CA1050529A - Alkylated pregnanes and process for obtaining same - Google Patents
Alkylated pregnanes and process for obtaining sameInfo
- Publication number
- CA1050529A CA1050529A CA204,503A CA204503A CA1050529A CA 1050529 A CA1050529 A CA 1050529A CA 204503 A CA204503 A CA 204503A CA 1050529 A CA1050529 A CA 1050529A
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- Prior art keywords
- alpha
- methyl
- beta
- dione
- delta
- Prior art date
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-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
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- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
Abstract of the Disclosure The invention relates to novel 21-alkylated steroids of the pregnane series having the formula:
, wherein X = H or halogen;
Y = H2, H(OH), H(Cacyl), O or H(halogen);
R1 = an alkyl group having 1-4 C-atoms;
22 = R1 or H;
R3 = H, CH3 or halogen;
Z = OH, Oalkyl or Oacyl or form together with R4 a group as indicated below;
Q = (when C15-C16 is saturated) alkylidene having 1-4 C-atoms or (.beta.H)(.alpha.R4), in which R4 together with Z is alkyl-idenedioxy having 3-5 C-atoms, alkylidene having 1-4 C-atoms, aralkylidene having 7-8 C-atoms, alkylene of the formula , wherein A = H or halogen and B = H, halogen, alkyl (1-4 C), haloalkyl, alkoxy or phenyl, or a [17.alpha.,16.alpha.-d]- or [16.alpha.,17.alpha.-d]-oxazolino-group, wherein the C-atom in 2'-position may be substituted by alkyl (1-4 C) or phenyl; or Q = (when C15-C16 is unsaturated) methyl or halomethyl, and a process for obtaining same.
The novel compounds possess strong anti-inflammatory conditions especially those associated with the skin and allergic reactions.
, wherein X = H or halogen;
Y = H2, H(OH), H(Cacyl), O or H(halogen);
R1 = an alkyl group having 1-4 C-atoms;
22 = R1 or H;
R3 = H, CH3 or halogen;
Z = OH, Oalkyl or Oacyl or form together with R4 a group as indicated below;
Q = (when C15-C16 is saturated) alkylidene having 1-4 C-atoms or (.beta.H)(.alpha.R4), in which R4 together with Z is alkyl-idenedioxy having 3-5 C-atoms, alkylidene having 1-4 C-atoms, aralkylidene having 7-8 C-atoms, alkylene of the formula , wherein A = H or halogen and B = H, halogen, alkyl (1-4 C), haloalkyl, alkoxy or phenyl, or a [17.alpha.,16.alpha.-d]- or [16.alpha.,17.alpha.-d]-oxazolino-group, wherein the C-atom in 2'-position may be substituted by alkyl (1-4 C) or phenyl; or Q = (when C15-C16 is unsaturated) methyl or halomethyl, and a process for obtaining same.
The novel compounds possess strong anti-inflammatory conditions especially those associated with the skin and allergic reactions.
Description
~5~
The present invention relates to novel 21-alkylated steroids of the pregnane series and to processes for their preparation.
More particularly, the invention relates to novel 21-alkylated steroids of the formula:
~,--c--~
c=o :, Y~"~z ~ ~ wherein ,. R2 , X = H or halogen;
y s H2, H(OH)~ H50acyl), 0 or H(halogen);
Rl = an alkyl group having 1~-4 C-atoms;
R2 ' Rl or H;
. R3 = H~ CH3 or halogen;
Z c OH, Oalkyl or Oacyl or f.orms together with R4 a group as l indicated below;
i~ ~ = twhen C15-C16 is saturated) alkylidene having 1-4 C-i 20 atoms or (~H)(aR4)~ in which R4 together with Z is alkyl-~l idenedioxy having 3-5 C-atoms, alkylidene having 1-4 C-.~ atoms, aralkylidene having 7-8 C-atoms~ alkylene of the formula -----/C\-~C~ , wherein ~ = H or halogen and A B A B
B = H, halogen, alkyl 51~4 C), haloalkyl, alkoxy or phenyl, or a [17a~16a-d]- or [16(x~17a-d]-oxazolino-group9 wherein ~; the C atom in 2~-position may be substituted by alkyl ~1-4 C) or phenyl; or Q - (when C15-C16 is unsaturated) methyl or halomethyl; Cl-C2 and C6-C7 may be saturated or un~
saturated; and halogen being preferably F or Cl~
., .
. ,, "
,,~
~5~
Of particular importance are the 21-alkylated pregnane compounds according to the invention having the partial formula R? Qz R2 _CH R,--CH Rl--C~
c = O
`C~R ~ C/ ~ C-.~
,Q2 ~2 R2 R~-c~
C o C-O C=
~---. N~ R ~ ....... oRg ~ ~oR~
~c~ QG ) ~0 ~`` R2 Q, - c~i ~ ~ C 5 ~
.` . `H...... c-~l c~R~o , wherein Rl and R2 have the meanings , ' .
given hereinbefore~ R6 = H or methyl, R7 = H or methyl, R8 ~ H, methyl or phenyl, Rg = H, alkyl or acyl, Rlo = H
or halogen and Rll ~ H, halogen or methyl~
Specific examples ~f compounds according to the invention are ll~-hydroxy-16a,17a-methylene-21-methyl-bl~4-pregnadiene-3,20-dione and its 9a-fluoro-analogue; 11~-i~op~op~ e~ ~G~,o~y 1 4 ~-1 hydroxy-16a,17a~ 21-methyl-~ ' -pregnadiene-3,20-dione and its 9a-~luoro-analogue; 11~-hydroxy-[16a,17a-30 d~-2'-methyl-oxazoline-21-methyl-~1'4-pregnadiene~3~20-dione
The present invention relates to novel 21-alkylated steroids of the pregnane series and to processes for their preparation.
More particularly, the invention relates to novel 21-alkylated steroids of the formula:
~,--c--~
c=o :, Y~"~z ~ ~ wherein ,. R2 , X = H or halogen;
y s H2, H(OH)~ H50acyl), 0 or H(halogen);
Rl = an alkyl group having 1~-4 C-atoms;
R2 ' Rl or H;
. R3 = H~ CH3 or halogen;
Z c OH, Oalkyl or Oacyl or f.orms together with R4 a group as l indicated below;
i~ ~ = twhen C15-C16 is saturated) alkylidene having 1-4 C-i 20 atoms or (~H)(aR4)~ in which R4 together with Z is alkyl-~l idenedioxy having 3-5 C-atoms, alkylidene having 1-4 C-.~ atoms, aralkylidene having 7-8 C-atoms~ alkylene of the formula -----/C\-~C~ , wherein ~ = H or halogen and A B A B
B = H, halogen, alkyl 51~4 C), haloalkyl, alkoxy or phenyl, or a [17a~16a-d]- or [16(x~17a-d]-oxazolino-group9 wherein ~; the C atom in 2~-position may be substituted by alkyl ~1-4 C) or phenyl; or Q - (when C15-C16 is unsaturated) methyl or halomethyl; Cl-C2 and C6-C7 may be saturated or un~
saturated; and halogen being preferably F or Cl~
., .
. ,, "
,,~
~5~
Of particular importance are the 21-alkylated pregnane compounds according to the invention having the partial formula R? Qz R2 _CH R,--CH Rl--C~
c = O
`C~R ~ C/ ~ C-.~
,Q2 ~2 R2 R~-c~
C o C-O C=
~---. N~ R ~ ....... oRg ~ ~oR~
~c~ QG ) ~0 ~`` R2 Q, - c~i ~ ~ C 5 ~
.` . `H...... c-~l c~R~o , wherein Rl and R2 have the meanings , ' .
given hereinbefore~ R6 = H or methyl, R7 = H or methyl, R8 ~ H, methyl or phenyl, Rg = H, alkyl or acyl, Rlo = H
or halogen and Rll ~ H, halogen or methyl~
Specific examples ~f compounds according to the invention are ll~-hydroxy-16a,17a-methylene-21-methyl-bl~4-pregnadiene-3,20-dione and its 9a-fluoro-analogue; 11~-i~op~op~ e~ ~G~,o~y 1 4 ~-1 hydroxy-16a,17a~ 21-methyl-~ ' -pregnadiene-3,20-dione and its 9a-~luoro-analogue; 11~-hydroxy-[16a,17a-30 d~-2'-methyl-oxazoline-21-methyl-~1'4-pregnadiene~3~20-dione
- 2 -~s~
and its 9~-fluoro-analogue; 9~-fluoro-16~17a-isopropylidenedioxy-21-methyl-~ ' -pregnadiene-3,11,20-trione; 9~ dichloro 16~,17~-isopropylidenedioxy-21-methyl-Al'4-pregnadiene-3,20-dione; 6~-fluoro-16~,17~-isopropylidenedioxy-21-methyl-~1'4-pregnadiene-3,20-dione; 9~-fluoro-[16~,17~-d]-2'-methyloxazoline-21-methyl-~1'4-pregnadiene-3,11,20-trione; 11~,17~-dihydroxy-16,16-methylene-21-methyl-~1'4-pregnadiene-3,20-dione, 11~-hydroxy-[17~,16~-d]-2'-methyl-oxazoline-21-methyl-~1'4-pregnadiene-3,20-dione and its 9a-fluoro-analogue;
ll~-hydroxy-16~,17a-ethylene-21-methyl-~1'4-pregnadiene-3,20-dione and its 9c~-fluoro-analogueO
The novel compounds of the invention possess strong anti-inflammatory properties when applied locally and cause lit~le or no systemic thymolytic, adrenolytic and salt-retaining effects, and thus show a marked dissociation of local from systemic action. Consequently, they are very useful in the treatment o~ inflammatory conclition5 especially those .
associated with the skin and allergic reacti.ons. The compounds can be administered topically in the form of ointments, creams, lotions or spray and suppositories or by injection for installce intraarticularly for the ~.
lacal treatment of inflammation, possibly in combination with other active ingredients.
:' 20. According to this invention~ there is provided a process for the preparation of novel alkylated steroids of the pregnane series having the formula l2 ~ :
Rl - C - H
C = O (I) '' ~ ""'Z :
Q ,wherein, X = H or halogen;
H2, H(OH), H(Oacyl), O or H(halogen), .', , .
, , .
.. . . . .
~CI 5~5~
R1 = an alkyl group having 1-4 C-atoms;
R2 = Rl or H;
: R3 = H, CH3 or halogen;
Z = OH, Oalkyl or Oacyl or forms together with Q a group as indicated below;
Q = ~when C15-C16 is saturated) alkylidene having 1~4 C-atoms or (~H~ ~R4), : in which R4 together with Z is alkylidenedioxy having 3-5 C-atoms, alkylidene ; having 1-4 C-atoms, aralkylidene having 7-8 C-atoms, alkylene of the formula ~ --, wherein A = H or halogen and B = H, halogen, alkyl (1-4 C), haloalkyl, alkoxy or phenyl, or a [17a,16-d]- or [16~,17~-d]-oxazolino-group, wherein the C-atom in 2'-position may be substituted by alkyl ~1-4 C) or phenyl; or Q = ~when C15-C16 is unsaturated) methyl or , halomethyl, which comprises (I) heating a compound of the formula ,,. CHRl R2 ~N ~Il) Rl~
', 3 wherein R6 is a protected hydroxyl or ketone group, and R7 is hydrogen or a pratected hydroxyl group, to split off nitrogen thereby producing a steroid of formula CI) wherein Q is ~H)CaR4) and Z and R4 form a 16,17-methylene bridge, in admixture with a corresponding 16-methyl-~16-steroid; or q ~ ~II) treating a compound of the formula : :
CHRlR ~
3a ~563 52~
with an acid to break the epoxide ring, thereby producing a steroid of formula (I~ wherein Z îs a-OH and Q is a 16J16 methylene group, in admixture with a steroid of formula I wherein Z is a-OH and Q is a ~15-16-me~hyl group;
or CIII) reacting a compound of the formula C
R7 ~ ~ OH
~ _ _OV (IV) 6 J ~ .
; 3 wherein V represents hydrogen or acetyl, with a ketone or aldehyde of 3 to 5 carbon atoms in the presence of an acid, thereby producing a steroid of formula (I) wherein Q is (~H)~aR4) and Z and R4 form a 16a,17a-(C3 to C5) alkylenedioxy group; or ~IV) reacting a compound of the formula l 2 tV~ ~
R
R3 ::~
uith an ole~in o the ~ormula A,,,_C = C thereby producing a steroid ~ ::
of formula (I) wherein Q is ~@H)(aR4) and Z and R4 form a 16a,17a-alkylene group in which the alkylene is of the formula ---,C -,C~---; or A B A B
~V) reducing a compound of the formula ' ' i ,~
', .' :
~ -3b-.. . ~:- ~' s~
`~ CHR R
CH CO
~ ~ - - O.COCH3 (Vl~
R
by catalytic hydrogenation, thereby obtaining a steroid of formula (I) wherein Z and Q form a 2~-methyl-17~,16~-oxazoline ring fused with the D-ring of the steroid; or (VI) ring closing a compound of the formula CHR R
R CH CO
7 ~ 3 :
. ! ~ ~ ~ OH
- - NH.COCH3 ~vII
and its 9~-fluoro-analogue; 9~-fluoro-16~17a-isopropylidenedioxy-21-methyl-~ ' -pregnadiene-3,11,20-trione; 9~ dichloro 16~,17~-isopropylidenedioxy-21-methyl-Al'4-pregnadiene-3,20-dione; 6~-fluoro-16~,17~-isopropylidenedioxy-21-methyl-~1'4-pregnadiene-3,20-dione; 9~-fluoro-[16~,17~-d]-2'-methyloxazoline-21-methyl-~1'4-pregnadiene-3,11,20-trione; 11~,17~-dihydroxy-16,16-methylene-21-methyl-~1'4-pregnadiene-3,20-dione, 11~-hydroxy-[17~,16~-d]-2'-methyl-oxazoline-21-methyl-~1'4-pregnadiene-3,20-dione and its 9a-fluoro-analogue;
ll~-hydroxy-16~,17a-ethylene-21-methyl-~1'4-pregnadiene-3,20-dione and its 9c~-fluoro-analogueO
The novel compounds of the invention possess strong anti-inflammatory properties when applied locally and cause lit~le or no systemic thymolytic, adrenolytic and salt-retaining effects, and thus show a marked dissociation of local from systemic action. Consequently, they are very useful in the treatment o~ inflammatory conclition5 especially those .
associated with the skin and allergic reacti.ons. The compounds can be administered topically in the form of ointments, creams, lotions or spray and suppositories or by injection for installce intraarticularly for the ~.
lacal treatment of inflammation, possibly in combination with other active ingredients.
:' 20. According to this invention~ there is provided a process for the preparation of novel alkylated steroids of the pregnane series having the formula l2 ~ :
Rl - C - H
C = O (I) '' ~ ""'Z :
Q ,wherein, X = H or halogen;
H2, H(OH), H(Oacyl), O or H(halogen), .', , .
, , .
.. . . . .
~CI 5~5~
R1 = an alkyl group having 1-4 C-atoms;
R2 = Rl or H;
: R3 = H, CH3 or halogen;
Z = OH, Oalkyl or Oacyl or forms together with Q a group as indicated below;
Q = ~when C15-C16 is saturated) alkylidene having 1~4 C-atoms or (~H~ ~R4), : in which R4 together with Z is alkylidenedioxy having 3-5 C-atoms, alkylidene ; having 1-4 C-atoms, aralkylidene having 7-8 C-atoms, alkylene of the formula ~ --, wherein A = H or halogen and B = H, halogen, alkyl (1-4 C), haloalkyl, alkoxy or phenyl, or a [17a,16-d]- or [16~,17~-d]-oxazolino-group, wherein the C-atom in 2'-position may be substituted by alkyl ~1-4 C) or phenyl; or Q = ~when C15-C16 is unsaturated) methyl or , halomethyl, which comprises (I) heating a compound of the formula ,,. CHRl R2 ~N ~Il) Rl~
', 3 wherein R6 is a protected hydroxyl or ketone group, and R7 is hydrogen or a pratected hydroxyl group, to split off nitrogen thereby producing a steroid of formula CI) wherein Q is ~H)CaR4) and Z and R4 form a 16,17-methylene bridge, in admixture with a corresponding 16-methyl-~16-steroid; or q ~ ~II) treating a compound of the formula : :
CHRlR ~
3a ~563 52~
with an acid to break the epoxide ring, thereby producing a steroid of formula (I~ wherein Z îs a-OH and Q is a 16J16 methylene group, in admixture with a steroid of formula I wherein Z is a-OH and Q is a ~15-16-me~hyl group;
or CIII) reacting a compound of the formula C
R7 ~ ~ OH
~ _ _OV (IV) 6 J ~ .
; 3 wherein V represents hydrogen or acetyl, with a ketone or aldehyde of 3 to 5 carbon atoms in the presence of an acid, thereby producing a steroid of formula (I) wherein Q is (~H)~aR4) and Z and R4 form a 16a,17a-(C3 to C5) alkylenedioxy group; or ~IV) reacting a compound of the formula l 2 tV~ ~
R
R3 ::~
uith an ole~in o the ~ormula A,,,_C = C thereby producing a steroid ~ ::
of formula (I) wherein Q is ~@H)(aR4) and Z and R4 form a 16a,17a-alkylene group in which the alkylene is of the formula ---,C -,C~---; or A B A B
~V) reducing a compound of the formula ' ' i ,~
', .' :
~ -3b-.. . ~:- ~' s~
`~ CHR R
CH CO
~ ~ - - O.COCH3 (Vl~
R
by catalytic hydrogenation, thereby obtaining a steroid of formula (I) wherein Z and Q form a 2~-methyl-17~,16~-oxazoline ring fused with the D-ring of the steroid; or (VI) ring closing a compound of the formula CHR R
R CH CO
7 ~ 3 :
. ! ~ ~ ~ OH
- - NH.COCH3 ~vII
3 ~ ) 1 ~ hy the action of an acid, thereby obtaining a steroid of formula (I) wherein :: : :
Z and Q form a 2l-methyl-l6a~l7a-oxazoline ~ing fussd with the D-ring of the . ::
steroid; or - .
.j .
- 10 ~VII) 21~alkylating a compound of the formula ;
,~, CH2R5 ; .
,IZ (VllO ~
.'' ~ -i 6 : R3 whe~ein R5 represents H or halogen; the substituents R3, R6 and R7 in the starting materials of ormulae ~ to (VIII) inclusive being as follows:
. .~ ' .
....
52~
R3 = H, CH3 or halogen; R6 = a protected hydroxyl or keto group; and R7 =
hydrogen or a protected hydroxyl group; and the dotted lines in the steroid rings indicating optional double bonds; and removing any protecting group present on the 3-hydroxyl, 3-keto or ll-hydroxyl group of the product, converting a (~5-)3-hydroxyl system to a ~4- or ~1'4-3-keto system, introducing a ~6(7~ double bond with a quinone when required, acylating an ll-hydroxyl and a 17~-hydroxyl group when requiredJ introducing halogen atoms at the 9- and ll-position by halogenating a product having a ~9~11) double bond when required, and oxidizing an ll-hydroxyl group to ll-keto when required.
As indicated above the compounds of the in~ention are prepared from ~1 -21-alkyl-20-oxo- or ~16-21,21-dialkyl-20-oxo compounds of the pregnane series having ~he partial formula:
'~ C=O
, wherein Rl and R2 have the .
L ~ ~ -3d-~5Q5;2~
meanings glven hereinbefore by introducing the substituents required at the posltions 15, 16 and/or 17 of the end~
products by me'thods known ~ se or from 20-oxo compounds of the pregnane series having the partial formula:
H
C-o Z
1 L ~ , wherein Z and Q have the meanings :' given hereinbefore and R5 - H or halogen, by 21-mono- or 21~21~dlalkylation of these 20-oxo compounds according to the methods described in Belgian Pat. 793958 of Applicant ~- South-Afr. Pat. 72/9103 = Dutch Pat.ApplO 7300313).
Other substituents indicated in the formula of the end-products may be introduced subsequently by methods known Per se.
Starting from Q16 20-oxo compounds as indicated above the various substituents in the 15-, 16- and/or 17-position may be introduced as follows:
A sultable ~ 20-oxo compound is reacted for example with an appropriate diazo compound in a suitable organic solvent such as ethex or a halogenated hydrocarbon, and at a temperature preferably below ~0C to qive a [17a,16a-c]-pyrazolino-20-oxo-steroid. By heat treatment, usually 25 carried out at a temperature between 100C and 250C~
poss~bly in an inert solvent such as decalin or toluene, or by acid treatment (e.gO perchloric acid, borontri-fluoride or trifluoro acetic acid) of the pyrazolino compound nitrogen is split off, leaving a mixture of 30 16-alky1-~16-20-oxo- and 16~17-a1ky1ldene-20-oxo-sterolds, .
~5'~)5~
thelr ratio to one another being dependent on the reaction conditions and the choice of the starting compound, i.e.
the diazo-compound~ The isomers can be separated by chromatography or crystallization.
A very convenient method ~or the preparation of 16,17-(substituted methylene)-20-oxo-steroids is the method described in the British Specification No. 1,235,285.
The 16-alkyl-~16-20-oxo compound is converted into the 16p-alkyl-16a,17a-epoxy-20-oxo compound by reaction with9 for example, alkaline hydrogenperoxide, whereafter the epoxy compound is treated with an acid in a suitable solvent, e.g. HI in aqueous dioxan, p-toluene sulphonic acid in benzene, HBr in acetic acid, possibly followed by a reductive treatment which Raney nickel~ so as to obtain the 16-alkylidene-17tx-hydroxy-20-oxo-steroid, e.g~
the 16-methylene-17a-hydroxy compound.
a/ky/, c/e~ e Besides or instead of the 16-~hy~knnr compound a ~15-1~-methyl-17a-hydroxy-20-oxo-steroid is obtained, dependent on the reaction conditions. In this connection reference is made to the methods described in British Specification No. 1,016,955. The isomers can be separated and/or purified by chromatography or crystallization.
The ~16-20-oxo steroid may be oxidised, e.g. by means of potassium permanganate in a buffered solution, to yield the 16~,17tx-dihydroxy-20-oxo compound, which may be con-verted into the 16a,17tx-alkylenedioxy-20-oxo-steroid by reaction wLth a ketone or an aldehyde, such as acetone, acetaldehyde, ethyl methyl ketone, propionaldehyde and the like. The reaction is allowed to take place in 3CI suspenslon or solution of the steroid ir the ketone or :
~ - ~
31 ~5~
aldehyde, with or without an inert organic solvent (e.g.
dioxan) present, and in the presence of a mineral acid, e.g. HCl~ HC104, p.TsOH (temp. between 15 and 60 C, reaction time 1-18 hrs). After the reaction the acid is neutralized and the product recovered.
Another route to the 16~,17(~-alkylenedioxy-20-oxo-steroids is reacting the ~16-20-oxo steroid with alkaline hydrogenperoxide in the presence of methanol to yield the 16a,17a-epoxy compounds, splitting open the 16a,17a-epoxy group by reaction with acetic acid and a hydrazine~ e.g.
H2N.NHC02CzH5 and treating the 16a-acetoxy-17(x-hydroxy-20-hydrazone compound obtained with pyruvic acid/acetic acid to obtain the 16a-acetoxy-17a hydroxy-20 oxo compound, and finally reacting the 16a-acetoxy-17a-hydroxy-20-oxo compound with a ketone or an aldehyde, e.g. acetone or acetaldehyde3 in an alcohol, e~g. methanol, in the presence of an acid, e.g. perchloric acid so as to obtain the 16a,17a-alkylene-dioxy 20-oxo-steroid.
A 16a,17a-ethylene- or 16(~,17a-(substituted ethylene)-20 20-oxo-steroid may be obtained by reacting the ~16-20-oxo-steroid with an olefin, e.g. ethylene or substituted ethylene, in an organic solution, e.g. benzene or dioxan, by the action of ultraviolet llght (270-330 m~) for 1-15 hour s .
A Ll7a716a-d]-oxazolino-20-oxo-steroid may be obtained as follows:
The ~16 20-oxo steroid is reacted in a solvent, e.g~
tetrahydrofuran, with N-bromo-acetamide in the presence of HC10~, preferably in the dark, or with saturated HBr/
30 acetlc scld to glvF the 17[~-bromo-16~-hydroxy-20_one. This ~; .
;
/
~5~5i2~i 20-ketone is converted into the 16~,17~-epoxy-20-one by treating with KOH in boiling methanol. The B~epoxide is reacted with sodium azide in methanol, containing H2S04, under reflux to yield the 17a-azido-16a-hydroxy-20-one.
For the preparatlon of the L17a,16a-d]-2'-methyl-oxazolino-20-oxo compound the 17a-azido-16a-hydroxy compound is converted into the 16a-acetate, e.g. by reactlon with acetic anhydride/pyridine, whereafter the 17a-azido-16a-acetate is reduced, e~g~ with PtO2/H2 in methanol, to give the ~17a916a-d]-2'-methyl-oxazoline-20-oxo-steroid.
The [16a,17~-d]-isomer may be prepared as follows:
The ~16-20-oxo-steroid is reacted with alkaline hydrogenperoxide to give the 16a,17a-epoxy-20-oxo compound, which is reacted with sodium azide to obtain the 16~-a~ido-17a-hydroxy-20-one. Reaction of the last-mentioned compound with acetic anhydride/pyridine yields the corresponding 17a-acetate, which is reduced~ for example with H2/PtO2 or H2/
Raney Ni~ to the 16~-amino-17a-acetoxy-20-one. The 16~-amino-17a-acetoxy-20-one is converted into the corresponding 16~-chloramino compound by reaction wlth N-~hlorosuccinimide in e.g. methylenechloride. Subsequen~ heating of the 16~-chloramlno-17a-acetoxy-20-one with potassium acetate in a solvent, e.~ dimethylformamide gives the 16-imino-17(x-acetoxy-20-one, which is acetylated wlth acetic anhydride/
acetic acid to obtain the ~ -16-acetamido-17a-acetoxy-20-one. Subsequent base hydrolysis, e.g. with potassium carbonate/methanol affords the ~15-16-acetamido-17a-I hydroxy-20-one, which is reduced with H2/Pd on charcoal to the 16a-acetamido-17a-hydroxy-20-one. Ring closure is effected by heating the latter with an acid, e.g. p-..
,, ~L~5~5~
toluene sulphonic acid, to yield the [16a,17a-d]-2'-methyl-oxazolino-20-oxo steroidO
In all reactions described above reactive or vulnerable groups present elsewhere in the steroid molecule are protected according to methods known in the art~
Starting materials for the preparation of the compounds according to the invention can be 20-oxo-pregnanes of the formula:
.
R~ ~ ~
~6 ~ , wherein R3 R3 ~ H, CH3 or halogen~
,~'! 15 dotted lines indicate optional double bonds9 R = a protected hydroxyl or :keto group, i R7 = hydrogen or a protected hydroxyl group, and .`. D denotes the D-ring structure indicated by the partial : formulae ~iven hereinbefore.
During the alkylation procedure, it is preferable to protect an oxygen function at C-3 if one is present by reversible ether formation such as the tetrahydropyranyl ether in the case of a 3-hydroxyl group or a ~3'5-enol ether in the case of a ~ -3-keto grouping, or by ketal formation such as the dimethyl ketal in the case of a 3-- keto group to prevent unwanted alkylation reactions such ; as 0-alkylàtion which would take place at the same time as 21-alkylation if the starting material contained a free 3-hydroxyl group or 3-acyloxy group or to prevent unwanted C-alkylation reactions from taking place in the . .
. .
_ ~3 _ . ' ~1 ~15~5~9 ~-position to a free 3-keto group if such were present. It has been found that the 3-0-alkylated products which are formed if a free ~-hydroxyl group or its acyl derivative is present during the alkylation reaction are very difficult to hydrolyse back to the desired 3-hydroxyl group which is a necessary precursor for converting by oxidation to the 3-keto group in the final products according to the invention.
Slmilarly it is necessary to protect an ll-hydroxyl substituent if one is present in the starting material before carrying out the alkylation procedure to prevent the sirnulataneous formation of an ll-0-alkylated derivative which cannot be readily converted back to the free hydroxyl group~ When an lla-hydroxy-~roup is present, it is ~15 pre~erable to protect it by reversible ether formation such ;ias the tetrahydropyranyl ether but when an ll~-hydroxyl substituent is present, because of its very sterically hindered position in the steroid molecule it is sufficient to protect it as an ester such as the acetate in which case ;20 the acyl group may itself undergo alkylation.
, ,1 - After introduction of the substituents required at the positions 15, 16 and/or 17 of the 21-alkyl or 21,21-dialkyl compounds by the methods described above or of the 21-alkyl or 21,21-dialkyl substituents into the 20-oxo compounds i 25 already carrying the 15-, 16- and/or 17-substituents, as i indicated hereinbefore, other groups already present in . ' , .
- the starting materials may be modified and new groups of !
functions may be introduced by methods known ~ se to furnish the desired end-products according to the invention.
A 3-hydroxyl group may be oxidlsed after hydrolysis of _ 9 _ ,................. .
s~
the protecting ether group, for example, by Oppenauer ~oxidation in the case of a~ _steroid to furnish a~ -3_ keto-steroid, or with chromic acid in the case o~ either a 5~- or 5~-3-hydroxy derivative to give the corresponding saturated 3-ketone.
Where a 3-keto gro1-p in the starting material is protected as its ketal derivative, or in the case o~ a ~ -3-ketone, as the enol-ether for the purpose of the -~ alkylation reaction, it is only necessary to hydrolyse it to regenerate the keto group.
` In compounds containing a ~4-3-keto grouping, additional double bonds may be introduced at positions Cl-C2 and/or C6-C7 by known chemical means such as by reaction with suitable ~-quinone derivatives or microbiologically with an appropriate micro-organism.
A 3-keto-5~-steroid may be converted to a A ~ -3-keto-skeroid by means of selenium dioxide or by reaction with a quinone such as dichlorodicyanobenzoquinone or by halogenation at positions 2 and 4 and subsequent de~ydrohalogenation by methods known per se A 3-keto-5~-steroid may be converted into a ~-3-keto-steroid by means of selenium dioxide or by mono-bromination at position 4 followed by dehydrobromination and the so formed~ _3-ketone may be transformed into the ~1,4_3_ ketone by further reaction with selenium dioxide or di-;~ chlorodicyanobenzoquinone. Alternatively, a 3-keto-5 steroid may be converted directly into a~l'4-~-ketone by reaction with selenium dioxide or by reaction with a suitable quinone such as dichlorodicyanobenzoquinone, or ; 30 by di-halogen~tion for example di-bromination at positions .
': -- 10 _ ;
~L~5~5~91 2 and 4 and subsequent dehydrohalogenation by methods known per se.
A ~ -3-keto steroid may be converted into the cor~esponding ~ -derivative by reaction with a suitable quinone such as chloranil and the thus formed ~4'6-3-keto compound may then be converted to the corresponding ~ ~ ,6_ 3-keto derivative by reaction wlth an appropriate quinone such as dlchlorodlcyanoben7oquinone.
The microbiological introduction of a double bond at position Cl-C2 may be carrled out by lncubation with a 1,2-dehydrogenating mlcro-organism, for example Coryn-bacterium Simplex, Bacillus sphaericus or Bacillus sub-tilis.
Introduction of a 6-substituent, if not already lS present may be effected i~ desired by converting a 3-hydroxy-~5-steroid into the 5a,6~x-epoxide and treating the latter with methyl magnes'Lum haiide, a halogen acid, boron trifluoride or fluoroboric acid to give in each case the corresponding 5a-hydroxy-6~-substituted derivative which can then be converted into the corresponding ~4-3-keto-6~-substituted compound by oxidising the 3-hydroxy group wlthy for example, chromic acid and dehydrating the 5-hydroxyl group appropriately under acid or basic conditions. Isomerisation of the 6~-substituent may be brought about by treatment with acid or base.
A ~9(~ double bond if present may be con~erted to the 9a-bromo-11~-hydroxy compound or an ester thereof by methods known ~ se and then transformed under basic conditions into a 9~ epoxide which may be subsequently opened with a halogen acid to give the corresponding 9-.
~s~s~
halo~ hydroxy derivative which can then be oxidised to the corresponding 9a-halo~ ketone.
Introduction of an ll-hydroxyl group may be performed microbiologically, e.g. by incubation with an ll-hydroxyla-ting micro-organism such as Curvularia or a Rhizopus after which the ll-hydroxyl group may be oxidised to an ll-keto group, acylated or dehydrated to form a ~9(11)-double bond.
A A9(11) double bond may be converted to a 9,11-dihalogen derivative such as the dichloride by addition of a halogen such as chlorine.
After elaboration of the al'4-3-keto group an 11~-acyloxy group, if present, may be hydrolysed to the corresponding ll~-hydroxy derivative under relatively mild conditions with alcoholic alkali and the so formed 11~-hydroxy group may then be oxidized if desired to the corres-ponding ketone.
The acyloxy group present in the position 11 and/or 17 may be derived from a saturated or unsaturated organic carboxylic acid having 1-18 carbon atoms and is preferably a lower alkanoyloxy group, such as acetyloxy, propionyloxy, valerianyloxy and the like.
The 21-alkylated compounds according to the invention are very active ln the ~Ihuman vasoconstriction" test, indicating their good to excellent potency as antiinflam-matories. They have the further advantage over the known21-desmethyl compounds that they are more soluble in the usual vehicles for topical application.
~ 12 ~
, ~
~6DS~5~~9 The invention is further illustrated by the following examples .
Example 1 a) To a stirred suspension of 3~-hydroxy-~9(~ l6-5a-pregnadien-20-one in sodium-dried benzene was added excess dihydropyran .and a catalytic quantity of p-toluenesulphonic acid.
After 1 hour the solution was washed with sodium carbonate solution9 then to neutrality with water, dried and evaporated to a gummy solid, which was crystallised from petroleum ether to give 3~-hydroxy-~9(11)'16-5a pregnadien-20 one 3-tetrahydropyranyl ether.
b) To a stirred solution of lithium diisopropylamide in sodium-dried tetrahydrofuran under nitrogen at 0C was added a solution of 3~-hyclroxy-~9(1l)9l6 5a-pregnadien-20-one 3-tetrahydropyranyl. ether (0.66 mole equivalents) in sodium-dried tetrahydrofuran. After the solution had been stirred for 30 minute!s at room temperature, external cool.~ng was again applied and excess dry methyl iodide was added. The cooling bath was removed, and after 45 minutes the solYent was evaporated under vacuum. The residue was dissolved in aqueous acetic acid and after 4 hours the product was precipitated by the addition of water.
~,: Crystallisation from acetone/hexane gave 3~-hydroxy-21-~h 1 ~9(11~16_5~_pregnadien-20-One-c) To a stirred solution of lithium diisopropylamide in dry tetrahydrofuran under nitrogen at 0C was added a solution of 3~-hydroxy-21-me~hyl-~9(~ 6-Sa-pregnadien- -: 20-one 3-tetrahydropyranyl ether (0,66 mole equivalents) in dry tetrahydrofuran. After the solution had been . - 13 _ ;
:~ [9Sg~5~1 stirred for 30 minutes at room temperature9 external coollng was again applied and excess dry methyl iodide was added. The cooling bath was removed, and after 45 minutes the solvent was evaporated under vacuum. The S residue was dissolved in aqueous acetic acid and t~e solution allowed to stand overnight. The product was precipitated by the addition of water, filtered, dried and crystallised frorn acetone~hexane to glve 3~-hydroxy-21~21-dimethYl-~9~11) 9 16-5a-pregnadien-20-one .
d) To a solution of 3~-hydroxy-21-methyl--~9(~ l6-5a-pregnadien 20-one (9.97 g) in methylene chloride and methanol wa added 4N sodium hydroxide (20 ml) followed by 30% hydrogen peroxide (20 ml). The reaction mixture was shielded from light and allowed to stand overnight.
External cooling was applied and sodium sulphite solution was added to decompose excess hydrogen peroxide. The methylene chloride was then evaporated under vacuum and the reaction mixture was poured into water. Filtratlon of the solid gave 3p-hydroxy-16a,17a-epoxy-21-methyl-~9511)-5a-pregnen-20-one-!
In a slmilar manner 3~hydroxy-21,21-dlmethyl-~9(ll)7l6-5a-pregnadien-20-one was converted to 3~-hydroxy-16~,17a-epoxy-21,21-dimethyl-~9(11)-5a-pregnen-20-one.
- e) To a stirred solution of 3~-hydroxy-16~17a-epoxy-21-methyl-~9( 1)-5a-pregnen-20-one (9.5 g) in acetic acid was added a solution of carbethoxy hydrazine (9.5 g) in acetic acld. The reaction mixture was stirred overnight then poured into ice-waterO Filtration gave 3~,16~x,17a-trihydroxy-21-rnethyl-~9(~ 5(x-pregnen-20-one 16-acetate 20-carbethoxy hydrazone.
. , 3~s~
In a similar manner 3~-hydroxy-16a,17a-epoxy-21,21-di-methyl-a9(11)-5-pregnen-20-one was converted to 3~16a, 17-trihydroxy-21,21-dimethyl-~9(11)-5a-pregnen-20-one 16-acetate 20 carbethoxy hydrazoneO
f) 3~l6a~l7a-Trihydroxy-2l-methyl-~9(ll)-5a pregnen-20-one 16-acetate 20-carbethoxy hydrazone (13.3 9) was dissolved in acetic acid at 100 C and 50% aqueous pyruvic acld (13.3 ml) was added~ After 10 minutes at 100C water was slowly added for a further 20 minutes after whlch the solution was allowed to cool and with the continued slow addition of water. The solid was filtered to give 3~16ag 17a-trihydroxy-21-methyl-~9tll)-5a-pregnen-20-one 16-acetake.
In a similar way 3~,16a,17a-trihydroxy-21,21-dimethyl-~9(11)-5a-pregnen-20-one 16 acetate 20-carhethoxy hydra-~ zone was converted to 3~916(~,17a-trihydroxy-21,21-di-!~ methyl-~9(11)-5a-pregnen-20-Gne 16-acetate.
g) To a solution of 3~,16a,17a-trihydroxy-21-methyl-a9 Sa;pregnen 20-one 16-acetate (7~5 g) in acetone and methanol was added 70% perchloric acid (7.5 ml) and the solution was heated to reflux for 1 hour, then cooled and poured into water containing sodium acetate.
~Filtration of the product gave 3~-hydroxy-16a~17a-iso-propylidenedloxy-2l-methyl-~9(ll)-5a-pre9nen-2o-Qne~
In a similar way 3~,16a917a~trihydroxy-21~21-dimethyl-~9(11)-5a~pregnen-20-one 16-acetate was converted to 3~-hydroxy-16a,17a-isopropylidenedioxy-21,21~dimethyl-~9(11~_5a pregnen~20-one-h) 3~-Hydroxy 16atl7a-isopropylldenedioxy-21-methyl-Q9( 5a-pregne~-20-one was dissolved in acetone and the .
~1~5~
stirred solution was cooled in an ice bath. 6.24 N Jones Reagent was added dropwise until excess was present, and after the addition of a little isopropanol to decompose the excess,the solution was poured into water. The product was filtered off and purified by chromatography on sili-cagel and elution with mixtures of toluene/ethyl acetate.
Crystalllsation of the appropriate fractions from ether/
hexane gave 16,17-isopropylidenedioxy-21~methyl-~g( Sa-pregnene-3 9 20 dione.
In a simllar way 3~-hydroxy-16a,17a-isopropylidenedioxy-21,21-dimethyl-~9(11)-5 pregnen-20-one was converted to 16,17a-isoproylidenedioxy-21,21-dimethyl-~9(11)-Sa-pregnene-3,20-dione~
` i) A solution of 16~17-isopropylidenedloxy-21-methyl-~9(~ 5à pregnene-3,20-dione and dichlorodicyanobenzo-quinone (2.4 mole equivale!nts) in toluene/acetic acid 10:1 was heated to reflux with stirring overnight. The cooled reaction mixture was filtered, then the filtrate was evapor ted to dryness and the residue purged three times with toluene to remove acetic acid. The residue was then dissolved ~n toluene and the solution passed throu~h a column o~ grade H alumina. Elut~on w~th ether and evaporation of the eluant gave the crude product. This was purif ied by chromatography on silicagel, w1th toluene/ethyl acetate mixture~ The approp~iate fractions were combined and crystallised from methylene chloride/methanol to g~ve 16a,17a-iso-P~opylidenedioxy-2l-methy~ 4 9 9(11)-pregnatr~ene-3 9 20-dione.
In a similar manner 16a~17-isopropylidenedloxy-21,21-. .:
~5a 5;~
dimethyl~9(~ SA-pregnene-3,20-dione was converted to 16~,17~-isopropylidenedioxy-21,21-dimethyl ~ ,4,9(1L)_ pregnatriene-3,20-dioneO
j) Toa stirred solution of 16a,17a-isopropylidenedioxy-21_methyl~ 4~9(~L~_pregnatriene_3~20_dione (2 g) in tetrahydrofuran was slowly added 0.5 N perchLoric acid (10 ml) followed by N-bromoacetamide (1 g) with exclusion of Light. After 30 minutes, sodium sulphite solution was added and the reaction m~xture was poured into water.
Filtration of the solid gave ~-bromo~ -hydroxy-16q, 17q-isopropylidenedioxy-21-methyl-~' -pregnadiene-3,20-dione.
In a similar manner 16~17~-isopropyLidenedioxy-21,21~
thyl-~l74~9{~ pregnatriene-3~2o-dione was converted to 9~-bromo-11 ~hydroxy-16~,:L7o~isopropyl-idenedioxy-21,21-dimethyl/-~'4-pregnadiene-3,20-dione~
k) To a stirred solution of n-butane thiol (3~6 mL) in dimethyl sulphoxide under oxygen-free nitrogen was added freshLy prepared chromous acetate ~4.74 g), followed by a solution of crude 9~-bromo-11~-hydroxy_ 16d,17~-isopropyLidenedioxy-2I-methyl~ ' -pregnadiene-3~20~dione (2.37 g) in dimethyl sulphoxide~
The reaction flask was stoppered and the solution stirred magnetically overnightO
~" ~
e mixture was then poured into saturated sodium chloride solution and the product extracted into ethyl acetate. The solwtion was washed with 5% sodium carbonate solution, then to neutrality with water, dried and evaporated to dryness.
~:;
Crystallisation of the residue from methylene chloride/
methanol gave 11 ~hydroxy-16~,17~ -isopropylidenedioxy-.
, ,, . ,, . : . : ~ , ~ , . :
~15~9S2~
21-methyl-Ql' -pregnadiene-3,20-dione. M.p. 286-306C.
In a similar manner 9a-bromo~ hydroxy 16,17a-iso-propylidenedioxy-21921-dimethyl-A ' -pregnadiene-3 9 20-dione was converted to ll~-hydroxy-16~,17a-isopropyl-S idenedioxy-21,21-dimethyl-Al'4-pregnadiene-3~20-dione.
M.p. ~65 271C.
Example 2 a) A Quspension of 3~3-hydroxy-16~,17-epoxy-21-methyl-~9(11)-5a-pregnen-20-one in aqueous dimethyl sulphoxide was treated with sodium azide and conc. H2S04 and stirred under reflux for 2 hours. The reaction mixture was cooled~
poured into water and the solid product was filtered and dried. The crude diol was suspended in glacial acetic acid and acetic anhydride, and the mixture was warmed in a hot water bath for 15 minutes with a catalytic quantity of p-toluene sulphonic acid. The resultant solution was poured onto Lce-chips, allowed to attain room temperature and the brown solid filtered and dried.
Crystallisation from methylene chloride/methanol gave ; 20 pure 3~,17a-dihydroxy-16~--azido-21-methyl-~9(11)-5a-pregnen-20-one-3~17-diacetate.
." :
In a s~milar way the corresponding 21,21-dimethyl epoxide ~ gave 3~,17a-dihydroxy 16p-aæido-21,21~dimethyl-~9(11)-5a-`` pregnen-20-one 3,17-diacetate.
b) A mixture of 3~,17a-dihydroxy-16~-azido-21-methyl-~9( 1)_ ~, Sa--pregnen-20-one 3,17-diacetate, in acetic acid and 3 platinum oxide was shaken in an atmosphere of hydrogen for 4 hours. The catalyst was filtered~off and the filtrate evaporated to low volu~e, diluted with water and 30 extracted with ether. The extract was washed with 2N HCl and ~' ,, ~
~ ., .
/
~D5~52~
the acid extracts basified to gi~e a solid which was filtered and dried to yield pure 3~17a-dihydroxy-16~-amino-21-methyl-~9(11)-5a-pregnen-20-one 3,17-diacetate.
In a similar manner the 21,21-dimethyl-16~-azide was converted to the corresponding amine.
c3 A mixture of 3~917a-dihydroxy-16~-amino-21-methyl-Q9(ll)-5a-pregnen-20-one diacetate, methylene chloride and N-chlorosuccinimide was stirred at room temperature for 60 minutes then diluted with water. The organic layer was separated, dried and evaporated and the resldue crystallised from ether/n~hexane to give 3~,17a-di-hydroxy-16~-chloramino-21-methyl-~9(~ 5a-pregnen-20-one diacetate.
The chloramine was suspended in dimethyl formamide, ; 15 solid potassium acetate was added and the mixture stirred for 60 minutes at 40 C under nitrogen. The reaction mixture was cooled~ diluted with water and the resultant solid filtered and dried. Crystalllsation from acetone/n hexane gave 3~17a-dihydroxy-16-imino-2~-methyl-~9tll)-pregnen-2o-one diacetate.
In a slmilar manner, treatment of the 16~-amino-21921-;7'. dimethyl-pregnane under the same conditions yielded ; 3~17a-dihydroxy-16-imino-21,21--dimethyl-~9(11)-5a-i ~ pregnen-20-one diacetate.
d) A suspension of 3~,17~-dihydroxy-16-imino-21-methyl-i ~9(11)~5a-Pregnen-20-one diacetate in 95:5 acetic acid:
-~ acetic anhydride was stirred for 30 minutes at room ~ temperature, then diluted with water and the resultant : .
white solid was filtered and dried to give 3~917.~-dihydroxy-16-acetamide-21-methyl-~9(ll)715 pregnadien-, .
.~ .
. , .
~s~
20-one diacetate. The crude acetamide was suspended in methanolic potassium carbonate and the mixture stirred at room temperature. After 3 hours the solution was poured into water and the white solid filtered and drled to yield 3~,17a-dihydroxy-16-acetamido-21-methyl ~9(~ 5-pregnadien-20-one. The crude diol was dissol~ed in 1:1 pyridine:acetic anhydride and left for 3 hours at room temperature~ The solution was poured onto crushed ice, allowed to attain room temperature before the solid was filtered and dried. Crystallisation from methylene chloride/methanol yielded pure 3~,17a-dihy-droxy-~6-acetamido-21-methyl-~9(-11)~15-pregnadien-20-one 3-acetate. This acetamide was dissolved in acetic acid, and the mixture hydrogenated for 5 hours in the `I
presence of platinum oxide catalyst~ The catalyst was removed by filtration, the acetic acid was evaporated and the residue dissolved in ethyl acetate, washed, dried and evaporated to giLve the product as a crystal-line massO Recrystallisation from methylene chloride/
methanol gave pure 3~,17-dihydroxy-16~-acetamido-21-methyl-a9(ll)-5a-pregnen-2o-one 3-acetate~
Treatment o 3~jl7a-dihydroxy-16-imino-21,21-dimethyl-~9(ll)9l5-pregnadien-3,20 dione 3~17-diacetate under the same reaction conditions yielded 3~17a-dihydroxy-16a acetamido~21,21-dimethyl-~9(11)-5a-pregnen_2~_ 3acetate.
e) A mixture of 3~,17a-dihydroxy-16a-acetamido-21 methyl-a9~ 5a-pregnen-20-one 3 acetate and methanolic potassium carbonate was stirred for 4 hours then poured into water. The white solid was ~iltered and dried to give 3~,17(x-dihydroxy-16(~--acetamido-21-methyl-~9(~
5a-pregnen-20-one. The diol was suspended in acetone and treated with 8N chromic acid at 0 . After 10 minutes the mixture was treated with isopropanol then diluted to S five volumes of waterr The product was extracted into ethylacetate, dried and evaporated to gi~e 16a-acetamido-17a-hydroxy-21-methyl-A9(~ 5a-pregnen~-3,20 dione as a gumv The crude dione was dissolved in dry benzene, p-toluene sulphonic acid was added and the mixture stirred under reflux. Ater 30 minutes the reaction was cooled and washed with potassium bicarbonate solution and water, then dried and evaporated to give a crystalline mass.
; Crystallication from acetone/n-hexane gave pure [16a, 17a-~d]-2'-methyl-oxazoline-21-methyl-~9(11)-Sa-pregnene-3,20-dione.
Treatment of 3~,17(x-dihydroxy-16~-acetamido-21,21-di-methyl-a9(11)-pregnen-20-one 3~acetate under the same ~; conditions furnished L16~,17a-d]-2'-methYl oxazoline-21j21_dimethyl-~9~11)-5~-pregnene-3,20-dione.
f) A solution of bromine ln clioxan was added dropwise to a stirred solution of [16a~17~d]-2'-methyloxazoline-21-methyl-~9(11) 5a-pregnene-3,20-dione in dioxan containing a little hydrogen bromide/acetic acid solutionO After 1 hour the reaction was poured into an ice-cold sodium carbonate solution and the product filtered and dried.
The crude 2,4-dlbromo derivative in dimethyl-acetamide was added to a mixture of lithlum bromide, lithium carbonate in dimethyl-acetamide, stirred and heated at 100C under a nitrogen atmosphere. After 12 hours the mlxture was cooled, poured into sodium chloride solution .
:. . .
:
:
s~
and tr~ated with acetic acid. The solid product was filtered, dried and purified by chromatography to gl~e [16a,17-d]-2'-methyl-oxa~oline-21-methyl-Qla4'9(11)-pregnatriene-3,20~dione.
: 5 Treatment of [16a717a-d]-2'-methyl-oxaæoline-21;Zl-di-methyl-~9(11~5a-pregnene-3,20-dione in the above manner yielded the corresponding [16~,17a-d]-2~-methyl-oxazoline-2192l_dlmeth~ 4~9(ll)-5a-pregnatriene-3t20-dlone-g) A solution of Ll6a917a-d]-2'-methyloxazoline-21-methyl-~1'4'9(1I)-pre~natriene-3,20-dione in tetrahydrofuran was treated with 0O5 N perchloric acid and N-bromo acetamideJthen the resultant mixture was stirred in the . dark~ After 1 hour the solution was treated with sodium -~ bisulphite diluted with water and the white precipitate ~"
filtered and dried to yield 9a-bromo~ hydroxy-[16a, .`. 17a-d]-2' methyl-oxaæoline-21-methyl-~1'4-pregnadiene-3,20-dioneO "
Treatment of [16a,17a-d]-2'-methyloxazoline-21~21-di-methyl-~l'4'9~ pregnatriene-3,20-dione under the . 20 same conditions furnlshed 9a-bromo~ hydroxy-[16a~
17a-d]~2'-methyloxazoline-21,21-dimethyl~ 4-pregna-` diene-3,20-dione~
h) n-Butane thiol was added to a stirred solution of di-' methyl sulphoxide under "oxygen-~ree" nitrogen. Freshly prepared chromous acetate was then added in one portion '~ followed by a solutlon of 9a-b~romo-11~-hydroxy-[16aal7a-~-' d]-2'-methyloxazoline-21-methyl-~1 7 4-pregnadiene-3,20-dione~ After 5 hours the reaction mixture was poured into a saturated sodium chloride solution, extracted : 30 with e~hyl acetate and the organic extract washed with .:
~5~5;Z~
sodium carbonate 9 water, dried and evaporated.
Crystallisation of the crude yielded pure ll~-hydroxy ~16a,17a-d]-2'-methyloxazoline-21-methyl-~1'4-pregna-diene-3,20-dione. M.P. 263-270~C
Treatment of corresponding 21,21-dlmethyl bromohydrin under the same conditions furnished ll~-hydroxy-[16a, 17a-d]-2'-methyloxazoline-21,21-dimethyl-al'4-pregnadiene-3,20-dione. M.p. 202-208 C.
Example 3 a) A solution of 3~ -dihydroxy-21-methyl-~16-5a-pregnen-20-one 3~ -diacetate in methylene chloride was added to an ice-cold solution of excess diazomethane in ether.
The solution was allowed t:o stand ln a refrigerator for
Z and Q form a 2l-methyl-l6a~l7a-oxazoline ~ing fussd with the D-ring of the . ::
steroid; or - .
.j .
- 10 ~VII) 21~alkylating a compound of the formula ;
,~, CH2R5 ; .
,IZ (VllO ~
.'' ~ -i 6 : R3 whe~ein R5 represents H or halogen; the substituents R3, R6 and R7 in the starting materials of ormulae ~ to (VIII) inclusive being as follows:
. .~ ' .
....
52~
R3 = H, CH3 or halogen; R6 = a protected hydroxyl or keto group; and R7 =
hydrogen or a protected hydroxyl group; and the dotted lines in the steroid rings indicating optional double bonds; and removing any protecting group present on the 3-hydroxyl, 3-keto or ll-hydroxyl group of the product, converting a (~5-)3-hydroxyl system to a ~4- or ~1'4-3-keto system, introducing a ~6(7~ double bond with a quinone when required, acylating an ll-hydroxyl and a 17~-hydroxyl group when requiredJ introducing halogen atoms at the 9- and ll-position by halogenating a product having a ~9~11) double bond when required, and oxidizing an ll-hydroxyl group to ll-keto when required.
As indicated above the compounds of the in~ention are prepared from ~1 -21-alkyl-20-oxo- or ~16-21,21-dialkyl-20-oxo compounds of the pregnane series having ~he partial formula:
'~ C=O
, wherein Rl and R2 have the .
L ~ ~ -3d-~5Q5;2~
meanings glven hereinbefore by introducing the substituents required at the posltions 15, 16 and/or 17 of the end~
products by me'thods known ~ se or from 20-oxo compounds of the pregnane series having the partial formula:
H
C-o Z
1 L ~ , wherein Z and Q have the meanings :' given hereinbefore and R5 - H or halogen, by 21-mono- or 21~21~dlalkylation of these 20-oxo compounds according to the methods described in Belgian Pat. 793958 of Applicant ~- South-Afr. Pat. 72/9103 = Dutch Pat.ApplO 7300313).
Other substituents indicated in the formula of the end-products may be introduced subsequently by methods known Per se.
Starting from Q16 20-oxo compounds as indicated above the various substituents in the 15-, 16- and/or 17-position may be introduced as follows:
A sultable ~ 20-oxo compound is reacted for example with an appropriate diazo compound in a suitable organic solvent such as ethex or a halogenated hydrocarbon, and at a temperature preferably below ~0C to qive a [17a,16a-c]-pyrazolino-20-oxo-steroid. By heat treatment, usually 25 carried out at a temperature between 100C and 250C~
poss~bly in an inert solvent such as decalin or toluene, or by acid treatment (e.gO perchloric acid, borontri-fluoride or trifluoro acetic acid) of the pyrazolino compound nitrogen is split off, leaving a mixture of 30 16-alky1-~16-20-oxo- and 16~17-a1ky1ldene-20-oxo-sterolds, .
~5'~)5~
thelr ratio to one another being dependent on the reaction conditions and the choice of the starting compound, i.e.
the diazo-compound~ The isomers can be separated by chromatography or crystallization.
A very convenient method ~or the preparation of 16,17-(substituted methylene)-20-oxo-steroids is the method described in the British Specification No. 1,235,285.
The 16-alkyl-~16-20-oxo compound is converted into the 16p-alkyl-16a,17a-epoxy-20-oxo compound by reaction with9 for example, alkaline hydrogenperoxide, whereafter the epoxy compound is treated with an acid in a suitable solvent, e.g. HI in aqueous dioxan, p-toluene sulphonic acid in benzene, HBr in acetic acid, possibly followed by a reductive treatment which Raney nickel~ so as to obtain the 16-alkylidene-17tx-hydroxy-20-oxo-steroid, e.g~
the 16-methylene-17a-hydroxy compound.
a/ky/, c/e~ e Besides or instead of the 16-~hy~knnr compound a ~15-1~-methyl-17a-hydroxy-20-oxo-steroid is obtained, dependent on the reaction conditions. In this connection reference is made to the methods described in British Specification No. 1,016,955. The isomers can be separated and/or purified by chromatography or crystallization.
The ~16-20-oxo steroid may be oxidised, e.g. by means of potassium permanganate in a buffered solution, to yield the 16~,17tx-dihydroxy-20-oxo compound, which may be con-verted into the 16a,17tx-alkylenedioxy-20-oxo-steroid by reaction wLth a ketone or an aldehyde, such as acetone, acetaldehyde, ethyl methyl ketone, propionaldehyde and the like. The reaction is allowed to take place in 3CI suspenslon or solution of the steroid ir the ketone or :
~ - ~
31 ~5~
aldehyde, with or without an inert organic solvent (e.g.
dioxan) present, and in the presence of a mineral acid, e.g. HCl~ HC104, p.TsOH (temp. between 15 and 60 C, reaction time 1-18 hrs). After the reaction the acid is neutralized and the product recovered.
Another route to the 16~,17(~-alkylenedioxy-20-oxo-steroids is reacting the ~16-20-oxo steroid with alkaline hydrogenperoxide in the presence of methanol to yield the 16a,17a-epoxy compounds, splitting open the 16a,17a-epoxy group by reaction with acetic acid and a hydrazine~ e.g.
H2N.NHC02CzH5 and treating the 16a-acetoxy-17(x-hydroxy-20-hydrazone compound obtained with pyruvic acid/acetic acid to obtain the 16a-acetoxy-17a hydroxy-20 oxo compound, and finally reacting the 16a-acetoxy-17a-hydroxy-20-oxo compound with a ketone or an aldehyde, e.g. acetone or acetaldehyde3 in an alcohol, e~g. methanol, in the presence of an acid, e.g. perchloric acid so as to obtain the 16a,17a-alkylene-dioxy 20-oxo-steroid.
A 16a,17a-ethylene- or 16(~,17a-(substituted ethylene)-20 20-oxo-steroid may be obtained by reacting the ~16-20-oxo-steroid with an olefin, e.g. ethylene or substituted ethylene, in an organic solution, e.g. benzene or dioxan, by the action of ultraviolet llght (270-330 m~) for 1-15 hour s .
A Ll7a716a-d]-oxazolino-20-oxo-steroid may be obtained as follows:
The ~16 20-oxo steroid is reacted in a solvent, e.g~
tetrahydrofuran, with N-bromo-acetamide in the presence of HC10~, preferably in the dark, or with saturated HBr/
30 acetlc scld to glvF the 17[~-bromo-16~-hydroxy-20_one. This ~; .
;
/
~5~5i2~i 20-ketone is converted into the 16~,17~-epoxy-20-one by treating with KOH in boiling methanol. The B~epoxide is reacted with sodium azide in methanol, containing H2S04, under reflux to yield the 17a-azido-16a-hydroxy-20-one.
For the preparatlon of the L17a,16a-d]-2'-methyl-oxazolino-20-oxo compound the 17a-azido-16a-hydroxy compound is converted into the 16a-acetate, e.g. by reactlon with acetic anhydride/pyridine, whereafter the 17a-azido-16a-acetate is reduced, e~g~ with PtO2/H2 in methanol, to give the ~17a916a-d]-2'-methyl-oxazoline-20-oxo-steroid.
The [16a,17~-d]-isomer may be prepared as follows:
The ~16-20-oxo-steroid is reacted with alkaline hydrogenperoxide to give the 16a,17a-epoxy-20-oxo compound, which is reacted with sodium azide to obtain the 16~-a~ido-17a-hydroxy-20-one. Reaction of the last-mentioned compound with acetic anhydride/pyridine yields the corresponding 17a-acetate, which is reduced~ for example with H2/PtO2 or H2/
Raney Ni~ to the 16~-amino-17a-acetoxy-20-one. The 16~-amino-17a-acetoxy-20-one is converted into the corresponding 16~-chloramino compound by reaction wlth N-~hlorosuccinimide in e.g. methylenechloride. Subsequen~ heating of the 16~-chloramlno-17a-acetoxy-20-one with potassium acetate in a solvent, e.~ dimethylformamide gives the 16-imino-17(x-acetoxy-20-one, which is acetylated wlth acetic anhydride/
acetic acid to obtain the ~ -16-acetamido-17a-acetoxy-20-one. Subsequent base hydrolysis, e.g. with potassium carbonate/methanol affords the ~15-16-acetamido-17a-I hydroxy-20-one, which is reduced with H2/Pd on charcoal to the 16a-acetamido-17a-hydroxy-20-one. Ring closure is effected by heating the latter with an acid, e.g. p-..
,, ~L~5~5~
toluene sulphonic acid, to yield the [16a,17a-d]-2'-methyl-oxazolino-20-oxo steroidO
In all reactions described above reactive or vulnerable groups present elsewhere in the steroid molecule are protected according to methods known in the art~
Starting materials for the preparation of the compounds according to the invention can be 20-oxo-pregnanes of the formula:
.
R~ ~ ~
~6 ~ , wherein R3 R3 ~ H, CH3 or halogen~
,~'! 15 dotted lines indicate optional double bonds9 R = a protected hydroxyl or :keto group, i R7 = hydrogen or a protected hydroxyl group, and .`. D denotes the D-ring structure indicated by the partial : formulae ~iven hereinbefore.
During the alkylation procedure, it is preferable to protect an oxygen function at C-3 if one is present by reversible ether formation such as the tetrahydropyranyl ether in the case of a 3-hydroxyl group or a ~3'5-enol ether in the case of a ~ -3-keto grouping, or by ketal formation such as the dimethyl ketal in the case of a 3-- keto group to prevent unwanted alkylation reactions such ; as 0-alkylàtion which would take place at the same time as 21-alkylation if the starting material contained a free 3-hydroxyl group or 3-acyloxy group or to prevent unwanted C-alkylation reactions from taking place in the . .
. .
_ ~3 _ . ' ~1 ~15~5~9 ~-position to a free 3-keto group if such were present. It has been found that the 3-0-alkylated products which are formed if a free ~-hydroxyl group or its acyl derivative is present during the alkylation reaction are very difficult to hydrolyse back to the desired 3-hydroxyl group which is a necessary precursor for converting by oxidation to the 3-keto group in the final products according to the invention.
Slmilarly it is necessary to protect an ll-hydroxyl substituent if one is present in the starting material before carrying out the alkylation procedure to prevent the sirnulataneous formation of an ll-0-alkylated derivative which cannot be readily converted back to the free hydroxyl group~ When an lla-hydroxy-~roup is present, it is ~15 pre~erable to protect it by reversible ether formation such ;ias the tetrahydropyranyl ether but when an ll~-hydroxyl substituent is present, because of its very sterically hindered position in the steroid molecule it is sufficient to protect it as an ester such as the acetate in which case ;20 the acyl group may itself undergo alkylation.
, ,1 - After introduction of the substituents required at the positions 15, 16 and/or 17 of the 21-alkyl or 21,21-dialkyl compounds by the methods described above or of the 21-alkyl or 21,21-dialkyl substituents into the 20-oxo compounds i 25 already carrying the 15-, 16- and/or 17-substituents, as i indicated hereinbefore, other groups already present in . ' , .
- the starting materials may be modified and new groups of !
functions may be introduced by methods known ~ se to furnish the desired end-products according to the invention.
A 3-hydroxyl group may be oxidlsed after hydrolysis of _ 9 _ ,................. .
s~
the protecting ether group, for example, by Oppenauer ~oxidation in the case of a~ _steroid to furnish a~ -3_ keto-steroid, or with chromic acid in the case o~ either a 5~- or 5~-3-hydroxy derivative to give the corresponding saturated 3-ketone.
Where a 3-keto gro1-p in the starting material is protected as its ketal derivative, or in the case o~ a ~ -3-ketone, as the enol-ether for the purpose of the -~ alkylation reaction, it is only necessary to hydrolyse it to regenerate the keto group.
` In compounds containing a ~4-3-keto grouping, additional double bonds may be introduced at positions Cl-C2 and/or C6-C7 by known chemical means such as by reaction with suitable ~-quinone derivatives or microbiologically with an appropriate micro-organism.
A 3-keto-5~-steroid may be converted to a A ~ -3-keto-skeroid by means of selenium dioxide or by reaction with a quinone such as dichlorodicyanobenzoquinone or by halogenation at positions 2 and 4 and subsequent de~ydrohalogenation by methods known per se A 3-keto-5~-steroid may be converted into a ~-3-keto-steroid by means of selenium dioxide or by mono-bromination at position 4 followed by dehydrobromination and the so formed~ _3-ketone may be transformed into the ~1,4_3_ ketone by further reaction with selenium dioxide or di-;~ chlorodicyanobenzoquinone. Alternatively, a 3-keto-5 steroid may be converted directly into a~l'4-~-ketone by reaction with selenium dioxide or by reaction with a suitable quinone such as dichlorodicyanobenzoquinone, or ; 30 by di-halogen~tion for example di-bromination at positions .
': -- 10 _ ;
~L~5~5~91 2 and 4 and subsequent dehydrohalogenation by methods known per se.
A ~ -3-keto steroid may be converted into the cor~esponding ~ -derivative by reaction with a suitable quinone such as chloranil and the thus formed ~4'6-3-keto compound may then be converted to the corresponding ~ ~ ,6_ 3-keto derivative by reaction wlth an appropriate quinone such as dlchlorodlcyanoben7oquinone.
The microbiological introduction of a double bond at position Cl-C2 may be carrled out by lncubation with a 1,2-dehydrogenating mlcro-organism, for example Coryn-bacterium Simplex, Bacillus sphaericus or Bacillus sub-tilis.
Introduction of a 6-substituent, if not already lS present may be effected i~ desired by converting a 3-hydroxy-~5-steroid into the 5a,6~x-epoxide and treating the latter with methyl magnes'Lum haiide, a halogen acid, boron trifluoride or fluoroboric acid to give in each case the corresponding 5a-hydroxy-6~-substituted derivative which can then be converted into the corresponding ~4-3-keto-6~-substituted compound by oxidising the 3-hydroxy group wlthy for example, chromic acid and dehydrating the 5-hydroxyl group appropriately under acid or basic conditions. Isomerisation of the 6~-substituent may be brought about by treatment with acid or base.
A ~9(~ double bond if present may be con~erted to the 9a-bromo-11~-hydroxy compound or an ester thereof by methods known ~ se and then transformed under basic conditions into a 9~ epoxide which may be subsequently opened with a halogen acid to give the corresponding 9-.
~s~s~
halo~ hydroxy derivative which can then be oxidised to the corresponding 9a-halo~ ketone.
Introduction of an ll-hydroxyl group may be performed microbiologically, e.g. by incubation with an ll-hydroxyla-ting micro-organism such as Curvularia or a Rhizopus after which the ll-hydroxyl group may be oxidised to an ll-keto group, acylated or dehydrated to form a ~9(11)-double bond.
A A9(11) double bond may be converted to a 9,11-dihalogen derivative such as the dichloride by addition of a halogen such as chlorine.
After elaboration of the al'4-3-keto group an 11~-acyloxy group, if present, may be hydrolysed to the corresponding ll~-hydroxy derivative under relatively mild conditions with alcoholic alkali and the so formed 11~-hydroxy group may then be oxidized if desired to the corres-ponding ketone.
The acyloxy group present in the position 11 and/or 17 may be derived from a saturated or unsaturated organic carboxylic acid having 1-18 carbon atoms and is preferably a lower alkanoyloxy group, such as acetyloxy, propionyloxy, valerianyloxy and the like.
The 21-alkylated compounds according to the invention are very active ln the ~Ihuman vasoconstriction" test, indicating their good to excellent potency as antiinflam-matories. They have the further advantage over the known21-desmethyl compounds that they are more soluble in the usual vehicles for topical application.
~ 12 ~
, ~
~6DS~5~~9 The invention is further illustrated by the following examples .
Example 1 a) To a stirred suspension of 3~-hydroxy-~9(~ l6-5a-pregnadien-20-one in sodium-dried benzene was added excess dihydropyran .and a catalytic quantity of p-toluenesulphonic acid.
After 1 hour the solution was washed with sodium carbonate solution9 then to neutrality with water, dried and evaporated to a gummy solid, which was crystallised from petroleum ether to give 3~-hydroxy-~9(11)'16-5a pregnadien-20 one 3-tetrahydropyranyl ether.
b) To a stirred solution of lithium diisopropylamide in sodium-dried tetrahydrofuran under nitrogen at 0C was added a solution of 3~-hyclroxy-~9(1l)9l6 5a-pregnadien-20-one 3-tetrahydropyranyl. ether (0.66 mole equivalents) in sodium-dried tetrahydrofuran. After the solution had been stirred for 30 minute!s at room temperature, external cool.~ng was again applied and excess dry methyl iodide was added. The cooling bath was removed, and after 45 minutes the solYent was evaporated under vacuum. The residue was dissolved in aqueous acetic acid and after 4 hours the product was precipitated by the addition of water.
~,: Crystallisation from acetone/hexane gave 3~-hydroxy-21-~h 1 ~9(11~16_5~_pregnadien-20-One-c) To a stirred solution of lithium diisopropylamide in dry tetrahydrofuran under nitrogen at 0C was added a solution of 3~-hydroxy-21-me~hyl-~9(~ 6-Sa-pregnadien- -: 20-one 3-tetrahydropyranyl ether (0,66 mole equivalents) in dry tetrahydrofuran. After the solution had been . - 13 _ ;
:~ [9Sg~5~1 stirred for 30 minutes at room temperature9 external coollng was again applied and excess dry methyl iodide was added. The cooling bath was removed, and after 45 minutes the solvent was evaporated under vacuum. The S residue was dissolved in aqueous acetic acid and t~e solution allowed to stand overnight. The product was precipitated by the addition of water, filtered, dried and crystallised frorn acetone~hexane to glve 3~-hydroxy-21~21-dimethYl-~9~11) 9 16-5a-pregnadien-20-one .
d) To a solution of 3~-hydroxy-21-methyl--~9(~ l6-5a-pregnadien 20-one (9.97 g) in methylene chloride and methanol wa added 4N sodium hydroxide (20 ml) followed by 30% hydrogen peroxide (20 ml). The reaction mixture was shielded from light and allowed to stand overnight.
External cooling was applied and sodium sulphite solution was added to decompose excess hydrogen peroxide. The methylene chloride was then evaporated under vacuum and the reaction mixture was poured into water. Filtratlon of the solid gave 3p-hydroxy-16a,17a-epoxy-21-methyl-~9511)-5a-pregnen-20-one-!
In a slmilar manner 3~hydroxy-21,21-dlmethyl-~9(ll)7l6-5a-pregnadien-20-one was converted to 3~-hydroxy-16~,17a-epoxy-21,21-dimethyl-~9(11)-5a-pregnen-20-one.
- e) To a stirred solution of 3~-hydroxy-16~17a-epoxy-21-methyl-~9( 1)-5a-pregnen-20-one (9.5 g) in acetic acid was added a solution of carbethoxy hydrazine (9.5 g) in acetic acld. The reaction mixture was stirred overnight then poured into ice-waterO Filtration gave 3~,16~x,17a-trihydroxy-21-rnethyl-~9(~ 5(x-pregnen-20-one 16-acetate 20-carbethoxy hydrazone.
. , 3~s~
In a similar manner 3~-hydroxy-16a,17a-epoxy-21,21-di-methyl-a9(11)-5-pregnen-20-one was converted to 3~16a, 17-trihydroxy-21,21-dimethyl-~9(11)-5a-pregnen-20-one 16-acetate 20 carbethoxy hydrazoneO
f) 3~l6a~l7a-Trihydroxy-2l-methyl-~9(ll)-5a pregnen-20-one 16-acetate 20-carbethoxy hydrazone (13.3 9) was dissolved in acetic acid at 100 C and 50% aqueous pyruvic acld (13.3 ml) was added~ After 10 minutes at 100C water was slowly added for a further 20 minutes after whlch the solution was allowed to cool and with the continued slow addition of water. The solid was filtered to give 3~16ag 17a-trihydroxy-21-methyl-~9tll)-5a-pregnen-20-one 16-acetake.
In a similar way 3~,16a,17a-trihydroxy-21,21-dimethyl-~9(11)-5a-pregnen-20-one 16 acetate 20-carhethoxy hydra-~ zone was converted to 3~916(~,17a-trihydroxy-21,21-di-!~ methyl-~9(11)-5a-pregnen-20-Gne 16-acetate.
g) To a solution of 3~,16a,17a-trihydroxy-21-methyl-a9 Sa;pregnen 20-one 16-acetate (7~5 g) in acetone and methanol was added 70% perchloric acid (7.5 ml) and the solution was heated to reflux for 1 hour, then cooled and poured into water containing sodium acetate.
~Filtration of the product gave 3~-hydroxy-16a~17a-iso-propylidenedloxy-2l-methyl-~9(ll)-5a-pre9nen-2o-Qne~
In a similar way 3~,16a917a~trihydroxy-21~21-dimethyl-~9(11)-5a~pregnen-20-one 16-acetate was converted to 3~-hydroxy-16a,17a-isopropylidenedioxy-21,21~dimethyl-~9(11~_5a pregnen~20-one-h) 3~-Hydroxy 16atl7a-isopropylldenedioxy-21-methyl-Q9( 5a-pregne~-20-one was dissolved in acetone and the .
~1~5~
stirred solution was cooled in an ice bath. 6.24 N Jones Reagent was added dropwise until excess was present, and after the addition of a little isopropanol to decompose the excess,the solution was poured into water. The product was filtered off and purified by chromatography on sili-cagel and elution with mixtures of toluene/ethyl acetate.
Crystalllsation of the appropriate fractions from ether/
hexane gave 16,17-isopropylidenedioxy-21~methyl-~g( Sa-pregnene-3 9 20 dione.
In a simllar way 3~-hydroxy-16a,17a-isopropylidenedioxy-21,21-dimethyl-~9(11)-5 pregnen-20-one was converted to 16,17a-isoproylidenedioxy-21,21-dimethyl-~9(11)-Sa-pregnene-3,20-dione~
` i) A solution of 16~17-isopropylidenedloxy-21-methyl-~9(~ 5à pregnene-3,20-dione and dichlorodicyanobenzo-quinone (2.4 mole equivale!nts) in toluene/acetic acid 10:1 was heated to reflux with stirring overnight. The cooled reaction mixture was filtered, then the filtrate was evapor ted to dryness and the residue purged three times with toluene to remove acetic acid. The residue was then dissolved ~n toluene and the solution passed throu~h a column o~ grade H alumina. Elut~on w~th ether and evaporation of the eluant gave the crude product. This was purif ied by chromatography on silicagel, w1th toluene/ethyl acetate mixture~ The approp~iate fractions were combined and crystallised from methylene chloride/methanol to g~ve 16a,17a-iso-P~opylidenedioxy-2l-methy~ 4 9 9(11)-pregnatr~ene-3 9 20-dione.
In a similar manner 16a~17-isopropylidenedloxy-21,21-. .:
~5a 5;~
dimethyl~9(~ SA-pregnene-3,20-dione was converted to 16~,17~-isopropylidenedioxy-21,21-dimethyl ~ ,4,9(1L)_ pregnatriene-3,20-dioneO
j) Toa stirred solution of 16a,17a-isopropylidenedioxy-21_methyl~ 4~9(~L~_pregnatriene_3~20_dione (2 g) in tetrahydrofuran was slowly added 0.5 N perchLoric acid (10 ml) followed by N-bromoacetamide (1 g) with exclusion of Light. After 30 minutes, sodium sulphite solution was added and the reaction m~xture was poured into water.
Filtration of the solid gave ~-bromo~ -hydroxy-16q, 17q-isopropylidenedioxy-21-methyl-~' -pregnadiene-3,20-dione.
In a similar manner 16~17~-isopropyLidenedioxy-21,21~
thyl-~l74~9{~ pregnatriene-3~2o-dione was converted to 9~-bromo-11 ~hydroxy-16~,:L7o~isopropyl-idenedioxy-21,21-dimethyl/-~'4-pregnadiene-3,20-dione~
k) To a stirred solution of n-butane thiol (3~6 mL) in dimethyl sulphoxide under oxygen-free nitrogen was added freshLy prepared chromous acetate ~4.74 g), followed by a solution of crude 9~-bromo-11~-hydroxy_ 16d,17~-isopropyLidenedioxy-2I-methyl~ ' -pregnadiene-3~20~dione (2.37 g) in dimethyl sulphoxide~
The reaction flask was stoppered and the solution stirred magnetically overnightO
~" ~
e mixture was then poured into saturated sodium chloride solution and the product extracted into ethyl acetate. The solwtion was washed with 5% sodium carbonate solution, then to neutrality with water, dried and evaporated to dryness.
~:;
Crystallisation of the residue from methylene chloride/
methanol gave 11 ~hydroxy-16~,17~ -isopropylidenedioxy-.
, ,, . ,, . : . : ~ , ~ , . :
~15~9S2~
21-methyl-Ql' -pregnadiene-3,20-dione. M.p. 286-306C.
In a similar manner 9a-bromo~ hydroxy 16,17a-iso-propylidenedioxy-21921-dimethyl-A ' -pregnadiene-3 9 20-dione was converted to ll~-hydroxy-16~,17a-isopropyl-S idenedioxy-21,21-dimethyl-Al'4-pregnadiene-3~20-dione.
M.p. ~65 271C.
Example 2 a) A Quspension of 3~3-hydroxy-16~,17-epoxy-21-methyl-~9(11)-5a-pregnen-20-one in aqueous dimethyl sulphoxide was treated with sodium azide and conc. H2S04 and stirred under reflux for 2 hours. The reaction mixture was cooled~
poured into water and the solid product was filtered and dried. The crude diol was suspended in glacial acetic acid and acetic anhydride, and the mixture was warmed in a hot water bath for 15 minutes with a catalytic quantity of p-toluene sulphonic acid. The resultant solution was poured onto Lce-chips, allowed to attain room temperature and the brown solid filtered and dried.
Crystallisation from methylene chloride/methanol gave ; 20 pure 3~,17a-dihydroxy-16~--azido-21-methyl-~9(11)-5a-pregnen-20-one-3~17-diacetate.
." :
In a s~milar way the corresponding 21,21-dimethyl epoxide ~ gave 3~,17a-dihydroxy 16p-aæido-21,21~dimethyl-~9(11)-5a-`` pregnen-20-one 3,17-diacetate.
b) A mixture of 3~,17a-dihydroxy-16~-azido-21-methyl-~9( 1)_ ~, Sa--pregnen-20-one 3,17-diacetate, in acetic acid and 3 platinum oxide was shaken in an atmosphere of hydrogen for 4 hours. The catalyst was filtered~off and the filtrate evaporated to low volu~e, diluted with water and 30 extracted with ether. The extract was washed with 2N HCl and ~' ,, ~
~ ., .
/
~D5~52~
the acid extracts basified to gi~e a solid which was filtered and dried to yield pure 3~17a-dihydroxy-16~-amino-21-methyl-~9(11)-5a-pregnen-20-one 3,17-diacetate.
In a similar manner the 21,21-dimethyl-16~-azide was converted to the corresponding amine.
c3 A mixture of 3~917a-dihydroxy-16~-amino-21-methyl-Q9(ll)-5a-pregnen-20-one diacetate, methylene chloride and N-chlorosuccinimide was stirred at room temperature for 60 minutes then diluted with water. The organic layer was separated, dried and evaporated and the resldue crystallised from ether/n~hexane to give 3~,17a-di-hydroxy-16~-chloramino-21-methyl-~9(~ 5a-pregnen-20-one diacetate.
The chloramine was suspended in dimethyl formamide, ; 15 solid potassium acetate was added and the mixture stirred for 60 minutes at 40 C under nitrogen. The reaction mixture was cooled~ diluted with water and the resultant solid filtered and dried. Crystalllsation from acetone/n hexane gave 3~17a-dihydroxy-16-imino-2~-methyl-~9tll)-pregnen-2o-one diacetate.
In a slmilar manner, treatment of the 16~-amino-21921-;7'. dimethyl-pregnane under the same conditions yielded ; 3~17a-dihydroxy-16-imino-21,21--dimethyl-~9(11)-5a-i ~ pregnen-20-one diacetate.
d) A suspension of 3~,17~-dihydroxy-16-imino-21-methyl-i ~9(11)~5a-Pregnen-20-one diacetate in 95:5 acetic acid:
-~ acetic anhydride was stirred for 30 minutes at room ~ temperature, then diluted with water and the resultant : .
white solid was filtered and dried to give 3~917.~-dihydroxy-16-acetamide-21-methyl-~9(ll)715 pregnadien-, .
.~ .
. , .
~s~
20-one diacetate. The crude acetamide was suspended in methanolic potassium carbonate and the mixture stirred at room temperature. After 3 hours the solution was poured into water and the white solid filtered and drled to yield 3~,17a-dihydroxy-16-acetamido-21-methyl ~9(~ 5-pregnadien-20-one. The crude diol was dissol~ed in 1:1 pyridine:acetic anhydride and left for 3 hours at room temperature~ The solution was poured onto crushed ice, allowed to attain room temperature before the solid was filtered and dried. Crystallisation from methylene chloride/methanol yielded pure 3~,17a-dihy-droxy-~6-acetamido-21-methyl-~9(-11)~15-pregnadien-20-one 3-acetate. This acetamide was dissolved in acetic acid, and the mixture hydrogenated for 5 hours in the `I
presence of platinum oxide catalyst~ The catalyst was removed by filtration, the acetic acid was evaporated and the residue dissolved in ethyl acetate, washed, dried and evaporated to giLve the product as a crystal-line massO Recrystallisation from methylene chloride/
methanol gave pure 3~,17-dihydroxy-16~-acetamido-21-methyl-a9(ll)-5a-pregnen-2o-one 3-acetate~
Treatment o 3~jl7a-dihydroxy-16-imino-21,21-dimethyl-~9(ll)9l5-pregnadien-3,20 dione 3~17-diacetate under the same reaction conditions yielded 3~17a-dihydroxy-16a acetamido~21,21-dimethyl-~9(11)-5a-pregnen_2~_ 3acetate.
e) A mixture of 3~,17a-dihydroxy-16a-acetamido-21 methyl-a9~ 5a-pregnen-20-one 3 acetate and methanolic potassium carbonate was stirred for 4 hours then poured into water. The white solid was ~iltered and dried to give 3~,17(x-dihydroxy-16(~--acetamido-21-methyl-~9(~
5a-pregnen-20-one. The diol was suspended in acetone and treated with 8N chromic acid at 0 . After 10 minutes the mixture was treated with isopropanol then diluted to S five volumes of waterr The product was extracted into ethylacetate, dried and evaporated to gi~e 16a-acetamido-17a-hydroxy-21-methyl-A9(~ 5a-pregnen~-3,20 dione as a gumv The crude dione was dissolved in dry benzene, p-toluene sulphonic acid was added and the mixture stirred under reflux. Ater 30 minutes the reaction was cooled and washed with potassium bicarbonate solution and water, then dried and evaporated to give a crystalline mass.
; Crystallication from acetone/n-hexane gave pure [16a, 17a-~d]-2'-methyl-oxazoline-21-methyl-~9(11)-Sa-pregnene-3,20-dione.
Treatment of 3~,17(x-dihydroxy-16~-acetamido-21,21-di-methyl-a9(11)-pregnen-20-one 3~acetate under the same ~; conditions furnished L16~,17a-d]-2'-methYl oxazoline-21j21_dimethyl-~9~11)-5~-pregnene-3,20-dione.
f) A solution of bromine ln clioxan was added dropwise to a stirred solution of [16a~17~d]-2'-methyloxazoline-21-methyl-~9(11) 5a-pregnene-3,20-dione in dioxan containing a little hydrogen bromide/acetic acid solutionO After 1 hour the reaction was poured into an ice-cold sodium carbonate solution and the product filtered and dried.
The crude 2,4-dlbromo derivative in dimethyl-acetamide was added to a mixture of lithlum bromide, lithium carbonate in dimethyl-acetamide, stirred and heated at 100C under a nitrogen atmosphere. After 12 hours the mlxture was cooled, poured into sodium chloride solution .
:. . .
:
:
s~
and tr~ated with acetic acid. The solid product was filtered, dried and purified by chromatography to gl~e [16a,17-d]-2'-methyl-oxa~oline-21-methyl-Qla4'9(11)-pregnatriene-3,20~dione.
: 5 Treatment of [16a717a-d]-2'-methyl-oxaæoline-21;Zl-di-methyl-~9(11~5a-pregnene-3,20-dione in the above manner yielded the corresponding [16~,17a-d]-2~-methyl-oxazoline-2192l_dlmeth~ 4~9(ll)-5a-pregnatriene-3t20-dlone-g) A solution of Ll6a917a-d]-2'-methyloxazoline-21-methyl-~1'4'9(1I)-pre~natriene-3,20-dione in tetrahydrofuran was treated with 0O5 N perchloric acid and N-bromo acetamideJthen the resultant mixture was stirred in the . dark~ After 1 hour the solution was treated with sodium -~ bisulphite diluted with water and the white precipitate ~"
filtered and dried to yield 9a-bromo~ hydroxy-[16a, .`. 17a-d]-2' methyl-oxaæoline-21-methyl-~1'4-pregnadiene-3,20-dioneO "
Treatment of [16a,17a-d]-2'-methyloxazoline-21~21-di-methyl-~l'4'9~ pregnatriene-3,20-dione under the . 20 same conditions furnlshed 9a-bromo~ hydroxy-[16a~
17a-d]~2'-methyloxazoline-21,21-dimethyl~ 4-pregna-` diene-3,20-dione~
h) n-Butane thiol was added to a stirred solution of di-' methyl sulphoxide under "oxygen-~ree" nitrogen. Freshly prepared chromous acetate was then added in one portion '~ followed by a solutlon of 9a-b~romo-11~-hydroxy-[16aal7a-~-' d]-2'-methyloxazoline-21-methyl-~1 7 4-pregnadiene-3,20-dione~ After 5 hours the reaction mixture was poured into a saturated sodium chloride solution, extracted : 30 with e~hyl acetate and the organic extract washed with .:
~5~5;Z~
sodium carbonate 9 water, dried and evaporated.
Crystallisation of the crude yielded pure ll~-hydroxy ~16a,17a-d]-2'-methyloxazoline-21-methyl-~1'4-pregna-diene-3,20-dione. M.P. 263-270~C
Treatment of corresponding 21,21-dlmethyl bromohydrin under the same conditions furnished ll~-hydroxy-[16a, 17a-d]-2'-methyloxazoline-21,21-dimethyl-al'4-pregnadiene-3,20-dione. M.p. 202-208 C.
Example 3 a) A solution of 3~ -dihydroxy-21-methyl-~16-5a-pregnen-20-one 3~ -diacetate in methylene chloride was added to an ice-cold solution of excess diazomethane in ether.
The solution was allowed t:o stand ln a refrigerator for
4 days, then excess diazomethane was destroyed by the addition of a 10% solution of acetic acid in ether. The :
solution was evaporated to dryness and purged with toluene to remove acetic acid.
The product was dissolved in dimethyl formamide and the solu~ion was heated to reflux with stirring ~or one hour, then cooled and poured into water. The solid product was filtered, dried and crystallised from acetone/ether to glve 3~ dihydroxy-16,21-dimethyl-
solution was evaporated to dryness and purged with toluene to remove acetic acid.
The product was dissolved in dimethyl formamide and the solu~ion was heated to reflux with stirring ~or one hour, then cooled and poured into water. The solid product was filtered, dried and crystallised from acetone/ether to glve 3~ dihydroxy-16,21-dimethyl-
-5-pregnen-20-one 3~,11p-diacetate.
Treatment of 3~,11p-dihydroxy-21,21-dimethyl-~16-5a-pregnen-20-one 3~ -diacetate in a similar manner -~ gave 3~ -dihydroxy-16,21,21-trimethyl-~16-Sa-pregnen--.' 20-one~
b) To a solution of 3p,11~-dihydrox~-16,21-dimethyl-~16-S~-pregnen20--one 3~ diacetate (10 g) in methylene , ~5~52~
chloride and methanol was added 4N sodium hydroxide solution (20 ml) and 30% hydrogen peroxide solution ; (20 ml~. Light was excluded and the reaction mixture immersed in a constant temperature bath at 40C. ~urther 30% hydrogen peroxide solution tS mll was added after 18 hours and again after 25 hours. After 41 hours the reaction mixture was cooled in ice and sodium sulphite solution added. The methylene chloride was removed under reduced pressure and the mixture was poured into water.
The solid product was filtered and dried to give 3~
dihydroxy-16~21-dimethyl-16a~17a-epoxy-Sa-pregnan-20-one ll~-acetate.
In a similar manner 3~911~-dihydroxy-16,21,21-trimethyl-~,~
A16-5a-pregnen-20-one 3~ -diacetate was converted to 3~ dihydroxy-16~,21,21-trimethyl-16(x,17a-epoxy-5a-pregnan-20-one 11~ acetate.
c) A solution of 3~ -dihydroxy-16p,21-dimethyl-16a,17a-epoxy-5a~pregnan-20-one ll~-acetate (10 g) in tetrahydro-furan was treated with hydrogen bromide in acetic acid (3.1% w/v; 10 ml) and the solution was allowed to stand at room temperature~ After 2 hours the solution was poured into dilute aqueous sodium acetate. The solid ~; product was filtered, dried and crystallised from acetone/ether to give 3~ ,17a-trihydroxy-16,16-methylene-21-methyl-5a-pregnan-20-one ll~-acetate.
Treatment of 3~ dihydroxy-16~92I~21-trimethyl-16a, . .
17a-epoxy~Sa-pregnan~20-one ll~-acetate in a similar manner gave 3~ ,17a-trihydroxy-16~16-methylene~21, 21-dimethyl-5(x-pregnan-20-one 11~-qcetate.
:.
i- 30 d) In the manner as described in the Examples 1 h) and i) . . .
, . .
~ - 24 -., 3~gll~17~-trihydroxy-16,16-methylene-21-methyl-5~-pregnan-20-one 1~ -acetate and ~ 17~-trihydroxy-16,16-methylene-21,21-dimethyl-5~-pregan-20-one 11 ; acetate were converted to 11~,17~-dihydroxy-16,16-methylene-21-methyl-~ '4-pregnadiene-3,20_dione 11~
acetate (m.p. 184-189C) and llhl7~-dihydroxy-16,16-methylene-21,21-dimethyl-~1'4-pregnadiene-3,20-dione -acetate (m.p. 172-175C), respectivelyO
e) A solution of Il~,17~-dihydroxy-16,16-methylene-21-o methyl-~'4-pregnadiene-3,20-'dione ll~acetate in methanol was treated with a large excess of lON
potassium hydroxide solution and the mixture stirred overnight under nitrogen. me mixture was then neutralised with acetic acid and poured into water~
me solid product was filtered, dried and crystallized ' from methylene chloride/methanol to give 11~17~-di-;~ hydroxy_l6~16.methylene-21_methyl ~l~4.pregnadiene 3~20_dione~ m.p. 191-195C.
' In a siLilar manner 11~,17d-dihydroxy-16,16~methylene-21,21_dimethyl ~1'4-pregnadiene-3,20-dione 11 ~-acetate was converted to ll~ dihydroxy-16,16-methylene-21 21~dimethyl_Q 1'4-pregnadiene-3~20-dione~ m.p. 180-185C.
-" Exa~ple 4 a) A suspension of 3~ dihydro~'y~ 5dLpregnen-20-one ~ (50 g) in dry benzene (750 ml) was treated with dihydro-'~ pyran (S0 ml) and p-toluene sulphonic acid (2 g). After 1 hour the mixture was washed with 5% sodium carbonate solution then with water, dried and filtered. The filtrate was evaporated to gi~e 3~ -dihydroxy~ _ , ~' ' - 25 -.; ' ' .
., ~ . . .
. . .: . . ~: .. , : , ~5~S;~
5a-pregnen-20-one 3,11-ditetrahydropyranyl ether as an oil ~97 9).
The crude ditetrahydropyranyl ether (97 g) in cold tetrahydrofuran (1,250 ml) was added to a solution of lithium diisopropylamide in tetrahydrofuran at 0C, the mixture stlrred for 30 minutes at room temperature, then re-cooled and treated with methyl iodide ~250 ml).
After 10 minutes the mixture was evaporated in vacuo and the residue dissolved in acetic acid (250 ml) and water (100 ml), warmed on a steam bath for 30 minutes, cooled, diLuted to 3 litres with water and the resultant solid filtered and dried. Crystallisation from ethyl acetate gave 3~ dihydroxy-21-methyl-~16-5~-pregnen-20-one.
In a similar manner 3p,11~-dihydroxy-21-methyl-~16-5n-pregnen-20-one was converted via its 3,11-ditetrahydro-i pyranyl ether to 3~511~-dihydroxy-21,21-dimethyl-Al6- 5a-pregnen-20-one~
b) A mixture of 3~ -dihydroxy-21-methyl-~ 6-5-pregnen-20-one ~40 g)~ acetic anhydride (160 ml) and pyridine (80 ml) was treated at reflux for 7 hours. Methylamine hydrochloride (0,8 g) was then added and the heating continued for a further 3 hours. The resultant mixture was cooled~ poured onto crushed ice9 allowed to reach room temperature and the brown solid filtered and dried. Crystallisation from diethyl ether gave 3prllp-~ d1hydroxy-21-methyl-~16-5(x-pregnen-20-one diacetate.
`~s In a similar manner 3~ dihydroxy-21,21-dimethyl-~16-5(x-pregnen-20-one furnished the corresponding diacetate~
,, , ~015~5~
c) A mixture of 3~ dihydroxy-21-methyl-~1 -5a-pregnen-20-one 3,11~diacetate t24 g) 7 N-bromosuccinimide (11.9 g), dimethyl ~ormamide (240 ml) and perchloric acid (70%, 6.6 ml) was stirred in the dark at 10C. After 24 hours the excess N-bromosuccinimide was destroyed with aqueous sodium bisulphite and the mlxture poured into water (1200 ml). The product was filtered and dried at room temperature to give 3p,11p,16l~-trihydroxy-17a-bromo-21-methyl-5a-pregnan-20-one 3,11-diacetate 16-~ormate.
The crude formate (30 g) in methanolic potassium carbonate (400 ml) was stirred at room temperature for 2 hoursO The excess base was neutralised with acetic acld, the reaction mixture concentrated in vacuo, poured into water and extracted with ether. The organic extract was washed, dried, and the filtrate evaporated to give 3~ .dihydroxy-16~,17~-epoxy-21-methyl-5a-pregnan-20-one ll-acetate as an amorphous solid.
Treatment of 3~ 911 p-dihydroxy-21,21-dimethyl ~l6 5a-pregnen-20-one 3,11-diacetate in a similar manner gave 3~ dihydroxy-16pl17p-epoxy-21,21-dimethyl-5a-preg-nan-20-one~ acetate (amorphous).
d) A mixture o~ 3~ -dihydroxy-16~,17~ epoxy-?l-methyl-5a-pregnan-20-one ll-acetate (40 ~), sodium azlde (120 g), ethanol (600 ml), water (300 ml) and sulphuric acid (8.4 ml) was stirred at reflux for 10 hours, cooled, and poured into water (1800 ml) and the resulting solid filtered and dried. The product was purified on silica gel to give 3p,11p,16a-trihydroxy-17a-azido-21-methyl-5a-pregnan-20-one ll-acetate.
A mixture of 3~,11p,16a-trlhydroxy-17~-azido-21-methyl-:
5a-pregnan-20-one ll-acetate (6.3 g), pyridine (19 ml) and ~cetic anhydride (13 ml) was allowed to stand at room temperature for 16 hours. The solution was then poured onto washed ice, allowed to reach room temperature and the white solid filtered and dried to give 3~ ,16a-trihydroxy-17a~azido-21-methyl-5a-pregnan-20-one 3,11,16-triacetate.
Treatment of 3~,11p-dihydroxy-16~,17~-epoxy-21,21-di-methyl-5a-pregnan-20-one ll-acetate in a similar manner gave 3~ ,16a-trihydroxy-17a-azido-21,21-dimethyl-5a-pregnan-20-one 3,11,16-triacetate~
e) A mixture of 3~ ,16a-trihydroxy-17a-azido-21-methyl-5a-pregnan-20-one 3,11,16-triacetate (S.l g) and platinum oxide (0O5 g) in methanol (300 ml) was hydrogenated for 2 hours then filtered. rhe filtrate was evaporated to dryness to give 3~ ,16a-trihydroxy-17-amino-21-methyl-5a-pregnan-20-one 3,11,16-triacetate which was suspended in dry benzene (250 ml) in the presence of p-toluene-sulphonic acid (2.5 g). The reaction mixture was stlrred at reflux for 1.5 hours then cooled and washed with 5~ sodium carbonate, water, dried over magnesium sulphate, filtered, and the filtrate ; evaporated to dryness. Crystallisation from acetone/
n-hexane furnished 3~ dihydroxy-[17a,16a-d]-2'-methyloxazoline-21-methyl-5a-pregnan-20-one 3911-diacetate.
Treatment of 3~ ,16a-trihydroxy-17a-azido-21,21-dimethyl 5a-pregnan-20-one 3,11,16-triaceate in a ~imilar manner gave 3~ dihydroxy-C17a,16-d]-2'-3~ methyloxazoline-21~21-dimethyl~5a-pregnan-20-one 3,11-diacetate.
~s~si~
f) A suspension of 3~ dihydroxy-[17a,16a-d]-2'-methyl-oxazoline-21-methyl-5a-pregnan-20-one 3~11-diacetate (3 5 g) in methanolic potassium carbonate (100 ml) was stirred at room temperature for 90 mlnutes then poured into water (500 ml) and extracted with etherO The organic extract was washed, dried, and evaporated to give 3~ 911~-dihydroxy-[17a,16a-d]-2'-methyloxazoline-21 methyl-5a-pregnan-20-one ll-acetate.
Treatment of 21,21-dimethyl analogue :Ln a similar manner gave 3~ -dihydroxy-[17a,16a-d]-2'-methyloxazoline-21,21-dimethyl-S(x-pregnan~20-one ll-acetate.
g) In the manner as described in Example 1 h) 3~ -di-hydroxy-[17a,16a-d]-2'-methyloxazoline-21-methyl-5a-j pregnan-20-one ll-acetate (8 g) was converted to 11~-j 15 hydroxy-L17~,16a-d]-2'-methyloxazoline-21-methyl-5a-pregnane-3,20-dione 11-acetate.
Treatment of 3~911~-dihydroxy-L17a,16a-d~-2'-methyl-; oxazoline-21,21-dimethyl-Sa-pregnan-20-one ll-acetate in a similar manner gave ll~-hydroxy-[17a,16a-d]-2'-methyloxazoline-21,21-dimethyl-Sa-pregnane-3,20-dione ll-acetate.
h) In the manner as described in Example 2 f) ll~-hydroxy-[17a,lG~-d]-2'-methyloxazoline-21-methyl-5a-pregnane-3920-dione ll-acetate (20 g) was convérted via the 2,4 dibromo derivative to 11~-hydroxy-~17a,16a-d]-2'-methyl-oxazoline-21-methyl-a ' -pregnadienè-3,20-dione 11-acetate m.p. 157-168C.
Treatment of ll~-hydroxy-L17a,16a-d]-2'-methyloxazoline-21,21-dimethyl-S~-pregnane-3,20-dione in a similar manner gave 11~-hydroxy~17a,16(x-d~-2'-methyloxazoline-2l,21-, ~ , 1 4 ~ 5~ ~% ~
dimethyl~ pregnadiene-3,20-dione ll-acetate m.p.
212-214C.
i) A solution of ll~-hydroxy-[17a,16a-d]-2'-methyloxazoline-21-methyl-Al'4-pregnadiene-3,20-dione ll-acetate (23.6 g) in methanol (472 ml~ and lON potassium hydroxide (94.4 ml) was heated at reflux. After 3Q minutes the cooled reaction mixture was neutralised with acetic acid, the methanol distilled off in vacuo and the product filtered.
Crystallisation from ethyl acetate ga~e ll~-hydroxy-[17a, 16a-dJ-2'-methyloxazoline-21-methyl-~1'4-pregnadiene-3,20-dione ~.p. 256-258C.
Treatment of ll~hydroxy-[17a,16a-d]-2'-methyloxazoline-21,21-dimethyl-Ql'4-pregnadiene-3,20-dione ll-acetate in a similar manner gave ll~--hydroxy-[17a,16a-d]-2'-methyl-j 15 oxazoline-21,21-dimethyl-~1'4-pregnadiene-3,20-dione, ` m.p. 258-265C.
~3~E~5 i a) A mixture of 3~-hydroxy-[17a,16a-d]-2'-methyloxazollne-~9(11)-5a-pregnen-20-one ~10 g), dry benzene ~150 ml), dihydropyran (10 ml) and p-toluene sulphonic acid (5 g) was stirred at room temperatureO After 2 hours the solutlon was washed with sodium carbonate, water, dried over magnesium sulphate then filtered~ The filtrate was evaporated to give 3~-hydroxy-~17a~16a-d]-2'-methyl~
oxazoline-~9(11)-Sa-pregnen-20-one 3 tetrahydropyranyl ether (15 g). This product was alkylated with lithium diisopropylamide as described ln Example 4 a), deprotected then purified by chromatography on silica gel to give 3~-hydroxy-L17a,16-d]-2'-methyloxazoline-., ~
21-methyl-~9(~ 5~-pregnen-20-one~
b) By the method of the Examples 1 h) and i) 3~-hydroxy-[17a,16-d]-2'~methyloxazoline-21-methyl-~9(11)-5~-pregnen-20-one was converted via [17a,16a-d]-2'-methyl-oxazoline-21-methyl-~9(11)-5a-pregnene-3~20-dione to [17a,16a-d]-2t-methyloxazoline-21-methyl-Al'4'9( pregnatriene-3 9 20-dione, m.p. 202-205C.
Example 6 a) A solution of 3~,11p-dihydroxy-16~921-dlmethyl-16.x,17a-epoxy-5(~-pregnan-20-one ll~-acetate from Example 3 b) (10 g) in dry methanol and methylene chloride was treated with a solutlon of hydrogen bromide in acetic acld (3.0N; 10 ml) and allowed to stand at room temperature for 24 hours~ The solution was diluted with methylene chloride, washed with water, sodium carbonate solution then water to neutrality, dried over sodium sulphate and evaporated to dryness. The residue was crystallised from methylene chloride/methanol to give 3~ 17a-trihydroxy-16,21-dimethyl-~15-5a pregnen-20-one ll~-acetate.
Treatment of 3~911~-dihydroxy-16~21,21-trimethyl-16a,17a-epoxy-5a-pregnan-20-one ll~-acetate in a sim~lar manner gave 3~ ,17a-trihydroxy-16921,21-tri-methyl~al5-5(x-pregnen-20~one ll~-acetate.
b~ By the method of Example 1 h) and i) 3~ ,17a-tri-hydroxy-16~21-dimethyl-~15-S[Y-pregnen-20-one llB- ~
acetate and 3~ ,17~ trihydroxy-16,21,21-trimethyl-Q -5a-pregnen-20-one ll~-acetate were converted via the corresponding 3-ketones to 11~,17a~dihydroxy-16, ' ' .
~ 31 -5~
21-dimethyl~ 4~15~pregnatriene-3~2-dione ll~-acetate, mOpO 184-188C, and 11~,17a-dihydroxy-16,21,21-trimethyl-'4'15-pregnatriene-3,20-dione ll~-acetate, m~pO 170-175C, respectively.
Hydrolysis of the ll~-acetates by the method of Example 3 e) gave 11~5 1 7a dihydroxy-16,21-dimethyl-Ql'4'15-pregnatriene-3,20-dione, m.p. 192-195C, and 11~,17a-dihydroxy-l6~2l~2l-trimethyl-~l74~l5-preg dione, m.p. 181-185C, respectively.
lC) Lxample 7 a) ~ solution of 3~-hydroxy-~9(~ 6-5~-pregnadien-20-one acetate (50 g) in methylene chloride (100 ml) was added to an ice~cold solution of excess diazomethane in ether~
The solution was allowed t:o stand in a refrigerator for 4 days~ then excess diazomethane was destroyed by the addition of a 10% solution of acetic acid in ether. The solution was evaporated to dryness to give the 16a,17a-pyrazoline~
The crude pyrazoline (56 y) was dissolved in acetone (750 ml) and stirred at room temperature with boron trifluoride etherate (33 ml). After evolution of nitrogen ceased, excess reagent was destroyed with potassium bi-carbonate solution and water added to precipitate the product whlch was filtered, washed with water~ and driedO Crystallisation from methylene chloride/methanol gave 3~-hydroxy-16a~17a-methylene_~9(1l)_5a_p one acetate.
b) The product from Example 7 a) was hydrolysed with potassium carbonate in warm methanol to give 3~-hydroxy-., .
~ - 32 -~os~sz~
16~ 17~methylene-~9(ll)-sa-pregnen-2o-one~ which was converted by the method of Example 1 h~ to 16a,17a-methylene-~9(ll)-5a-pr~gnene-3~2o-di~ne c) To a stirred suspension of 16aJ17a-methylene-Q9(11)-5~-pregnene-3,20-dione (27.6 g) in methanol (S00 ml) was added p-toluenesulphonic acid (0.55 g). After 30 minutes triethylorthoformate (12 ml) was added, followed 5 minutes later by potassium bicarbonate (4 g). The volume of the reaction mixture was reduced to 250 ml and the product precipitated by pouring lnto water.
The dimethyl ketal was filtered and dried.
To a stirred solution of lithium diisopropylamide in ; dry tetrahydrofuran at 0 under nitrogen was added 16a,17a-methylene-~9(11)-5a-pregnene-3,20-dione 3,3-dimethyl ketal (31 g) in dry tetrahydrofuran (600 ml).
After 30 minutes the reacl:ion mixture was treated with dry methyl iodide (155 ml~ and the cooling bath removed.
Ten minutes later the mixture was evaporated and the residue d~ssolved in aqueous acetic acid. This solution was warmed on the steam-bath for 1 hour and the product precipitated with water. Recrystallisation from acetone/
n-hexane gave 16a,17a-methylene-21-methyl-A9(11)-5a-., .
pregnene-3,20-dione.
i Treatment of 16a,17a-methylene-21-methyl-~9(11)-5a-pregnene-3,20-dione, 16a~17a-isopropylidenedioxy-Q9(11)-5a-pregnene-3,20-dione and 16a,17a-isopropyl-idenedioxy-21-methyl-~9(~ 5a-pregnene-3,20-dione, in a similar manner gave 16a,17a-methylene 21921-di-methyl-~9(11)-5a-pregnene-3,20-dLone~ 16a,17a-iso-propylidenedioxy-2l-methyl-~9(ll)-5a-pre9ne~e-3 ~S~5~
dione and 16a,17~-isopropylidenedioxy-21721-dimethyl-~9(11)-5~-pregnene-3,20-dione, respectively.
d) By the method of Example 1 i)~ j) and k) 16l~,17a-methylene-21-methyl-~9(11)-5a-pregnene-3,20-dione and 16a,17~-methylene-21,21-dimethyl-~9(11)-5a-pregnene-3920-dione were converted to 11~-hydroxy-16~,17-methyl-ene-21-methyl-~1'4-pregnadiene-3,20-dione, m.pu 229-230C, and l]p-hydroxy-16a917~-methylene-21,21-dimethyl-~l'4-pregnadiene-3,20-dione, m.p. 221-225C, respectively.
Example 8 a) To a stirred solution of 16917-isopropylidenedioxy-21-methyl-~ (11)-5a-pregnene-3,20-dione from Example 1 h) in 20/1 chloroform/acetic acid was added a solution lS of hydrogen bromide in acetic acid. Bromine (1.1 mole equivalents) as a 10% solution in chloroform was added dropwise. After the addition of sodium acetate solution the organic layer was separated, washed with sodium carbonate solution, then to neutrality with water, dried and evaporated to give the crude 2~-bromo s derivative.
A solut1on of this product in dimethyl formamide was quickly added to a stirred sus~ension of lithium bromide and calcium carbonate in dimethyl formamide refluxing in a nitrogen atmosphere.
A~ter 15 minutes the cooled mixture was poured into stirred 1% aqueous acetic acid. After 30 minutes the solid product was filtered off, washed to neutrality with water and dried to give the crude 16~,17~-iso-propylidenedioxy-2l-methyl A1~9tll~-5a_pregnadiene_ ~ 34 -3,20-dione.
The product was converted by the method of Example 1 i) to 16a,17a isopropylidenedioxy-21-methyl-~ 9(11)_ pregnatrien~-3,20-dione, m.p. 236-244C~
In a similar manner 16~x,17a-isopropylidenedioxy-21~21-dimethyl-~9(11)-5a-pregnene-3,20-dione was converted to 16a,17a-isopropylidenedioxy-21,21-dimethyl-al'4'9(11)-pregnatriene-3,20-dione, m.p. 251-258C~
b) To a stirred solution of 16a,17a-isopropylidenedioxy-21-methyl-~9(11)-5a-pregnene-3,20-dione from Example 1 h) in 20/1 chloroform/acetic acid immersed in an ice-bath was added a solution of hydrogen bromide in acetic acid.
Bromine (2.2 mole equivalents) as a 10% solution in chloroform was then added dropwise. After the addition of sodium bisulphite and sodium acetate solutions the organic layer was separated and washed with sodium carbonate solution, then with water to neutrality, dried and evaporated to give the crude dibromo derivative.
A solution of the crude product in dimethyl acetamide was dehydrobrominated by the method described in Example 8 a) and the product crystallised from methylene chloride/methanol to give 16a,17a-isopropylidenedioxy-_methyl~al~4~9(11)_pregnatriene 3,20-dione, m-p-236-244C.
- In a similar manner 16a,17a-isopropylidenedioxy-21,21-dimethyl-a9(11)-Sa-pregnene~3,20-dione was converted to 16a,17a-isopropylidenedioxy-21,21-dimethyl-a1'4'9( pregnatriene-3~20-dione, m.p. 251-258C.
., .
., .
~5~5~
Example 9 a) Ethylene was bu~bled through a solution of 3~
dihydroxy-21-methyl-~16-5a-pregnen-20-one 3,11-di-acetate (10 g) in benzene (250 ml) and the reaction mixture irradiated with ultraviolet light. After 10 hours the reaction was evaporated to dryness and the residue purified by chromatography on silica to furnish 3~ -dihydroxy-16a,17a-ethylene~21-methyl-5a-pregnan-20-one 3911-diacetate.
In a similar manner, 3p,11~-dihydroxy-21,21-dimethyl--5a-pregnen-20-one 3,11-diacetate was converted to 3~ dihydroxy-16a,17a-ethylene-21,21-dimethyl-5a-pregnan-20-one 3,11-diacetate.
b) By the method of Example 4 f) 3~ -dihydroxy-16,17a-ethylene-21-methyl-Sa-pregnan-20-one 3,11-diacetate and 3~ dihydroxy-16,17a-ethylene-21,21-dimethyl-5-pregnan~20-one 3~11-diacetate gave 3~ -dihydroxy-16,17a-ethylene-21-methyl-5a-pregnan-20-one ll-acetate and 3~911~-d~hydroxy-16a,17a-ethylene-21921-dimethyl-5a-pregnan-20-one ll-acetate, respectively.
¦ c) By the method of Example 1 h) 3~ -dihydroxy-16a,17a-ethylene-21-methyl-Sa-pregnan-20-one ll-acetate and `~ ~ 3~ dihydroxy-16a,17a-ethylene~21,21-dimethyl-5-pregnan-20-one ll-acetate gave 11~-hydroxy-16~,17a-1 25 ethylene 21-methyl-5a-pregnane-3,20-dione 11-acetate and ll~-hydroxy-16a,17a-e~hylene-21,21-dimethyl-S-pregnane-3~20-dione ll-acetate~ respectively.
d) By the method o~ Example 8 a) 11~-hydroxy-16a,17~-ethylene-21-methyl-5a-pregnane-3,20-dione ll_acetate and 11~-hydroxy-16a,17a-ethylene-21,21-dimethyl-5a-.' ' , , , ' , . .
.r_~
pregnane-3,20-dione ll-acetate gave ll~-hydroxy-16917a-ethylene-21-methyl-Ql'4-pregnadiene-3,20-dione ll-acetate 7 mOp. 177-179C9 and 11~-hydroxy-16a,17~-ethylene-21,21-dimethyl al9 4-pregnadiene-3,20-dione ll-acetate, m.p~
200-201C, respectively.
Hydrolysis of the ll-acetates by the method of Example 3 e) gave llp-hydroxy-16a,17a-ethylene-21-methyl-~1'4-pregnadiene-3,20-dione, m.p. 210~212C, and llp-hydroxy-16a,17a-ethylene-21,21-dlmethyl-~1'4-pregnadiene 3,20-dione9 m.p. 188-190C, respectively.
Example 10 a) llp-Hydroxy-[17~,16~-d]-2'-methyloxazoline 21-methyl-'4-pregnadiene-3,20-dione t502 g) in dimethyl forma-mide (30 ml) and collidene (10.4 ml) at 10C was treated dropwise with methanesulphonyl chloride (3.4 ml) and 5%
sulphur dioxide in dimethylformamide (5.4 ml). The temperature was allowed to rise to 30C then cooled to about 10 C and water (5 ml) slowly added. The resulting solutlon was poured into water (300 ml) containing sodium acetate (8 g), stirred, and the light yellow solid filtered and dried to give [17a, 16a-d]-2'-methyloxazoline-21-methyl-~1'4'9(11)-pregnatriene-3 7 20-dione m.p~ 202-205C.
Treatment of llp-hydroxy-[17~x,16~-d]-2l-methyloxazoline-21,21-dimethyl~ pregnadiene-3,20-dione, llp-hydroxy-16a,17a-ethylene-21-methyl-~l94-pregnadiene-3,20-dione and ll~-hydroxy-16~,17a-ethylene-21,21-dimethyl-~1' -pregnadiene~3~20-dione in a similar manner gave [17~, 16a-d]-2'-methyloxazoline-21,21-dimethyl~ 9(11)_ ~5~i25~
pregnatriene-3,20-dione, 16a,17-ethylene-21-methyl-~1~ '9(11)-pregnatriene-3,20-dione and 16a,17a-ethylene-21~21 dimethyl ~1~4~9(11)_pregnatriene-3~2~di respectively.
By the method of Exam~le 1 ~) each of the above four ~9(11)-compounds was converted to the corresponding 9a-bromo-11~-hydroxy-compound.
b) A mixture of 9(~-bromo-ll~-hydroxy-[17a716a-d]-2'-methyl-oxazoline-21-methyl-~1'4~pregnadiene-3,20-dione (7.39 g), tetrahydrofuran (180 ml), methanol (180 ml) and lN sodium methoxide/methanol (21.6 ml) was stirred at room temperature. After 15 minutes the excess base was neutralised with acetic acid and poured into water (1~5 litres). The product was filtered and dried to give 9~ epoxy-L17,16a-d]-2~-methyloxazoline~21-methyl-Ql'4-pregnadiene-3,20-dione.
Treatment of 9a-bromo~ -hydroxy-[17a916a-d]-2'-methyl-oxazoline-21,21-dimethyl-~'' -pregnadiene-3,20-dione~
9a-bromo-11~-hydroxy-16(~,17a-isopropylidenedioxy-21-methyl-~l' -pregnadiene-3S?0-dione~ 9a-bromo-11~-hydroxy-16a,17a-isopropylidenedioxy-21,21-dimethyl-'4-pregnadiene-3,20-dione, 9a-bromo-11~-hydroxy-L 16a,17a-d]-2'-methyloxazoline-21-methyl-~1'4-pregna-diene-3,20-dione, 9a-bromo-11~-hydroxy-[16a,17a-d~-2 e_ methyloxazoline-21,21-dimethyl-~1'4-pregnadiene-3,20-dione9 9a-bromo~ -hydroxy-16a~17a-methylene-21 methyl-~1 ~ 4-pregnadiene-3, 20-dione g 9 a-bromo~ -hydroxy-1 6 a l 1 7a-methylene-21~21-dimethyl-al'4-pregnadiene-3,20-dione, 9a-bromo-111~-hydroxy-16a, 17a-ethylene-21 -methyl~ ' 4-30 pregnadiene~3,20-dione and 9a-bromo~ -hydroxy-16a~17a- -.
~ql s~ .
ethylene-21,21-dimethyl-~1' -pregnadiene-3 9 20-dione in a similar manner gave the corresponding 9p,11p-epoxy-compound 9 respectively.
c) An ice cold solution of 9~ -epoxy-[17a~16a-d]-2'~
methyloxazoline (206 g) in chloroform (26 ml) was added to a mixture of anhydrous hydrogen fluoride (5.2 g) 9 dry tetrahydrofuran ~10.5 ~1) and chloroform (5.3 ml) cooled to -30C~ ~fter 2 hours at 0C the excess hydrogen fluoride was neutralised with potassium carbonate (61 g) in water (600 ml). The product was extracted with ether, washed with water, dried over - sodium sulphate and filtered. The filtrate was evaporated to dryness then crystallised from acetone to give 9a-fluoro-llp-hydroxy-[17a,16a-d]-2'-methyl-oxazoline-21-methyl-~1'4-pregnadiene-3,20-dione, m.p.
282-284C.
Treatment of 9p,11~epoxy-L17a,16a-d]-2'-nlethyloxazo-., line-21,21-dimethyl-~1'4-pregnadiene-3,20-dione, 9F~, llp-epoxy-16a,17a-isopropylidened~oxy-21-methyl-~1'4-pregnadiene-3,20-dione, 9p,11p-epoxy-16a,17a-isopropyl-idenedioxy-21,21-dimethyl-~1'4-pregnadiene-3,20-dione, . 9p,11p-epoxy-L16a~17a-d]-2'-methyloxazoline-21-methyl-'4-pregnadiene-3,20-dione, 9p,11p-epoxy~[16a,17a-d~-2'-methyloxazoline-21,21-dimethyl-~1' -pregnadiene-3,20-dione, 9p 9 llp-epoxy-16a,17a-methylene-21-methyl-al'4 pregnadiene-3,20-dione, 9~,11p-epoxy-16a,17a-methylene-21,21-dimethyl-Q1'4-pregnadiene-3,20-dione, 9p,11p-epoxy-16~,17a-ethylene-21-methyl-~1'4-pregnadiene-3,20-dione and 9p,11p-epoxy-16a,17a-ethylene-21,21-dimethyl-~0 Ql94-pregnadiene-3,20-dione in a similar manner gave 9~-3~5~
fluoro~ hydroxy-L17a,16a-d]-2l-methyloxazoline-21,21-dimethyl-~l'4-pregnadiene-3,20-dione, m.p. 264-265C1 9a-fluoro-ll~hydroxy-16a,17~-isopropylidenedioxy-21-methyl-~1~4-pregnadiene-3 9 20-dione, m.p. 315-327C
(decomp.), 9(~-fluoro~ -hydroxy-16a,17(~-isopropylidene-dioxy-21~21 dimethyl-~ ' -pregnadiene-3~20-dione~ m.p.
285-301C (decomp.)9 9(1-fluoro-ll~-hydroxy-[16a,17a-d]-; 2'-methyloxazoline-21-methyl-~1'4-pregnadiene-3,20-dione~
m.p. 295-299C, 9a-fluoro-11~-hydroxy-L16a,17a-d]-2'-methyloxazoline-21,21-dimethyl-~1'4-pregnadiene-3~20-dione, m.p. 265-267C9 9a-fluoro-11~-hydroxy-16a,17a-methylene-21-methyl-~1' -pregnadiene-3,20-dione, m.p.
223-225C, 9a-fluoro-11~-hydroxy-16a,17a-methylene-21, 21^-dimethyl-~1'4-pregnadiene-3,20-dione, m.p. 251-258C, 9a-fluoro~ hydroxy-16a917a-ethylene-21-methyl-~l'4-pregnadiene-3,20-dione9 m.p. 230-232C~ and 9(x-fluoro-llp-hydroxy-16a,17a-ethylene-21,21-dimethyl-~1'4-pregnadiene-3,20-dione, m.p. 215-217C, respectively.
. .
Exam~le 11 A solution of 9a-fluoro~ -hydroxy-16a,17a-isopropyl-idenedioxy-21-methyl-~1'4-pregnadiene-3~20-dione in acetone ., was treated with excess 6.24N Jones Reagent. After a few minutes a little isopropanol was added, followed by the slow addition of water~ The volatile solvent was removed under vacuum and thè solid product was filtered off and crystallised from acetone/hexane to ~ive 9a-fluoro-16a, 17~-isopropylidenedioxy-21-methyl-~ pregnadiene-3,11, 20-trione, m.p. 215-220C.
In a similar manner 9a-fluoro-11~-hydroxy-16a,17a-.
~L~S~ 2~ 4 isopropylidenedioxy-21721-dimethyl~ pregnadiene-3,20 dione was oxidlsed to 9a~fluoro-16a,17a-isopropylidenedioxy-21,21-dimethyl-~l'4-pregnadiene-3,11120-trione, m.p. 235-Similarly the other 9(x-fluoro~ hydroxy compounds obtained in ~xample 10 were oxidised to their corresponding 9(x-fluoro-11-ketonesO 9a-fluoro-~16a,17a-d]-2'-methyloxazo-line-21-methyl-~1'4-pregnadiene-3,11,20-trione, [a]D =
+189 in CHC13.
Example 12 Into a sol~t~on of 16,17a-isopropylidenedioxy-21-methyl_~l'4'9(11)-pregnatrlene-3,20-dlone (1 g) in 9/1 chloroform/pyrldine (50 ml) dry chlorine was passed for 1 minute, and the reaction was then stirred for 30 minutes at room temperature. Excess chlorine was destroyed by the addition of sodium sulphite solution and the mixture was ~ filtered to remove sulphur. The organic phase was washed i successively with water, 2N HCl, water~ saturated potassium bicarbonate solution and water to neutral~ty. The dried ; ~ extract was evaporated to dryness, then the residue was purified on a silica column and crystallised from methanol to give 9a,11~-dichloro-16~,17a-isopropylidenedioxy-21-methyl-~l'4-pregnadien-3,20-dione (630 mg), m.p. 213-227C.
In a similar manner 9a,11~-dichloro-16a~17a-methylene-21-methyl-al'4-pregnadiene-3,20-dione, 9a,11~-dichloro-[16a~17a-d~2'-methyloxazollne-21-methyl-~1'4 pregnadiene-3~20-dione, 9a,11~-dichloro-16a,17a-isopropylidenedioxy-21,21-dimethyl-~1'4-pregnadiene~3~20-dione, 9a,11~-dichloro-16a/17a-ethylene-21-methyl-Al' -pregnadlene-3,20-dione and .
~5~52~
9~ dichloro-16916-methylene-17a-hydroxy-21-methyl-~pregnadiene-3~20-dione were prepared from the corresponding Q (ll)-compounds.
Example 13 ~,l7a-methylene-2l-methyl~ 4 7 9 ( 11 ) -pre~natriene-3,20-dione (800 mg) were dissolved in 10% aqueous dioxan (35 ml), cooled to 10C and 72% perchloric acid (0.2 ml) was added followed by N-chloro succinimide (0.5 g) and the reaction stirred overnight. The product was watered out, filtered, dried and recrystallised from methylene chloride to give 9a-chloro-11~-hydroxy-16a,17a-methylene-~1 methyl-~1'4-pregnadiene-3,20-dione (550 mg).
Example 14 `. A solution of [16a,17(Y-d]--2' methyloxazoline-21-methyl-~1'4'9(11)-pregnatriene-3,20-dione (1 g) in chloroform (30 : ml) and pyridine (5 ml) was treated with a solution of HF
(1.5 g) in tetrahydrofuran (5 ml) and chloroform (2 ml) r~llow~d by N-chlorosuccinimide (0.5 g). After a week at ,, room temperature the reactioD was poured into excess 10%
sodium acetate solution and the product isol~ted via met}lylene chloride. The crude product was purlfied on a silica gel and crystallised from ether to give 9a-chloro~ fluoro-[16a,17a-d]-2'-methyloxazoline-21-methyl~ 4-pregnadlene-3,20-dione (0.5 g).
~ Hydroxy-16a,17a-isopropylidenedioxy-21-methyl-~1'4-~reqnadiene-3,20-dione ll-acetate (2 g) and dichloro-_ ~2 -s2g di~yanoqulnone (1.3 g) were dissolved in dioxan (35 ml).
Hydrogen chloride was passed into the solution until a precipitate started to form and the reaction mixture was allowed to stand for a further 20 minutes. The solid was removed ~y filtration and the filtrate was pour~d into aqueous sodium carbonate solution. The product was iso-lated via ether and purified by chromatography on silica gel to give ll~-hydroxy-16a,17a-isopropylidenedioxy-21-; methyl-~1'4'6-pregnatriene-3,20-dione ll-acetate (1.2 g) as an amorphous solid.
Example 16 By the method of Examples 1 d)-g) 3~-hydroxy-21-methyl-A5'16-pregnadien-20-one was converted to 3~-hydroxy-16~Y,17~-isopropylidenedioxy-21-methyl~ -pregnen-20-one. ~ solution of this ~5-compound (5 g) in chloro~orm (50 ml) was stirred with peracetic acid (5 ml) and sodium acetate (0.5 g) for onl~ hour, after which excess peracid was destroyed with sodium bisulphite. Further processin~ gave 3~-acetoxy-5~-
Treatment of 3~,11p-dihydroxy-21,21-dimethyl-~16-5a-pregnen-20-one 3~ -diacetate in a similar manner -~ gave 3~ -dihydroxy-16,21,21-trimethyl-~16-Sa-pregnen--.' 20-one~
b) To a solution of 3p,11~-dihydrox~-16,21-dimethyl-~16-S~-pregnen20--one 3~ diacetate (10 g) in methylene , ~5~52~
chloride and methanol was added 4N sodium hydroxide solution (20 ml) and 30% hydrogen peroxide solution ; (20 ml~. Light was excluded and the reaction mixture immersed in a constant temperature bath at 40C. ~urther 30% hydrogen peroxide solution tS mll was added after 18 hours and again after 25 hours. After 41 hours the reaction mixture was cooled in ice and sodium sulphite solution added. The methylene chloride was removed under reduced pressure and the mixture was poured into water.
The solid product was filtered and dried to give 3~
dihydroxy-16~21-dimethyl-16a~17a-epoxy-Sa-pregnan-20-one ll~-acetate.
In a similar manner 3~911~-dihydroxy-16,21,21-trimethyl-~,~
A16-5a-pregnen-20-one 3~ -diacetate was converted to 3~ dihydroxy-16~,21,21-trimethyl-16(x,17a-epoxy-5a-pregnan-20-one 11~ acetate.
c) A solution of 3~ -dihydroxy-16p,21-dimethyl-16a,17a-epoxy-5a~pregnan-20-one ll~-acetate (10 g) in tetrahydro-furan was treated with hydrogen bromide in acetic acid (3.1% w/v; 10 ml) and the solution was allowed to stand at room temperature~ After 2 hours the solution was poured into dilute aqueous sodium acetate. The solid ~; product was filtered, dried and crystallised from acetone/ether to give 3~ ,17a-trihydroxy-16,16-methylene-21-methyl-5a-pregnan-20-one ll~-acetate.
Treatment of 3~ dihydroxy-16~92I~21-trimethyl-16a, . .
17a-epoxy~Sa-pregnan~20-one ll~-acetate in a similar manner gave 3~ ,17a-trihydroxy-16~16-methylene~21, 21-dimethyl-5(x-pregnan-20-one 11~-qcetate.
:.
i- 30 d) In the manner as described in the Examples 1 h) and i) . . .
, . .
~ - 24 -., 3~gll~17~-trihydroxy-16,16-methylene-21-methyl-5~-pregnan-20-one 1~ -acetate and ~ 17~-trihydroxy-16,16-methylene-21,21-dimethyl-5~-pregan-20-one 11 ; acetate were converted to 11~,17~-dihydroxy-16,16-methylene-21-methyl-~ '4-pregnadiene-3,20_dione 11~
acetate (m.p. 184-189C) and llhl7~-dihydroxy-16,16-methylene-21,21-dimethyl-~1'4-pregnadiene-3,20-dione -acetate (m.p. 172-175C), respectivelyO
e) A solution of Il~,17~-dihydroxy-16,16-methylene-21-o methyl-~'4-pregnadiene-3,20-'dione ll~acetate in methanol was treated with a large excess of lON
potassium hydroxide solution and the mixture stirred overnight under nitrogen. me mixture was then neutralised with acetic acid and poured into water~
me solid product was filtered, dried and crystallized ' from methylene chloride/methanol to give 11~17~-di-;~ hydroxy_l6~16.methylene-21_methyl ~l~4.pregnadiene 3~20_dione~ m.p. 191-195C.
' In a siLilar manner 11~,17d-dihydroxy-16,16~methylene-21,21_dimethyl ~1'4-pregnadiene-3,20-dione 11 ~-acetate was converted to ll~ dihydroxy-16,16-methylene-21 21~dimethyl_Q 1'4-pregnadiene-3~20-dione~ m.p. 180-185C.
-" Exa~ple 4 a) A suspension of 3~ dihydro~'y~ 5dLpregnen-20-one ~ (50 g) in dry benzene (750 ml) was treated with dihydro-'~ pyran (S0 ml) and p-toluene sulphonic acid (2 g). After 1 hour the mixture was washed with 5% sodium carbonate solution then with water, dried and filtered. The filtrate was evaporated to gi~e 3~ -dihydroxy~ _ , ~' ' - 25 -.; ' ' .
., ~ . . .
. . .: . . ~: .. , : , ~5~S;~
5a-pregnen-20-one 3,11-ditetrahydropyranyl ether as an oil ~97 9).
The crude ditetrahydropyranyl ether (97 g) in cold tetrahydrofuran (1,250 ml) was added to a solution of lithium diisopropylamide in tetrahydrofuran at 0C, the mixture stlrred for 30 minutes at room temperature, then re-cooled and treated with methyl iodide ~250 ml).
After 10 minutes the mixture was evaporated in vacuo and the residue dissolved in acetic acid (250 ml) and water (100 ml), warmed on a steam bath for 30 minutes, cooled, diLuted to 3 litres with water and the resultant solid filtered and dried. Crystallisation from ethyl acetate gave 3~ dihydroxy-21-methyl-~16-5~-pregnen-20-one.
In a similar manner 3p,11~-dihydroxy-21-methyl-~16-5n-pregnen-20-one was converted via its 3,11-ditetrahydro-i pyranyl ether to 3~511~-dihydroxy-21,21-dimethyl-Al6- 5a-pregnen-20-one~
b) A mixture of 3~ -dihydroxy-21-methyl-~ 6-5-pregnen-20-one ~40 g)~ acetic anhydride (160 ml) and pyridine (80 ml) was treated at reflux for 7 hours. Methylamine hydrochloride (0,8 g) was then added and the heating continued for a further 3 hours. The resultant mixture was cooled~ poured onto crushed ice9 allowed to reach room temperature and the brown solid filtered and dried. Crystallisation from diethyl ether gave 3prllp-~ d1hydroxy-21-methyl-~16-5(x-pregnen-20-one diacetate.
`~s In a similar manner 3~ dihydroxy-21,21-dimethyl-~16-5(x-pregnen-20-one furnished the corresponding diacetate~
,, , ~015~5~
c) A mixture of 3~ dihydroxy-21-methyl-~1 -5a-pregnen-20-one 3,11~diacetate t24 g) 7 N-bromosuccinimide (11.9 g), dimethyl ~ormamide (240 ml) and perchloric acid (70%, 6.6 ml) was stirred in the dark at 10C. After 24 hours the excess N-bromosuccinimide was destroyed with aqueous sodium bisulphite and the mlxture poured into water (1200 ml). The product was filtered and dried at room temperature to give 3p,11p,16l~-trihydroxy-17a-bromo-21-methyl-5a-pregnan-20-one 3,11-diacetate 16-~ormate.
The crude formate (30 g) in methanolic potassium carbonate (400 ml) was stirred at room temperature for 2 hoursO The excess base was neutralised with acetic acld, the reaction mixture concentrated in vacuo, poured into water and extracted with ether. The organic extract was washed, dried, and the filtrate evaporated to give 3~ .dihydroxy-16~,17~-epoxy-21-methyl-5a-pregnan-20-one ll-acetate as an amorphous solid.
Treatment of 3~ 911 p-dihydroxy-21,21-dimethyl ~l6 5a-pregnen-20-one 3,11-diacetate in a similar manner gave 3~ dihydroxy-16pl17p-epoxy-21,21-dimethyl-5a-preg-nan-20-one~ acetate (amorphous).
d) A mixture o~ 3~ -dihydroxy-16~,17~ epoxy-?l-methyl-5a-pregnan-20-one ll-acetate (40 ~), sodium azlde (120 g), ethanol (600 ml), water (300 ml) and sulphuric acid (8.4 ml) was stirred at reflux for 10 hours, cooled, and poured into water (1800 ml) and the resulting solid filtered and dried. The product was purified on silica gel to give 3p,11p,16a-trihydroxy-17a-azido-21-methyl-5a-pregnan-20-one ll-acetate.
A mixture of 3~,11p,16a-trlhydroxy-17~-azido-21-methyl-:
5a-pregnan-20-one ll-acetate (6.3 g), pyridine (19 ml) and ~cetic anhydride (13 ml) was allowed to stand at room temperature for 16 hours. The solution was then poured onto washed ice, allowed to reach room temperature and the white solid filtered and dried to give 3~ ,16a-trihydroxy-17a~azido-21-methyl-5a-pregnan-20-one 3,11,16-triacetate.
Treatment of 3~,11p-dihydroxy-16~,17~-epoxy-21,21-di-methyl-5a-pregnan-20-one ll-acetate in a similar manner gave 3~ ,16a-trihydroxy-17a-azido-21,21-dimethyl-5a-pregnan-20-one 3,11,16-triacetate~
e) A mixture of 3~ ,16a-trihydroxy-17a-azido-21-methyl-5a-pregnan-20-one 3,11,16-triacetate (S.l g) and platinum oxide (0O5 g) in methanol (300 ml) was hydrogenated for 2 hours then filtered. rhe filtrate was evaporated to dryness to give 3~ ,16a-trihydroxy-17-amino-21-methyl-5a-pregnan-20-one 3,11,16-triacetate which was suspended in dry benzene (250 ml) in the presence of p-toluene-sulphonic acid (2.5 g). The reaction mixture was stlrred at reflux for 1.5 hours then cooled and washed with 5~ sodium carbonate, water, dried over magnesium sulphate, filtered, and the filtrate ; evaporated to dryness. Crystallisation from acetone/
n-hexane furnished 3~ dihydroxy-[17a,16a-d]-2'-methyloxazoline-21-methyl-5a-pregnan-20-one 3911-diacetate.
Treatment of 3~ ,16a-trihydroxy-17a-azido-21,21-dimethyl 5a-pregnan-20-one 3,11,16-triaceate in a ~imilar manner gave 3~ dihydroxy-C17a,16-d]-2'-3~ methyloxazoline-21~21-dimethyl~5a-pregnan-20-one 3,11-diacetate.
~s~si~
f) A suspension of 3~ dihydroxy-[17a,16a-d]-2'-methyl-oxazoline-21-methyl-5a-pregnan-20-one 3~11-diacetate (3 5 g) in methanolic potassium carbonate (100 ml) was stirred at room temperature for 90 mlnutes then poured into water (500 ml) and extracted with etherO The organic extract was washed, dried, and evaporated to give 3~ 911~-dihydroxy-[17a,16a-d]-2'-methyloxazoline-21 methyl-5a-pregnan-20-one ll-acetate.
Treatment of 21,21-dimethyl analogue :Ln a similar manner gave 3~ -dihydroxy-[17a,16a-d]-2'-methyloxazoline-21,21-dimethyl-S(x-pregnan~20-one ll-acetate.
g) In the manner as described in Example 1 h) 3~ -di-hydroxy-[17a,16a-d]-2'-methyloxazoline-21-methyl-5a-j pregnan-20-one ll-acetate (8 g) was converted to 11~-j 15 hydroxy-L17~,16a-d]-2'-methyloxazoline-21-methyl-5a-pregnane-3,20-dione 11-acetate.
Treatment of 3~911~-dihydroxy-L17a,16a-d~-2'-methyl-; oxazoline-21,21-dimethyl-Sa-pregnan-20-one ll-acetate in a similar manner gave ll~-hydroxy-[17a,16a-d]-2'-methyloxazoline-21,21-dimethyl-Sa-pregnane-3,20-dione ll-acetate.
h) In the manner as described in Example 2 f) ll~-hydroxy-[17a,lG~-d]-2'-methyloxazoline-21-methyl-5a-pregnane-3920-dione ll-acetate (20 g) was convérted via the 2,4 dibromo derivative to 11~-hydroxy-~17a,16a-d]-2'-methyl-oxazoline-21-methyl-a ' -pregnadienè-3,20-dione 11-acetate m.p. 157-168C.
Treatment of ll~-hydroxy-L17a,16a-d]-2'-methyloxazoline-21,21-dimethyl-S~-pregnane-3,20-dione in a similar manner gave 11~-hydroxy~17a,16(x-d~-2'-methyloxazoline-2l,21-, ~ , 1 4 ~ 5~ ~% ~
dimethyl~ pregnadiene-3,20-dione ll-acetate m.p.
212-214C.
i) A solution of ll~-hydroxy-[17a,16a-d]-2'-methyloxazoline-21-methyl-Al'4-pregnadiene-3,20-dione ll-acetate (23.6 g) in methanol (472 ml~ and lON potassium hydroxide (94.4 ml) was heated at reflux. After 3Q minutes the cooled reaction mixture was neutralised with acetic acid, the methanol distilled off in vacuo and the product filtered.
Crystallisation from ethyl acetate ga~e ll~-hydroxy-[17a, 16a-dJ-2'-methyloxazoline-21-methyl-~1'4-pregnadiene-3,20-dione ~.p. 256-258C.
Treatment of ll~hydroxy-[17a,16a-d]-2'-methyloxazoline-21,21-dimethyl-Ql'4-pregnadiene-3,20-dione ll-acetate in a similar manner gave ll~--hydroxy-[17a,16a-d]-2'-methyl-j 15 oxazoline-21,21-dimethyl-~1'4-pregnadiene-3,20-dione, ` m.p. 258-265C.
~3~E~5 i a) A mixture of 3~-hydroxy-[17a,16a-d]-2'-methyloxazollne-~9(11)-5a-pregnen-20-one ~10 g), dry benzene ~150 ml), dihydropyran (10 ml) and p-toluene sulphonic acid (5 g) was stirred at room temperatureO After 2 hours the solutlon was washed with sodium carbonate, water, dried over magnesium sulphate then filtered~ The filtrate was evaporated to give 3~-hydroxy-~17a~16a-d]-2'-methyl~
oxazoline-~9(11)-Sa-pregnen-20-one 3 tetrahydropyranyl ether (15 g). This product was alkylated with lithium diisopropylamide as described ln Example 4 a), deprotected then purified by chromatography on silica gel to give 3~-hydroxy-L17a,16-d]-2'-methyloxazoline-., ~
21-methyl-~9(~ 5~-pregnen-20-one~
b) By the method of the Examples 1 h) and i) 3~-hydroxy-[17a,16-d]-2'~methyloxazoline-21-methyl-~9(11)-5~-pregnen-20-one was converted via [17a,16a-d]-2'-methyl-oxazoline-21-methyl-~9(11)-5a-pregnene-3~20-dione to [17a,16a-d]-2t-methyloxazoline-21-methyl-Al'4'9( pregnatriene-3 9 20-dione, m.p. 202-205C.
Example 6 a) A solution of 3~,11p-dihydroxy-16~921-dlmethyl-16.x,17a-epoxy-5(~-pregnan-20-one ll~-acetate from Example 3 b) (10 g) in dry methanol and methylene chloride was treated with a solutlon of hydrogen bromide in acetic acld (3.0N; 10 ml) and allowed to stand at room temperature for 24 hours~ The solution was diluted with methylene chloride, washed with water, sodium carbonate solution then water to neutrality, dried over sodium sulphate and evaporated to dryness. The residue was crystallised from methylene chloride/methanol to give 3~ 17a-trihydroxy-16,21-dimethyl-~15-5a pregnen-20-one ll~-acetate.
Treatment of 3~911~-dihydroxy-16~21,21-trimethyl-16a,17a-epoxy-5a-pregnan-20-one ll~-acetate in a sim~lar manner gave 3~ ,17a-trihydroxy-16921,21-tri-methyl~al5-5(x-pregnen-20~one ll~-acetate.
b~ By the method of Example 1 h) and i) 3~ ,17a-tri-hydroxy-16~21-dimethyl-~15-S[Y-pregnen-20-one llB- ~
acetate and 3~ ,17~ trihydroxy-16,21,21-trimethyl-Q -5a-pregnen-20-one ll~-acetate were converted via the corresponding 3-ketones to 11~,17a~dihydroxy-16, ' ' .
~ 31 -5~
21-dimethyl~ 4~15~pregnatriene-3~2-dione ll~-acetate, mOpO 184-188C, and 11~,17a-dihydroxy-16,21,21-trimethyl-'4'15-pregnatriene-3,20-dione ll~-acetate, m~pO 170-175C, respectively.
Hydrolysis of the ll~-acetates by the method of Example 3 e) gave 11~5 1 7a dihydroxy-16,21-dimethyl-Ql'4'15-pregnatriene-3,20-dione, m.p. 192-195C, and 11~,17a-dihydroxy-l6~2l~2l-trimethyl-~l74~l5-preg dione, m.p. 181-185C, respectively.
lC) Lxample 7 a) ~ solution of 3~-hydroxy-~9(~ 6-5~-pregnadien-20-one acetate (50 g) in methylene chloride (100 ml) was added to an ice~cold solution of excess diazomethane in ether~
The solution was allowed t:o stand in a refrigerator for 4 days~ then excess diazomethane was destroyed by the addition of a 10% solution of acetic acid in ether. The solution was evaporated to dryness to give the 16a,17a-pyrazoline~
The crude pyrazoline (56 y) was dissolved in acetone (750 ml) and stirred at room temperature with boron trifluoride etherate (33 ml). After evolution of nitrogen ceased, excess reagent was destroyed with potassium bi-carbonate solution and water added to precipitate the product whlch was filtered, washed with water~ and driedO Crystallisation from methylene chloride/methanol gave 3~-hydroxy-16a~17a-methylene_~9(1l)_5a_p one acetate.
b) The product from Example 7 a) was hydrolysed with potassium carbonate in warm methanol to give 3~-hydroxy-., .
~ - 32 -~os~sz~
16~ 17~methylene-~9(ll)-sa-pregnen-2o-one~ which was converted by the method of Example 1 h~ to 16a,17a-methylene-~9(ll)-5a-pr~gnene-3~2o-di~ne c) To a stirred suspension of 16aJ17a-methylene-Q9(11)-5~-pregnene-3,20-dione (27.6 g) in methanol (S00 ml) was added p-toluenesulphonic acid (0.55 g). After 30 minutes triethylorthoformate (12 ml) was added, followed 5 minutes later by potassium bicarbonate (4 g). The volume of the reaction mixture was reduced to 250 ml and the product precipitated by pouring lnto water.
The dimethyl ketal was filtered and dried.
To a stirred solution of lithium diisopropylamide in ; dry tetrahydrofuran at 0 under nitrogen was added 16a,17a-methylene-~9(11)-5a-pregnene-3,20-dione 3,3-dimethyl ketal (31 g) in dry tetrahydrofuran (600 ml).
After 30 minutes the reacl:ion mixture was treated with dry methyl iodide (155 ml~ and the cooling bath removed.
Ten minutes later the mixture was evaporated and the residue d~ssolved in aqueous acetic acid. This solution was warmed on the steam-bath for 1 hour and the product precipitated with water. Recrystallisation from acetone/
n-hexane gave 16a,17a-methylene-21-methyl-A9(11)-5a-., .
pregnene-3,20-dione.
i Treatment of 16a,17a-methylene-21-methyl-~9(11)-5a-pregnene-3,20-dione, 16a~17a-isopropylidenedioxy-Q9(11)-5a-pregnene-3,20-dione and 16a,17a-isopropyl-idenedioxy-21-methyl-~9(~ 5a-pregnene-3,20-dione, in a similar manner gave 16a,17a-methylene 21921-di-methyl-~9(11)-5a-pregnene-3,20-dLone~ 16a,17a-iso-propylidenedioxy-2l-methyl-~9(ll)-5a-pre9ne~e-3 ~S~5~
dione and 16a,17~-isopropylidenedioxy-21721-dimethyl-~9(11)-5~-pregnene-3,20-dione, respectively.
d) By the method of Example 1 i)~ j) and k) 16l~,17a-methylene-21-methyl-~9(11)-5a-pregnene-3,20-dione and 16a,17~-methylene-21,21-dimethyl-~9(11)-5a-pregnene-3920-dione were converted to 11~-hydroxy-16~,17-methyl-ene-21-methyl-~1'4-pregnadiene-3,20-dione, m.pu 229-230C, and l]p-hydroxy-16a917~-methylene-21,21-dimethyl-~l'4-pregnadiene-3,20-dione, m.p. 221-225C, respectively.
Example 8 a) To a stirred solution of 16917-isopropylidenedioxy-21-methyl-~ (11)-5a-pregnene-3,20-dione from Example 1 h) in 20/1 chloroform/acetic acid was added a solution lS of hydrogen bromide in acetic acid. Bromine (1.1 mole equivalents) as a 10% solution in chloroform was added dropwise. After the addition of sodium acetate solution the organic layer was separated, washed with sodium carbonate solution, then to neutrality with water, dried and evaporated to give the crude 2~-bromo s derivative.
A solut1on of this product in dimethyl formamide was quickly added to a stirred sus~ension of lithium bromide and calcium carbonate in dimethyl formamide refluxing in a nitrogen atmosphere.
A~ter 15 minutes the cooled mixture was poured into stirred 1% aqueous acetic acid. After 30 minutes the solid product was filtered off, washed to neutrality with water and dried to give the crude 16~,17~-iso-propylidenedioxy-2l-methyl A1~9tll~-5a_pregnadiene_ ~ 34 -3,20-dione.
The product was converted by the method of Example 1 i) to 16a,17a isopropylidenedioxy-21-methyl-~ 9(11)_ pregnatrien~-3,20-dione, m.p. 236-244C~
In a similar manner 16~x,17a-isopropylidenedioxy-21~21-dimethyl-~9(11)-5a-pregnene-3,20-dione was converted to 16a,17a-isopropylidenedioxy-21,21-dimethyl-al'4'9(11)-pregnatriene-3,20-dione, m.p. 251-258C~
b) To a stirred solution of 16a,17a-isopropylidenedioxy-21-methyl-~9(11)-5a-pregnene-3,20-dione from Example 1 h) in 20/1 chloroform/acetic acid immersed in an ice-bath was added a solution of hydrogen bromide in acetic acid.
Bromine (2.2 mole equivalents) as a 10% solution in chloroform was then added dropwise. After the addition of sodium bisulphite and sodium acetate solutions the organic layer was separated and washed with sodium carbonate solution, then with water to neutrality, dried and evaporated to give the crude dibromo derivative.
A solution of the crude product in dimethyl acetamide was dehydrobrominated by the method described in Example 8 a) and the product crystallised from methylene chloride/methanol to give 16a,17a-isopropylidenedioxy-_methyl~al~4~9(11)_pregnatriene 3,20-dione, m-p-236-244C.
- In a similar manner 16a,17a-isopropylidenedioxy-21,21-dimethyl-a9(11)-Sa-pregnene~3,20-dione was converted to 16a,17a-isopropylidenedioxy-21,21-dimethyl-a1'4'9( pregnatriene-3~20-dione, m.p. 251-258C.
., .
., .
~5~5~
Example 9 a) Ethylene was bu~bled through a solution of 3~
dihydroxy-21-methyl-~16-5a-pregnen-20-one 3,11-di-acetate (10 g) in benzene (250 ml) and the reaction mixture irradiated with ultraviolet light. After 10 hours the reaction was evaporated to dryness and the residue purified by chromatography on silica to furnish 3~ -dihydroxy-16a,17a-ethylene~21-methyl-5a-pregnan-20-one 3911-diacetate.
In a similar manner, 3p,11~-dihydroxy-21,21-dimethyl--5a-pregnen-20-one 3,11-diacetate was converted to 3~ dihydroxy-16a,17a-ethylene-21,21-dimethyl-5a-pregnan-20-one 3,11-diacetate.
b) By the method of Example 4 f) 3~ -dihydroxy-16,17a-ethylene-21-methyl-Sa-pregnan-20-one 3,11-diacetate and 3~ dihydroxy-16,17a-ethylene-21,21-dimethyl-5-pregnan~20-one 3~11-diacetate gave 3~ -dihydroxy-16,17a-ethylene-21-methyl-5a-pregnan-20-one ll-acetate and 3~911~-d~hydroxy-16a,17a-ethylene-21921-dimethyl-5a-pregnan-20-one ll-acetate, respectively.
¦ c) By the method of Example 1 h) 3~ -dihydroxy-16a,17a-ethylene-21-methyl-Sa-pregnan-20-one ll-acetate and `~ ~ 3~ dihydroxy-16a,17a-ethylene~21,21-dimethyl-5-pregnan-20-one ll-acetate gave 11~-hydroxy-16~,17a-1 25 ethylene 21-methyl-5a-pregnane-3,20-dione 11-acetate and ll~-hydroxy-16a,17a-e~hylene-21,21-dimethyl-S-pregnane-3~20-dione ll-acetate~ respectively.
d) By the method o~ Example 8 a) 11~-hydroxy-16a,17~-ethylene-21-methyl-5a-pregnane-3,20-dione ll_acetate and 11~-hydroxy-16a,17a-ethylene-21,21-dimethyl-5a-.' ' , , , ' , . .
.r_~
pregnane-3,20-dione ll-acetate gave ll~-hydroxy-16917a-ethylene-21-methyl-Ql'4-pregnadiene-3,20-dione ll-acetate 7 mOp. 177-179C9 and 11~-hydroxy-16a,17~-ethylene-21,21-dimethyl al9 4-pregnadiene-3,20-dione ll-acetate, m.p~
200-201C, respectively.
Hydrolysis of the ll-acetates by the method of Example 3 e) gave llp-hydroxy-16a,17a-ethylene-21-methyl-~1'4-pregnadiene-3,20-dione, m.p. 210~212C, and llp-hydroxy-16a,17a-ethylene-21,21-dlmethyl-~1'4-pregnadiene 3,20-dione9 m.p. 188-190C, respectively.
Example 10 a) llp-Hydroxy-[17~,16~-d]-2'-methyloxazoline 21-methyl-'4-pregnadiene-3,20-dione t502 g) in dimethyl forma-mide (30 ml) and collidene (10.4 ml) at 10C was treated dropwise with methanesulphonyl chloride (3.4 ml) and 5%
sulphur dioxide in dimethylformamide (5.4 ml). The temperature was allowed to rise to 30C then cooled to about 10 C and water (5 ml) slowly added. The resulting solutlon was poured into water (300 ml) containing sodium acetate (8 g), stirred, and the light yellow solid filtered and dried to give [17a, 16a-d]-2'-methyloxazoline-21-methyl-~1'4'9(11)-pregnatriene-3 7 20-dione m.p~ 202-205C.
Treatment of llp-hydroxy-[17~x,16~-d]-2l-methyloxazoline-21,21-dimethyl~ pregnadiene-3,20-dione, llp-hydroxy-16a,17a-ethylene-21-methyl-~l94-pregnadiene-3,20-dione and ll~-hydroxy-16~,17a-ethylene-21,21-dimethyl-~1' -pregnadiene~3~20-dione in a similar manner gave [17~, 16a-d]-2'-methyloxazoline-21,21-dimethyl~ 9(11)_ ~5~i25~
pregnatriene-3,20-dione, 16a,17-ethylene-21-methyl-~1~ '9(11)-pregnatriene-3,20-dione and 16a,17a-ethylene-21~21 dimethyl ~1~4~9(11)_pregnatriene-3~2~di respectively.
By the method of Exam~le 1 ~) each of the above four ~9(11)-compounds was converted to the corresponding 9a-bromo-11~-hydroxy-compound.
b) A mixture of 9(~-bromo-ll~-hydroxy-[17a716a-d]-2'-methyl-oxazoline-21-methyl-~1'4~pregnadiene-3,20-dione (7.39 g), tetrahydrofuran (180 ml), methanol (180 ml) and lN sodium methoxide/methanol (21.6 ml) was stirred at room temperature. After 15 minutes the excess base was neutralised with acetic acid and poured into water (1~5 litres). The product was filtered and dried to give 9~ epoxy-L17,16a-d]-2~-methyloxazoline~21-methyl-Ql'4-pregnadiene-3,20-dione.
Treatment of 9a-bromo~ -hydroxy-[17a916a-d]-2'-methyl-oxazoline-21,21-dimethyl-~'' -pregnadiene-3,20-dione~
9a-bromo-11~-hydroxy-16(~,17a-isopropylidenedioxy-21-methyl-~l' -pregnadiene-3S?0-dione~ 9a-bromo-11~-hydroxy-16a,17a-isopropylidenedioxy-21,21-dimethyl-'4-pregnadiene-3,20-dione, 9a-bromo-11~-hydroxy-L 16a,17a-d]-2'-methyloxazoline-21-methyl-~1'4-pregna-diene-3,20-dione, 9a-bromo-11~-hydroxy-[16a,17a-d~-2 e_ methyloxazoline-21,21-dimethyl-~1'4-pregnadiene-3,20-dione9 9a-bromo~ -hydroxy-16a~17a-methylene-21 methyl-~1 ~ 4-pregnadiene-3, 20-dione g 9 a-bromo~ -hydroxy-1 6 a l 1 7a-methylene-21~21-dimethyl-al'4-pregnadiene-3,20-dione, 9a-bromo-111~-hydroxy-16a, 17a-ethylene-21 -methyl~ ' 4-30 pregnadiene~3,20-dione and 9a-bromo~ -hydroxy-16a~17a- -.
~ql s~ .
ethylene-21,21-dimethyl-~1' -pregnadiene-3 9 20-dione in a similar manner gave the corresponding 9p,11p-epoxy-compound 9 respectively.
c) An ice cold solution of 9~ -epoxy-[17a~16a-d]-2'~
methyloxazoline (206 g) in chloroform (26 ml) was added to a mixture of anhydrous hydrogen fluoride (5.2 g) 9 dry tetrahydrofuran ~10.5 ~1) and chloroform (5.3 ml) cooled to -30C~ ~fter 2 hours at 0C the excess hydrogen fluoride was neutralised with potassium carbonate (61 g) in water (600 ml). The product was extracted with ether, washed with water, dried over - sodium sulphate and filtered. The filtrate was evaporated to dryness then crystallised from acetone to give 9a-fluoro-llp-hydroxy-[17a,16a-d]-2'-methyl-oxazoline-21-methyl-~1'4-pregnadiene-3,20-dione, m.p.
282-284C.
Treatment of 9p,11~epoxy-L17a,16a-d]-2'-nlethyloxazo-., line-21,21-dimethyl-~1'4-pregnadiene-3,20-dione, 9F~, llp-epoxy-16a,17a-isopropylidened~oxy-21-methyl-~1'4-pregnadiene-3,20-dione, 9p,11p-epoxy-16a,17a-isopropyl-idenedioxy-21,21-dimethyl-~1'4-pregnadiene-3,20-dione, . 9p,11p-epoxy-L16a~17a-d]-2'-methyloxazoline-21-methyl-'4-pregnadiene-3,20-dione, 9p,11p-epoxy~[16a,17a-d~-2'-methyloxazoline-21,21-dimethyl-~1' -pregnadiene-3,20-dione, 9p 9 llp-epoxy-16a,17a-methylene-21-methyl-al'4 pregnadiene-3,20-dione, 9~,11p-epoxy-16a,17a-methylene-21,21-dimethyl-Q1'4-pregnadiene-3,20-dione, 9p,11p-epoxy-16~,17a-ethylene-21-methyl-~1'4-pregnadiene-3,20-dione and 9p,11p-epoxy-16a,17a-ethylene-21,21-dimethyl-~0 Ql94-pregnadiene-3,20-dione in a similar manner gave 9~-3~5~
fluoro~ hydroxy-L17a,16a-d]-2l-methyloxazoline-21,21-dimethyl-~l'4-pregnadiene-3,20-dione, m.p. 264-265C1 9a-fluoro-ll~hydroxy-16a,17~-isopropylidenedioxy-21-methyl-~1~4-pregnadiene-3 9 20-dione, m.p. 315-327C
(decomp.), 9(~-fluoro~ -hydroxy-16a,17(~-isopropylidene-dioxy-21~21 dimethyl-~ ' -pregnadiene-3~20-dione~ m.p.
285-301C (decomp.)9 9(1-fluoro-ll~-hydroxy-[16a,17a-d]-; 2'-methyloxazoline-21-methyl-~1'4-pregnadiene-3,20-dione~
m.p. 295-299C, 9a-fluoro-11~-hydroxy-L16a,17a-d]-2'-methyloxazoline-21,21-dimethyl-~1'4-pregnadiene-3~20-dione, m.p. 265-267C9 9a-fluoro-11~-hydroxy-16a,17a-methylene-21-methyl-~1' -pregnadiene-3,20-dione, m.p.
223-225C, 9a-fluoro-11~-hydroxy-16a,17a-methylene-21, 21^-dimethyl-~1'4-pregnadiene-3,20-dione, m.p. 251-258C, 9a-fluoro~ hydroxy-16a917a-ethylene-21-methyl-~l'4-pregnadiene-3,20-dione9 m.p. 230-232C~ and 9(x-fluoro-llp-hydroxy-16a,17a-ethylene-21,21-dimethyl-~1'4-pregnadiene-3,20-dione, m.p. 215-217C, respectively.
. .
Exam~le 11 A solution of 9a-fluoro~ -hydroxy-16a,17a-isopropyl-idenedioxy-21-methyl-~1'4-pregnadiene-3~20-dione in acetone ., was treated with excess 6.24N Jones Reagent. After a few minutes a little isopropanol was added, followed by the slow addition of water~ The volatile solvent was removed under vacuum and thè solid product was filtered off and crystallised from acetone/hexane to ~ive 9a-fluoro-16a, 17~-isopropylidenedioxy-21-methyl-~ pregnadiene-3,11, 20-trione, m.p. 215-220C.
In a similar manner 9a-fluoro-11~-hydroxy-16a,17a-.
~L~S~ 2~ 4 isopropylidenedioxy-21721-dimethyl~ pregnadiene-3,20 dione was oxidlsed to 9a~fluoro-16a,17a-isopropylidenedioxy-21,21-dimethyl-~l'4-pregnadiene-3,11120-trione, m.p. 235-Similarly the other 9(x-fluoro~ hydroxy compounds obtained in ~xample 10 were oxidised to their corresponding 9(x-fluoro-11-ketonesO 9a-fluoro-~16a,17a-d]-2'-methyloxazo-line-21-methyl-~1'4-pregnadiene-3,11,20-trione, [a]D =
+189 in CHC13.
Example 12 Into a sol~t~on of 16,17a-isopropylidenedioxy-21-methyl_~l'4'9(11)-pregnatrlene-3,20-dlone (1 g) in 9/1 chloroform/pyrldine (50 ml) dry chlorine was passed for 1 minute, and the reaction was then stirred for 30 minutes at room temperature. Excess chlorine was destroyed by the addition of sodium sulphite solution and the mixture was ~ filtered to remove sulphur. The organic phase was washed i successively with water, 2N HCl, water~ saturated potassium bicarbonate solution and water to neutral~ty. The dried ; ~ extract was evaporated to dryness, then the residue was purified on a silica column and crystallised from methanol to give 9a,11~-dichloro-16~,17a-isopropylidenedioxy-21-methyl-~l'4-pregnadien-3,20-dione (630 mg), m.p. 213-227C.
In a similar manner 9a,11~-dichloro-16a~17a-methylene-21-methyl-al'4-pregnadiene-3,20-dione, 9a,11~-dichloro-[16a~17a-d~2'-methyloxazollne-21-methyl-~1'4 pregnadiene-3~20-dione, 9a,11~-dichloro-16a,17a-isopropylidenedioxy-21,21-dimethyl-~1'4-pregnadiene~3~20-dione, 9a,11~-dichloro-16a/17a-ethylene-21-methyl-Al' -pregnadlene-3,20-dione and .
~5~52~
9~ dichloro-16916-methylene-17a-hydroxy-21-methyl-~pregnadiene-3~20-dione were prepared from the corresponding Q (ll)-compounds.
Example 13 ~,l7a-methylene-2l-methyl~ 4 7 9 ( 11 ) -pre~natriene-3,20-dione (800 mg) were dissolved in 10% aqueous dioxan (35 ml), cooled to 10C and 72% perchloric acid (0.2 ml) was added followed by N-chloro succinimide (0.5 g) and the reaction stirred overnight. The product was watered out, filtered, dried and recrystallised from methylene chloride to give 9a-chloro-11~-hydroxy-16a,17a-methylene-~1 methyl-~1'4-pregnadiene-3,20-dione (550 mg).
Example 14 `. A solution of [16a,17(Y-d]--2' methyloxazoline-21-methyl-~1'4'9(11)-pregnatriene-3,20-dione (1 g) in chloroform (30 : ml) and pyridine (5 ml) was treated with a solution of HF
(1.5 g) in tetrahydrofuran (5 ml) and chloroform (2 ml) r~llow~d by N-chlorosuccinimide (0.5 g). After a week at ,, room temperature the reactioD was poured into excess 10%
sodium acetate solution and the product isol~ted via met}lylene chloride. The crude product was purlfied on a silica gel and crystallised from ether to give 9a-chloro~ fluoro-[16a,17a-d]-2'-methyloxazoline-21-methyl~ 4-pregnadlene-3,20-dione (0.5 g).
~ Hydroxy-16a,17a-isopropylidenedioxy-21-methyl-~1'4-~reqnadiene-3,20-dione ll-acetate (2 g) and dichloro-_ ~2 -s2g di~yanoqulnone (1.3 g) were dissolved in dioxan (35 ml).
Hydrogen chloride was passed into the solution until a precipitate started to form and the reaction mixture was allowed to stand for a further 20 minutes. The solid was removed ~y filtration and the filtrate was pour~d into aqueous sodium carbonate solution. The product was iso-lated via ether and purified by chromatography on silica gel to give ll~-hydroxy-16a,17a-isopropylidenedioxy-21-; methyl-~1'4'6-pregnatriene-3,20-dione ll-acetate (1.2 g) as an amorphous solid.
Example 16 By the method of Examples 1 d)-g) 3~-hydroxy-21-methyl-A5'16-pregnadien-20-one was converted to 3~-hydroxy-16~Y,17~-isopropylidenedioxy-21-methyl~ -pregnen-20-one. ~ solution of this ~5-compound (5 g) in chloro~orm (50 ml) was stirred with peracetic acid (5 ml) and sodium acetate (0.5 g) for onl~ hour, after which excess peracid was destroyed with sodium bisulphite. Further processin~ gave 3~-acetoxy-5~-
6(~-epoxy-16a,17a-isopropylidenedioxy-21-methyl-5l~-pregnan-20-one. Treatment of this compound with borontrifluoride etherate~HF gave 3~-acetoxy-5~-hydroxy-6p-fluoro-16~,17~-- isopropylidenedioxy-21-methyl-5~-pregnan-20-one, which after hydrolysis of the 3~-3-acetoxy group and oxidation of the 3p-hydroxy group with Jones' reagent~to the 3-keto group, was dehydrated and isomerised in acetic acid/HCl to 6-~luoro-16~,17a-isopropylidenedioxy-21-methyl-~4 pregnene-3~20-dione. The latter compound was refluxed in henzene with DDQ for 15 hours to give 6a-fluoro-16,17-isopropylidenedioxy-21~methyl~ pregnadiene-3~20-dione, m.p. 283-290C.
, - ~3 -
, - ~3 -
Claims (45)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. Process for the preparation of novel alkylated steroids of the pregnane series having the formula (I) ,wherein, X = H or halogen;
Y = H2, H(OH), H(Oacyl), O or H(halogen);
R1 = an alkyl group having 1-4 C-atoms;
2 = R1 or H;
R3 = H, CH3 or halogen;
Z = OH, Oalkyl or Oacyl or forms together with Q a group as indicated below;
Q = (when C15-C16 is saturated) alkylidene having 1-4 C-atoms or (.beta.H) (.alpha.R4), in which R4 together with Z is alkylidenedioxy having 3-5 C-atoms, alkylidene having 1-4 C-atoms, aralkylidene having 7-8 C-atoms, alkylene of the formula , wherein A = H or halogen and B = H, halogen, alkyl (1-4 C), haloalkyl, alkoxy or phenyl, or a [17.alpha.,16.alpha.-d]- or [16.alpha.,17.alpha.-d]-oxazolino-group, wherein the C-atom in 2'-position may be substituted by alkyl (1-4 C) or phenyl; or Q = (when C15-C16 is unsaturated) methyl or halomethyl, which comprises (I) heating a compound of the formula (II) wherein R6 is a protected hydroxyl or ketone group, and R7 is hydrogen or a protected hydroxyl group, to split off nitrogen whereby producing a steroid of formula (I) wherein Q is (.beta.H)(.alpha.R4) and Z and R4 form a 16,17-methylene bridge, in admixture with a corresponding 16-methyl-.DELTA.16-steroid; or (II) treating a compound of the formula (III) with an acid to break the epoxide ring, thereby producing a steroid of formula (I) wherein Z is .alpha.-OH and Q is a 16,16 methylene group, in admixture with a steroid of formula I wherein Z is .alpha.-OH and Q is a .DELTA.15-16-methyl group;
or (III) reacting a compound of the formula (IV) wherein V represents hydrogen or acetyl, with a ketone or aldehyde of 3 to 5 carbon atoms in the presence of an acid, thereby producing a steroid of formula (I) wherein Q is (.beta.H)(.alpha.R4) and Z and R4 form a 16.alpha.,17.alpha.(-(C3 to C5)al-kylenedioxy group; or (IV) reacting a compound of the formula (V) with an olefin of the formula thereby producing a steroid of formula (I) wherein Q is (.beta.H)(.alpha.R4) and Z and R4 form a 16.alpha.,17.alpha.-alkylene group in which the alkylene is of the formula ; or (V) reducing a compound of the formula (VI) by catalytic hydrogenation, thereby obtaining a steroid of formula (I) wherein Z and Q form a 2'-methyl-17.alpha.,16.alpha.-oxazoline ring fused with the D-ring of the steroid; or (VI) ring closing a compound of the formula (VII) by the action of an acid, thereby obtaining a steroid of formula (I) wherein Z and Q form a 2'-methyl-16.alpha.,17.alpha.-oxazoline ring fused with the D-ring of the steroid; or (VII) 21-alkylating a compound of the formula (VIII) wherein R5 represents H or halogen; the substituents R3, R6 and R7 in the starting materials of formulae (II) to (VIII) inclusive being as follows:
R3 = H, CH3 or halogen; R6 = a protected hydroxyl or keto group; and R7 = hydrogen or a protected hydroxyl group; and the dotted lines in the steroid rings indicating optional double bonds; and removing any protecting group present on the 3-hydroxyl, 3-keto or 11-hydroxyl group of the product, converting a (.DELTA.5-)3-hydroxyl system to a .DELTA.4 - or .DELTA.1-4-3-keto system, intro-ducing a .DELTA.6(7) double bond with a quinone when required, acylating an 11-hydroxyl and a 17.alpha.-hydroxyl group when required, introducing halogen atoms at the 9- and 11-position by halogenating a product having a.DELTA.9(11) double bond when required, and oxidizing an 11-hydroxyl group to 11-keto when required.
Y = H2, H(OH), H(Oacyl), O or H(halogen);
R1 = an alkyl group having 1-4 C-atoms;
2 = R1 or H;
R3 = H, CH3 or halogen;
Z = OH, Oalkyl or Oacyl or forms together with Q a group as indicated below;
Q = (when C15-C16 is saturated) alkylidene having 1-4 C-atoms or (.beta.H) (.alpha.R4), in which R4 together with Z is alkylidenedioxy having 3-5 C-atoms, alkylidene having 1-4 C-atoms, aralkylidene having 7-8 C-atoms, alkylene of the formula , wherein A = H or halogen and B = H, halogen, alkyl (1-4 C), haloalkyl, alkoxy or phenyl, or a [17.alpha.,16.alpha.-d]- or [16.alpha.,17.alpha.-d]-oxazolino-group, wherein the C-atom in 2'-position may be substituted by alkyl (1-4 C) or phenyl; or Q = (when C15-C16 is unsaturated) methyl or halomethyl, which comprises (I) heating a compound of the formula (II) wherein R6 is a protected hydroxyl or ketone group, and R7 is hydrogen or a protected hydroxyl group, to split off nitrogen whereby producing a steroid of formula (I) wherein Q is (.beta.H)(.alpha.R4) and Z and R4 form a 16,17-methylene bridge, in admixture with a corresponding 16-methyl-.DELTA.16-steroid; or (II) treating a compound of the formula (III) with an acid to break the epoxide ring, thereby producing a steroid of formula (I) wherein Z is .alpha.-OH and Q is a 16,16 methylene group, in admixture with a steroid of formula I wherein Z is .alpha.-OH and Q is a .DELTA.15-16-methyl group;
or (III) reacting a compound of the formula (IV) wherein V represents hydrogen or acetyl, with a ketone or aldehyde of 3 to 5 carbon atoms in the presence of an acid, thereby producing a steroid of formula (I) wherein Q is (.beta.H)(.alpha.R4) and Z and R4 form a 16.alpha.,17.alpha.(-(C3 to C5)al-kylenedioxy group; or (IV) reacting a compound of the formula (V) with an olefin of the formula thereby producing a steroid of formula (I) wherein Q is (.beta.H)(.alpha.R4) and Z and R4 form a 16.alpha.,17.alpha.-alkylene group in which the alkylene is of the formula ; or (V) reducing a compound of the formula (VI) by catalytic hydrogenation, thereby obtaining a steroid of formula (I) wherein Z and Q form a 2'-methyl-17.alpha.,16.alpha.-oxazoline ring fused with the D-ring of the steroid; or (VI) ring closing a compound of the formula (VII) by the action of an acid, thereby obtaining a steroid of formula (I) wherein Z and Q form a 2'-methyl-16.alpha.,17.alpha.-oxazoline ring fused with the D-ring of the steroid; or (VII) 21-alkylating a compound of the formula (VIII) wherein R5 represents H or halogen; the substituents R3, R6 and R7 in the starting materials of formulae (II) to (VIII) inclusive being as follows:
R3 = H, CH3 or halogen; R6 = a protected hydroxyl or keto group; and R7 = hydrogen or a protected hydroxyl group; and the dotted lines in the steroid rings indicating optional double bonds; and removing any protecting group present on the 3-hydroxyl, 3-keto or 11-hydroxyl group of the product, converting a (.DELTA.5-)3-hydroxyl system to a .DELTA.4 - or .DELTA.1-4-3-keto system, intro-ducing a .DELTA.6(7) double bond with a quinone when required, acylating an 11-hydroxyl and a 17.alpha.-hydroxyl group when required, introducing halogen atoms at the 9- and 11-position by halogenating a product having a.DELTA.9(11) double bond when required, and oxidizing an 11-hydroxyl group to 11-keto when required.
2. Process according to claim 1, characterized in that the 21-alkyla-tion is carried out by treating the 20-keto pregnane derivative with an alkali metal, an alkali metal amide or an organometallic compound and an alkyl halide in a suitable solvent.
3. Process according to claim 2, characterized in that the alkali metal amide is an alkali metal dialkylamide.
4. Process according to claim 3, characterized in that the alkali metal dialkylamide is lithium diisopropylamide.
5. Process according to claim 2-4 characterized in that the 21,21-di-alkylated compound is prepared by treating a 21-mono alkylated compound ac-cording to the methods of the claims 2-4.
6. Process according to claim 1 wherein in the starting materials of formulae (II), (III), (IV), (V), (VI) or (VII), R1 is methyl and R2 is hydro-gen, or wherein a starting material of formulae (VIII) is monomethylated.
7. Process according to claim 1 wherein in the starting materials of formulae (II), (III), (IV), (V), (VI) or (VII), R1 and R2 are both methyl or a starting material of formula (VIII) is dimethylated.
8. 3,20-Diketo-.DELTA.4-steroids of the pregnane series having the general formula (I) defined in claim 1 when prepared by the process of claim 1 or of a chemical equivalent thereof.
9. A process in whic}l 16.alpha.,17.alpha.-methylene-.DELTA.9(11)-5.alpha.-pregnene-3,20-dione is 21-methylated to produce 16.alpha.,17.alpha.-methylene-21-methyl-.DELTA.9(11)-5.alpha.-pregnene-3,20-dione.
10. A process according to claim 9 in which the product obtained is subjected to the additional steps of:
(a) 1,4-dehydrogenation to produce 16.alpha.,17.alpha.-methylene-21-methyl-.DELTA.1,4,9(11)-pregnatriene-3,20-dione.
(b) reacting the 16.alpha.,17.alpha.-methylene-21-methyl-.DELTA.1,4,9(11)-pregnatriene-3,20-dione so obtained with hypobromous acid; and (c) debrominating the 9.alpha.-bromo-11.beta.-hydroxy-16.alpha.,17.alpha.-methylene-21-methyl-.DELTA.1,4-pregnadiene-3,20-dione produced in step (b) to produce 11.beta.-hydroxy-16.alpha.,17.alpha.-methylene-21-methyl-.DELTA.1,4-pregnadiene-3,20-dione.
(a) 1,4-dehydrogenation to produce 16.alpha.,17.alpha.-methylene-21-methyl-.DELTA.1,4,9(11)-pregnatriene-3,20-dione.
(b) reacting the 16.alpha.,17.alpha.-methylene-21-methyl-.DELTA.1,4,9(11)-pregnatriene-3,20-dione so obtained with hypobromous acid; and (c) debrominating the 9.alpha.-bromo-11.beta.-hydroxy-16.alpha.,17.alpha.-methylene-21-methyl-.DELTA.1,4-pregnadiene-3,20-dione produced in step (b) to produce 11.beta.-hydroxy-16.alpha.,17.alpha.-methylene-21-methyl-.DELTA.1,4-pregnadiene-3,20-dione.
11. A process according to claim 10 in which the 9.alpha.-bromo-11.beta.-hydroxy-16.alpha.,17.alpha.-methylene-21-methyl-.DELTA.1,4-pregnadiene-3,20-dione produced in step (b) is subjected to the additional steps of:
(i) dehydrobromination to give 9.beta.,11.beta.-epoxy-16.alpha.,17.alpha.-methylene-21-methyl-.DELTA.1,4-pregnadiene-3,20-dione, which is (ii) reacted with hydrogen fluoride to give 9.alpha.-fluoro-11.beta.-hydroxy-16.alpha.,17.alpha.-methylene-21-methyl-.DELTA.1,4-pregnadiene-3,20-dione.
(i) dehydrobromination to give 9.beta.,11.beta.-epoxy-16.alpha.,17.alpha.-methylene-21-methyl-.DELTA.1,4-pregnadiene-3,20-dione, which is (ii) reacted with hydrogen fluoride to give 9.alpha.-fluoro-11.beta.-hydroxy-16.alpha.,17.alpha.-methylene-21-methyl-.DELTA.1,4-pregnadiene-3,20-dione.
12. A process in which 16.alpha.,17.alpha.-isopropylidene-dioxy-21-methyl-.DELTA.9(11)-5.alpha.-pregnene-3,20-dione is prepared by oxidising the corresponding 3.beta.-hydroxy-16.alpha.,17.alpha.-isopropylidenedioxy-21-methyl-.DELTA.9(11)-5.alpha.-pregnene-20-one.
13. A process according to claim 12 in which the product obtained is subjected to the additional steps of:
(a) 1,4-dehydrogenation to produce 16.alpha.,17.alpha.-isopropylidenedioxy-21-methyl-.DELTA.1,4,9(11)-pregnatriene-3,20-dione;
(b) reacting the product of (a) with hypobromous acid; and (c) debrominating the 9.alpha.-bromo-11.beta.-hydroxy-16.alpha.,17.alpha.-isopropylidene dioxy-21-methyl-.DELTA.1,4-pregnadiene-3,20-dione produced in step (b) to produce 11.beta.-hydroxy-16.alpha.,17.alpha.-isopropylidenedioxy-21-methyl-.DELTA.1,4-pregnadiene-3,20-dione.
(a) 1,4-dehydrogenation to produce 16.alpha.,17.alpha.-isopropylidenedioxy-21-methyl-.DELTA.1,4,9(11)-pregnatriene-3,20-dione;
(b) reacting the product of (a) with hypobromous acid; and (c) debrominating the 9.alpha.-bromo-11.beta.-hydroxy-16.alpha.,17.alpha.-isopropylidene dioxy-21-methyl-.DELTA.1,4-pregnadiene-3,20-dione produced in step (b) to produce 11.beta.-hydroxy-16.alpha.,17.alpha.-isopropylidenedioxy-21-methyl-.DELTA.1,4-pregnadiene-3,20-dione.
14. A process according to claim 13 in which the 9.alpha.-bromo-11.beta.-hydroxy-16.alpha.,17.alpha.-isopropylidenedioxy-21-methyl-.DELTA.1,4-pregnadiene-3,20-dione produced in step (b) is subjected to the additional steps:
(i) dehydrobromination to give 9.beta.,11.beta.-epoxy-16.alpha.,17.alpha.-isopropylidene-dioxy-21-methy-.DELTA.1,4-pregnadiene-3,20-dione, which is (ii) reacted with hydrogen fluoride to give 9.alpha.-fluoro-11.beta.-hydroxy-16.alpha.,17.alpha.-isopropylidenedioxy-21-methyl-.DELTA.1,4-pregnadiene-3,20-dione.
(i) dehydrobromination to give 9.beta.,11.beta.-epoxy-16.alpha.,17.alpha.-isopropylidene-dioxy-21-methy-.DELTA.1,4-pregnadiene-3,20-dione, which is (ii) reacted with hydrogen fluoride to give 9.alpha.-fluoro-11.beta.-hydroxy-16.alpha.,17.alpha.-isopropylidenedioxy-21-methyl-.DELTA.1,4-pregnadiene-3,20-dione.
15. A process in which [16.alpha.,17.alpha.-d]2'-methyl-oxazoline-21-methyl-.DELTA.9(11)-5.alpha.-pregnene-3,20-dione is prepared by ring-closing 16.alpha.-acetamido-17.alpha.-hydroxy-21-methyl-.DELTA.9(11)-5.alpha.-pregnene-3,20-dione.
16. A process according to claim 15 in which the product obtained is subjected to the additional steps of:
(a) bromination to produce the corresponding 2,4-dibromo-derivative;
(b) dehydrobromination of this 2,4-dibromo derivative to give [16.alpha., 17.alpha.-d]-2'-methyl-oxazoline-21-methyl-.DELTA.1,4,9(11)-pregnatriene-3,20-dione;
(c) reacting the pregnatriene resulting from step (b) with hypo-bromous acid; and (d) debrominating the 9.alpha.-bromo-11.beta.-hydroxy-[16.alpha.,17.alpha.-d]-2'-methyl-oxazoline-21-methyl-.DELTA.1,4-pregnadiene-3,20-dione produced in step (c) to pro-duce 11.beta.-hydroxy-[16.alpha.,17.alpha.-d]-2'-methyloxazoline-21-methyl-.DELTA.1,4-pregnadiene-3,20-dione.
(a) bromination to produce the corresponding 2,4-dibromo-derivative;
(b) dehydrobromination of this 2,4-dibromo derivative to give [16.alpha., 17.alpha.-d]-2'-methyl-oxazoline-21-methyl-.DELTA.1,4,9(11)-pregnatriene-3,20-dione;
(c) reacting the pregnatriene resulting from step (b) with hypo-bromous acid; and (d) debrominating the 9.alpha.-bromo-11.beta.-hydroxy-[16.alpha.,17.alpha.-d]-2'-methyl-oxazoline-21-methyl-.DELTA.1,4-pregnadiene-3,20-dione produced in step (c) to pro-duce 11.beta.-hydroxy-[16.alpha.,17.alpha.-d]-2'-methyloxazoline-21-methyl-.DELTA.1,4-pregnadiene-3,20-dione.
17. A process according to claim 16 in which the 9.alpha.-bromo-11.beta.-hydroxy-[16.alpha.,17.alpha.-d]-2'-methyloxazoline-21-methyl-.DELTA.1,4-pregnad.alpha.iene-3,20-dione produced in step (c) is subjected to the additional steps of:
(i) dehydrobromination to give 9.beta.,11.beta.-epoxy [17a,16.alpha.-d]-2'-methyl-oxazoline-21-methyl-.DELTA.1,4-pregnadiene-3,20-dione, which is (ii) reacted with hydrogen fluoride to give 9.alpha.-fluoro-11.beta.-hydroxy-[17.alpha.,16.alpha.-d]-2'-methyloxazoline-21-methyl-.DELTA.1,4-pregnadiene-3,20-dione.
(i) dehydrobromination to give 9.beta.,11.beta.-epoxy [17a,16.alpha.-d]-2'-methyl-oxazoline-21-methyl-.DELTA.1,4-pregnadiene-3,20-dione, which is (ii) reacted with hydrogen fluoride to give 9.alpha.-fluoro-11.beta.-hydroxy-[17.alpha.,16.alpha.-d]-2'-methyloxazoline-21-methyl-.DELTA.1,4-pregnadiene-3,20-dione.
18. A process according to claim 14 in which the product obtained is oxidised to give 9.alpha.-fluoro-16.alpha.,17.alpha.-isopropylidenedioxy-21-methyl-.DELTA.1,4-preg-nadiene-3,11,20 trione.
19. A proccss according to claim 13 in which the 16.alpha.,17.alpha.-isopropylidene-dioxy-21-methyl-.DELTA.1,4,9(11)-pregnatriene-3,20-dione produced in step (a) is re-acted with chlorine to produce 9.alpha.,11.beta.-dichloro-16.alpha.,17.alpha.-isopropylidenedioxy-21-methyl.DELTA.1,4-pregnadiene-3,20-dione.
20. A process in which 3.beta. -hydroxy-16.alpha.,17.alpha.-isopropylidenedioxy-21-methyl-.DELTA.5-pregnen-20-one is prepared by reacting 3.beta.,16.alpha.,17.alpha.-trihydroxy-21-methyl-.DELTA.9(11)-5.alpha.-pregnen-20-one 16-acetate with acetone in the presence of an acid.
21. A process according to claim 20 in which the product subjected to the additional steps of:
(a) oxidation by reaction with a mixture of peracetic acid and sodium acetate:
(b) reaction of the 3.beta. -acetoxy-5.alpha.,6.alpha.-epoxy-16.alpha.,17.alpha.-isopropylidene dioxy-21-methyl-5.alpha.-pregnan-20-one obtained in step 9a) with hydrogen fluoride;
(c) hydrolysis of the 3.beta. -acetoxy group of the 3.beta. -acetoxy-5.alpha.-hydroxy-6.beta.-fluoro-16.alpha.,17.alpha.-isopropylidenedioxy-21-methyl-5.alpha.-pregnan-20-one obtained in step (b);
(d) oxidation of the 3.beta. -hydroxy group of the 3.beta. -hydroxy-5.alpha.-hydroxy-6.beta.-fluoro-16.alpha.,17.alpha.-isopropylidenedioxy-21-methyl-5.alpha.-pregnan-20-one produced in step (c);
(e) dehydration and isomerisation of the product of step (d) to give 6.alpha.-fluoro-16.alpha.,17.alpha.-isopropylidenedioxy-21-methyl-.DELTA.4-pregnene-3,20-dione, which is (f) dehydrogenated to give 6.alpha.-fluoro-16.alpha.,17.alpha.-isopropylidenedioxy-21-methyl-.DELTA.1,4-pregnadiene-3,20-dione.
(a) oxidation by reaction with a mixture of peracetic acid and sodium acetate:
(b) reaction of the 3.beta. -acetoxy-5.alpha.,6.alpha.-epoxy-16.alpha.,17.alpha.-isopropylidene dioxy-21-methyl-5.alpha.-pregnan-20-one obtained in step 9a) with hydrogen fluoride;
(c) hydrolysis of the 3.beta. -acetoxy group of the 3.beta. -acetoxy-5.alpha.-hydroxy-6.beta.-fluoro-16.alpha.,17.alpha.-isopropylidenedioxy-21-methyl-5.alpha.-pregnan-20-one obtained in step (b);
(d) oxidation of the 3.beta. -hydroxy group of the 3.beta. -hydroxy-5.alpha.-hydroxy-6.beta.-fluoro-16.alpha.,17.alpha.-isopropylidenedioxy-21-methyl-5.alpha.-pregnan-20-one produced in step (c);
(e) dehydration and isomerisation of the product of step (d) to give 6.alpha.-fluoro-16.alpha.,17.alpha.-isopropylidenedioxy-21-methyl-.DELTA.4-pregnene-3,20-dione, which is (f) dehydrogenated to give 6.alpha.-fluoro-16.alpha.,17.alpha.-isopropylidenedioxy-21-methyl-.DELTA.1,4-pregnadiene-3,20-dione.
22. A process according to claim 17 in which the product obtained is oxidised to give 9.alpha.-fluoro-[16.alpha.,17.alpha.-d]-2'-methyloxazoline-21-methyl-.DELTA.1,4-pregnadiene-3,11,20-trione.
23. A process in which 3.beta.,11.beta.,17.alpha.-trihydroxy-16,16-methylene-21-methyl-5.alpha.-pregnan-20-one 11.beta.-acetate is prepared by reacting 3.beta.,11.beta.-dihydroxy-16.beta.,21-dimethyl-16.alpha.,17.alpha.-epoxy-5.alpha.-pregnan-20-one 11.beta.-acetate with acid.
24. A process according to claim 23 in which the product obtained is subjected to the additional steps of:
(a) oxidation to produce 11.beta.,17.alpha.-dihydro-16,16-methylene-21-methyl-5.alpha.-pregnan-3,20-dione 11.beta.-acetate; which is (b) dehydrogenated to give 11.beta.,17.alpha.-dihydroxy-16,16-methylene-21-methyl-.DELTA.1,4-pregnadiene-3,20-dione 11.beta.-acetate; which is (c) hydrolysed to give 11.beta.,17 -dihydroxy-16,16-methylene-21-methyl-.DELTA.1,4-pregnadiene-3,20-dione.
(a) oxidation to produce 11.beta.,17.alpha.-dihydro-16,16-methylene-21-methyl-5.alpha.-pregnan-3,20-dione 11.beta.-acetate; which is (b) dehydrogenated to give 11.beta.,17.alpha.-dihydroxy-16,16-methylene-21-methyl-.DELTA.1,4-pregnadiene-3,20-dione 11.beta.-acetate; which is (c) hydrolysed to give 11.beta.,17 -dihydroxy-16,16-methylene-21-methyl-.DELTA.1,4-pregnadiene-3,20-dione.
25. A process in which 3.beta.,11.beta.-dihydroxy-[l7.alpha.,16.alpha.-d]-2'-methyloxazoline 21-methyl-5.alpha.-pregnan-20-one 3,11-diacetate is prepared by reducing 3.beta.,11.beta., 16.alpha.-trihytroxy-17-azido-21-methyl-5.alpha.-pregnan-20-one 3,11,16-triacetate and ring-closing the corresponding 17.alpha.-amino compound so obtained.
26. A process according to claim 25 in which the product obtained is subjected to the additional steps of:
(a) oxidation to produce 11.beta.-hydroxy-[17.alpha.,16.alpha.-d]-2'-methyloxazoline-21-methyl-5.alpha.-pregnane-3,20-dione 11-acetate, (b) bromination to produce the corresponding 2,4-dibromo derivative;
(c) dehydromination of this 2,4-dibromo derivative to give 11.beta.-hydroxy-[17.alpha.,16.alpha.-d]-2'-methyloxazoline-21-methyl-.DELTA.1,4-pregnadiene-3,20-dione 11-acetate; which is (d) hydrolysed to give 11.beta.-hydroxy-[17.alpha.,16.alpha.-d]-2'-methyloxazoline 21-methyl .DELTA.1,4-pregnadiene-3,20-dione.
(a) oxidation to produce 11.beta.-hydroxy-[17.alpha.,16.alpha.-d]-2'-methyloxazoline-21-methyl-5.alpha.-pregnane-3,20-dione 11-acetate, (b) bromination to produce the corresponding 2,4-dibromo derivative;
(c) dehydromination of this 2,4-dibromo derivative to give 11.beta.-hydroxy-[17.alpha.,16.alpha.-d]-2'-methyloxazoline-21-methyl-.DELTA.1,4-pregnadiene-3,20-dione 11-acetate; which is (d) hydrolysed to give 11.beta.-hydroxy-[17.alpha.,16.alpha.-d]-2'-methyloxazoline 21-methyl .DELTA.1,4-pregnadiene-3,20-dione.
27. A process according to claim 26 in which the 11 -hydroxy-[17.alpha.,16.alpha.-d]-2'-methyloxazoline-21-methyl-.DELTA.1,4-pregnadiene-3,20-dione is subjected to tho additional steps of:
(a) dehydration to give [17.alpha.,16.alpha.-d]-2'-methyloxazoline-methyl-.DELTA.1,4,9(11)-pregnatriene-3,20-dione; which is (b) reacted with hypobromous acid to give 9.alpha.-bromo-11.beta.-hydroxy-[17.alpha.,16.alpha.-d]-2'-methyloxazoline-21-methyl-.DELTA.1,4-pregnadiene-3,20-dione;
(c) which is dehydrobrominated to give 9.beta.,11.beta.-epoxy-[17.alpha.,16.alpha.-d]-2'-methyloxazoline-21-methyl-.DELTA.1,4-pregnadiene-3,20-dione, which is (d) reacted with hydrogen fluoride to give 9.alpha.-fluoro-11.beta.-hydroxy-[17.alpha.,16.alpha.-d]-2'-methyloxazoline-21-methyl-.DELTA.1,4-pregnadiene-3,20-dione.
(a) dehydration to give [17.alpha.,16.alpha.-d]-2'-methyloxazoline-methyl-.DELTA.1,4,9(11)-pregnatriene-3,20-dione; which is (b) reacted with hypobromous acid to give 9.alpha.-bromo-11.beta.-hydroxy-[17.alpha.,16.alpha.-d]-2'-methyloxazoline-21-methyl-.DELTA.1,4-pregnadiene-3,20-dione;
(c) which is dehydrobrominated to give 9.beta.,11.beta.-epoxy-[17.alpha.,16.alpha.-d]-2'-methyloxazoline-21-methyl-.DELTA.1,4-pregnadiene-3,20-dione, which is (d) reacted with hydrogen fluoride to give 9.alpha.-fluoro-11.beta.-hydroxy-[17.alpha.,16.alpha.-d]-2'-methyloxazoline-21-methyl-.DELTA.1,4-pregnadiene-3,20-dione.
28. A process in which 3.beta.,11.beta.-dehydroxy-16.alpha.,17.alpha.-ethylene-21-methyl-5.alpha.-pregnan-20-one 3,11-diacetate is prepared by reacting 3.beta.,11.beta.-dihydroxy-21-methyl-.DELTA.16-5.alpha.-pregnan-20-one 3,11-diacetate with ethylene.
29. A process according to claim 28 in which the product obtained is subjected to the additional steps of:
(a) hydrolysis to give 3.beta.,11.beta.-dihydroxy-16.alpha.,17.alpha.-ethylene-21-methyl-5.alpha.-pregnan-20-one 11-acetate; which is (b) oxidised to give 11.beta.-hydroxy-16.alpha.,17.alpha.-ethylene-21-methyl-5.alpha.-pregnane-3,20-dione 11-acetate; which is (c) brominated to give the corresponding 2,4-dibromo derivative;
which is (d) dehydrobrominated to give 11.beta.-hydroxy-16.alpha.,17.alpha.-ethylene-21-methyl-.DELTA.1,4-pregnadiene-3,20-dione 11-acetate; which is (e) hydrolysed to give 11.beta.-hydroxy-16.alpha.,17.alpha.-ethylene-21-methyl-.DELTA.1,4-pregnadiene-3,20-dione.
(a) hydrolysis to give 3.beta.,11.beta.-dihydroxy-16.alpha.,17.alpha.-ethylene-21-methyl-5.alpha.-pregnan-20-one 11-acetate; which is (b) oxidised to give 11.beta.-hydroxy-16.alpha.,17.alpha.-ethylene-21-methyl-5.alpha.-pregnane-3,20-dione 11-acetate; which is (c) brominated to give the corresponding 2,4-dibromo derivative;
which is (d) dehydrobrominated to give 11.beta.-hydroxy-16.alpha.,17.alpha.-ethylene-21-methyl-.DELTA.1,4-pregnadiene-3,20-dione 11-acetate; which is (e) hydrolysed to give 11.beta.-hydroxy-16.alpha.,17.alpha.-ethylene-21-methyl-.DELTA.1,4-pregnadiene-3,20-dione.
30. A process according to clalm 29 in which the product obtained is subjected to the additional steps of:
(i) dehydration to give 16.alpha.,17.alpha.-ethylene-21-methyl-.DELTA.1,4,9(11) pregnatriene-3,20-dione; which is (ii) reacted with hypobromous acid to give 9.alpha.-bromo-11.beta.-hydroxy-16.alpha.,17.alpha.-ethylene-21-methyl-.DELTA.1,4-pregnadiene-3,20-dione; which is (iii) dehydrobrominated to give 9.beta.,11.beta.-epoxy-16.alpha.,17.alpha.-ethylene-21-methyl-.DELTA.1,4-pregnadiene-3,20-dione; which is (iv) reacted with hydrogen fluoride to give 9.alpha.-fluoro-11.beta.,hydroxy-16.alpha.,17.alpha.-ethylene-21-methyl-.DELTA.1,4-pregnadiene-3,20-dione.
(i) dehydration to give 16.alpha.,17.alpha.-ethylene-21-methyl-.DELTA.1,4,9(11) pregnatriene-3,20-dione; which is (ii) reacted with hypobromous acid to give 9.alpha.-bromo-11.beta.-hydroxy-16.alpha.,17.alpha.-ethylene-21-methyl-.DELTA.1,4-pregnadiene-3,20-dione; which is (iii) dehydrobrominated to give 9.beta.,11.beta.-epoxy-16.alpha.,17.alpha.-ethylene-21-methyl-.DELTA.1,4-pregnadiene-3,20-dione; which is (iv) reacted with hydrogen fluoride to give 9.alpha.-fluoro-11.beta.,hydroxy-16.alpha.,17.alpha.-ethylene-21-methyl-.DELTA.1,4-pregnadiene-3,20-dione.
31. 11.beta.-Hydroxy-16.alpha.,17.beta.-methylene-21-methyl-.DELTA.1,4-pregnadiene-3,20-dione whenever prepared by the process of claim 10 or by an obvious chemical equivalent thereof.
32. 9.alpha.-Fluoro-11.beta.-hydroxy-16.alpha.,17.alpha.-methylene-21-methyl-.DELTA.1,4-pregnadiene-3,20-dione, whenever prepared by the process of claim 11 or by an obvious chemical equivalent thereof.
33. 11.beta.-Hydroxy-16.alpha.,17.alpha.-isopropylidenedioxy-21-methyl-.DELTA.1,4-pregnadiene-3,20-dione, whenever prepared by the process of claim 13 or by an obvious chemical equivalent thereof.
34. 9.alpha.-Fluoro-11.beta.-hydroxy-16.alpha.,17.alpha.-isopropylidenedioxy-21-methyl-.DELTA.1,4-pregnadiene-3,20-dione, whenever prepared by the process of claim 14 or by an obvious chemical equivalent thereof.
35. 11.beta.-Hydroxy-[16.alpha.,17.alpha.-d]-2'-methyloxazoline-21-methyl-.DELTA.1,4-preg-nadiene-3,20-dione, whenever prepared by the process of claim 16 or by an obvious chemical equivalent thereof.
36. 9.alpha.-Fluoro-11.beta.-hydroxy-[17.alpha.,16.alpha.-d]-2'-methyloxazoline-21-methyl-.DELTA.1,4-pregnadiene-3,20-dione, whenever prepared by the process of claim 17 or by an obvious chemical equivalent thereof.
37. 9.alpha.-Fluoro-16.alpha.,17.alpha.-isopropylidenedioxy-21-methyl-.DELTA.1,4-pregnadiene-3,11,20-trione, whenever prepared by the process of claim 18 or by an obvious chemical equivalent thereof.
38. 9.alpha.,11.beta.-dichloro-16.alpha.,17.alpha.-isopropylidenedioxy-21-methyl-.DELTA.1,4-preg-nadiene-3,20-dione, whenever prepared by the process of claim 19 or by an obvious chemical equivalent thereof.
39. 6.alpha.-Fluoro-16.alpha.,17.alpha.-isopropylidenedioxy-21-methyl-.DELTA.1,4-pregnadiene-3,20-dione, whenever prepared by the process of claim 21 or by an obvious chemical equivalent thereof.
40. 9.alpha.-Fluoro-[16.alpha.,17.alpha.-d]-2'-methyloxazoline-21-methyl-.DELTA.1,4-pregnadiene-3,11,20-trione, whenever prepared by the process of claim 22 or by an obvious chemical equivalent thereof.
41. 11.beta.,17.alpha.-Dihydroxy-16,16-methylene-21-methyl-.DELTA.1,4-pregadiene-3,20-dione, whenever prepared by the process of claim 24 or by an obvious chemical equivalent thereof.
42. 11.beta.-Hydroxy-[17.alpha.,16.alpha.-d]-2'-methyloxazoline-21-methyl-.DELTA.1,4-pregna-diene-3,20-dione, whenever prepared by the process of claim 26 or by an ob-vious chemical equivalent thereof.
43. 9.alpha.-Fluoro-11.beta.-hydroxy-[17.alpha.,16.alpha.-d]-2'-methyloxazoline-21-methyl-.DELTA.1,4-pregnadiene-3,20-dione, whenever prepared by the process of claim 27 or by an obvious chemical equivalent thereof.
44. 11.beta.-Hydroxy-16.alpha.,17.alpha.-ethylene-21-methyl-.DELTA.1,4-pregnadiene-3,20-dione, whenever prepared by the process of claim 29 or by an obvious chemical equi-valent thereof.
45. 9.alpha.-Fluoro-11.beta.-hydroxy-16.alpha.,17.alpha.-ethylene-21-methyl-.DELTA.1,4-pregnadiene-3,20-dione, whenever prepared by the process of claim 30 or by an obvious chemical equivalent thereof.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB33149/73A GB1478968A (en) | 1973-07-11 | 1973-07-11 | Alkylated pregnanes |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1050529A true CA1050529A (en) | 1979-03-13 |
Family
ID=10349189
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA204,503A Expired CA1050529A (en) | 1973-07-11 | 1974-07-10 | Alkylated pregnanes and process for obtaining same |
Country Status (14)
| Country | Link |
|---|---|
| JP (1) | JPS5047968A (en) |
| BE (1) | BE817543A (en) |
| CA (1) | CA1050529A (en) |
| DE (1) | DE2433178A1 (en) |
| DK (1) | DK134700B (en) |
| ES (1) | ES428132A1 (en) |
| FI (1) | FI52100C (en) |
| FR (1) | FR2236508B1 (en) |
| GB (1) | GB1478968A (en) |
| HU (1) | HU171711B (en) |
| IE (1) | IE39593B1 (en) |
| NL (1) | NL7409298A (en) |
| SE (1) | SE402920B (en) |
| ZA (1) | ZA744381B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3064460D1 (en) * | 1979-01-24 | 1983-09-08 | Akzo Nv | Novel alkylated pregnanes, processes for their preparation and pharmaceutical compositions containing same |
| IT1134455B (en) * | 1980-11-26 | 1986-08-13 | Lepetit Spa | PROCEDURE FOR THE PREPARATION OF 16ALPHA-HYDROXY-17ALPHA-AMINOPREGNANIC DERIVATIVES |
| WO1991014700A2 (en) * | 1990-03-27 | 1991-10-03 | Schering Corporation | PROCESS FOR 9α-HYDROXY STEROID DEHYDRATION |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3064017A (en) * | 1962-11-13 | Preparation viii | ||
| GB1416427A (en) * | 1972-01-12 | 1975-12-03 | Akzo Nv | Alkylated pregnanes and process for obtaining same |
-
1973
- 1973-07-11 GB GB33149/73A patent/GB1478968A/en not_active Expired
-
1974
- 1974-07-05 IE IE1428/74A patent/IE39593B1/en unknown
- 1974-07-08 ZA ZA00744381A patent/ZA744381B/en unknown
- 1974-07-09 FI FI742103A patent/FI52100C/en active
- 1974-07-10 ES ES428132A patent/ES428132A1/en not_active Expired
- 1974-07-10 DE DE2433178A patent/DE2433178A1/en active Pending
- 1974-07-10 JP JP49079023A patent/JPS5047968A/ja active Pending
- 1974-07-10 CA CA204,503A patent/CA1050529A/en not_active Expired
- 1974-07-10 NL NL7409298A patent/NL7409298A/en not_active Application Discontinuation
- 1974-07-10 DK DK371174AA patent/DK134700B/en unknown
- 1974-07-10 SE SE7409046A patent/SE402920B/en unknown
- 1974-07-11 HU HU74AO00000386A patent/HU171711B/en unknown
- 1974-07-11 BE BE146467A patent/BE817543A/en unknown
- 1974-07-11 FR FR7424189A patent/FR2236508B1/fr not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| AU7104074A (en) | 1976-01-15 |
| DK371174A (en) | 1975-03-17 |
| FI52100B (en) | 1977-02-28 |
| FR2236508B1 (en) | 1978-07-28 |
| NL7409298A (en) | 1975-01-14 |
| FI52100C (en) | 1977-06-10 |
| IE39593B1 (en) | 1978-11-22 |
| SE7409046L (en) | 1975-01-13 |
| FR2236508A1 (en) | 1975-02-07 |
| IE39593L (en) | 1975-01-11 |
| HU171711B (en) | 1978-03-28 |
| SE402920B (en) | 1978-07-24 |
| DE2433178A1 (en) | 1975-01-30 |
| FI210374A (en) | 1975-01-12 |
| JPS5047968A (en) | 1975-04-28 |
| DK134700B (en) | 1976-12-27 |
| DK134700C (en) | 1977-07-11 |
| ES428132A1 (en) | 1976-07-16 |
| ZA744381B (en) | 1975-07-30 |
| BE817543A (en) | 1975-01-13 |
| GB1478968A (en) | 1977-07-06 |
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