JPS6214559B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION Technical Field of the Invention The present invention relates to a novel compound 3β-acetoxy-7-oxo-24-trifluoroacetyloxy-Δ5-
Regarding cholene, this compound is useful as a raw material for the synthesis of ursodeoxycholic acid (3α,7β-dihydroxycholanic acid), which is useful as a choleretic agent, and chenodeoxycholic acid (3α,7α-dihydroxycholanic acid), which is useful as a gallstone dissolving agent. be.

Prior Art Ursodeoxycholic acid, which is useful as a choleretic agent, and chenodeoxycholic acid, which is in increasing demand as a gallstone dissolving agent useful in the treatment of patients with cholelithiasis, which is increasing year by year, has traditionally been mixed with glycine or taurine in cow bile. It is manufactured from cholic acid, which exists in bound form. However, such natural raw materials are difficult to obtain, and moreover, it takes 300 to 400 cows to obtain 1 kg of cholic acid from cow bile, so the price has gradually increased as the demand for cholic acid increases. There is.

In view of this current situation, and since producing chenodeoxycholic acid or ursodeoxycholic acid using cholic acid as a starting material requires a large number of steps and is problematic in terms of efficiency, it is difficult to produce chenodeoxycholic acid or chenodeoxycholic acid from another starting material. Research is underway to synthesize.

Purpose of the Invention Therefore, an object of the present invention is to provide an intermediate useful for the synthesis of ursodeoxycholic acid or chenodeoxycholic acid using cholesterol contained in wool fat or the like as a raw material.

Structure of the invention According to the invention, the formula (wherein Ac represents an acetyl group) 3β-acetoxy-7-oxo-24-trifluoroacetyloxy-Δ5-cholene is provided.

Specific Description of Structure and Effects of the Invention According to the present invention, as described above, a novel compound 3β-acetoxy-7-oxo-24-trifluoro which can be used as an intermediate for producing ursodeoxycholic acid and chenodeoxycholic acid. Acetyloxy-Δ5-cholene is provided, and this compound can be synthesized from cholesterol contained in wool fat etc. by the following synthetic route, and the synthesized 3β-acetoxy-7-oxo-
24-Trifluoroacetyloxo-Δ5-cholene can be used in the production of ursodeoxycholic acid or chenodeoxycholic acid.

Hereinafter, a method for producing 3β-acetoxy-7-oxo-24-trifluoroacetyloxy-Δ5-cholene and a method for producing ursodeoxycholic acid and chenodeoxycholic acid from it will be explained according to the above synthetic reaction route. .

As mentioned above, cholesterol (compound of the formula) obtained by recrystallizing unsaponifiable materials such as wool fat and fish oil, which are easily obtained industrially, is generally used as a raw material compound, but the basic structure is similar to that of cholesterol. Compounds such as cholestane compounds such as Δ5-cholestenone can also be used.

First, in step A, the raw material compound cholesterol is acetylated according to a conventional method to acetylate the hydroxyl group at the 3-position of cholesterol to protect the hydroxyl group. Acetylation can be by any method of acetylating such hydroxy groups, for example, using acetic anhydride/pyridine.

The 3β-acetoxycholesterol of the formula obtained in Step A is oxidized in Step B to oxidize the allyl position of the steroid without cleaving the double bond at the 5-position to produce a 7-oxo form. Although it is relatively difficult to oxidize the allylic position of steroids without cleavage of double bonds or generation of OH groups,
For example, the compound may be mixed with a solvent having a suitable boiling point favorable for the reaction and resistant to chromic acid oxidation, such as a hydrocarbon such as benzene, toluene, xylene, n-pentane, n-hexane, n-heptane, n-octane, or cyclohexane. Chromic acid and a heterocyclic compound such as pyridine or pyrazole (these have one or more alkyl atoms in the heterocycle) in a halogenated hydrocarbon solvent such as methylene chloride or ethane dichloride at room temperature or above, preferably 50 to 120°C. ), for example, pyridium chlorochromate, pyridinium dichlorochromate, 3,5-dimethylpyrazole-chromic acid complex, etc., and preferably these oxidizing agents are used. The desired compound can be produced by carrying and dispersing it on a carrier such as alumina or silica and oxidizing it for an appropriate period of time. In addition, N
-Other known allyl oxidizing agents such as chlorosuccinimide, hypochlorite, etc. can also be used.

Next, in Step C, the compound synthesized in Step B undergoes oxidative cleavage at the 24-position of cholesterol to form trifluoroacetyloxygen, resulting in the formula 3β-acetoxy-
7-oxo-24-trifluoroacetyloxy-
Converted to Δ5-cholene. This reaction requires oxidative cleavage of the 24-position without attacking the acetoxy group at the 3-position, the double bond at the 5-position, and the C=O at the 7-position. trifluoroacetic anhydride or CF ₃ COOH in the presence of sulfuric acid,
It has been found that the reaction can proceed favorably by reacting CF ₃ COOM (M: alkali metal) or the like with hydrogen peroxide. It is important to carry out this reaction in the presence of sulfuric acid; in the absence of sulfuric acid, the desired oxidative cleavage reaction at position 24 of cholesterol will hardly proceed. Although the reaction may be carried out in the presence of a suitable solvent, it is usually preferable to use the above-mentioned trifluoroacetic anhydride or the like in large excess relative to the raw material compound to also serve as a solvent. In this case, there are no strict restrictions on the amount of trifluoroacetic anhydride, concentrated sulfuric acid, hydrogen peroxide, etc., but in general, at least 1 ml of trifluoroacetic anhydride is used per 1 mmol of the raw material compound, and sulfuric acid , hydrogen peroxide is 0.1 to 0.3 ml as 98% H ₂ SO ₄ 30% to 1 ml of trifluoroacetic anhydride, respectively.
About 0.05 to 0.2 ml of H ₂ O ₂ is used. However, this is just a guideline, and it is desirable to adjust it as necessary. There are no restrictions on the reaction temperature and time, but it is usually 10℃.
Thereafter, the reaction mixture is allowed to react at a temperature above the freezing point for an appropriate period of time, for example, about 3 to 5 hours. Compound 3 of formula () according to the present invention produced in this way
β-acetoxy-7-oxo-24-trifluoroacetyloxy-Δ5-cholene is a new compound that has not been described in any literature.

The compound synthesized in step C is converted into formula 3 by alcoholysis or hydrolysis in step D.
β-Hydroxy-7-oxo-24-hydroxy-
It can be Δ5-cholene. This process is
For example, hydroxides, carbonates, bicarbonates of alkalis, such as alkali metals, alkaline earth metals or ammonia, in particular NaOH, KOH, Ca(OH) ₂ , in lower alcohols, water or aqueous solvents,
_NH4OH , _Na2CO3 , _K2CO3 , _{CaCO3 , NaHCO3 ,}
This can be carried out using KHCO ₃ or the like at room temperature or at the boiling point of the reaction solution. The compound 3β-hydroxy-7-oxo- of the formula () thus produced
24-Hydroxy-Δ5-cholene is also a new compound that has not been described in any literature.

The compound synthesized in this way is first hydrogenated at the 5-position double bond in the presence of a platinum, palladium, or nickel catalyst to form 3β-hydroxy-7-oxo-24-hydroxycholane. , then this 3β-hydroxy-7-oxo-24
- Hydroxycholan is oxidized to 3,7-dioxocholanic acid by oxidizing hydroxymethyl at position 24 and hydroxy at position 3 by general chromic acid oxidation, and then selectively only at position 3 in the presence of a Raney-nickel catalyst. Hydrogenation is performed to obtain 3α-hydroxy-7-oxocholanic acid, and this 3α-hydroxy-7-oxocholanic acid is further treated with metallic sodium, metallic potassium, metallic lithium, etc. in an alcoholic solvent such as secondary butanol or isopropanol. Ursodeoxycholic acid () can be synthesized by reduction (or hydrogenation) using an alkali metal. Note that this reduction can also be carried out by so-called Birch reduction using liquid ammonia and an alkali metal or other reduction methods.

Furthermore, chenodeoxycholic acid () can be synthesized by reducing the above-mentioned 3α-hydroxy-7-oxocholanic acid with hydrogen in the presence of a palladium, platinum, nickel catalyst, or the like. All of these methods are well known and variously described in literature and patents.

As explained above, 3β-acetoxy-7-oxo-24-trifluoroacetyloxy-Δ5-cholene according to the present invention is synthesized using cholesterol, which can be obtained in relatively large quantities and at low cost from wool fat, as a starting material. It can be used as an intermediate for the production of ursodeoxycholic acid or chenodeoxycholic acid.

Examples of the present invention will be described below, but it goes without saying that the scope of the present invention is not limited to these Examples. In addition, in the following examples, "%" indicates "% by weight" unless otherwise specified.

Example 1 Synthesis of 3β-acetoxy-7-oxocholesterol (compound of the above formula) 100 g of cholesterol (compound of the above formula) collected and purified from wool fat according to a conventional method was mixed with 300 g of pyridine.
ml, add 62g of acetic anhydride to this and bring to temperature
Acetylated at 40℃, 3 with acetylated at position 3
103 g of β-acetoxycholesterol (compound of the above formula) was obtained (mp 107-110°C).

4.0 g of 3β-acetoxycholesterol of the formula obtained above and 12.9 g of pyridine chlorochromate were added to 60 ml of benzene, and the mixture was refluxed for 64 hours. After refluxing, the reaction solution was cooled and the reaction product was transferred to a silica gel column (hexane:ether=10:
1), 0.82g of raw material and desired product
1.95g (yield 59.4%) was obtained.

The physical properties of the obtained product were as follows.

Melting point: 158-161°C IR (Nudiol): 1730, 1670 (1/cm) NMR (CDCl ₃ ): Methyl: 0.70 (s), 0.93
(s), 1.23 (s), 2.05 (s) 3β-1H: 4.67 (bs; 1H) 6-1H: 5.68 (s; 1H) MS: 442 (parent peak not expressed) 382 (-Ac), 269 , 174 Example 2 Synthesis of 3β-acetoxy-7-oxo-24-trifluoroacetyloxy-Δ5-cholene (compound of the above formula) 3β-acetoxy-7- of the formula synthesized in Example 1
Oxocholesterol 300 mg, trifluoroacetic anhydride [(CF ₃ CO) ₂ O] 5 ml, concentrated sulfuric acid 2.1 ml and 30
% hydrogen peroxide aqueous solution over 10 minutes while stirring under ice cooling, stirred for 3 hours under ice cooling, added 10.5 ml of triethylamine under cooling, and returned to room temperature while stirring. . Low-boiling substances were distilled off from the resulting reaction solution at room temperature under reduced pressure, and the mixture was dissolved in dichloride methane.
The dichloride methane solution was thoroughly washed with sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated to yield 270 mg of crude product.

This crude product was transferred to a silica gel column (hexane:
Ether = 1:5) was used to obtain 21 mg of the raw material and 93 mg of the desired product (yield: 28.7%). The physical properties of the obtained compound were as shown below.

Melting point: 105-107℃ IR (nujiol): 1790, 1730, 1670 (1/
cm) NMR (CDCl ₃ ): Methyl: 0.70 (s), 1.23
(s), 2.03 (s) 24-2H: 4.30 (2H, Triplet, J = 6) 6-1H: 5.63 (s; 1H) MS: 512 (parent peak not expressed) 452, 269, 187, 164 cases 3 Synthesis of 3β-hydroxy-7-oxo-24-hydroxy-Δ5-cholene (compound of the above formula) 3β-acetoxy-7- of the formula synthesized in Example 2
Oxo-24-trifluoroacetyloxy-Δ5
-270 ml of the crude cholene product and 1 g of potassium carbonate were added to 60 ml of methanol, and the mixture was stirred at room temperature for 30 minutes. After separating the insoluble matter from the resulting reaction solution, the methanol solvent in the solution was distilled off, the residue was extracted with a solvent (methane dichloride), and the extract was applied to a silica gel column (hexane:ether = 1:5) to obtain a crude solution. product
67.9 mg of V [yield: 28.7% (based on raw materials)] was collected.

This product was purified by recrystallization from methanol, and the physical properties of the target compound were measured. The results are as follows.

Melting point: 208-210℃ IR (film): 3350, 1660, 1620 (1/
cm) NMR (D ₆ DMSO): 5.53 (1H; s) MS: 374 ⁺ , 356, 341 High-Mass data: C ₂₄ H ₃₈ O ₃ (calculated value) 374.2819 (actual value) 374.2819 C ₂₄ H ₃₆ O ₂ (Calculated value) 356.2721 (Actual value) 356.2721 C ₂₃ H ₃₃ O ₂ (Calculated value) 341.2483 (Actual value) 341.2483

Claims (1)

[Claims] 1 formula (In the formula, Ac represents an acetyl group) 3β-acetoxy-7-oxo-24-trifluoroacetyloxy-Δ5-cholene.