JPS6244560B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a process for producing 9α-halo-11β-hydroxy-corticosteroids, intermediates used in the process for producing steroids, and a process for producing the intermediate itself. The invention particularly relates to steroids with anti-inflammatory action, such as biclomethasone dipropionate.

9α-halo-11β-hydroxy-corticosteroids are known to have anti-inflammatory properties;
Many are used, especially for topical applications. An example of these steroids is “Steroid Chemistry and Pharmacology” by M.H. Brix and J. Brotherton.
(Academic Press 1970), pages 161-168. Biclomethasone dipropionate (9α-chloro-16β-methylprednisolone)
17,21-dipropionate or 9α-chloro-11
β-Hydroxy-16β-methyl-17α-21-dipropionyloxypregna-1,4-diene-
3,20-dione) is representative of these steroids and is described in British Patent Specification No. 1047519. (As a method for producing the corresponding 17α,21-diol or 17α-hydroxy-21-acyloxy compound) The corresponding 9β,11 of 9α-halo-11β-hydroxy-corticosteroids
Methods of preparation from the reaction of β-epoxy derivatives with halogenating agents are known.

9β,11β-epoxy derivatives have the corresponding 9α
- prepared by dehydrobromination of bromo-11β-hydroxy-corticosteroids (e.g. using sodium hydroxide or sodium methoxide in methanol or potassium or sodium acetate in methanol, ethanol or acetone) However, this known method is associated with undesirable side reactions such as ester cleavage, epoxide ring opening, D-homocyclic structuring of the D-ring, and rearrangement of side chains. The dehydrobromination process described in US Pat. No. 3,255,185 uses large amounts of high boiling solvents which are difficult to remove during product purification.

Applicants have prepared new 9α-halo-11β-hydroxy-corticosteroids which are conveniently obtained from the corresponding 9α-bromo-11β-hydroxy-corticosteroids. He developed a manufacturing method.

One form of the invention is represented by the formula (): , R ¹ and R ² each independently represent an alkanoyloxy group having 2 to 7 carbon atoms, R ³ represents hydrogen or methyl, and R ⁴ represents hydrogen, chlorine, fluorine or methyl or 2
It is intended to provide steroids of formula () such that the dotted line represents a fluorine atom and optionally represents a double bond in the 1,2-position. This epoxide has the structure (): It is preferable to have

When this epoxide is used in the production of biclomethasone dipropionate (as shown below), the structure (): It is named 16β-methyl-17α,21-dipropionyloxy-pregna-1,4,9(11)-triene-3,20-dione-9β,11β-oxide.

By the reaction of the compound having the formula () of the present invention with hydrogen chloride or hydrogen fluoride, the formula (): (wherein R ¹ , R ² , R ³ and R ⁴ are as defined above, R ⁷ represents chlorine or fluorine, and 1,
A dotted line at the 2-position optionally represents a double bond. ) 9α-halo-11β-hydroxy-corticosteroid is obtained.

This method is a method of opening the epoxide ring in a compound having formula () and inserting a 9α-chloro or 9α-fluoro group to generate a 11β-hydroxy group. This reaction is preferably carried out under substantially anhydrous conditions (eg, using anhydrous hydrogen chloride or hydrogen fluoride gas). This reaction is for example compound ()
Low temperature (-10 to +10
This can be easily carried out by saturating the solution with anhydrous hydrogen chloride or hydrogen fluoride at temperatures (°C).

The second form of the present invention is the formula (): (In the formula, R ¹ , R ² , R ³ and R ⁴ are as defined above, and the dotted lines at the 1,2-positions optionally represent double bonds.) and a base which is a salt of a weak organic acid or a tertiary amine.

Conversion of steroid ( ) to steroid ( ) can be carried out in a solvent suitable for the reactants. Examples of solvents include alkanols such as methanol, propanol and t -butanol;
There are cyclic ethers such as tetrahydrofuran. Certain bases used to process steroids also act as solvents themselves.

This reaction can be carried out over a wide range of temperatures and reaction times. This is preferably done by heating for a sufficient period of time to produce a substantial amount of the steroid(s). Generally the reaction mixture is heated to reflux for 0.5 to 10 hours. The ratio of the base to the steroid () may vary over a wide range, but it is preferable to use at least 1 mol to a considerable excess of the base per 1 mol of the steroid ().

Three examples of bases that can be used to convert steroids ( ) to steroids ( ) are alkali metal alkoxides (such as sodium methoxide, sodium propoxide, potassium t-butoxide), alkali metal alkanoates (such as potassium acetate, (such as potassium propionate), pyridine, 2,6-lutidine, collidine and diazabicyclo compounds (1,5-diazobicyclo[5,4,0]undec-5-ene, 1,4-diazabicyclo[2,2 ,2] Octane, 1,5-
(such as diazobicyclo[4,3,0]non-5-ene). Among these, potassium propionate and 1,5-diazabicyclo[5,4,0]-undec-5-ene ("DBU") are preferred because they provide a high yield of steroid (). Especially using potassium propionate in propanol or DBU in alkanols like tetrahydrofuran or t -butanol, isopropanol.
It is better to use This DBU can be used in equimolar amounts to the steroid (2) and precipitated from the reaction mixture as the hydrobromide salt, thereby reducing costs. This salt can be easily converted back into a reusable DBU. Use of a hindered base such as DBU will not separate unhindered 21-ester groups and can be conveniently used when esters or other groups sensitive to bases or nucleophiles are present.

If an alkanoate (e.g. potassium propionate in the case of a propionate ester group as in biclomethasone dipropionate) is used as the base, corresponding to the alkanoate ester group in the steroid with formula (), the ester Advantageously, cleavage and transesterification are avoided.

A starting material having formula () can be prepared by reacting the corresponding 9,11-dehydro-steroid with N-promosuccinimide.

For the production of biclomethasone dipropionate starting from 16β-methyl-17α,21-dihydroxypregna-1,4,9(11)-triene-3,20-dione (formula in the reaction system) The reaction system used in the above method is shown below. Each intermediate with the formula (,, and) is a known compound.

reaction system Steroids of formula () are known to have useful anti-inflammatory effects on the human body and can be incorporated into pharmaceutical compositions for appropriate medical administration, such as oral administration, or for topical use.

The following examples illustrate the invention.

General Methods Melting points were determined using a Thomas-Hoover melting point instrument and were uncorrected. NMR spectra were performed in deuteriochloroform solution. The δ value is
It was expressed in Hertz (Hz) on the down magnetic field side from TMS and was taken at the position of the peak observed on the spectrum. Functions with the same or closely related protons were considered to be radicals. For example, in the case of methyl protons, we did not test for specific NMR signals for any specific methyl group.

Thin layer chromatography test was carried out using Brinkmann silica gel 60F-254, 5 x 20 cm pre-coated TLC.
This was done on a board (Catalog No. 5761).

Production of starting material () used for epoxide production (see reaction scheme)
4,9(11)-triene-3,20-dione () 16β-methyl-17α,21-dihydroxypregna-1,4,9(11)-triene-3,20-dione () 2.10 g. , (6 mmol), 20 ml of triethyl orthopropionate, 4 ml of anhydrous dimethyl formamide and 0.5 g of pyridine hydrochloride was stirred in a curved bath at 100° C. under nitrogen atmosphere for over 45 minutes. After cooling, 1 ml of pyridine and 200 ml of ether were added, and the resulting solution was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. This was concentrated under reduced pressure and evaporated to dryness on a steam bath at about 1 mm pressure. The solid residue was recrystallized from methanol containing a small amount of methylene chloride to give 2.15 g (81.5% yield) of the material. It was homogeneous by TLC and had a melting point of 179-182°C. A small amount was further recrystallized as an analytical sample. Melting point 178-181.5℃. [α] ²⁵ _D +2.9゜(1%
CHCl ₃ ); uvλ _nax (10γ/mlEtOH) 238 mμ (ε
17200); Mass spectrum M/e440 (M ⁺ ); ir
max (KBr): 1730 (C=0), 1670 (conj.C=
0), 1635 and 1610 cm ^-1 (C=0); NMRδ:
43, 55, 63, 68, 71, 77, 85 (15H, CH ₃ ); 98
-180 (multiplet, CH and CH ₂ ); 200, 209,
214, 223 (2H, O-CH ₂ ); 239, 240 (2H, O-
CH ₂ C=O) and 330-440Hz (multiplet, 4H, C
= CH).

Analytical values for C ₂₇ H ₃₆ O ₅ (molecular weight 440.6): Calculated: C, 73.60; H, 8.25 Measured: C, 73.56; H, 8.21.

b 21-Hydroxy-16β-methyl-17α-propionyloxy-pregnane-1,4,9(11)-
Triene-3,20-dione () 17α,21-(1′-) in 2 ml of glacial acetic acid containing 1 drop of water
Ethyl-1′-ethoxymethylenedioxy-16β
-Methyl pregnathyl-1,4,9(11)-triene-
A solution of 0.264 g (0.6 mmol) of 3,20-dione () was stirred at room temperature for 4.5 hours, and TLC showed that the () compound had completely disappeared.
(Note: Reaction time varies depending on the amount of water present. The reaction was stopped upon completion of the conversion to minimize the formation of overly hydrolyzed by-products.) Water was then gently added to remove the precipitated solids. The residue was filtered, washed with water, and dried to obtain 0.205 g of a crude product. Recrystallization from ethyl acetate (a small amount of hexane was added to improve recovery) gave 0.145 g of analytically pure sample (). Melting point 188.5-189.5°C; [α] ²⁵ _D +4.4° (1%
CHl ₃ ); mass spectrum M/e412 (M ⁺ ), uvλ _nax
(10γ/mlEtOH)238mμ(ε16000);ir
max3425(OH), 1725(C=O), 1670(conj.C
=O), 1615, 1620 and 1630cm ^-1 (C=C);
NMRδ: 41, 61, 69, 74, 84, 86, 88 (12H,
CH ₃ ); 98-200 (multiplet, CH and CH ₂ );
242, 247 (2H, O-CH ₂ ) and 330-445 (multiplet, 4H, C=CH).

Analytical values for _C25H32O5 (molecular weight _412.5 ): Calculated _values : C, 72.79; H, 7.82.

Measured value: C, 72.91; H, 7.94.

c 16β-methyl-17α,21-dipropionyloxypregna-1,4,9(11)-triene-3,
20-Dione () 1 step starting from () 7 ml of anhydrous methylene chloride and anhydrous triethylamine
21-hydroxy- in 0.243g (2.4 mmol)
A solution of 0.83 g (2 mmol) of 16β-methyl-17α-propionyloxypregnane-1,4,9(11)-triene-3,20-dione () was cooled to 0°C, and while stirring, 0.222 g of propionyl chloride was added. (2.4 mmol) was added dropwise. After stirring at 0°C for 30 minutes, cold water was added and the product was extracted with methylene chloride. The lower layer was washed three times with water and once with brine, and then dried over anhydrous sodium sulfate. Evaporate under reduced pressure on a steam bath at about 1 mm to obtain 0.92 g of amorphous solid product (yield:
98%). [α] ²⁵ _D +16.8° (1% CH ₃ Cl);
uv λ _nax (10γ/ml EtOH) 238mμ (ε
15000); Mass spectrum M/e468 (M ⁺ ); ir
max (KBr): 1740 (C=O), 1670 (conj.C=
O), 1630 and 1610 cm ^-1 (C=C); NMR
δ: 46, 63, 71, 79, 86 (15H, CH ₃ ); 100—
200 (multiplet, -CH and -CH ₂ ); 252, 269,
287, 304 (2H, O—CH ₂ —C=O); and 335
-440Hz (multiplet, 4H, C=CH) Analysis value for C ₂₈ H ₃₆ O ₆ (molecular weight 468.6): Calculated value: C, 71.77; H, 7.74 Measured value: C, 71.38; H, 7.56 Starting from () 3 steps: 17α,21-dihydroxy-16β-methyl pregnathic-1,4,9(11)-triene-3,20-dione () 5.258 g (15 mmol), triethyl orthopropionate 30 ml, anhydrous dimethyl formamide A mixture of 20 ml and pyridine hydrochloride (0.75 to 1 g) was heated in an oil bath at 100° C. for 3 hours, and the reaction was examined by TLC. Then, cool, add 1 ml of pyridine, and evaporate the liquid under reduced pressure (approximately 1 mm, on a steam bath) to obtain a crude solid.
6.77g was obtained. Add this to 50ml of glacial acetic acid and 0.2ml of water.
After 4 hours of stirring at room temperature, TLC showed complete disappearance of starting material.
Then, water was added and the precipitated product was extracted with chloroform. The lower layer was washed three times with water, once with saturated sodium bicarbonate solution, once with saturated brine and dried over magnesium sulfate. This was evaporated under reduced pressure to obtain 6.12 g of crude product (). Half of this solid, 3.06 g (approximately 7.5 mmol), was dissolved in 20 ml of anhydrous methylene chloride containing anhydrous triethylamine (1.01 g, 10 mmol) and stirred at 0°C. Add propionyl chloride to this solution in 5 ml of anhydrous methylene chloride.
A solution containing 0.93 g (10 mmol) was added dropwise over 5 minutes. Then after stirring for 25 hours, TLC showed the reaction was complete. Cold water was added and the product was extracted with methylene chloride. The lower layer was washed three times with water, once with saturated sodium bicarbonate solution, once with brine and dried over anhydrous sodium sulfate. This was evaporated under reduced pressure to obtain 3.4 g of an amorphous solid. This benzene solution was mixed with Fissure alumina adsorbent 300 in benzene.
It was placed in an alumina column made using g. A solvent mixture containing 10-30% benzene and ethyl ether was first passed through a column to remove the less polar impurities present. Next is ether 40-80%
Continuing elution with benzene containing 3.01 g of pure amorphous solid product (88% yield over 3 steps)
or an average one-step yield of 95.5%). [α] ²⁵ _D +
17.4゜(0.85% _CHCl3 ); uvλ _nax (EtOH) 237m
μ (ε17500) measurement analysis value: C, 71.46; H,
7.42.

d 9α-bromo-11β-hydroxy-16β-
Methyl-17α,21-dipropionyloxypregna-1,4-diene-3,20-dione () 16β-Methyl-17α,21-dipropionyl-oxypregna-1,4,9(11) in 50 ml of acetone ―
A liquid containing 2.343 g (6 mmol) of triene-3,20-dione () was cooled and stirred on ice, and 1.335 g (7.5 mmol) of N-bromosuccinimide was added thereto. The reaction flask was covered with aluminum foil to prevent exposure to light. To this was added 3 ml of 0.2N perchloric acid solution, and the mixture was stirred at 0°C for 3.5 hours. then number
ml of saturated sodium bisulfite solution was added, and the mixture was stirred at 0°C for 15 minutes and then at room temperature for 15 minutes. Then 300ml of water
was added gently to form crystals and the mixture was frozen overnight. The crystallized solid was filtered, washed with water, and dried in a vacuum oven to obtain 2.75 g of product (97.4% yield). Melting point 163-164° (decomposed). This was homogeneous by TLC and correctly analyzed as bromohydrin ().

Analytical values for C ₂₈ H ₃₇ BrO ₇ (molecular weight 568.5): Calculated values: C, 59.47; H, 6.59; Br, 14.3 Measured values: C, 59.30; H, 6.84; Br, 14.1 A small amount from benzene containing a few drops of methanol The sample was recrystallized. (Recovery rate 90%) Melting point 162-163° (decomposition). (Preheating the melting point measuring device will make the melting point higher.); [α] ²⁵ _D +98.2 (0.5% CHCl ₃ ); uvλ
_n
ax (12.1γ/mlEtOH): 243mμ (ε18100); ir
max (KBr): 3450 (OH), 1735 (C=O),
1660 (conj.C=O), and 1620cm ^-1 (C=
C); NMR δ: 61, 71, 78, 85, 103 (15H,
CH ₃ ); 104-200 (multiplet, CH and CH ₂ ),
253, 271, 289, 294, 306 (3H, OCH and
OCH ₂ ) and 368-445Hz (multiplet, 3H, C=
CH), measured analysis value: C, 59.24; H, 6.50; Br,
14.11.

Example 1 16β-methyl-17α,21-dipropionyloxypregna-1,4,9(11)-triene-3,20
-dione 9β,11β-oxide () 9α-bromo-11β-hydroxy-16β-methyl-17α,21-dipropionyloxypregna-1,4-diene-3,20-dione ()0.568
g (1 mmol), 10 ml of anhydrous THF and 1,5-
Diazabishizaro [5,4,0] Undesen-5-
A mixture of 0.167 g (1.1 mmol) of enene was distilled under reflux for 6 hours with stirring. This was cooled and precipitated.
The crystalline hydrobromide salt of DBU was overseparated and washed with ether. (0.21g (yield: about 90%) of this salt can be used for reagent regeneration) The solution was diluted with water and extracted with ether. The ether layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate.
Evaporation under reduced pressure yielded 0.493 g of crude solid product. This was homogeneous on TLC and suitable for conversion to biclomethasone dipropionate without purification. Recrystallization from 90% methanol gave 0.39 g (81% yield) of crystalline product. melting point
158-159.5°. A small sample was further recrystallized from methanol to obtain an analytical sample of (). melting point
159.5-161.5゜; uvλ _nax (9.2γ/mlEtOH):
248 mμ (ε17600); [α] ²⁵ _D +40.2 (1%
CHCl ₃ ); ir max (KBr): 1740 (C=O), 1670
(conj.C=O), 1635 and 1610cm ^-1 (C=C);
NMRδ: 54, 62, 70, 78, 83, 87 (15H,
CH ₃ ); 100-170 (multiplet, CH and CH ₂ ); 197
(1H, OCH); 251, 268, 283, 299 (2H,
OCH ₂ C=O) and 370-407Hz (multiplet, 3H,
C=CH).

Analytical values for C ₂₈ H ₃₆ O ₇ (molecular weight 484.6): Calculated value: C, 69.40; H, 7.48 Measured value: C, 69.44; H, 7.46 Example 2 9α-bromo-11β-hydroxy-16β-methyl-17α ,21-dipropionyloxypregnane-1,4-diene-3,20-dione ()0.284
g (0.5 mmol), potassium propionate 0.284
a mixture of 50 g and 20 ml of anhydrous propanol.
Distilled under reflux for 60 minutes. After cooling, water was added and the mixture was extracted with benzene. The benzene layer was washed twice with water and once with saturated brine, and dried over anhydrous magnesium sulfate. This was evaporated under reduced pressure to obtain a crude product of 0.233
I got g. It was homogeneous in TLC. Recrystallization was performed twice from 90% methanol to obtain 139 mg (yield: about 60%) of pure analytical sample of (). Melting point 158.5―
160.5゜; [α] ²⁵ _D +41.8 (1% CHCl ₃ ); uv λ _na
x (10 γ/ml EtOH) 248 mμ (ε 17300); ir and NMR spectra were identical to those of the product obtained in Example 1. Measured analysis value: C,
69.44; H, 7.46.

Reference Example 9 α-Chloro-11β-hydroxy-16β-methyl-17α,21-dipropionyloxypregna-1,4-diene-3,20-dione (biclomethasone dipropionate) Methanol-free chloroform 30ml inside
A liquid containing 200 mg (0.413 mmol) of 16β-methyl-17α,21-dipropionyloxypregna-1,4,9(11)-triene-3,20-dione 9β,11β-oxide () was mixed with ice and water. The mixture was cooled and saturated with anhydrous hydrogen chloride gas (made by passing commercially available hydrogen chloride gas through concentrated sulfuric acid and drying it). After stirring the solution at 0° for 4 hours, 2 g of solid sodium bicarbonate was added and stirring continued for an additional 0.5 hour. The sodium bicarbonate residue was filtered and washed with chloroform. The liquid was evaporated under reduced pressure (water aspirator) to obtain 0.213 g (yield 99%) of a crude product. this is
It was homogeneous in TLC. This was crystallized twice from isopropyl ether-ethyl acetate and
Vacuum drying was carried out for 2 hours at 50°C (boiling point of water) to obtain 145 mg (yield 67%) of an analytically pure sample of the title product. melting point
209.5−210.5°; [α] ²⁵ _D +85.7 (0.43% CHCl ₃ )
;
uv λ _nax (9γ/mlEtOH): 238mμ (ε
18000); ir max (KBr): 3450 (OH), 1740
(C=O), 1640 (conj.C=O) and 1620 cm ^-1
(C=C); NMRδ: 62, 71, 79, 85, 101
(15H, CH ₃ ); 102-200 (multiplet, CH and
CH ₂ ); 251, 268, 380, 289, 306 (3H, OCH and OCH ₂ ) and 365-445Hz (multiplet, 3H, C
= CH).

Analytical values for C ₂₈ H ₃₇ ClO ₇ (molecular weight 521.05): Calculated value: C, 64.54; H, 7.15; Cl, 6.80 Measured value: C, 64.31; H, 7.09; Cl, 7.01

Claims (1)

[Claims] 1 Formula (): , R ¹ and R ² each independently represent an alkanoyloxy group having 2 to 7 carbon atoms, and R ³
represents hydrogen or methyl, R ⁴ represents hydrogen bonded to the 6-carbon atom, and the dotted line at the 1-2 position optionally represents a double bond. 2 Formula (): (In the formula, R ¹ and R ² each independently represent an alkanoyloxy group having 2 to 7 carbon atoms, and R ⁴
represents hydrogen bonded to the 6-carbon atom. ) The compound according to claim 1, which is represented by: 3. Claim 1 in which the compound is 16β-methyl-17α,21-dipropionyloxy-pregna-1,4,9(11)-triene-3,20-dione-9β,11β-oxide Compounds described. 4 Formula (): , R ¹ and R ² each independently represent an alkanoyloxy group having 2 to 7 carbon atoms, R ³ represents hydrogen or methyl, R ⁴ represents hydrogen bonded to a 6-carbon atom, and 1,2 The dotted line at the - position optionally represents a double bond Formula () characterized in that the steroid represented by the formula () is treated with an alkoxide, a salt of a strong base and a weak organic acid, or a base which is a tertiary amine: (In the formula, R ¹ , R ² , R ³ and R ⁴ and the dotted line at the 1,2-position are as defined above.) 5. The method according to claim 4, wherein the treatment is carried out in a solvent. 6. The method according to claim 5, wherein the solvent is selected from alkanols and cyclic ethers. 7. The method according to claim 4, wherein the treatment is carried out by heating the reaction mixture under reflux for 0.5 to 10 hours. 8. Process according to claim 4, in which at least 1 mole of base per mole of steroid is used in the treatment. 9 Base is alkali metal alkoxides, alkali metal alkanoates, pyridine, 2,6-
The method according to claim 4, wherein the method is selected from lutidine, collidine and diazobicyclo compounds. 10 The base is potassium propionate or 1,5-
Diazobicyclo[5,4,0]undecene-5-
10. The method according to claim 9, wherein 11. Claims in which the base is potassium propionate and the solvent is propanol, or the base is 1,5-diazobicyclo[5,4,0]undecen-5-ene and the solvent is tetrahydrofuran or an alkanol. The method according to paragraph 10. 12 The base is 1,5-diazobicyclo[5,4,
0] Undecen-5-ene and used in an equimolar amount with the compound () Claim 1
The method described in item 0. 13. The method according to claim 9, wherein the base is an alkanoate having the same alkanoyl group as in the compound having formula ().