JPS60188398A - Production of 6beta-fluoro-delta1,4-pregnadiene derivative - Google Patents

Abstract

PURPOSE:To produce the titled fluorine-containing steroid compound useful as an anti-inflammatory agent, in high yield, by reacting an alkali metal salt of an organic acid with fluorine gas, reacting the product with DELTA<3.5>-pregnadiene derivative, and separating the objective product from the reaction product. CONSTITUTION:An organic acid alkali metal salt (e.g. CH3COONa) is made to react with fluorine gas (usually diluted to <=20mol% with an inert gas such as N2) preferably in a chlorofluorocarbon solvent at about -75 deg.C. The obtained reaction mixture is made to react with a DELTA<3.5>-pregnadiene derivative, and the objective compound is separated from the product by column chromatography, high-performance liquid chromatography, etc.

Description

[Detailed description of the invention] The present invention relates to a method for producing a fluorine-containing steroid compound.

It is known that fluorine-containing steroid compounds, particularly compounds in which fluorine is introduced into adrenal cortical hormones, have excellent anti-inflammatory effects.

The general manufacturing method of this fluorine-containing steroid compound (fluorine-containing adrenal cortical hormone) consists of reacting the steroid compound with a fluorinating agent, and the positions where fluorine can be introduced are 2.4.6.9.15 When fluorine is introduced into the 9β-position and/or the 9β-position, a marked enhancement of the anti-inflammatory effect is observed.

In addition, it can suppress the use of these steroids, and can be used as an excellent anti-inflammatory agent to treat rheumatism and the like.

, etc. The position numbers of steroid compounds are indicated as follows.

Further, for example, an isomer of a compound in which fluorine is introduced at the 6th position is expressed as F F (6β position) (6β position).

Conventionally, fluorinating agents used when fluorinating steroid compounds include F2, XeF2, FCIOs, C
FsOF, CFsCOOF, etc. are known. However, no matter which of these fluorinating agents is used to fluorinate steroid compounds, the yield of fluorine-containing steroid compounds is low.

Recently, CTh C00F (CH, + CO in the presence of acetic acid
It is said that this occurs when F2 is applied to ONa. )
Several fluorinating agents have been developed, and fluorinated aromatic compounds or fluorinated sugars have been successfully synthesized. Typically, the aromatic ring of the former is substituted with hydrogen and fluorine, while the double bond of the latter saccharide has fluorine and acetoxyl groups added to both ends, respectively.

Therefore, the present inventors further conducted intensive research to utilize the CHs C00F in the fluorination reaction of steroid compounds, and surprisingly found that the fluorination reaction mechanism of steroid compounds was similar to reactions (1) and (2). ), the reaction mechanism was completely different from that of fluorine-containing steroid compounds, and the unexpected production of fluorine-containing steroid compounds in good yield was avoided [7] and the present invention was achieved.

That is, the gist of the present invention is to react an alkali metal salt of an organic acid with fluorine gas, and to react with the resulting reaction mixture and △3?5.
- 6β-fluoro-Δ114- characterized in that a pregnagene derivative is reacted and a 6β-fluoro-Δ1+4-pregnagene derivative is separated from the reaction mixture.
The invention consists in a method for producing pregnagen derivatives.

The reaction of the present invention is illustrated by a reaction formula (in the formula, - indicates a mixture of α and β forms, and -1 indicates that a double bond may be present). This fluorination reaction of steroid compounds is completely unexpected from the fluorination reactions of aromatic compounds and sugars, and as seen in the above reaction formula, fluorine is added to the 6-position and the electronic configuration of the A and B rings is changed. The acetoxyl group at the 3-position is converted to an oxo group, and 6α and 6β-fluoro-Δ4-pregnane derivatives and 6β-fluoro-Δ114-pregnagene derivatives are simultaneously produced.

The production method of the present invention involves the production of 6β-
The method further includes the step of separating the fluoroΔ14-pregnagene visiting conductor. As a separation method, ordinary column chromatography or high performance liquid chromatography is used.

The alkali metal salt of an organic acid in the present invention refers to an alkali metal salt of a lower carboxylic acid, such as CH3COON.
a , CH3C)h COONa 1CH3CH2C
Examples include H2COONa, and K corresponding to Na salt is also preferably used.

The fluorine gas used in the reaction of the present invention is usually diluted with an inert gas such as N2 or He, and is generally used at a concentration of 20 mol% or less.
This is usually carried out using a neutral or weakly acidic solvent inert to fluorine, preferably a chlorofluorocarbon solvent and/-! It is carried out in a mixed solvent of bamboo organic acids. The reaction temperature of the chlorofluorocarbon solvent (around -75'C)
For example, CC13F (Freon-1
1), 6-CCJ2F+ (7El non-2), CBrF3 (Freon-13 [3]), CHCez F (7o 7-21)
, cncfp2()on-22'), CC/JFz C
ClF2 (Freon-114), CB r Fz CB
Examples include rF* (Freon-11482).

Further, the organic acid is a lower carboxylic acid, for example, CH3
Coot(.

CH3CI(2C00H1CHx CJT2 CH2C
00II and the like.

The steroid compound to be fluorinated in the reaction of the present invention is a △3+I-pregnagene derivative represented by 2"ON/ゝOR+ (in the above formula, R1, R2 and R3 are hydrogen or a lower acyl group). However, it is not limited to these (and others).

It is a compound represented by fluorostero-r-doped F F (in the above formula, R1, R2, R3, - and ---- are the same as above), etc. produced by the reaction of the present invention, and the production method of the present invention The compound obtained is 6β of the fluorosteroid compounds listed above.
-Fluoro-Δ114-pregnagene derivative.

Some of the above-mentioned raw material steroid compounds are difficult to dissolve when added to a solvent in a solid state, so C may be added as necessary.
CL, C) IC71s, C) 12 C/! x etc. 7.7
It is also possible to dissolve the compound in advance in a solvent inert to the hydrogenation reaction, and then add this solution to the reaction solvent for use in the reaction.

Within 1 hour.

Next, the present invention will be specifically explained with reference to Examples and Comparative Examples.

Example 2 In a 00 ml polyethylene container, 4 ml of CCl5F (Freon-11) 100 tnlSCHs COOH and 600 ”f of CHs CO0Na (fine powder) were added.
F2 gas (12 mmol) diluted to 10 mol% with N2 gas was added to the liquid in the flask and cooled externally with dry ice-acetone while stirring vigorously.
mol) was passed for 30 minutes at a flow rate of 1-00+++/minute. Next, steroid compound (1) 930 W (2
, 5 mmol) into the flask and heated to -75°.
The mixture was stirred and reacted at C for 10 minutes. After that, a saturated Na25Oa aqueous solution (1,5#+t) was added to the flask to stop the reaction, and the solvent was removed using an evaporator and the resulting solid was subjected to silica gel column chromatography. (Wako Gel C-200°3cM
〆x20m, solvent: methylene chloride/acetate; tolyl-9
/1, but by volume), and the fractionated solution was developed with silica gel thin layer chromatography (same as above) to obtain R,
Although a spot was generated at =0.43, 10-10% was collected and the solvent was removed under reduced pressure to obtain 531 da of white crystals. Next, 100q of this white crystal is 1ttt
The resulting solution was subjected to high performance liquid chromatography (Waters Model 510,
Column: Radial Pack C-18, Eluent: Methanol/Water-8/2, only 1, '# amount, Effluent-N: 0.9
M//min, detection wavelength: 25411 m),
Rf = 12.7 minutes [with compound ('IT-a)]? f=
Compounds showing a peak at 10.5 minutes [compound (11'-b)] were each fractionated 12 and subjected to nuclear magnetic resonance (NMR) analysis. In addition, the peak area change (IT
-2)/(TI-b)-4/2.

The NMR analysis results are shown below.

One Compound (T-a)-'H-NMR (Solvent: CDC/s, Internal Standard: Tetramethylsilane) In the above table, 6α-form and 6α-form represent 6α-fluoro form and 6β-fluoro form, respectively. Same meaning below.

19F-NMR (solvent: Cr) (J13, internal standard, pencitrifluoride) The signal intensity of +11p was 1/2 of 6α form/6β form.

(Bendaiku Imadai) On page K ~Drying compound (U-b) LH-NMR (Solvent and internal standard are the same as above.) 1
9F-NMR (Solvent and internal standard are the same as above.) 1
4- From the above analysis results, compounds (II-3) and (T-
b) were identified as the compounds shown in the table below in c.

Comparative Example CI (s COONa replaced by CF3Co0N)
The fluorination reaction, separation and analysis of the product were carried out in the same manner as in the example except that a 1/(7.4 mmol) was used. The results are shown in the table below.

0 Kazuo Sugi, Director General of the Patent Office, June 1980, 1, Indication of the case, Patent Application No. 45285, filed in 1982, 2,
Title of the invention Process for producing 6β-fluoro-Δ・4-pregnagene derivative 3, Relationship to the case of the person making the amendment Patent applicant address New Hankyu Pill 5, 1-12-39 Umeda, Kita-ku, Osaka
, Subject of amendment Column 6 of "Detailed Description of the Invention" of the specification, Contents of amendment (attached sheet) A visiting conductor.

Some of the above-mentioned raw material steroid compounds are difficult to dissolve when added to a solvent in a solid state, so c.
It is also possible to preliminarily dissolve ce4% CHC, CH2Cl3, etc. in a solvent inert to the fluorination reaction, and add this solution to the reaction solvent for use in the reaction.

The reaction temperature of the reaction of the present invention is usually 30-(00'0, preferably 0 to -80°C, and the reaction time is usually 1
Within hours.

Next, Examples and Comparative Examples will be shown to illustrate the present invention (the following margin continues on the first page) 2-

Claims (1)

[Claims] 1. Reacting an alkali metal salt of an organic acid with fluorine gas,
The obtained reaction mixture is reacted with a Δ2,6-pregnadiene derivative, and 6β-fluoro-Δl is produced from this reaction mixture.
A method for producing a 6β-fluoro-Δ1,4-pregnadiene derivative, which comprises separating a +4-gregnadiene derivative.