed by the formula, etc., is treated with a trialkylsilane (e.g. trimethylsilane, triethylsilane or dimethylethylsilane) in the presence of a compound expressed by the formula AlX3 (X is halogen) to selectively reduce the hydroxyl group of the compound expressed by the formula. Furthermore, the hydroxyl group in the compound expressed by the formula, etc., may be brominated once and then treated with the trialkylsilane in the presence of the compound expressed by the formula AlX3.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION The reduction method of the present invention relates to a method for selectively reducing the hydroxyl group of an allyl alcohol type compound used as a raw material for the production of various drugs, and can be widely used for the production of various drugs. For example, a 15-deoxyprostaglandin derivative has recently been shown to be promising as a therapeutic agent for glaucoma, but it is particularly important for selective reduction of 15-hydroxy in the production of the derivative.

[0002]

2. Description of the Related Art As a method of indirectly reducing a hydroxyl group of a compound having an allyl alcohol type partial structure, for example, a method of brominating the hydroxyl group and then reducing it with NaBH ₄ is Proceedings of the National Academy of Sciences of the Yuwe Sway. Vol. 74, No. 4
007 (1977) (Proc. Natl. Acad. Sic. USA,
74 , 4007, (1977)). Further, as a direct return method, Journal of Organic Chemistry, Vol. 51, page 3038 (1986) (J. Or.
g. Chem., 51 , 3038 (1986)) in NaBH ₃ CN / ZnI ₂
The method of using is reported. However, in the reduction method, the ester group other than the hydroxyl group of the allyl alcohol moiety is reduced, and allyl rearrangement is likely to occur, so that selectivity is not observed and the yield is not preferable.
See also Tetrahedron Letters, page 2447 (196).
7) (Tetrahedoron Letters, 2447 (1967))
Although a method using H ₄ / AlCl ₃ has been reported, it is generally known that the ester group is also reduced in this method.

[0003]

As described above, in the conventional reduction method, an allyl rearrangement occurs as a side reaction when reducing the hydroxyl group of the allyl alcohol portion, and a substituent other than the hydroxyl group such as an ester group is also generated. Since it is reduced, it is difficult to selectively reduce only the hydroxyl group of the allyl alcohol portion in a high yield. Further, since it is often difficult to separate the isomer produced by the allyl rearrangement and the target unsaturated compound by column chromatography, it has been extremely difficult to obtain only the target product in a high yield. Therefore, also from the viewpoint of industrial production, in the compound having an allyl alcohol type partial structure, there has been a demand for a method of reducing only the hydroxyl group of the allyl alcohol portion in a high yield without allylic rearrangement.

[0004]

In view of the above situation, the inventors of the present invention have conducted extensive studies and as a result, found that a new method for reducing allyl alcohol type compounds, namely, AlX ₃ (wherein X represents halogen) is present. The present invention has completed the present invention by finding a method for selectively reducing the hydroxyl group of an allyl alcohol type compound by treating with a trialkylsilane.

In the present invention, the allyl alcohol type compound has the formula II:

[Chemical 2] (Wherein R ¹ , R ² , R ³ , and R ⁴ each independently represent a substituent) means a compound having a structure (hereinafter referred to as compound (II)). The substituent is not particularly limited, but is, for example, hydrogen, lower alkyl, cycloalkyl, cycloalkyl lower alkyl, lower alkoxy, amino, mono-lower alkylamino, di-lower alkylamino, carboxy, aryl, heterocycle, aralkyl. ,
It is arbitrarily selected from aryloxy, aralkyloxy, alkanoyloxy, aroyloxy, alkylthio, alkoxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl, hydroxycarbamoyl, carbazoyl, carbamoyloxy and the like. Preferably,
At least one of R ¹ and R ² is a substituent having larger steric hindrance than R ³ and R ⁴ , and in that sense, R ¹ and R ² are each independently dialkylmethyl (i-propyl, i-butyl, s-butyl, t-butyl, i-pentyl, neopentyl,
s-pentyl, t-pentyl, neohexyl, i-hexyl,
s-hexyl, t-hexyl, etc.), cycloalkyl, aryl, heterocycle and the like. On the other hand, R ³ , R
⁴ is preferably a substituent having as little steric hindrance as possible, and more preferably at least one is hydrogen.
Incidentally, the above-mentioned substituents may further have substituents such as hydroxy, amino and carboxy.

In applying the reduction method of the present invention, one example of compound (II) is formula I:

[Chemical 3] Examples thereof include compounds represented by (hereinafter referred to as compound (I)). The 15-deoxy form of compound (I) (however, the number is based on the prostaglandin nomenclature)
Formula III is:

[Chemical 4] The compound represented by 15-is useful as a therapeutic agent for glaucoma.
It can be an important synthetic intermediate of deoxyprostaglandins. Further, the hydroxy-protected form is disclosed in Japanese Patent Application No. 2-57.
No. 476.

The reduction method of the present invention will be described in more detail.
The present invention is a method of treating the allyl alcohol type compound with trialkylsilane in the presence of AlX ₃ (wherein X represents halogen) to selectively reduce the hydroxyl groups of the allyl alcohol type compound. The allyl alcohol type compound may be reduced as it is by the method of the present invention, or the alcohol may be once halogenated and then reduced by the method of the present invention. One of the major features of the present invention is that the target compound can be obtained in high yield by direct reduction reaction without halogenation. This method is very preferable because it is not necessary to use an extra reagent. However, the target compound can be obtained in a high yield even if the compound is once halogenated (more preferably brominated) and then reduced by the method of the present invention, which is of course intended by the present invention.

The halogenation may be any of chlorination, bromination and iodination, and is carried out by a method known per se. For example, bromination can be performed using an organic phosphorus compound such as triphenylphosphine and a brominating agent such as carbon tetrabromide. AlX ₃ (wherein X represents halogen) means AlF ₃ , AlCl ₃ , AlBr ₃ , AlI ₃
However, AlCl ₃ is preferable. AlX ₃
The molar ratio of the compound (1) to the compound (II) is about 1-fold or more, and particularly for the compound (I), about 3-fold or more is preferable. The trialkylsilane means trimethylsilane, triethylsilane, tripropylsilane, dimethylethylsilane, diethylmethylsilane, or the like in which three lower alkyl groups are substituted on Si atoms. The amount of the trialkylsilane used is about 1 time or more the molar ratio of the compound (II), and particularly about 5 times or more the amount of the compound (I) is preferable.

This reaction is preferably carried out in a solvent, and the type of solvent used may be appropriately selected depending on the type of compound (II). Usually, halogenated hydrocarbons such as dichloromethane and chloroform are used. used. Further, a solvent (benzene, nitrobenzene, carbon disulfide, etc.) generally used in the Friedel-Crafts reaction can also be used. The reaction temperature is not necessarily limited as it may vary depending on the type of compound (II), the amount of the reagent used, etc., but is usually about −25 to about 50 ° C., preferably about −10.
It is about 40 ° C. and the reaction is completed in a few minutes to a few hours.

When applying the reduction method of the present invention,
When the compound (II) has a substituent such as hydroxy, amino or carboxy which is easily affected by the reduction method of the present invention, it is desirable to protect the substituent with a suitable protecting group known per se. .. For example, for hydroxy, those which are not deprotected by the reduction method of the present invention can be widely used among those commonly used as a hydroxy protecting group, for example, Protective Groups
In Organic Synthesis (Protective groups i
n organic synthesis.TWGreene, John Wiley & Son
s, Inc., New York, P.10, 1981), especially various protecting groups, especially alkyl (thio) ethers such as methyl, methoxymethyl, methylthiomethyl, 2-methoxyethoxymethyl, 1-ethoxyethyl and the like. Type protecting group, silyl ether type protecting group such as triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, etc. Acyl type such as acetyl, benzoyl, p-methylbenzoyl, o-methoxybenzoyl, p-phenylbenzoyl And aralkyl-type protecting groups such as benzyl and p-methoxybenzyl. However, p-phenylbenzoyl is preferable for the compound (I) from the viewpoint of crystallization.

The terms used in this specification will be described below. Lower alkyl means linear or branched C _1-6 alkyl, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, Examples include n-pentyl, i-pentyl, neopentyl, s-pentyl, t-pentyl, n-hexyl, neohexyl, i-hexyl, s-hexyl, t-hexyl and the like, and these are further hydroxy, amino, carboxy and the like. It may have a substituent.

Cycloalkyl means C _3-7 cycloalkyl, and is exemplified by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. These may be substituted with one or more substituents. Examples of the substituent include a hydroxyl group and acetyloxy, and the cycloalkyl may be condensed with a lactone ring. Cycloalkyl lower alkyl is
It means the above lower alkyl substituted with the above cycloalkyl, and examples thereof include cyclopropylmethyl, cyclobutylethyl, cyclohexyl n-propyl and the like. Lower alkoxy means linear or branched C _1-6 alkyloxy, such as methoxy, ethoxy, n-propoxy, i-
Propoxy, n-butoxy, i-butoxy, s-butoxy, t-
Butoxy, n-pentyloxy, i-pentyloxy, neopentyloxy, s-pentyloxy, t-pentyloxy, n-hexyloxy, neohexyloxy, i-hexyloxy, s-hexyloxy, t-hexyloxy, etc. Are exemplified, and these may further have a substituent such as hydroxy, amino and carboxy.

The term "mono-lower alkylamino" means an amino group in which one of the lower alkyl is substituted with a nitrogen atom, and methylamino, ethylamino, n-propylamino,
i-propylamino, n-butylamino, i-butylamino,
s-butylamino, t-butylamino, n-pentylamino,
Examples include i-pentylamino, n-hexylamino, i-hexylamino and the like. Di-lower alkylamino means an amino group in which any two of the above-mentioned lower alkyls are substituted with nitrogen atoms, and includes dimethylamino, diethylamino, N-methyl-ethylamino, N-methyl-propylamino, N- Examples include ethyl-propylamino, dipropylamino, dibutylamino, dipentylamino, dihexylamino, N-pentyl-hexylamino and the like. Further, the two groups substituting the amino group can form, together with the nitrogen atom thereof, a cyclic imino group which may further have a nitrogen atom, an oxygen atom and / or a sulfur atom, and a polymethyleneimino (pyrrolidino) group can be formed. , Piperidino, piperazino, etc.), N-substituted piperazino,
Examples thereof include morpholino, thiomorpholino, homopiperazino, N-substituted homopiperazino and the like.

Examples of aryl include phenyl and (α or β) naphthyl. These may further have a substituent such as hydroxy, amino and carboxy.
The heterocycle means an aromatic heterocycle or a fully saturated heterocycle. The aromatic heterocycle means a 5- or 6-membered aromatic ring which contains at least one oxygen atom, sulfur atom or nitrogen atom in the ring and which may be condensed with other aromatic ring, and pyrrolyl , Indolyl, carbazolyl, imidazolyl, pyrazolyl,
Benzimidazolyl, indazolyl, indolizinyl,
Pyridyl, quinolyl, isoquinolyl, acridyl, phenanthridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, phenazinyl, 1,3,5-
Triazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, purinyl, pteridinyl, isoxazolyl, benzisoxazolyl, oxazolyl, benzoxazolyl,
1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,
2,5-oxadiazolyl, 1,3,4-oxadiazolyl, benzoxadiazolyl, isothiazolyl, benzisothiazolyl, thiazolyl, benzthiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2, Examples thereof include 5-thiadiazolyl, 1,3,4-thiadiazolyl, benzthiadiazolyl, furanyl, benzofuranyl, thienyl and benzothienyl. These may further have a substituent such as hydroxy, amino and carboxy.

The term “fully saturated heterocycle” means a 3- to 8-membered fully saturated heterocycle containing at least one oxygen atom, sulfur atom or nitrogen atom in the ring, and includes azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, Examples thereof include piperazinyl, oxiranyl, thietanyl and the like. These may further have a substituent such as hydroxy, amino and carboxy. Aralkyl means the above lower alkyl substituted with the above aryl, and is exemplified by benzyl, phenethyl, phenylpropyl, and (α or β) naphthylmethyl. Examples of aryloxy include phenyloxy and (α or β) naphthyloxy. These may further have a substituent such as hydroxy, amino and carboxy. As aralkyloxy,
Examples include phenethyloxy and phenylpropyloxy.

Alkanoyloxy means carbonyloxy substituted with the above lower alkyl, for example, acetyl, propionyl, butyroyl and the like. Aroyloxy means benzoyloxy, naphthoyloxy and the like. These may further have a substituent such as hydroxy, amino and carboxy. Alkylthio means the above lower alkyl bonded to a sulfur atom, and is exemplified by methylthio, ethylthio, propylthio, butylthio, hexylthio and the like. Alkoxycarbonyl means a carbonyl substituted with the above lower alkoxy, and is exemplified by methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and the like. Examples of aryloxycarbonyl include phenyloxycarbonyl and (α or β) naphthyloxycarbonyl. These may further have a substituent such as hydroxy, amino and carboxy. Examples of aralkyloxycarbonyl include phenethyloxycarbonyl and phenylpropyloxycarbonyl.

Hereinafter, reference examples and examples will be shown in order to explain the present invention in more detail, but these do not limit the present invention in any way. Reference Example 1 (1S, 6R, 7R) -2-oxa-3-oxo-6-
[(3R) -Bromo- (1E) -octenyl] -7-p
-Phenylbenzoyloxy-cis-bicyclo [3.3.
0] octane (compound 2) and (1S, 6R, 7R)-
2-oxa-3-oxo-6- [1-bromo- (3E)
-Octenyl] -7-p-phenylbenzoyloxy-
Combination of cis-bicyclo [3.3.0] octane (compound 3)
Formed (1S, 6R, 7R) -2-oxa-3-oxo-6-
[(3S) -Hydroxy- (1E) -octenyl] -7
-P-phenylbenzoyloxy-cis-bicyclo [3.3.0] octane (Compound 1) (750 mg, 1.
67 mmole) was dissolved in dichloromethane (15 ml) and carbon tetrabromide (665 mg, 2.00 mmol) was added at 0 ° C.
e) and triphenylphosphine (1.053 g, 4.
00 mmole) and stir for 30 minutes at the same temperature.
The reaction mixture was applied to a column of silica gel (25 g) and eluted with ethyl acetate-hexane (1: 3) to give the crude product (7
00 mg) is obtained. This was further purified by a row bar column (ethyl acetate-hexane (1: 3)) to obtain the target compound 3
(96 mg, 11%) and compound 2 (501 mg, 5
9%) was obtained in the order of elution. Compound 1 is a journal
Obj American Chemical Society (Journa
l of the American Chemical Society), 24, 1491 (1971).

Reference Example 2 (1S, 6R, 7R) -2-oxa-3-oxo-6-
[(1E) -octenyl] -7-p-phenylbenzoi
Luoxy-cis-bicyclo [3.3.0] octane (compound
Synthesis of compound 4) Compound 2 obtained from Reference Example 1 (451 mg, 0.88)
2 mmole) was dissolved in dimethyl sulfoxide (9 ml), and sodium borohydride (67 mg, 1.
765 mmole) is added and the mixture is stirred for 2 hours. After adding dilute hydrochloric acid, the mixture was extracted with dichloromethane, the extract was washed with water, dried and the solvent was distilled off to obtain a colorless oil (520 mg). This was applied to a column of silica gel (2.6 g) and eluted with ethyl acetate-hexane (1: 3) to give a colorless oil (330 g),
Elute with ethyl acetate to give a yellow oil (68 mg). The former is a row bar column (ethyl acetate-hexane (1: 3))
Further purification was carried out with to obtain standard compound 4 (214 mg, 56%).

Reference Example 3 (1S, 6R, 7R) -2-oxa-3-oxo-6-
[(2E) -octenyl] -7-p-phenylbenzoi
Luoxy-cis-bicyclo [3.3.0] octane (compound
Synthesis of product 5) Compound 3 obtained from Reference Example 1 (129 mg, 0.23
5 mmole) was dissolved in dimethyl sulfoxide (2 ml), and sodium borohydride (18 mg, 0.1 ml) was added at room temperature.
47 mmole) is added. The colorless oil (120 mg) obtained by treating in the same manner as in Reference Example 2 was applied to a column of silica gel (1.2 g) and eluted with ethyl acetate-hexane (1: 3) to obtain an oil (72 mg). This was further purified by a Rover column (ethyl acetate-hexane (1: 3)) to obtain a standard compound 5 (33 mg, 33%).

Example 1 (Direct reduction of compound 1) Triethylsilane (106.8 ml, 0.669 mol)
e) was dissolved in dichloromethane (360 ml), and aluminum chloride (71.4 g, 0.5352 mol) was added at 0 ° C.
e), then Compound 1 (60 g, 0.1338 mol
Add a solution of e) in dichloromethane (180 ml) and stir at the same temperature for 1 hour. The reaction mixture is poured into cold dilute hydrochloric acid and extracted with dichloromethane. The extract was washed with water, dried, and the solvent was evaporated to give a residue (84 g), which was washed with silica gel (1
70 g) and applied to a column, and eluted with hexane-dichloromethane-ethyl acetate = (40: 10: 3 to 40: 10: 5) to obtain a mixture of compound 4 and compound 5 (64 g, the ratio of compound 4 and compound 5 from HPLC is 97: 3). This was recrystallized from ethyl acetate-hexane to give a melting point of 74-
Compound 4 (55.3 g, 96%) at 76 ° C. was obtained.

Example 2 (Direct reduction of compound 1 ') Triethylsilane (11 ml, 0.069 mole) was dissolved in dichloromethane (37 ml), and aluminum chloride (7.36 g, 0.052 mole) and (1S,
6R, 7R) -2-oxa-3-oxo-6-[(3
R) -Hydroxy- (1E) -octenyl] -7-p-
Phenylbenzoyloxy-cis-bicyclo [3.3.
0] Octane (Compound 1 ′) (6.19 g, 0.0138
Mole) in dichloromethane (18 ml),
Stir for 1 hour at the same temperature. Thereafter, the same treatment as in Example 1 was conducted to prepare a mixture of Compound 4 and Compound 5 (6.5.
g, the ratio of compound 4 to compound 5 was 9 from HPLC.
6: 4) is obtained. This was recrystallized from ethyl acetate-hexane to give compound 4 (5.53 g, 9) having a melting point of 74-76 ° C.
3%) was obtained. The compound 1'is, like the compound 1, a compound described in the above literature.

Example 3 (Direct Reduction of Equivalent Mixture of Compound 1 and Compound 1 ') Triethylsilane (53.4 ml, 0.3345 mol)
e) was dissolved in dichloromethane (180 ml), and aluminum chloride (35.67 g, 0.2676 mol) was added at 0 ° C.
e), followed by an equal mixture of compound 1 and compound 1 '(30
g, 0.0669 mole) of dichloromethane (90 m
l) Add the solution and stir at the same temperature for 1 hour. Then, the same treatment as in Example 1 is carried out to obtain a mixture of compound 4 and compound 5 (38 g, the ratio of compound 4 and compound 5 from HPLC is 97: 3). This was recrystallized from ethyl acetate-hexane to give compound 4 (27.
33 g, 95%) was obtained.

Example 4 (Reduction of Compound 1 via Bromination) Compound 1 (61.92 g, 0.138 mole) was dissolved in dichloromethane (750 ml) and triphenylphosphine (76.04 g, 0.290 mole) was added at -40 ° C. ),
Then a solution of carbon tetrabromide (48.9 g, 0.145 mole) in dichloromethane (75 ml) is added and stirred for 1 hour. After concentrating until the volume becomes about half, triethylsilane (110 ml, 0.689 mole) and aluminum chloride (73.64 g, 0.552 mole) are added at room temperature, and the mixture is stirred at 35-40 ° C for 1 hour. It is poured into cooled dilute hydrochloric acid, extracted with ethyl acetate, washed with water, dried and evaporated. Toluene-hexane (4: 1) was added to the residue and the resulting precipitate was filtered off. The filtrate was purified by silica gel column (600 g, ethyl acetate-hexane) to give a mixture of compound 4 and compound 5 (44 .94 g, 75.3%,
4 : 5 = 9: 1) is obtained. This was recrystallized from ethyl acetate-hexane to obtain compound 4 (25 g, 42%).

Example 5 (Reduction of compound 1'via bromination) Compound 1 '(45 mg, 0.1 mmole) was dissolved in dichloromethane (5 ml) and triphenylphosphine (55 mg, 0.21 mmole) was added at -20 ° C. Then carbon tetrabromide (34.8 mg, 0.105 mmole) is added and stirred at room temperature for 30 minutes. Then, triethylsilane (80 μl, 0.5 mmole) and aluminum chloride (53.3 mg, 0.4 mmole) are added, and the mixture is stirred at room temperature for 1 hour. The reaction mixture is poured into ice water, extracted with dichloromethane, washed with water, dried and the solvent is distilled off. The residue was purified by silica gel column (5 g, ethyl acetate-hexane) to give a mixture of compound 4 and compound 5 (33 mg, 76%).
Got From HPLC, the ratio of compound 4 to compound 5 was 9
It was 1: 9.

Example 6 (Reduction of Equivalent Mixture of Compound 1 and Compound 1'via Bromination) Equivalent mixture of Compound 1 and Compound 1 '(45 mg,
0.1 mmole) was dissolved in dichloromethane (5 ml) and triphenylphosphine (55 mg, at -20 ° C).
0.21 mmole), then carbon tetrabromide (34.8 m
g, 0.105 mmole) and stirred at room temperature for 30 minutes. Then, triethylsilane (80 μl, 0.5
mmole), aluminum chloride (53.3 mg, 0.4
mmole) and stir at room temperature for 1 hour. After this,
The mixture was treated as in Example 5 to give a mixture of compound 4 and compound 5 (33 mg, 76%). From HPLC, the ratio of compound 4 to compound 5 was 96: 4.

[0026]

INDUSTRIAL APPLICABILITY According to the present invention, in various allyl alcohol type compounds, only the hydroxyl group of the allyl alcohol moiety is selectively yielded with high yield without affecting allyl rearrangement without affecting the ester group, ether group and the like. Can be reduced at a rate.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Teruo Sakata Inventor Teruo Sakata 5-26-10-406 Shimoshinjo, Higashiyodogawa-ku, Osaka-shi, Osaka (72) Inventor Kimio Takahashi 14-13 Nishinekita Aramaki, Kanegasaki-cho, Isawa-gun, Iwate Prefecture (72) ) Inventor Morio Kishi 31-26 Kashihara Tanodacho, Nishikyo-ku, Kyoto-shi, Kyoto Prefecture

Claims (5)

[Claims] 1. A method for selectively reducing the hydroxyl group of an allyl alcohol type compound, which comprises treating with trialkylsilane in the presence of AlX ₃ (wherein X represents halogen). 2. The method according to claim 1, wherein the allyl alcohol type compound is directly treated with a trialkylsilane in the presence of AlX ₃ (wherein X represents halogen) without halogenating the hydroxyl group. 3. The method according to claim 1, wherein the hydroxyl group of the allyl alcohol type compound is once halogenated and then treated with a trialkylsilane in the presence of AlX ₃ (wherein X represents halogen). 4. The method according to claim 3, wherein the halogenation is bromination. 5. The allyl alcohol type compound has the formula I: The method according to claim 1, 2 or 3, which is a compound represented by: