JPS58225099A - Steroid compound and its preparation - Google Patents

Abstract

NEW MATERIAL:The steroid compound of formula I [X and Y together form >C=O or >CH(OH) in the form of >X-Y; Z is H or Br; OR<1> and OR<2> are acyloxy, sulfate residue or phosphate residue.]. EXAMPLE:6beta,9alpha-Difluoro-5alpha,11beta,17alpha,21-tetrahydroxypre gna-3,20-dione-17,21-diacetate. USE:A useful intermediate of 6alpha,9alpha-difluorocorticoid having physiological activity. PROCESS:The 17alpha, 21-dihydroxy-5alpha-6alpha-epoxy-3, 3-ethylenedioxy-9alpha-fluoropregna- 11,20-dione-17,21-diester which can be obtained by using the easily and inexpensively available hydrocortisone-21-ester of formula II as a starting material, or the compound of formula IV obtained by the reduction of the compound of formulaIII, is treated with hydrogen fluoride to obtain a compound of formula I wherein Z is H, which can be converted to another compound of formula I wherein Z is Br by bromination.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to the general formula←wherein X and Y are X-Y and /C-0 represents a carbonyl group, or cs (oi
+ ) represents a β-hydroxyl group, and Z & hydrogen or t represents a bromine atom. This invention relates to a conventional steroid compound represented by OR' and OR'' representing the same or different acyloxy group, sulfuric acid ester, or phosphoric acid ester residue, and a method for producing the same.

The compound represented by the general formula (1) produced by the present invention is a useful intermediate for the known physiologically active 6α,9α-difluorocorticoid, and in particular, 2- Bromo-6β, 9α-difluoro-11β.

17(χ, 21-1- IJ hydroxy-1,4-7
"In the production of regnathien-1,20-dione-17,21-diesters (hereinafter referred to as compound 0), a novel product fl
No. 7-105367).

Compound 0 has fewer side effects such as weight loss, sodium retention, potassium depletion, collateral and pituitary gland suppression, etc., which are seen with various known physiologically active steroids, and especially anti-inflammatory or anti-rheumatoid arthritis effects. It is known to have valuable opacitive effects such as effects (Special Publication No. 56-1t677@Sateru). Antirheumatic effects have also been reported by intra-articular injection.

Furthermore, as a method for producing compound 0, a method using 11-shrimp hydrocortisone-21-ester as a starting material (for example, Japanese Patent Publication No. 56-14677, Japanese Patent Application Laid-Open No. 51-6955,
JP-A-55-154998) is known, but
11- Shrimp hydrocortisone is difficult to handle and expensive. on the other hand.

The compound represented by the general formula (I) according to the present invention is hydrocortisone-21-
Since the compound ◎ can be synthesized in a high yield using xx butyl, and as a result, a method for producing the compound ◎ at low cost and with a high yield has become redundant. The compound and the method for producing the compound are shown in Scheme-1.

(@@0 (In the formula, OR' and OR2 represent the same or different acyloxy group, sulfuric acid ester, or phosphoric acid ester residue.) Hereinafter, as specific examples of R1 and R2 in the formula, The case of an acetyl group will be explained, and regarding various compounds during the reaction process, for example, compound (2) will be abbreviated as "compound (2)," and the same shall apply to the others.

Now, the starting point in the present invention is 17α, 2, which is the ′+jJJ edition.
1-dihyα-fluoro-11β,17α,21-)dihydroxypregna-20-one-17,21-diester (compound @′) is the known compound 17(t,:li!1-
dihydroxy-9α-fluoro-4-pregnene-3,
11,20-) Rion-17゜21-diacetate (compound ■') is ketalized to form compound ■' and then oxidized with peracid to form compound (Y') or compound ■' is reduced to compound ■' It can be easily obtained in high yield by oxidizing with peracid after soaking or reducing compound O' to give compound U'.

6β,9α-difluoro-5α,11β,17Cχ,2
1-tetrahydroxybrebner-3,20-dione-1
7.21-Diacetate (compound Q') can be obtained by treating compound -' with hydrogen fluoride water. )
XLr, Q:F, the compound [phase]' may be added directly to the hydrogen fluoride water, but it is also possible to add a compound that is commonly understood as a common medium. The common organic medium used for this removal is tetrahydrofuran,
Examples include those with good precision in the starting material compound [phase]', such as chloroform. Further, the reaction can be carried out at a temperature of 0 to -80C, preferably -20 to -80C.

2.2-dibrome-6β,9α-difluoro-5α.

11β, 17α, 21-r trahydroxybrebnar-6
゜20-dione-17,21-diacetate (compound @
') can be obtained by bromination of compound 0'. Examples of the brominating agent include Fuso, N-turomosuccinimide, and the like. Acetic acid (IJ), potassium acetate, etc. are used in combination as the basic removal substance. Preferably, the reaction is carried out in acetic acid. Further, the 5-reaction knitting can be carried out at a temperature of 0 to 120C, but it is preferably carried out at a temperature of 80 to 120C for a short period of time.

2-bromo-6β, 9α-difluoro-11β, 17α
.

21-trihydroxy-1,4-pregnagene-17
21-Diacetate (compound 0') can be obtained by heating compound @' to perform dehydrobromination and dehydration.

There are 4 reactions! #The organic solvent used is N, although it is carried out in a solvent.

Amide thread media such as N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone are preferred.

A metal carbonate can be used in conjunction with a halogenide or a metal carbonate. As metal halides, enriched lithium or lithium bromide is good, metal carbonates, etc.
Alkali metal carbonate groups such as carbon r'l IJ tium and sodium carbonate, or alkaline earth metals such as calcium carbonate are formed. The reaction is carried out in a 80-160c tube knit or it
(Preferably, doing this between 100 and isoc will give good results.)

Is 6β,9α-difluoro-5(E,17α,21-}lihydroxypregna-3,11,20-}lion-17.21-diacetate (compound (f)') a compound from compound ■)'? In the same manner as the reaction to 10', treat the compound q' with a fluorine aqueous solution ゛(
It can be obtained by

2,2-dibrome-6β. 9α-dinolol-5 (t.
17α. 21-} Lyhydroxybregna-3, 1
1,20-trione-17.21-acetate (compound [phase]') can be obtained by brominating compound [phase]' in the same manner as the reaction from compound 0' to compound @'. .

2-bromo6β,9α-dinolol-1phα. 21-dihydroxy-1,4-pregnadiene-3.11.2
0-trione-17.21-diacetate (compound O'
) can be obtained by dehydrobrominating and dehydrating compound [phase]' in the same manner as the reaction from compound @' to compound 0'.

In addition, the compound qkJlili'1 can be led to the compound 0' by acting with a reducing agent.

According to the present invention, when OR" and OR" in the chemical formula are ester residues other than acetoxy, the general formula CI) can be obtained in much the same way as when they are acetoxy groups, or by a routine change by a person skilled in the art. The represented compounds can be prepared.

Inorganic acids constituting other ester residues include sulfonic acids, aliphatic, cycloaliphatic, aromatic, arylaliphatic and heterocyclic carboxylic acids, and thiocarboxylic acids. and aminocarboxylic acids such as unacarboxylic acids can be shown.

Examples of carboxylic acids include formic acid, acetic acid, chloroacetic acid, trifluoroacetic acid, propionic acid, butyric acid, valeric acid, trimethylacetic acid, diethyl acetic acid, cabroic acid, crotonic acid, enanthate, caprylic acid, capric acid, valmitic acid, undecanoic acid, Undecanoic acid, oxalic acid, succinic acid, glutaric acid, pimeline.

Tartar stone l. Maleic acid, lactic vinegar, carbamic acid, glycine,
Alkoxycarpone, hexahydrobenzo vinegar, cyclohentylprobion, cyclohexyl vinegar M. Preferred are cyclohexyl butylene, benzoic acid, phthalic acid, phenylacetic acid, phenylpropionic acid, furan-2-carboxylic acid, nicotinic acid and isonicotinic acid. As the sulfonic acid, methanesulfotetraic acid and toluenesulfonic acid are preferred.

Particularly preferred carboxylic acids are acetic acid, trimethylacetic acid, propionic acid, β-phenylpropionic acid, α-phenylzo1-lobionic acid, valeric acid, and dicarboxylic acids such as succinic acid.

The acyloxy group in OIL' is the above-mentioned acyloxy group,
In particular, it is often preferable to show the preferred carboxylic acid residues mentioned above. The reason for this is that the ester at position 21 exhibits particularly excellent biological activity. Also, OR' is particularly preferred as a residue of a late polycarbonate ester or a form of a bathing material or a residue that can be converted into this form.

By the method described above, the compound represented by the general formula (1) can be produced by a method different from conventional methods, and at a high bacterial yield.

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

Example 1 65% hydrogen fluoride water (250riJ) -70 to -5OC
Cool and stir while combining v! lJ[phase]'52.5
, 9 is slowly added over 3 hours FI. After further stirring at the same temperature for 1 hour, the crystals were poured into cold water (2.5 J), separated, and washed with water until the crystals became neutral. The obtained crystals were dried and then recrystallized from methylene chloride to obtain 55.0 g of white crystals of compound ◎'.
<70%) obtained.

Melting point: 119!5-120. DC (decomposition) IR, ctn
' (KBr) 5600 (m), 3500 (m) (νOH); 17
55 (s) (νoH): 1240(a) (C-Q
-C) H'NMR, δ(CD(J!B) 0.99 (5H, S, 18CH,), 1.61 (3B,
d, J = 4.5Hz.

19C) II), 2.08(5)1. S, CB, Co-
), 2.14 (3H.

S, CHaCO-), 4.34 (IH, dzn, J=4
9Hz, C-6B).

4.20-4.55 (IH, m, C-118), 4.6
4 (1B, d.

J=17Hz, -COCl, 0AC), 4.90 (IH
, d , J=17Hz , -COCH! 0AC) Elemental analysis (as C23 mouth 84 on r) i1゛ Calculated value open: c, 59.99; H, 6,85; F, 7.
59 actual measurement value (9'4: C, 60, 13; H, 6, 79;
F, 7.52 Example 2 Compound ■' 52.69 (0,1
mol ), the white crystals of compound vIJ◎′ are 64.1 (
70%) obtained.

Melting A: 217.5-217.8 CC min w4) IR,
is-' (KBr) 3625 (m) (νOH); 1755 (a)
-1740(m) -1725(aNνC~0);
1233 (a) (νC-0-C)H'NMR, δ
(CDCls) 0.76 (3H, S, 18CH1), 150 (31-1
, d, J=5Bz.

18C)j,), 2.13(3)1. s, C)j, C0
-), 2.16 (31-1°s, ci-t, co-),
4.57 (10* dm @ J -48Hz -C-
6H), 4.68 (IH, d, J=16.5Hz, -C
oC)1,0AC).

4.79(1)1,d,J=16.5Hz,-(O
CH,0AC) elemental analysis value (C2S ``h□c, b',
) calculation (ILi('l'4:C,60,23;)
j, 6.47: F, 7.62 central offshore 1 value (crab C
,60,40;H,6,43:F', 7.56 Example 3 Compound Q'50.19 (0.1 mol) and sodium acetate 50// were added to acetic acid (250 solution) and heated to 90C.
-ru. Bales containing 8% sodium acetate, bromine 16.8M
(0,105 mol) σ term'1 acid (50 ml) was heated for about 5 minutes. Fuyu Q) If you lose color power, bromine 16.8M (0,105mol) vinegar ff (50m
J) Add Kenshin to -Luni. When the color of bromine disappears, immediately move reaction d to the chamber vortex? 4fr cooled water (3,57)
Open it. The precipitated crystals were separated daily and dried to obtain 62.511 (95%) pale yellow crystals of compound Q'.

i Amazing: 136.2-137.0C (decomposition) I R*
cm' (KBr): 3590 (m), 3450
(m) (νOH); 1755(a).

1740(a), 1720(s) (νc=0): 124
5(a)(C-0-C)('NMR, δ(Cocl!s): 1.00(3
H, S, 18CHs), 185 (1.d in 3, J=5.
5Hz, 19CH,), 2.0El (31(,S,CH
, C0-), 2.17 (3H, S, C horse C0-), 4
．． 40-4.45 (IH, rn.

C-118,4,41 (IFi, drn, J=49
Hz, C-6H).

4.63(II(,d,J=17Hz,-COC)1
20Ac), 4.91 (IH, d, J=17Hz, -C
OCH20AC) elemental analysis (11(C25Ha 03
As Br2F2) Calculated value (%GC, 45, 61;)l
, 4.9[J:Hr, 24.27;F, 5
．． 77 Fresh d411E (%l: C, 45,39; H, 4,97
:Dr, 24.21 :F, 5.70 Example 4 Compound [phase]' 49.9N (
From 0.1 mol), 6 pale yellow crystals of compound [strain]' were obtained.
2.5g<95%) obtained.

[,4: 132.6-133.7C (min wt) IR,
cvi” (KBr) 3600 (rn) (νOH”); 17.55 (s), 1
740(a).

1730 (s) (νC=O); 1240 (1/C-0-
C) H' NMR, δ(CDCI!s) 0.76 (50,S, 1BCB,), 1.75 (31-
1, d, J =: 3Hz.

19Ckis)-215C5H,s, -CH5CO)
-2,16 (3H-8, C1i, Co-), 4.45 (
IH, dm, J = 45.5Hz.

C-614), 4.69<IH,d, J=18Hz
, -COCH,0AC).

4.81 (111, d, J=18Hz, C0CH*0
AC) Elemental analysis Tsukuda (Cts J1so04 Br2 F
as @)fl)9-f*('/4:('', 45.75
:)j, 4.61;Br, 24.35;F,
5.79 Real i11111Mf%l:C,45,91';H,4,
60; Br; 24.17; Ru. Stiffness at the same temperature) Compound l@ in fG solution
'(65,8y) and stir for 2 hours. The reaction solution was cooled to room temperature, poured into 6.5 liters of water, and the formed precipitate was separated and washed with water. After drying the resulting coarse crystals,
Separate by silica gel column chromatography.

From the chloroform-ethyl acetate (10:1) fraction, 38.6.9 (69%) of compound @' was obtained as white crystals.

Melting point: 298C (decomposition) Mass: M = 558 IR @ crn” (KBr): 3520 (m)
(νOH); 1758(n),' 1735(s).

1705(s), 1650(a) (νC=0): 123
5(II) (C-0-C) H'NMR, δ(d, -DMSO): (1,91 (SR0@, 18CH,), 1.60 (5B
, d, J=3.4Hz, 19C)13), 2.0
1 (3H, a, CH3C0-).

2.12 (5H, S, OH, C0-), 4.1-4.4
(1)1. broad.

C-11H), 4.80 (21(,S, -COCH
, 0AC), 5.39 (IH, dm, J=51Hz, C
-6H), 5.63(1)1. d.

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

C-41 (), 7.85 (1B, S, C-IH) Elemental analysis (as C25Hog 04Br Fl) Electron [
"9-1 (%l: C, 53,68: H, 5,23; B
r, 14.28; F, 6.79 夾d411 い (%l:c, 53.46: H,
5,23:Br, 14.21;F, 6.74 Examination Example 2 Compound Q'l' 65.69 (
0.1 mol), the white crystals of compound ■' are 39.5
/i/(71%) obtained.

One point: 262.7-263.5C (decomposition) IR, cm
' (KBr): 1750(a), 1740(a), 1676(*)(
1'c=0); 1640(m), 1601(m)(νC
=C): 1233 (s) (C-0-C) H' NMR, δ (CDC/,): 078 (3JS, 180H,), 1.63 (3H, d
, J=2Hz, 19CHn), 2.07(3B, S
, CB, C0-).

2.12 (6H, 8, CHllCo-), 4.67 (I
H, d, J=17.5Hz, -〇0CR20AC), 4
．． 80 (IH, d, J=17.5Hz, -COCHIO
AC), 5.20 (IH, dm, J=49Hz-, C-
68), 6.38 (11-1, d, J=7Hz, C-4
H), 7.88 (1B, S, C-IB).

Elemental analysis value (as C25H2q Og'Br F)
Side value (positive: C, 53, 87: H, 4, 88: Br,
14.34: F, 6.82 No! ff1ll(filguu2J:C,54,03
;H, 4,79;Br, 14.15:F, 6
．． 77 Diagnostic example 3 Compound QJ+'55.7# (0.1 mol)'
Commonly understood as l tetrahydrofuran (500+ag), water (
100#l1) Add y. Sodium borohydride is added to this bath solution while stirring at room temperature. When the disappearance of the compound @' is confirmed by rack JVJ chromatography on the 4th floor, water and chloroform are added to the solution to separate the solution. Yes &
After washing the layer with water, it is compressed under reduced pressure. The obtained Japanese crystals are recrystallized from acetone-hexane to obtain white sand crystals of compound [phase]' (44.7,180%). This material exhibits physical properties of 10J- compared to those obtained in eConsideration 111.

Special = + applicant Dainippon Ink Chemical Industry Co., Ltd.

Claims (1)

[Claims] (In the formula, x and y are '/X-Y, and c=o/represents a carbonyl group, or "';CH(OH
) represents a β-hydroxyl group, 2 represents a hydrogen atom, and T represents a bromine atom. Also, ott"s and OR" can represent di- or different acyloxy groups, trivalent esters, or phosphorus ester residues. ) is a sugeloid compound represented by 2. In the method for producing steroid compounds 1) 17α,
21-dihydroxy-5(t, (5α-epoxy-6,
3-ethylenedioxy-9α-fluoropregna-11
,20-dione-17,21-diester #I or 5
α,6α-Epoxy-6,6-Nythilene Diogycy 9α
-Fluoro-11β,17α,21-trihydroxypregna-20-one-17,21-diester μm is treated with hydrogen fluoride to produce 6β,9(t-difluoro-5α.17α,21-)dihydroxybutylene Regnar-3, 11, 2
0-trione-17,,21-diester 6
β, 9 (χ-difluoro-5α, 11β, 17α, 2l
--j) Hydroxypregner 3.20-dione-1
Generates 7,21-diesters: 11) 6β,9α-difluoro-5α,17α,21-
) Lihydroxypregna-3,11,20-trione-
17゜21-noester or 6β,9α-difluoro-5α,11β,17α,21-tetrahydroxypregna-6,20-dione-17,21-diester is brominated to produce 2,2-dibrome-6β,9 (t-dinolol-5α, 1phα, 21-trihydroxypregna-
5,11゜20-trione-17,21-diesters or 2゜2-dibromo-6β,9α-difluoro-5
α, 11β. 17α,21-tetrahydroxypregna-3,20-
Producing dione-17,21-diesters 1- represents a carbonyl group, or represents a β-hydroxyl group as /CH(OH), and Z represents a hydrogen or bromine atom. Also, OR' and OR'' are the same -1:T represents different acyloxy groups, pentanoic acid ester or phosphoric acid ester residues.