JPH046718B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel method for producing prostaglandins, and particularly to a method for producing prostaglandins having a hydroxyl group protected with a specific protecting group.

7-Fluoroprostaglandin I class ₂ (also known as
7-Fluoroproctacyclines) are known, for example, JP-A-57-99580, JP-A-57
It is described in JP-A-165382, JP-A-57-171988, JP-A-58-150583, etc. Natural prostaglandin I type ₂ (hereinafter including synthetic products)
PGI ₂ ) is chemically unstable and difficult to handle under neutral or weakly acidic conditions.
This 7-fluoroprostaglandin I ₂ (hereinafter referred to as 7-F PGI ₂ ) is extremely stable even under the above conditions, and is also considered to be useful in improving the selectivity of pharmacological action. This 7-FPGI ₂ is produced by a method of fluorinating 7-hydroxyPGI ₂ or by other methods described in the above publication. However, these known methods have various problems such as low selectivity and yield, and too complicated reaction steps, and it has been desired to solve these problems.

The present inventor previously proposed a method for producing 7-FPGI ₂ , in which 5,6-dehydro-7-
They discovered a method for converting fluoro-PGF _2a to 7-FPGI ₂ through a basically known cyclization reaction and filed a patent application (see Japanese Patent Application No. 1982-21995). Hereinafter, the compound represented by the following formula [] is 7-
It is called FPGF.

[Formula [], R ¹ is an alkyl group having 1 to 10 carbon atoms.

R ² is a linear, branched, or cyclic alkyl group having 3 to 7 carbon atoms.

R ₆ and R ⁷ are the same or different protecting groups or hydrogen atoms.

Note that the numbers 1 to 15 attached to carbon atoms represent the positions of the carbon atoms. ] 7-FPGF is produced by substituting the hydroxy group or trimethylsiloxy group of the corresponding 7-hydroxy compound or 7-trimethylsilyloxy compound with a fluorine atom (Japanese Patent Application No. 1999-21995 and Japanese Patent Application No. 1983-1999). (See No. 10288). In this fluorination reaction, it is necessary to protect not only the hydroxyl groups at the 11th and 15th positions but also the hydroxyl group at the 9th position, and these protecting groups are preferably other than the trimethylsilyl group. This is because if these protecting groups are trimethylsilyl groups, they may undergo fluorination. Therefore, 7-
As the precursor of FPGF, it is preferable to use a compound represented by the following formula [], and hereinafter the compound represented by this formula [] will be referred to as 7-XPGF.

[Formula [], R ¹ is an alkyl group having 1 to 10 carbon atoms, R ² is linear,
A branched or cyclic alkyl group having 3 to 7 carbon atoms, R ³ , R ⁴ and R ⁵ are the same or different protecting groups other than trimethylsilyl group. ] In addition, the 7-hydroxy compound is the above-mentioned 7-XPGF
It is obtained by deprotecting the trimethylsilyl group of

In the invention of the above-mentioned application, the above-mentioned 7-XPGF uses a diol in the above formula [] in which X is a hydrogen atom and R ⁵ is a hydrogen atom as a starting material, first, the hydroxyl group at the 7-position is protected with a trimethylsilyl group, and then the hydroxyl group at the 7-position is protected with a trimethylsilyl group, and then 9
It was produced by protecting the hydroxyl group at the position with a protecting group other than trimethylsilyl group (particularly triethylsilyl group). Conversely, it is extremely difficult to first protect the hydroxy group at the 9-position due to the difference in reactivity between the two hydroxy groups. Selectively protecting only the hydroxy group at the 7-position of the diol with a trimethylsilyl group takes advantage of the subtle difference in reactivity between both hydroxy groups, so there are large restrictions on reaction conditions, etc., and the yield is not high enough. That was the problem.

As a result of intensive research and study to solve the above problems, the inventors of the present invention have discovered a new method for producing 7-XPGF. The present invention involves protecting the 7-hydroxy group of prostaglandins (hereinafter referred to as 7-OHPGE) represented by the following formula [] with a trimethylsilyl group, converting the oxygen atom of the 9-position carbonyl group to a hydroxy group, and then This is a method for producing prostaglandins represented by the above formula [], characterized in that the hydroxy group is protected with a protecting group other than a trimethylsilyl group.

[Formula [], R ¹ is an alkyl group having 1 to 10 carbon atoms.

R ² is linear, branched or cyclic with 3 carbon atoms
~7 alkyl groups.

R ³ and R ⁴ are the same or different protecting groups other than trimethylsilyl group. ] In the structural formulas such as the above formulas [] to [],
Tapered lines (〓) represent substituents in the β orientation (above the plane of the molecule), dotted lines (…) represent substituents in the α orientation (below the plane of the molecule), and wavy lines () represent substituents in the α or Indicates substituents that are in the β orientation or a mixture of these isomers. Furthermore, these include optical isomers, racemates, and other types of compounds.

In 7-OH PGE represented by the above formula [] and 7-XPGF represented by the above formula [], R ¹ is preferably an alkyl group having 4 or less carbon atoms, particularly a methyl group or an ethyl group. R ² is preferably a linear alkyl group or a cyclic alkyl group (ie, a cycloalkyl group), and particularly preferably an n-amyl group or a cyclopentyl group. R ³ and R ⁴ are trialkylsilyl groups other than trimethylsilyl group (the three alkyl groups may be the same or different), alkanoyl group, tetrahydropyranyl group,
A tetrahydrofuranyl group, a benzoyl group, a methoxyethyl group, etc. are suitable, and a trialkylsilyl group having at least one alkyl group having 3 or more carbon atoms is particularly preferred, and a dimethyl-t-butylsilyl group is most preferred. R ⁵ in 7-XPGF may be the same protecting group as R ³ and R ⁴ above, but R ³
A protecting group that is easier to deprotect than R ⁴ is preferred.
This is because when converting 7-FPGF to 7-FPGI ₂ , at least the corresponding protecting group of the 9-hydroxy group of 7-FPGF needs to be deprotected, and the corresponding R ³ and R ⁴ are not necessarily deprotected. This is because it is not necessary to deprotect and it is often preferable in terms of yield that it is not deprotected. Therefore, R ³ and
When R ⁴ is a trialkylsilyl group having at least one alkyl group having 3 or more carbon atoms, especially when it is a dimethyl-t-butylsilyl group, R ⁵ is preferably a triethylsilyl group.

The hydroxy group at position 7 of 7-OH PGE can be protected with a trimethylsilyl group by a conventional method for protecting a hydroxy group with a trimethylsilyl group. For example, it can be carried out by reacting trimethylsilyl chloride in a solvent in the presence of a base such as piperidine. This reaction occurs almost quantitatively. The method of converting the oxygen atom of the carbonyl group at the 9-position into a hydroxy group can also be carried out by a conventional reduction reaction. For example, the reduction reaction is carried out in a solvent such as a hydrocarbon or alcohol using sodium borohydride, lithium trialkylboron hydride, potassium trialkylboron hydride, or diisobutylaluminum hydride as a reducing agent. This reduction reaction also proceeds almost quantitatively, and the product can be obtained in high yield.
The hydroxyl group at position 9 of the product is then protected with a protecting group other than the trimethylsilyl group. This protection method can also be carried out by a known method, and the reaction proceeds almost quantitatively. For example, protection with a triethylsilyl group is carried out by reacting triethylsilyl chloride in a solvent in the presence of a base such as piperidine.

As mentioned above, all the three-step reactions in the invention proceed almost quantitatively, and therefore the starting material (7-
The total yield from OH PGE) to the final product (7-XPGF) is extremely high. On the other hand, in the method using a diol as a starting material described in the previous invention of the present inventors, the yield of the reaction is to protect only the hydroxy group at the 7-position with a trimethylsilyl group without protecting the hydroxy group at the 9-position. It is difficult to achieve a sufficient yield, especially when R ² is a cyclic alkyl group. The method of the present invention can achieve extremely high yields regardless of the type of R ² .

7-XPGF obtained according to the present invention is directly
Alternatively, after deprotecting the trimethylsilyl group at the 7-position, it is fluorinated with a fluorinating agent and converted to 7-FPGF represented by the above formula []. The yield of deprotection of the trimethylsilyl group at position 7 of 7-XPGF is not very high (usually about 60-80%);
-7-FPGF by fluorination of hydroxy compounds
It is preferable that 7-XPGF is directly fluorinated without deprotection because the yield of 7-XPGF is lower than that in direct fluorination of 7-XPGF. The fluorinating agent is preferably an aminosulfate trifluoride type fluorinating agent such as piperidinosulfate trifluoride or diethylaminosulfate trifluoride, but is not limited thereto. The obtained 7-FPGF is preferably used as a starting material for 7-FPGGI ₂ as described above, but its use is not limited to this, for example, as a raw material for other fluorine-containing prostaglandins. It can be used. 7-
Regarding the production of 7-FPGI ₂ by the cyclization reaction of FPGF, basically known 5,6-dehydro-
A method for producing PGI ₂ by cyclization of PGF ₂ 〓 can be applied. This cyclization reaction is described, for example, in “J.
Amer.Chem.Soc.”, Volume 104, Pages 5842-5844
(1982), and “Tetrahedron Letters,” vol. 24,
1183-1187 (1983).

EXAMPLES The present invention will be specifically explained below using Examples, but the present invention is not limited to these Examples.

In addition, 15-cyclopentyl-PGF ₂
Compounds in which R ⁵ consists only of cyclopentyl groups (i.e., 16,17,18,19,20-pentanol-15
-cyclopentyl PGF ₂ ).

Example 1 5,6-dehydro-7-hydroxy-prostaglandin E ₂ methyl ester 11,15-bis(dimethyl-t-butyl)silyl ether [Formula []
, R ¹ is a methyl group, R ² is an n-amino group,
A compound in which R ³ and R ⁴ are dimethyl-t-butylsilyl groups] 705.3 mg (1.16 mmol) was dissolved in 8 ml of methylene chloride, cooled to 0°C, and then dissolved in pyridine.
938 μl (11.6 mmol) was added thereto, and then 294 μg (2.32 mmol) of trimethylsilyl chloride was added dropwise, followed by stirring at room temperature for 2 hours. 806 mg after post-processing using conventional methods
Crude 5,6-dehydro-7-trimethylsiloxy-prostaglandin E ₂ methyl ester of 11,
15-bis(dimethyl-t-butyl)silyl ether was obtained.

Dissolve the above product in a total volume of 11 ml of methanol,
Sodium borohydride 132mg at -30℃
Add a methanol solution (14 ml) of (3.48 mmol),
Stir for 10 minutes. 5 ml of saturated ammonium chloride solution was added to the reaction solution, the temperature was returned to room temperature, and methanol was removed under reduced pressure. Add 30 ml of saturated saline to the residue and
ml of ether three times, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and 808 mg of crude 5,6
-Dehydro-7-trimethylsiloxy-prostaglandin _F2 methyl ester 11,15-bis(dimethyl-t-butyl)silyl ether was obtained.

Dissolve the entire amount of the above product in 8 ml of pyridine,
398 μl (2.32 mmol) of triethyl chloride at −10°C
was added dropwise, and the mixture was stirred at room temperature for 2 hours. The resulting residue was purified by florisil column chromatography (hexane/ethyl acetate = 80/1) at 0°C to give 784.1 mg (0.98 mmol,
5,6-dehydro-7-trimethylsiloxy-prostaglandin _F2 (yield 84.7%) methyl ester 11,15-bis(dimethyl-t-butyl)silyl-9-triethylsilyl ether [formula], R ¹ is a methyl group, R ² is an n-amyl group, R ³
and R ⁴ is a dimethyl-t-butylsilyl group, R ⁵
was a triethylsilyl group] was obtained.

Example 2 5,6-dehydro-7-hydroxy-15-cyclopentyl-prostaglandin E ₂ methyl ester 11,15-bis(dimethyl-t-butyl)silyl ether [Formula [], R ¹ is a methyl group,
Compound where R ² is a cyclopentyl group and R ³ and R ⁴ are dimethyl-t-butylsilyl groups] 877.3 mg
(1.45 mmol) in methylene chloride solution (10 ml)
1.17 ml (14.5 mmol) of pyridine was added at °C, then 368 μl (2.90 mmol) of trimethylsilyl chloride was added dropwise, and the mixture was stirred at room temperature for 2 hours. Work-up was performed in a conventional manner to obtain 929.9 mg of unpurified 5,6-dehydro-7-trimethylsiloxy-15-cyclopentyl-prostaglandin E ₂ methyl ester.
11,15-bis(dimethyl-t-butyl)silyl ether was obtained.

The entire amount of the above product was dissolved in 14 ml of methanol in an unpurified state, and a methanol solution (12 ml) of 109.7 mg (2.90 mmol) of sodium borohydride was added at -30°C, followed by stirring for 10 minutes. A saturated ammonium chloride solution (5 ml) was added to the reaction solution, the temperature was gradually returned to room temperature, and methanol was removed under reduced pressure at room temperature. Saturated brine (50 ml) was added to the residue, extracted three times with 50 ml of ether, and the resulting organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate.
The solvent was removed under reduced pressure to yield 895.9 mg of crude 5,6-
Dehydro-7-trimethylsiloxy-15-cyclopentyl-prostaglandin _F2 methyl ester 11,15-bis(dimethyl-t-butyl)silyl ether was obtained.

Dissolve the entire amount of the above product in 10 ml of pyridine,
487 μl of triethylsilyl chloride (2.90 m
mol) was added dropwise, and the mixture was stirred at room temperature for 2 hours. The resulting residue was purified by florisil column chromatography (hexane/ethyl acetate = 100/1) at 0°C to obtain 872.2 mg (1.10 mmol, yield 75.8%) of 5,6 -Dehydro-7-trimethylsiloxy-15-cyclopentyl-prostaglandin F ₂ Methyl ester 11,15-bis(dimethyl-t-butyl)silyl-9-triethylsilyl ether [Formula [], R ¹ is a methyl group,
A compound in which R ² is a cyclopentyl group, R ³ and R ⁴ are a dimethyl-t-butylsilyl group, and R ⁵ is a triethylsilyl group] was obtained.

Claims (1)

[Claims] 1. After protecting the hydroxyl group at the 7th position of prostaglandins represented by the following formula [] with a trimethylsilyl group, the oxygen atom of the carbonyl group at the 9th position is converted to a hydroxyl group, and then the hydroxyl group A method for producing prostaglandins represented by the following formula [], which comprises protecting the compound with a protecting group other than a trimethylsilyl group. [Formula [], R ¹ is an alkyl group having 1 to 10 carbon atoms, R ² is a linear, branched, or cyclic alkyl group having 3 to 7 carbon atoms, and R ³ and R ⁴ are the same or different. Protecting groups other than trimethylsilyl group. ] [Formula [], R ¹ , R ² , R ³ , R ⁴ are the same as the above formula [], and R ⁵ is a protecting group other than trimethylsilyl group. ]