JPS58222100A - Preparation of steroid compound - Google Patents

Abstract

PURPOSE:To obtain the titled compound useful as an antiphlogistic having low side effect, etc., by converting a 9alpha-fluoro-4-pregnen-3,11,20-trione-17,21-diester into a ketal derivative, followed by oxidation, bromination, oxidation, fluorination, dehydrobromination, and dehydration. CONSTITUTION:A 17alpha, 21-dihydroxy -9alpha- fluoro -4- pregnen-3, 11, 20-trione-17, 21- diester shown by the formula I (OR<1> and OR<2> are acyloxy, sulfuric ester, or phosphoric ester) is converted into a ketal derivative, and oxidized to give a compound shown by the formula II (W-X is C=O, CH-OH; Y-Z is C=CH, epoxy, etc.), which is brominated, converted into an epoxy derivative, which is reacted with hydrogen fluoride to give a compound shown by the formula III(Q is H or Br). This compound is then dehydrobrominated and dehydrated, to give a compound shown by the formula IV.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides 2-bromo-6β,9α-difluoro-11
β.

The present invention relates to a novel method for producing 17α,21-to)hydroxy-1,4-pregnagene-3,20-dione-17,21-diesters.

2-bromo-6β,9α-difluoro-11β,17α,21-)dihydroxy-1, produced according to the present invention
4-Pregnadiene-3,20-dione-17,21-
The diester (hereinafter referred to as Compound 0) has fewer side effects, such as weight loss, sodium retention, potassium depletion, adrenal and pituitary suppression, which are seen with various known physiologically active steroids (especially anti-inflammatory effects). It is also known to have valuable medicinal effects such as anti-rheumatoid arthritis effects (see Publication No. 14677/1983).
. Antirheumatic effects have also been reported by intra-articular injection. ↑, 1 This compound @
There are some known methods for producing (for example, Japanese Patent Publication No. 14677/1983, Japanese Patent Application Laid-Open No. 6955/1982, and Japanese Patent Application Laid-open No. 154998/1989), but these all involve hydrocortisone-21-ester. (7) 11-c Himer is used as a starting material. 6β-fluoro-5α is produced through ketalization with ethylene glycol, epoxidation with peracid, and ring-opening of epoxy with hydrogen fluoride.

11α, 17α, 21-tetrahydroxypregna-6
, 20-dione-21-ester as the first important intermediate, followed by pro-protomization at the 2-position, formation of double bonds at the 1,2-position and 4,5-position, and the formation of a hydroxyl group at the 1″1-position. A combination of reactions such as mesylation of , acylation of the hydroxyl group at the 17th position, formation of double bonds at the 9th and 11th positions, bromohydrination at the 9th and 11th positions, epoxidation with a base, and ring opening of the epoxy compound with hydrogen fluoride. are synthesized.

Problems with each of the above synthesis methods of compounds @11 of raw materials
- Shrimp hydrocortisone-21-ester is difficult to obtain and expensive. Therefore, it is desirable to synthesize using cheaper and more readily available raw materials.

As a result of intensive studies, the present inventors have found that hydrocortisone-21-acetate, which is an inexpensive and easily available industrial raw material, can be used as a starting material with a higher yield than, for example, 11-shrimp hydrocortisone-21-acetate. Said compound [phase]
They completed the manufacturing method.

Next, the method for producing compound 0 according to the present invention is shown in Scheme-1 as Scheme-1 X. Ge, ■ o 0 (However,
(In the formula, OR' and OR'' represent the same or different acyloxy group, sulfate ester or phosphate ester residue.) Hereinafter, the case of an acetyl group will be explained as a specific example of R1 and R2 in the formula. Regarding various compounds during the reaction process, for example, compound (2) is abbreviated as "compound (1)", and the same applies to the others.

Now, Compound ■', which is one of the starting materials in the present invention, is a known compound, which is prepared by reacting hydrocortisone-2-door acetate (Compound ■') with pyridine and methanesulfonyl chloride in N,N-dimethylformamide. , converted to the compound ■′. It can be easily obtained in high yield by using an acetylating agent such as acetic anhydride or isopropenyl acetate in the presence of an acid catalyst such as perchloric acid or para-toluenesulfonic acid. 11
In order to obtain the Δ9 (11) form with a hydroxyl group at the hydroxyl position, conventionally known methods carry out a 2-step reaction via the 11-mesyloxy form, but by using the compound σ as the starting material, the reaction can be carried out in one step. , the reaction process is shortened.

9α-chlor or 9α-bromo-11β, 17α.

21-trihydroxy-4-pregnene-6,20-dione-17,21-diacetate (compound ■') is 1
7α.

It can be obtained by reacting 21-dihydroxy-4,9(11)-pregnagene-6,20-dione-17,21-diacetate ("Compound ■') with hypochlorous acid or hypobromous acid. The reaction is carried out using an acidic aqueous raw salt icing agent or a brominating agent, and examples of the chlorinating agent or brominating agent include N-chlorosuccinimide, N-promuconolylhydrimide, N-bromoacetamide, N- Examples include chloracetamide, and examples of acids include sulfuric acid and perchloric acid sieves.

Further, an organic solvent can be used as a co-solvent for the reaction, but any organic solvent may be used as long as it does not react with either the raw materials or the product, and preferred examples include dioxane, tetrahydrofuran, acetone, etc., which have good solubility in water. . Furthermore, the reaction temperature is usually 0 to 50°C, but the solvent used,
Varies depending on acid and chlorination (bromination) agent.

17α,21-dihydroxy-9β,11β-epoxy-4-pregnene-3,20-dione-17,21-diacetate (Compound ■Su & \Compound ■I As a basic substance, triethylamine, which has no nucleophilic property, , tertiary amines such as pyridine, delcali metal carbonates, and alkali metal hydrogen carbonates are preferable.
The reaction time may be shortened by adding the basic substance to the reaction system in which the compound ■' is produced and heating it to a temperature of 0 to 80°C, preferably 40 to 80°C. I can do it.

9α-Fluoro-11β,17α,21-trihydroxy-4-pregnene-6,20-dione-17,21-
Diacetate (compound 1) can be obtained by reacting compound 2' with hydrogen fluoride. Hydrogen fluoride is preferably introduced as an aqueous solution, and the reaction is preferably carried out at a low temperature such as 0)10°C. In the reaction, Compound 1' may be added directly to an aqueous hydrogen fluoride solution, or a solution of Compound 2' in an organic solvent may be added. The organic solvent to be used in this case may be one that does not react with the compound ζζ■' or hydrogen fluoride, but preferred are those that have good solubility in the compound ζ/g), such as tetrahydrofuran and chloroform.

17α,21-dihydroxy-9α-fluoro-4-pregny-3・11・2°-tri7-17・21
- Shea 10, Cetate (Compound ■ Liwo gas compound ■ Can be obtained by benzooxidation. At this time, an oxidizing agent is used. As an oxidizing agent, a chromium compound such as chromic anhydride, sodium dichromate, or dimethyl Sulfoxide (DMSO) is preferred.

The reaction is carried out in a solvent, but depending on the oxidation used, it is preferable to use pyridine in the case of chromic anhydride, and a mixed solvent of acetic acid and water in the case of sodium dichromate. Further, in the case of oxidation using DMSO, DMSO may be used as a solvent, or other organic solvents may be used in combination, such as tetrahydrofuran, methylene chloride, chloroform, etc. Further, in the case of oxidation using DMSO, the presence of a dehydrating agent is essential, and as the dehydrating agent used in this case, an acid anhydride or an acid nologide is suitable as the dehydrating agent. Preferred acid anhydrides include acetic anhydride, trichloroacetic anhydride, trifluoroacetic anhydride, sulfuric anhydride, methanesulfonic anhydride, and the like.

On the other hand, as the acid halide, acetyl chloride, acetyl bromide, benzoyl chloride, oxalyl chloride, methanesulfonic acid chloride, valatoluenesulfonyl chloride, etc. are preferable.

Furthermore, the reaction temperature is -2 in the case of oxidation with chromium compounds.
It is preferable to carry out the oxidation between 0°C and 40°C, depending on the dehydrating agent used in the case of DMSO-based oxidation.
It is carried out appropriately between -100 degreeC. By the method described above, compound (1) can be obtained in a high yield, and as a result, the ketalization accompanied by the movement of the double bond, which will be described later, proceeds in a high yield.

17α,21-dihydroxy-6,3-ethylenedioxy-9α-fluoro-5-pregnene-11,20-dione-17,21-diacetate (compound It can be obtained by reacting with glycol or its fermented derivative. Examples of the acid catalyst used include sulfonic acids such as methanesulfonic acid, p-toluenesulfonic acid, and trifluoromethanesulfonic acid, and sulfonic acid resins such as Amberlyst 150.

Further, as the ethylene glycol derivative, a ketal form of a carbonyl compound such as acetone egrene ketal or mesityl oxide ethylene ketal, or a ketalizing agent such as ethylene glycol di)IJ methylsilyl ether can be used. The reaction is carried out in an organic solvent, but any solvent may be used as long as it does not react with the raw materials or products.
Examples include solvents such as benzene, tetrahydrofuran, and chloroform. Also, the reaction is -20℃~100℃
It can be carried out at a temperature within the range of 200 to 3000, but it varies depending on the type of acid catalyst or ketalizing agent used. Furthermore, good results can be obtained by adding a dehydrating agent such as Molecu 2-Sheep or calcium sulfate as a reaction aid.

6.6-ethylenedioxy-9α-fluoro-11β.

17α,21-)dihydroxy-5-pregnene-20
=one-17,21-diacetate (compound ■/) ζ
As the ψ reducing agent that can be obtained by reacting 1 with a reducing agent, boron hydride (IJ) is inexpensive and has good stereoselectivity. The reaction is carried out in a solvent, and the solvents used include N, N-dimethylformamide, N
- An amide polar solvent such as methylpyrrolidone or a mixed solvent system of tetrahydrofuran and water, or an organic solvent such as dioxane and wood aroma and water is preferred.

In addition, the reaction temperature can be carried out between 0 and 50°C,
By carrying out gently, preferably between 0 and 60°C,
Side reactions can be prevented.

5α,6α-epoxy-3,3-ethylenedioxy-1
1β, 17α, 2l--ll) lyhydroxypregnar 20-one-17,21-diacetate (compound [phase]
can be obtained by reacting compound (1) with peracid. Examples of the peracid used include peracetic acid, pertrifluoroacetic acid, methachloroperbenzoic acid, perbenzoic acid, and permonophthalic acid. The reaction is carried out in an organic solvent, but any halogen-based solvent such as methylene chloride or chloroform is usually used as long as it does not react with the raw materials or products. Moreover, it is preferable that the reaction temperature is usually carried out between -20 and 50°C.

6β, 9α-difluoro-5α, 11β, 17α, 21
-tetrahydroxypregna-3,20-dione-17
゜21~Diacetate (compound ■l) is a compound [phase]'
It can be obtained by treating with hydrogen fluoride water.

In the reaction, the compound [phase]' may be added directly to the hydrogen fluoride water, or it may be dissolved in an organic solvent. Examples of the organic solvent used for this removal include those in which the raw material compound [phase]' has good solubility, such as tetrahydrofuran and chloroform. Furthermore, the reaction can be carried out at a temperature of 0 to -80°C, preferably at a temperature of -20 to -80°C.

2.2-dibrome-6β,9α-difluoro-5α.

11β, 17α, 21-tetrahydroxypregna-3
゜20-dione-17,21-diacetate (compound @
') can be obtained by bromination of compound Q/17). Examples of the brominating agent include bromine and N-bromosuccinimide. At this time, sodium acetate, potassium acetate, etc. are used in combination as basic substances. Preferably, the reaction is carried out in acetic acid. Moreover, although the reaction temperature can be carried out between 0 and 120°C, it is preferable to carry out the reaction at a temperature between 80 and 120°C for a short time.

2-bromo-6β, 9α-difluoro-11β, 17α
.

21-trihydroquine-1,4-pregnagene-17
21-Diacetate (compound) can be obtained by heating the compound to perform dehydrobromination and dehydration.

The reaction is carried out in an organic solvent, but the organic solvent used is N
.

Amide solvents such as N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone are suitable.

As a catalyst for dehydrogenation and dehydration, a metal chloride or a metal carbonate can be used in combination with the metal chloride. As the general halide, lithium chloride or lithium bromide is preferred, and as the metal carbonate, alkali metal carbonates such as lithium carbonate and sodium carbonate, or alkaline earth metal carbonates such as calcium carbonate can be used. The reaction is carried out at a high temperature of 80-160°C, preferably between 100-160°C to give good results.

17α,21-dihydroxy-5α,6α-epoxy-
6,3-ethylenedioxy-9α-fluoropregna
Compound 1 can also be obtained in the same manner as the oxidation of 11,20-dione-17,21-diacetate (compound @') & L compound 2' to compound [phase]'. In addition, when treated with a reducing agent in the same manner as in the reduction of compound G'& compound 6, compound [phase]' is obtained.

6β,9α-difluoro-5α,17α,21-)lyhydroxybregna-3,11,20-4ion-17.
21-diacetate (compound @ can be obtained by treating compound 1' with hydrogen fluoride in the same manner as the reaction of compound 2' from compound [phase]').

2.2-dibrome-6β,9α-difluoro-5α,1
7α,21-)lihydroxypregna-3,11,20
-trione-17,21-acetate (compound [phase]'
) can be obtained from compound 0' by brominating compound [phase]' in the same manner as the reaction of compound @.

2-bromo-6β, 9α-difluoro-17α, 21-
'lj! Dihydroxy-1,4-pregnadiene-3,11,2
0-trione-17,21-diacetate (compound 0'
) is a compound [
It can be obtained by dehydrobrominating and dehydrating phase]'.

Furthermore, compound o''4< can be obtained by adding a reducing agent to compound o bamboo compound ■' in the same manner as the reaction of compound I or compound @pe.

According to the present invention, even when OR' and OR'' in the chemical formula are ester residues other than acetoxy, the compound ◎ can be produced in substantially the same manner as in the case of an acetoxy group, or by a routine change by a person skilled in the art. can.

Inorganic acids constituting other ester residues include sulfuric acid, phosphoric acid, and organic acids include sulfonic acid, aliphatic, alicyclic,
Carboxylic acids can be referred to, including aromatic, arylaliphatic and heterocyclic carboxylic acids, and including carboxylic acids such as thiocarboxylic acids and aminocarboxylic acids. Examples of carboxylic acids include formic acid, acetic acid, chloroacetic acid, trifluoroacetic acid, propionic acid, butyric acid, valeric acid, trimethylacetic acid, diethyl acetic acid, caproic acid, crotonic acid, enanthic acid, caprylic acid, capric acid, valmitic acid, undecanoic acid, Undecanoic acid, oxalic acid, succinic acid, glutaric acid, pimelic acid, tartaric acid, maleic acid, lactic acid, carbamic acid, glycine, alkoxycarboxylic acid, hexahydrobenzoic acid, cyclopentylpropionic acid, cyclohexylacetic acid, cyclohexylbutyric acid, benzoic acid, phthalic acid ,
Preferred are phenylacetic acid, phenylpropionic acid, furan-2-carboxylic acid, nicotinic acid and isonicotinic acid. As the sulfonic acid, methanesulfonic acid and toluenesulfonic acid are preferred.

Particularly preferred carboxylic acids are acetic acid, trimethylacetic acid, propionic acid, β-phenylpropionic acid, α-7enylpropionic acid, valeric acid, and dicarboxylic acids such as succinic acid.

It is often preferred that the acyloxy group in OR' represents an acyloxy group as mentioned above, in particular a suitable carboxylic acid residue as mentioned above. The reason for this is that the ester at position 21 exhibits particularly excellent biological activity. It is particularly preferred that ORI represents a residue of a polycarboxylic acid ester or a water-soluble salt form or an inorganic acid residue that can be converted into this form.

By the method described above, 2-bromo-6β, 9α-difluoro-11β, 17α, 21-trihydroxy-1,4
-Pregnagene-6,20-dioy-17.21-diester can be produced in high yield and by a method different from conventional methods.

Next, the method of implementing the present invention will be explained in more detail with reference to the following examples, but the present invention is not limited thereto.

Reference Example 1 Compound ■'405g (1 mol) was added to N,N-dimethylformamide (21) and pyridine (350d), and methanesulfonyl chloride (26
0,! i'). Raise the temperature of the reaction mixture to 8D~8
After keeping at 5℃ for 1 hour, cool to room temperature and add methanol (7
Add 1). Separate the precipitated crystals and wash them with methanol and water.

By drying the obtained crystals under reduced pressure, 340 g of pure compound
)can get.

Reference Example 2 Compound ■'350&(0,90'6 mol) was added to 1,
2-tsuk0ruethane C6,21) Add VC and further p-
Toluenesulfonic acid monohydrate 16 & (0°084mol
) is added. Impropenyl acetate 150.5 & (1,305 mol) while heating the solution under reflux,
, slowly for about 1.5 hours, and heated under reflux for an additional 2 hours. After the reaction solution was cooled to room temperature, an aqueous sodium hydrogen carbonate solution was added to separate the layers, and the organic layer was washed twice with water. The organic layer was concentrated under reduced pressure, and the obtained crude crystals were recrystallized from benzene-hexane to obtain 34 white crystals of compound ■'.
9.190%, melting point 224-229.5°C).

Example 1 Compound ■'180. Add j9 (0.42 mol) to a mixed solvent of dioxa y(Il)□ and water (200 mol). 70% perchloric acid (while stirring at room temperature)
15i11) and further N-bromosuccinimide 8
1,! 9 (0,455 mol) is added. 1 at room temperature
After stirring for an hour, an aqueous sodium sulfite solution is added to destroy excess N-bromosuccinimide, and ethyl acetate is added to separate the layers. The organic layer is washed with an aqueous solution of hydrogen carbonate, and then further washed with water. The organic layer is concentrated under reduced pressure to obtain crude crystals of compound (2). This product is used in the next reaction without purification.

Melting point: 105.5-106°C (decomposed) IR, cm= (KBr): 3370 (m) (νOH); 1760 (s), 1740
(s), 1730 (B), ts50 (s) (νC=0)
;1240 (C-0--C) H'NMR, δ (CDCIs): 0.98 (3H, S, 18CH1), 1.74 (5H,
S, 19CH,).

2.12(3L S, CHsCO)-2,15(3H,
s, CHsCO-), 4. (52(IH, d, J=17
Hz, -COCH20AC).

4.88 (IH, d, J=17Hz, -COCH20A
C), 4.58-4.75 (IH, m, C-1fH)
, 5.73(1f(,d, J=1.5Hz, C-4
H) Elemental analysis value (as CzaHsaO□Br) Calculated value (%
): C, 57,15; H, 6,33; Br, 15.2
1 Actual measurement value (*): C, 57, 30; H, 6, 54; B
r, 15.14 Example 2 Compound ■'180y (0,42 mol
) The crude product of compound ■′ obtained from ) was mixed with acetone (1)
), potassium carbonate (75g) in water (500i+t
) Add the solution.

The reaction solution is heated to 40-50°C and stirred at this temperature for 4 hours. Cool the reaction solution, add chloroform and separate the liquid. The organic layer is washed with water until the aqueous layer becomes neutral, and then concentrated under reduced pressure.

The obtained crude crystals were recrystallized from benzene-hexane to obtain 1,681 white crystals of compound ■' (90% from compound ■'g).
H) Obtained.

Melting point: 189-191°C I R, cm-' (KB r ): 1750 (a)
, 1760(a), 1670(a) (νC=0); 16
20 (m) (1'c"C); 1240 (s) (j'c
-0-C)H'NMRδ (CDCls): 0.90 (5H, S, 18CHs) -1,41 (3H,
S, 19CHs)-2,08(3H,S, CH,Co
-), 2.14 (3H, S.

CH, C0-), 3.44 (IH, S, C-11H),
4.70 (IH.

d, J=16Hz, -COCH20Ac)t 4.89
(IH, d.

J=16Hz, -〇〇CH*0AC), 5.76 (IH
, S, C-4H).

Elemental analysis value (as C□HjtO'f) Calculated value (ch):
C, 67, 55; Approximately 7.26 Actual value (chi): C, 6
7,47; Lua, 24 Example 3 Compound ■'44.51 (0.1 mol) was dissolved in chloroform (50 t/), and this solution was mixed with 65 thihydrofluoric acid aqueous solution (120 m/) from -20 to - Slowly add dropwise to the mixture cooled to 30°C.

After the dropwise addition was completed, the mixture was stirred for an additional hour, and the reaction solution was slowly added to an aqueous solution of potassium carbonate (1) to neutralize the hydrofluoric acid. After adding chloroform and separating the layers, the organic layer was washed with water and then evaporated under reduced pressure to obtain crude crystals. When the obtained crude crystals were recrystallized from benzene-hexane, white crystals of compound 1' were obtained with 41.
8 g (90%) obtained.

Melting point: 180-181°C IR, cm' (KBr): 3430 (m) (νOH); 1750 (!l)t
1760Ca).

17□10(s), 1650(a)(νe=o); 1
620(m)(shiC-C)t 1240(!l)(shiC
-0-C)H'NMR, δ (cDem): 0.95 (3H, S, 18CHs), 1.50 (3H,
S, 19CHs)-2,05(3)I,S,CH,Co
-), 2.13 (1; S, CH, C0-) 4.20
~4.50 (IH, m, C-11H), 4.61
(IH, d.

J=15.3Hz, -COCH20AC), 4.86(
IH, d, J=15.3Hz, -COCH, OAC)
t 5.75 (IH, S, C-4t() elemental analysis value (as C□H and O□F) Calculated value (@: C, 64, 64; H, 7, 16; F, 4
．． 09 actual measurement value (11: C, 64,56; H, 7,15
;F, 4.10 Example 4 Compound ■'46.51 (0.1 mol) was dissolved in acetic acid (12
0? Dissolves in nJ. Add to this solution a 15-thiosulfuric acid aqueous solution containing 14.99 (o, osmol) of sodium dichromate (
1204) was slowly added dropwise at a temperature below 20°C. After stirring for 2 hours after the dropwise addition, the reaction solution was poured into water (1.2A).

The precipitate formed was separated, washed with water, and dried to yield a white powder of compound (4). ! 9 (95m) obtained.

, Melting point: 245.5-255.5°C (decomposition) I
R, am' (KBr): 1740(a), 1730(s), 1580(s)(ν
C=C); 1624 (m) (C2C) 'p 124
0 (s) (C-o-c)H'NMR, δ (C
DCA! s ): 0.83 (3H, S, 18CH,'
l, 1.48 (3H,S, 19CH3).

2.14 (611, S, CH, Co-), 4.66
(1H, d, J=16.5Hz, -COCH20A(
'), 4.78 (IH, d, J=16.5H1, C0C
) T20AC), 5.82 (1) L S, C4H) Elemental analysis value (as C1Il, O, F) Calculated value (CH):
C, 64, 92; H, 6, 76; F, 4.11 Actual value (@: C, 64, 79; H, 6, 77: F, 4.1
0 Example 5 Dimethyl sulfoxide 15.6 g (0.2 mol)
A methylene chloride (100 mm) solution was heated to -65 to -70°C.
Cool to 31.5% trifluoroacetic anhydride. ! i'(0
, 15 mol) in methylene chloride (100 m/) was added at the same temperature. After stirring for 10 minutes, compound ■'
46.5.9 (0.1 mol) 17) Methylene chloride C
After adding 500 tl) solution at the same temperature and stirring for 30 minutes,
Triethylamine 409 (0.4 mol) was added dropwise,
Raise the temperature to room temperature. Water is added to the reaction solution to separate the layers, and the organic layer is washed with water and concentrated under reduced pressure. The obtained crude crystals were recrystallized from chloroform-hexane to obtain 4s, 1 (9s*) of white crystals of compound 1'. This product shows the same physical properties as those obtained in Example 4.

Example 6 Stir at room temperature for 1 day. The reaction solution was added to a 5% aqueous sodium hydrogen carbonate solution to neutralize the acid, and then separated and extracted. The crude crystals obtained by condensing the organic layer under reduced pressure were recrystallized from chloroform-hexane to yield 48.1i95% white crystals of compound ■'.
)can get.

Melting point: 173.2-175.0°C.
, 5I R, cm-1 (KB
r): 1758(s), 1740(easy)t 1732(a)(
νc=o); 1240(C-o-C) HI NMR, δ(CDCIs) α69(5H,8,18CH1), 1.27(5)(
, 舊, 19CH,).

2.11 (3H,S, CH,C0-), 2.14
(3kus, C mountain Cg).

5.90 (4H,S, -OCH,CH2O-), 4
．． 64C1) (, d.

J=16.5Hz, -Go-CH! 0AC), 4.
78 (1'H, d, J=16.5Hz, -COC
H, OAC), 5.25/V5.45 (I H, m
.

C-6H) Elemental analysis value (calculated value range as CxyHsaOsF):
C, 64,02; H, 6,96; F, 3.75 actual value (@: C, 63,93;) L 6.95; F,
3.73 Example 7 Compound ■'50.7,! Dissolve i' (0.1 mol) in tetrahydrofuran (5ooWLt), and add 20% potassium carbonate aqueous solution (100-). Sodium borohydride is added to the solution while stirring at room temperature. When the disappearance of Compound (1) is confirmed by thin layer chromatography, water and chloroform are added to the reaction solution to separate the reaction mixture. After washing the organic layer with water, it is concentrated under reduced pressure.

When the obtained crude crystals are recrystallized from methanol, the compound ■
45.9 g (90%) of white crystals of 1 are obtained.

Melting point: 125.8-126.3°C (decomposed) IR, am →
(KBr) 3510 (m) (νOH); 1760 (II), 173
5(a) (νC=O); 1650(W) (νC=C);
1237 (11) (C-0-C) HI NMR, a (cDcls) 0.94 (3H, a, 18CHs), 1.37 (3H,
S, 19CHm).

2.06 (3H, 8, CH, C0-), 2.15 (3
H, S, CH, C0-).

3.91 (4n, S, -OCH,CH,0-),
4.25-4.55 (IH.

m-011H)s 4.61 (IH-d, J-17H
z, COCHtOAc)t 4.89 (IH
, d, J=17Hz, -COCHloAc).

5.16-5.40 (I H, m, C-6H) Elemental analysis value (as CrrHs, OaF) Calculated value (%):
C, 65,76; H, 7,33; F, 3.74 Actual value (chi): C, 65,99; H, 7,37; F, 3
．． 71 Example 8 (0.18 mol) is added. After 10 minutes, -10 to -2
Cool to 0°C and add compound ■'50.911 while stirring.
(D, Lmol) is slowly added. 1 at the same temperature
After reacting for 0 hours, the reaction solution was poured into an aqueous solution of 50% sodium bicarbonate, and methylene chloride was added thereto for liquid separation and extraction. After concentrating the organic layer under reduced pressure, the organic layer was recrystallized from benzene-hexane to obtain 41.9 g (80%) of white crystals of Compound [Y]'.

Melting point: 196°C (decomposed) IR, cm-1 (KBr): 3455 (m) (νOH); 1755 (a), 1740
(a) (1'C=O); 1235(s)+123
0(a)Dc-0-C)H'NMR, δ(d, -DMS
O) 0.77 (5H1!l, 18 CHI) - 1,56
(6H9S-19CHs)s2.06(3H,S,
C1l, Co), 2.08(3H,S, CHs
CO-), 3.75-5.82 (4H, m, -0
CR, CH20-).

5.8-4.2 (IH, m, C-11H), 4.7
5 (2H, s.

COCH20Ac)t 5.03 (I H-d,
J=4.5Hz, C110H) Elemental analysis value (c!?)
T37o. Calculated value (%): c, 61.
82; H, 7, 11; p, 3.62 Actual value (%):
C, 61,, 78; H, 7, 13; F, 3.59+
1 Example 9 In the same manner as in Example 8, compound ■'50.7. li'
(0.1 mol) gives 40.8 white crystals of compound 0'
p(784) is obtained.

Melting point: 1758~17Z8℃ IR, am'' (KBr): 1760 (a), 1750 (s), 1730 (a) (ν
C=O);1240m5)(C-C-0-C)HIN, δ(CDCA!m): 0.64(3H,S,18CHa), 129("+i
, 8.19 CHs).

2.13(6H,S,C)GCO-), 2.85(IH
, S, C-6H), 3.70-4.10 (4H, m
, -OCH,OH,0-), 4.61(IH,d,
J=16.5Hz, -(OCH,OAe)t 4゜76(IH,, d, J=16.5Hz, -COCH20
Ac) Elemental analysis value (as CztHsiOeF) Calculated value (correspondence): C, 62,06; H, 6,75; F, 3.
64 actual measurement value (@: C, 61, 88; H, 6, 76; F,
5.62 Example 10 Compound @'52.5 g (0,
From 1 mol), white crystals of compound [phase]' were 47.2.
9 (90%) obtained. This material exhibits the same physical properties as those obtained in Example 8.

Example 11 65% hydrogen fluoride water (25QWLt) at -70 to -80°C
The compound [phase] '52. ! Add 11 slowly over about 3 hours. After further stirring at the same temperature for 1 hour, the mixture was poured into cold water (2.5N), the precipitated crystals were separated, and washed with water until the washing solution became neutral. The obtained crystals were dried and then recrystallized from methylene chloride to give 35. oy(7oqb>Samurai IR, am-1(K
Br) 3600 (m), 3500 (m) (νOH); 1735
(a) (νOH); 1240 (s) (c-o-c)H
INMR, δ (CDCA's) 0.99 (6H, S, 18CHm), 1.61
(5H, d, J=45Hz.

19CH3), 2.08(3H,S,CH,C0-),
2.14 (3H.

S, CH3C0-), 4.34 (IH, dm, J
=49Hz, C-<SH).

4.20-4.55 (IH, m, C-11H), 4.6
4 (IH, d.

J=17 Hz-COCH! OA C), 4-90
(I IL as J=17Hz, -COCH20A
C) Elemental analysis value (as CzIIH1401F!) Calculated value (
): C, 59,99; H, 6,85; F, 7.5
9 actual measurements (@: C, 60, 13; H, 6, 79; F,
7.52 Example 12 Compound ■'52.39 (0,
s4.9g of white crystals of compound [phase]l from 1mol)
(7o*) obtained.

Melting point: 217.5-217.8°C (decomposition) I R, am
' (KBr) 3625 (mMνOH); 1755 (a), 1740 (
a).

1725 (s) (νC=O); 1233 (s) (C-
C-0-C) HIN, δ (CDCA!a) 0.76 (!IH, S, 18CH3), 1.50 (5H
, d, J=3Hz.

18CHm), 2.16(3II-S, CHsCO
)-216(5)LS, CH3C0-), 4.37(I
H, dm, J=48Hz, C-6H), 4.68CDI
, d, J=1? L5Hz, -COCHtOAC).

4.79(IH, d, J=16.5Hz, -(OCH2
0AC) Elemental analysis value (as Co Hs20B Fz)
Calculated value (%): C, 60,25; H, 6,47; F,
7.62 Actual value (correspondence): C, (50, 40; H, 6
, 43; F, 7.56 Example 13 Compound ■'50.1.9 (0.1 mol) and sodium acetate';
Lt) and heat to 9 [1'C]. After the sodium acetate has dissolved, a solution of 16.8 g (0.105 mol) of bromine in acetic acid (50 ml) is added dropwise over about 5 minutes. When the color of bromine disappears, bromine 16.8. li' (0,105 mol
) in acetic acid (501d) is added all at once. When the color of bromine disappears, immediately cool the reaction solution to room temperature and add cold water (3
，! Open it in M). The precipitated crystals were separated daily and dried to obtain 62.5 g (95%) of pale yellow crystals of compound @'.

Melting point: 136.2-16zO℃ (decomposition) IR, cm=
(KBr): 5590 (m), 3450 (m) (νOH); 1755
(s).

1740(a), 172-0(s) (νc=o); 12
45 (s) (C=0-C) H'NMR, δ (CDCIs): 1.00 (3H, S, 18CHs), 1.85 (!IH
, d, J=5.5Hz, 19CH8), 2.08(3H
, S, CH, Co-), 2.17 (3HIS, CHaC
O) = 4.40-4.45 (IH, m.

C-11) L 4.41 (IH, dm, J=49H
z, C-6H)-4,63(jH;-d, J=17H
z, -COCH, 0AC), 4.91 (IH, d, J=
17Hz, -COCH20AC) elemental analysis value (CuHs
Calculated value (as tOaBrtFt) (@: C, 45, 6
1; H, 4,90; Br, 24.27; F, 5.77 Actual value (@: C, 45,39; H, 4,97; Br, 2
4.21; F, 5.70 Example 14 Compound (f)'49.911 was prepared in the same manner as in Example 13.
(0.1 mol) gives 62% of the compound [phase] pale yellow crystals.
．． 3F (95%) obtained.

Melting point: 132.6-156.7℃ (decomposed) IR, cm→
(KB r ) 3600(m)(ν0H)z 1755(a)-174
0(s).

1730 (s) (νc=o); 1240 (vC-0-
C) HINMR, δ (CDC1s) 0.76 (3H, S, 18CHs), 1.75 (3H,
d, J = 3Hz.

19 CHa )y 2.13 (3H-Be CHB
CO)-2-16 (3H-8, CHICO-), 4.
45 (IH, dm, J=45.5Hz.

C-6H), 4.69 (I H, d, J=18H
z, -COCH10mC).

4.81 (IH, d, J=18Hz, -COCH,0A
C) Elemental analysis value (as C25HsoOaBrtFt)
Calculated value (%): C, 45,75; H, 4,61; Br
, 24.55; F, 5.79 Actual value (@: C, 45,91; H, 4,60; Br,
24.17; F, 5.74 Example 15 Anhydrous lithium chloride (65 g) is added to 11 N, N-dimethylformamide (650d) and dissolved by heating to 110-120°C. Compound d' (65,81
Add 1) and react with stirring for 2 hours. The reaction solution was cooled to room temperature, poured into water (6, 57), and the precipitate formed was separated daily.
Wash with water. After drying the obtained crude crystals, they are separated by silica gel column chromatography. White crystals of Compound 0' (38.6169%) were obtained from a chloroform-ethyl acetate (10:1) fraction.

Melting point: 298°C (decomposition) Masa: M""55 B IR, cm-1 (KBr): 3520 (m) (νOH); 1758 (a), 173
3(,a)s1705(a),1650(s)(νC=
0); 1235(s) (C-0-C) H”NMR, δ(a, -DMs o ): 0.91(
3H, s, 18CHs), 1.60 (3H, d, J=5
．． 4Hz, 19CHs), 2.01 (KL a
, OH, GO-).

2.12 (3H,S, CH3C0-), 4.1-4
．． 4 (IH, broad.

C-11H), 4.80 (2 remaining 8.-COCH, 0AC
), 5. ! 19 (IH, dm, J=51Hz, C-6H
), 5.65 CIH, d.

J = 6Hz, C-110H), 6.51 (IH, d, J
=4Hz.

C-4H), 7.85 (IH, S, C-IH) elemental analysis value (as CHHHOlBrFl) calculated value (1):
C, 55,68; H, 5,23; Br, 14.28
;F, 6.79 Actual value: c, 55.46;H, 5,23;Br,
14.21; F, (S, 74 Example 16 Compound e'<55.6g (11
39.5 g (71 mol) of white crystals of compound O'
1) Obtained.

One point: 262.7-2655℃ (decomposition) IR, cm=
(KBr): 1750 (s), 1740 (a), 1676 (a) (SiC-0); 1640 (m), 160'1 (m) (νC=
C); 1253 (s) (c-o-c) H"NMR, δ (CDCIs)" 0.78 (3H, S, 18CH,), 1.63 (3H,
d, J=2H2,19CH8), 2.07(3H,S,
CH, C0-) t2.12 (3H, S, C horse Co-),
4.67(1)L d, J=17.5Hz, -COCH
,0AC), 4.80(IH,d,J=17.5Hz,
-COCH,0AC), 5.20(IH,dm, J=4
9Hz, C-6H), 6.38 (1a d, J=7Hz
, C-4H), 7.88 (IH, S, C-IH).

Elemental analysis value (as exa HB70 @ B r Fl) Calculated value (%): C, 53,87; H, 4,88; B
r, 14.54; F, 6.82 Actual value (%): C, 54,03; H, 4,79; Br
, 14.15; F, &77 Example 17 Compound @'55.7, ! 9 (
0.1 mol), the white crystals of compound 0' are 44.7,
9 (8i) obtained.

This product exhibits the same physical properties as those obtained in Example 15.

Patent Applicant Dainippon Ink & Chemicals Co., Ltd. Procedural Amendment (Spontaneous) June 27, 1980 Kazuo Wakasugi, Commissioner of the Patent Office1, Indication of Case 9Wf Application No. 105367 of 1982, Name of Invention Steroid Compound Manufacturing method 3, relationship with the case of the person making the amendment Patent applicant: 3-35-58 Sakashita, Itabashi-ku, Tokyo 174 (288
) Dainippon Ink & Chemicals Co., Ltd. Representative Shigekuni Yomura 4, Agent Address: 3-7-20 Nihonbashi, Chuo-ku, Tokyo 103 Dainippon Ink & Chemicals Co., Ltd. Tel: Tokyo C05) 272-. 1511 (Major Representative) 'Claims column of the specification and statement BA0) Detailed explanation column 6 Contents of amendment (11 The claims column of the specification is amended as shown in the attached sheet.

(2) Insert the following statement next to the third line of page 9 in the detailed description of the invention section of the specification.

“Among the compounds shown here, compounds ■, ■, [phase]
and 0 can be collectively represented by the following general formula (1), and all of these are novel compounds that were previously unknown.

Compounds 1, 0, [phase] and [phase] are also novel compounds represented by the general formula (IO).

(In the formula, >-X represents >C=0 or >CH-OH, and y-z- represents ', c=cn- or >q-CH
-, Q represents hydrogen or bromine atom, OR
' and OR'' have the above meanings.) (3) On page 11, line 9 of the same, the description of [... for compound C as a basic substance...J] has been changed to ``For compound C... ■ 1.Basic substance obtained by acting on / with a basic substance...song'' is corrected.

(4) On page 13, line 4 of the same page, the statement [Song: The type of solvent varies depending on the oxidizing agent used] was changed to ``The type of song: The type of solvent varies depending on the oxidizing agent used. ” he corrected.

(5) From the last line of page 14 to the next page for toughness, the description ``1... song Amber ~ List 150... song'' was changed to 1 song Amber List 15 (Rohm & Haas Company product name)...
"..." I corrected myself.

(6) The description of "Example 1" on page 25, line 5 and page 27, line 2 is amended to read "Reference Example 3."

(7) The description of “Example 2” in the first line of page 27 of the same
°Clinical Examination Example 4”.

(8) The description of ``Example 3'' on page 28, line 9 is amended to 1゛Reference 5''.

(9) The description of "Example 4" on page 30, line 6 and page 32, line 4 is amended to 1"Reference Example 6."

(The description of "Example 5" in IQ, page 61, line 8 is amended to read "Reference Example 7".

fill The description of "Example 6" on page 32, line 6 is amended to read "Example 1."

(Similarly, 4 lines from the bottom of page 33, 6th line of page 35
line, 2 lines from the bottom of page 36, last line of page 37, 4th page of page 68
line, 5 lines from the bottom of page 69, 4 lines from the bottom of page 40, 42nd line
``Each Example Heading Number'' in the 9th line of the page, the 4th line from the bottom of the 43rd page, the 6th line from the bottom of the 45th page, and the first line of the 47th page are changed to ``2.6,...''・11.12”.

(I) "Example 11" in the 6th line from the bottom of page 39 of the same
" has been amended to read "Example 6."

I "Example 7" and 4th page 47, line 2 of the same
The description of "Example 15" in the row is corrected to "Example 2" and "Example 10", respectively.

7. Attached document 1 (1) Attachment 1 stating "In scope of claims"
General formula +1 (Claim 1, General formula 1) where 〉Y-Z- is〉C=CH- or >c, :, c
How to do H-.

By ketalizing Ru (compound ■), 17α
.

21-dihydroxy-3,5-ethylenedioxy-9α
-73-ethylenedioxy-9α-fluorebrevner
ii.

5α,6α-epoxy-3,3-ethylenedioxy-9
6β,9α-difluoro-5α,17α,21-trihydroxypregna-s,ii by treatment with α-fluoro-11β,17α,21-)-trihydroxypregna-s,ii.

20-trione-17,21-diester (compound@)
or 6β, 9α-difluoro-5α, 11β, 17α
, 21-tetrahydroxypregna-3,20-dione-17,21-diester (compound (1)).

z 6β゛, 9α-difluoro-5α, 17α, 21-
) lyhydroxypregna-3,11,20-)lione-17,21-diester (compound [phase]) or 6β
, 9α-difluoro-μ, /, 17 (X, 21-) Claim 1 or 6
Manufacturing method described in section.

Oro-4-gregnene-5,11,2O-)I3one-17゜x-4,9(11)-pregnagen-3
,20-dione 1) 17α,21-dihydroxy-4,
9(11)-pregnagene-6,20-dione-17
, 21-diester (compound ■) is treated with hypochlorous acid or hypobromite to produce halohydrin (compound ■), which is then treated with a basic substance to form 9β and 11β.
- 17α,21-dihydroxy-3,3-ethylenedioxy-9α-fluoro-5-pregnene-11,20-dione-17,21-
Generating diester (compound ■): 2) Compound ■ obtained in the previous step is treated with hydrogen hydride to form 6β-fluoro-5α-hydroxy, followed by dehydrobromination and dehydration to form the desired 2-bromine. -6β, 9α-difluoro-11β, 17α, 21
-trihydroxy-1,4-pregnagene-6,20
-Dione-17,21-diester (compound 0): or II) treated with peracid to produce 5α,6α-epoxy (
6β-fluoro-5α-hydroxy-6
-keto or +2 li+) 5α2,6α by treatment with peracid
-Epoxy form (compound 6β-fluoro-5α-hydroxy-6-keto form (compound @):

Claims (1)

[Claims] 2-bromo-6β, 9α-difluoro-11β, 17α
. 21-trihydroxy-1,4-pregnagene-3,
In producing 20-dione-17,21-diesters, 1) 17α,21-dihydroxy-4,9(11
)-pregnagene-6,20-dione-17,21-
The diester is converted into a halohydrin with hypochlorous acid or hypobromous acid, and then a salt substance is applied to form 9β, 11β.
-After being made into an epoxy form, it was treated with hydrogen fluoride to form a 9α-fluoro-11β-)”1lff oxy form, which was oxidized to form an 11-keto form, and then ketalized to 17α, 2
1-dihydroxy-3,3-ethylenedioxy-9α-
Fluor-5-gregnene-11.20-cyone-17
．． 2) Generate a 21-diester (referred to as compound ■): 2) Compound ■ obtained in the previous step is reduced to a 11β-hydroxy form, and then treated with peracid to form a 5α,6α-epoxy form. , treated with hydrogen fluoride to give 6β-fluoro-5α-hydroxy-3-keto, which was brominated, followed by dehydrobromination and dehydration to give 2-bromo-6β,9α-difluoro-11
β, 17α. 21-trihydroxy-1,4-pregnagene-3,
20-dione-17,21-diester is produced: or 11) treated with peracid to form the 5α,6α-epoxy form, followed by reduction to form the 11β-hydroxy form, and then treated with hydrogen fluoride. 6β-fluoro-5α-hydroxy-
The 3-keto form is obtained, which is brominated, followed by dehydrobromination and dehydration to yield 2-7'rom-6β, 9α-difluoro-11β. 1-7α,21-) dihydroxy-1,4-pregnadiene-5,20-dione-17,21-diester: or 111) treatment with peracid to form the 5α,6α-epoxy form, followed by The 6β-fluoro-5α-hydroxy-3-keto compound is obtained by treatment with hydrogen chloride, followed by bromination, followed by dehydrobromination and dehydration, which is then reduced to give 2
-bromo-6β, 9α-difluoro-11β, 17α,
21-1-lihydroxy-1,4-pregnagene-6
, 20-dione-17,21-diester is produced. 2-brome-6β1
9α-difluoro-11β,17α,21-trihydroxy-1,4-pregnagene-3,20-dione-1
Method for producing 7,21-diesters.