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Патент USA US3100782

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United States Patent 6 "ice
Patented Aug. 13, 1963
9 Claims. (Cl. 260—-397.3)
This invention relates to certain novel steroids, more
Hadiene-B‘JO-dione, 6-methy1~9a-?uoro-4,6-pregnadiene-3,
‘11,20-trione, 6,16a-dimethy1- 9o: 4 ?uoro-11?-l1ydroxy-4,6
pregnadiene-3,20-dione, 6,1606 - dimethyl - 9a - ?uoro-4,6
lpregnadiene-ll1,20-trione, the l-dehydro derivatives of
the foregoing and processes for the production of all of
‘these compounds.
The novel compounds of this invention can‘he nreptared
‘in'accordance' ‘with the following ?ow sheets, the various
steps‘ of which‘ are‘ illustrated in the preparations and
. examples, below.
No Drawing. Filed May 31, 1962, Ser. No. 198,748
particularly to 6~methy1-9a-?uoro-11B-hydroxy-4,6-preg-
George B. Spero, Kalamazoo, Mich., hssignor to The
Upjohn Company, Kalamazoo, Mich, a corporation of
‘ ‘
wherein R is selected from the group consisting of hydro
gen and methyl.
ventional ‘manner, vfor example with N-halo-acylamide
and sulfur dioxide, or alternatively for example an acid
The novel compounds of the present invention of For;
‘ such as sulfuric acid in aceticacid, to obtain 6a-methyl
'4,9(l1)-pregnadiene-3,20édione (II); adding to a ‘solu- ~
mulae IX, X, XI and XII can be represented by the fol
lowing formula '
methyl - 9a.- halo - 11B - hydroxy-4-pregnene-3,ZO-drone .
(HI); treating compound ‘IIIwith a mild base to obtain
10 60c -methy1-9/3,l1/3-oxido - 4 - pregnene-3,20‘-,dione (IV);
treating this oxido compound .(IV) with a source of hy
tion of the ‘thus-obtained 4,91( 1‘1)-pregnadiene <(II), dis
solved in an organic solvent, a N-haloacylamide in the
' presence of an acid to obtain the corresponding_6a.
droxy-4-pregnene-3,20-dione (V).
Oxidizing 6m-methyl-9m-?uoro - 11B - hydroxy-4-preg
' '15
nene-3,20-dione (V) with achromic acid; oxidant, or
hypohalous acid preferably produced .in’ situ, results in
6a - methyl - 9m - ?uoro-4-pregnene-3,l1,20-trione (VI).
Submitting, 6a-methyl-9oc-?uoro-lIB-hydroxy - 4-preguen
I wherein X is selected from the grouplconsisting of they
V1S—hydroxymethylene radical
3-one (.V) or 6a-methyl-9zx~?uoro-4-pregnem3,l1,20;
trione (VI) to, dehydrogenation by a microorganism such
as SeptomyXa, 'Calonectria, Alternaria, Colletotrichum,
Cylindrocarpon, Ophiobolus, Listeria, Corynebacterium,
Erysipelothrix, species of the family Tuberculariaceae,
Nocardia, ,Cucurbita'ria, Leptosphaeriae, Tricothecium,
andlthe carbonyl radical (>C:=:Q), R is selected from
25 Mycobacterium, Fusarium,‘Didymella and the like, or de
hydrogenation with selenium dioxide’ results in the pro
duction, of ‘6u-methyl-9u-?uoro-1l?-hydroxy-l,4-pregna
diene_-3,20-dione (VII) and 60a -methyl-9a-?uoro-1,4
the'g'roup consistingpofrhydrogen and "methyl and the
linkage between carbon atoms 1 and 2 is selected ‘from
, those consisting of single and double bonds. The com~
pounds embraced by the above composite formula possess 30
" highanti-in?ammatory activity. The novel compounds
pregnadiene-‘3,1l,20-trione (VIII), respectively. ‘~ , -
The compounds of ‘Formulae V, VI, VII and VIII _
' are converted to the corresponding Y6-dehydro derivatives
are'useful as topical or systemic anti-inflammatory agents
of Formulae IX, X, XI and XII in accordance with
procedures well known in the steroid art. vThe com—
pounds‘ represented by Formulae V and VI when reacted
‘with chlora'nil, in the manner disclosed in J. Amer.‘
Chem. Soc. 79, . 1257 (1957), yield the corresponding
'6-methyl-6ldehydroprogesterones of Formulae IX and X,
respectively,:e.g., .6~,m‘ethy1-9a-j?u0roj — 11?-1-»hydroxy-4,6‘
~ for‘the treatment of inflammation of the skin,‘ eye‘ and
V ears landv'systemic'ally for arthritis. The compounds are
inoreover useful in vthe estrus synchronization of valuable
domesticwanimals. . In the practice‘ of veterinary medi->
. time, the novel compounds provide bene?cial'and advan
tageous-‘results in the hormonal'control of the reproduc-' ,
tive'cyclein .a‘nimals- ‘by synchronization of the .est'rual '
Ipregnadiene-3,20,-dione (IX) andits-yll-keto, counterpart
period in a vvgroup "of swine, cattle, horses, sheep,'dog‘s or
(X); The compounds of'Formula ,X can also be :pre-v
cats?“ For example,‘ in the raising ‘of ‘cattle 'on a largev
by the oxidation, e.g.,‘ with chromic‘acid, of the
‘scale, Ttlie'fcompounds ‘can be advantageously employed ' j pared
corresponding llp-hydroxy steroids .(IX). The A455
i . jtocontrol the timeof ovulatioinnof entire ‘groups of cows
compounds'ernbra'ced by Formulae \‘IX andX can be
j ;for arti?cial insemination at‘one time, instead-'rof ran
‘ jdomly; Cewslin ya'r'ious‘ stages of the ZI-dayestr'us- cycle '
1 : l-dehydrogenated, e.g., with selenium dioxide, to give
thatregularly follows ovulation will all be- prevented from 5
the "correspondingAbbe-compounds (XI and XII), e.g.,
6 .- methyl£9a - ?uoro - 1LB-hydroxy-1,4,6-pregnatriene
byulatin'g during administration of th'e‘iiew compounds, 1 . medians (XI') audits ll-keto analogue (XII) ; pref- '
and all will "then begin a new cycle together and ovulate
erably, they can be prepared by the, 6-dehydrogenation of
‘after treatment at the same time, regardless of their phase - the corresponding Ale-compounds '(VI‘I andVIII) by re
of estrus when the compounds were administered to‘ them. 0 action with ohlora'nil. (The, compounds, of- Formula XII
Since the bitch comes into heat (estrus) at about six
can also be Eprepared Zfrom' the corresponding ll?-hy
monthintervals, ‘the novel compounds need be employed. , droxy compounds, e.g., by oxidation with chromic acid.
only prior to these anticipated; times rto‘cause inhibition
The ARM-compounds (Xland XII’) can also be prepared
,of, estrus. The new compoundsi are also'useful in pre
directly from 'the corresponding n‘i-compounds of For!
yenting estrua-l ‘activity in fattening meat animals, e.g., 55' mulae V and VI by reaction with chloranil at elevated
‘ifezed‘lot heifers. "In birds the compounds can be'utiliz‘ed
‘temperatures in accordance with the method set forth in
'10 interrupt broodiness in laying hens, toqcont'rol ‘the ,J. Amer. Chem. Soc. 82,4293 (1960).
I nioulting period and: the'egg laying period of a/?ock, and
The process of this invention, disclosed above for the
‘to increase the number of eggs.
preparation of the compounds of Formulae IX, X, XI and
compounds of the present invention can be pre- 60 XIII, wherein R is hydrogen, from the starting material
vpared andadministered to. mammals, birds, humans and
of Formula I, wherein R is hydrogen, can readly be
animals ina wide variety of oral and parenteral dosage
utilized for the preparation of the corresponding com
forms, simply or in admixture with other. co-‘acting' com
R is methyl. This canreadily ‘be ac
pounds. They also can be used in the form of ointments,
complished "by substituting 6 a,l6u.-dimethyl-l IB-hydroxy
lotions, creams, jellies and drops suitable for the treat- 65 progesterone (It) as starting material for the correspond
' The
ment of in?amed skin areas, eyes,‘ea‘rs, or nose irritations.
Thesoli'd compositions can take the form of tablets,
powders, capsules or the like, preferably in unit dosage
forms for simple "administration of precise
/ dosages. Liq
, ing ‘IGu-desmethyl' compound (I), to yield the ,_com-.
pounds of Formulae IX, X, XI and XII wherein R is
methyl, namely 6,16oc-dl1l‘l6thYl-9oz-?ll01‘0 - 11,8 - hydroxy
' ‘4,6-Vpregnadiene - 3,20 - dione’ (IX), 6,16oc-dilfn6thYl-9u
fuid compositions can be prepared of these compounds 0' ?uoro~4,6-pregnadiene-3,11,20-trione
' taking the form of solution, (emulsions, suspensions or ,
e'lixirs and'injectibljes, particularly intra-articular injec
(X), 6,16ot-dimeth
yl-9u.-fluoro-1lp-hydroxy-1,4,6-pregnatriene - 3,20 - dione
(XI) and 6,16a-dimethyl - 9o: -?uoro-1,4,6-pregnatriene
3,11,20-trione (XII).
The processrof the'pre'sent' inventioncomprises: de
The starting material, of Formula I of the ?ow-sheet
:hydrating 6a-methyl-l l?-hydroxyprogesterone (I) in con 75 wherein
R is hydrogen, is 6oc-methy1-1lp-hydroxypro
gesterone (I); it is prepared in the manner disclosed in
of Formula a is readily carried out by the method dis
closed in ‘US. Patent 2,602,769 and yields the com
Example 16 of US. Patent 2,968,655.
The starting material of Formula I of the ?ow-sheet,
pound of Formula b, namely, éogl?a-dimethYl-llm-IIY
wherein R is methyl, is prepared from the known com
droxyprogesterone. An effective method of converting
pound 6a,l6a-dimethylprogesterone (a) (J. Org. Chem.
the llor-hydroxy compound of Formula b to the corre
26, 2047 [1961] ), in accordance with the following ?ow
sheet, the various steps of which are illustrated in the
sponding ll/s-hydroxy epimer (I) is readily available by
preparations below.
655 for an analogous synthesis. In a similar manner,
wherein n is an integer selected from the group consist
ing of one and two and R’ is selected from the group
adapting the procedure disclosed in US. Patent 2,968,
6a,16a-dimethyl-11a ‘-hydroxyprogesterone (b) is con
verted to the corresponding ll-keto compound (c) by
oxidation, e.g., with chromic acid, chromic anhydride or
N-bromoacetamide in pyridine, in ‘accordance with the
The compound represented by Formula a can be 115 65 usual procedures well known in the steroid art. The
‘consisting of hydrogen and a lower-alkyl radical con
‘ taining from one to six carbon atoms, inclusive.
or llarhydroxylated with one of the many species of ‘
thus produced 6a,16a.-dimethyl-1l-ketoprogesterone (c)
is diketalized, e.g., with ethylene glycol and p-toluene
sulfonic acid to give 6,l6a-dimethyl-ll-ketoprogesterone
3,20-bis(ethylene ketal) (d); the compound of Formula’
hamella blakesleeana.
70 d is reduced to its corresponding ll?-hydroxy analogue
(e), e.'g., with lithium aluminum hydride, to yield 6,160:
ll?-hydroxylation of 611,16oz-dimethylprogesterone (a)
dimethyl - 11B - hydroxyprogesterone 3,20-his (ethylene
by fermentation, e.g., with Cunninghamella blakesleeana
ketal) (e). The compound of Formula e is hydrolyzed,
(ATCC 8688b), is directly productive of 6u,l6a-dimeth
fungi known to oxygenate in that position, e.g., one of
the order of Mucorales, Aspergillis, Penicillium, such
as, Rhizopus nigrz'cans, Curvularea lunata or Cunning
with a mineral acid such as sulfuric to give ‘6a,l6a-di
The fermentative lla-hydroxylation of the compound 75 methyl-1lp-hydroxyprogesterone (I),
The following preparations and examples are illustrative
in a minimum of methylene chloride and chromatographed
over Florisil. The product, eluted with increasing pro
portions of acetone in vSkellysolve \B (hexanes), is re
of the products and processes of‘the present invention.
crystallized from methanol to yield light colored, crystal
line 6a,16a-dimethyl-l 1 a-hydroxy-4-pregnene-3 ,~2O~d1one
604,16 a-Dim ethy l-l 1p-Hydroxys4-Pregnene-i205Di0ne
(60¢,1-6a-Dimethyl-Jl?rHydroxyprogesterone) (I)
‘ A seed culture of Cunn'ihghame‘lla bla'k'esleeana (ATCC
‘ 8688b), obtained from spores grown on a 2% agar, 5%
malt extract solids at a pH of -6.0 is prepared by growth
in a medium containing, per liter of tap water, 10 g. of 10
dextrose (Cerelose) and 20 g. of liquid corn steep liquor
6a,]6a-Dimethyl-4-Pregnene-3,11,20-Trione (6a,16rx-Di
methyl-IZ-Ketoprogesterone (c)
A solution is prepared containing 3.5g. of 6a,l6a
(containing about 12 g. solids) adjusted to a pH of about
dimethyl-lla-hydroxyprogesterone (b) in 50 ml. of acetic
j 6a,16a-dimethyl-4-pregnene-3,20édione (a), in 30 ml.’ of
‘alcohol is added to each ?ask and fermentation continued
after \for another period of 1.5 hours. The reaction mix
turev is then diluted with 1 l. of water and extracted’ with
acid at room temperature. Thereto is added drop-Wise av ,
5 with 25% aqueous‘sodium hydroxide.
solution of 2 g. of chromium trioxide in 50 ml. ofpacetic
Five one-liter portions of the above medium are inocu:
_ lated With the seed culture and growth with aeration and 15 acid and 0.5 ml. of water.‘ During the (addition, the tem
perature is maintained between 20 to 23° C. and there
shaking was continued for 48 hours.‘ Then ‘0.2. g. of
for another 48 hours, at which time the pH is 5.9. '
The mycelium is ?ltered from the beer and the beer '
extracted four times with one-fourth by volume amounts ,
of methylene chloride containing 25% ethyl acetate. The
extracts are evaporated to dryness. The residue thus ob
six 150 ml. portions ‘of methylene chloride.’ The ex
tracts are combined, washed with dilute sodium bicar
bonate solution and water, dried over anhydrous sodium
sulfate andrevaporated to dryness under reduced pressure.
The thus obtained sol-id is recrystallized from ethanol to
yield light colored, crystalline, "6a,16a-dimethyl-4-preg
, tained is redissolved inrl50 ml. of methylene chloride and
chromatographedon a column of Florisil (synthetic mag 25 nene13,ll,'20-trione (c).
nesium silicate). The column is developed with hexanes
containing increasing proportions ofacetone to elute a
6,]6u-Dimethyl . 5 - Pregnene - 3,11,20
mixture containing: the desired’ '1 lB-hydroxyproduct.
- Trione 3,20-Bu ‘
The crude iproduct is crystallized from a mixture of
hexanes and acetone and recrystillized from the same sol 30
' . (Ethylene 'Kez‘al) [646a -“Dimethyl ¢ 11 - Ketoprogc's
vent pair to yield light colored, crystalline 6d,].6Dt-dl
A mixture of 300 mg. of 6,l6a-dimethyl-4-pregnene7
3,l1,20-trione.(c), 5 ml. ofethylene glycol, 50 mg. of
methyl-1l?-hydroxy-4jpregnene-3,20-dione (l) .
terone~3,20-Bis‘(Ethylene Ketal )] (d)
paratoluenesulfonicr acid monohydrate and 100‘ ml. of
, 6a,]6d-Dir71ethyl-1Jtx-Hydroxy-4-Pregnene-3;20-Dione
benzene is placed in a reaction ‘flask equipped with a re~
?ux condenser and a Water trap so arranged that’ the con
' ( 6 0a,] 6 q—Dimrethy [-1 1 a-Hydroxyprogresterone) (b)
densed vapors pass through the water trap before return
‘A medium is prepared containing 10 g. of Cerelose" »ing to the reaction ?ask. ' The mixtureis heated tore?ux
I and allowed to re?ux forvabout 5 hours While'at the same
dextrose technical grade and 20 g. of corn steep liquor
time being agitated. The Water of reaction formed is "
(60% solids) in su?icient tap Water to make up-one liter
continuously'removed by codistillation with the re?uxing ‘
of solution. vOne hundred liters of'such a vmedium is‘ ' benzene
and is collected in the Water trap. The benzene
adjusted by the addition of ‘25% sodium hydroxide solu- .
solution is then washed with successive portions‘ of ‘a _,
‘tion‘ to a pH of 5. Thereto is then added 400 ml. of '
dilute sodium bicarbonate solution and water, and then '
. lard oil and lard-oil octadecanol as an anti-foaming ‘agent,
dried. The residue ‘remaining after evaporationof the ‘Y
This medium is sterilized for 45 minutes at 20 lbs. pres
sure and inoculated‘with .Rhizopus nigricans minus strain, 45 solvent is crude 6,16a-dirnethylr5-pregnene-3,11,20-trione
ketal) (d) which is recrystallized from
American Type Culture Collection No. 622712, andincu- ‘ i3,20i-bis-(_ethylene
ethyl acetate to give‘the pure, light ‘colored, crystalline
' 'bate'd‘ifor ‘24 .hours at a temperature of 28° C. vusing a
rateof aeration and stirring such that the oxygen uptake
is 6.3‘to 7 millimoles per hour per m1. of sodium sul?te
according to the method of Cooper, Eernstrorn and Miller,
6,1504 - Dimethyl - 11/3 - Hydroxy - 5 - Pregizeize - 3,20
Dione 3,20-Bz's(Ethylene lKetal) ,[6,I6a-Dimethyl-11;3
Hydroxyprogesterone 3,20-Bis (Ethylene Ketpal)] (6)
Ind. Eng. Chem. 36, 504 (1944). To this medium con
taining a 24-hour growth of Rhizopu‘s nigricans minus
strain is added 6. g. of 6a,l6a-dimethyl-4-pregnene-3,2‘0
~ To a solution'of 10 g. of lithium aluminum hydride
dione (a) in 150 ml. of acetone to provide a suspension
‘suspended in 800
of ether is. added ‘10 g. of 6,16ot-di
of the steroid in the culture. After an additional 24 55’ methyl-5-pregnene-3,l1,20-trione 3,20-bis (ethylene ketal)
> hour period of incubation ‘under the same conditions of
(d) dissolved in 560 ml. of ether. This mixture is stirred
temperature‘ and aeration, the beer'and mycelium .are ex- ‘
‘for about‘4'5 minutes at room'temperature after which
_ tracted. The mycelium is ?ltered, washed twice each time
time it is re?uxed for about one hour and then cooled and
‘with a volume of acetone approximately "equal to the
60 .hydrolyzed with water. ' The precipitate and water are
volume of’thevmycelium, ‘and extracted twice, each time. »_extracted repeatedly with ether andthercombinedether .
with a volume of methylene chloride approximately equal
extracts evaporated after washing with water and drying '
.to the :volume of the 'myceliurn.- The acetoneand methyl
with anhydrous sodium sulfate. The resulting crystalline
ene chloride extracts .inclu'dingsolventsare added to the
.residue is essentially ‘a quantitative yield of crude 6,160:
beer?ltratel ‘The mixediextracts andbeer ?ltrate are 65 dimethyl - 11,8 ~ hydroxy~pr0gesterone 3,20-bis(ethylene
extracted successively with two one-half by volumejpor
*ketal) (e), WhlCh'OIl recrystallization gives the pure, light
‘tions of methylene chloride andthen with tWoJone
'colored, crystalline. product.
_ fourthi'by volume .portionsof “methylene chloride.‘ The
.combined methylene chloride extracts ‘are Washed with
.tWo one-tenth by volume portions of a 2% aqueous solu
tion'of sodium‘bicarbonate and then with two one-tenth
‘ V by ‘volume portions of water.
After, drying the. methyl- '
-ene chloride extracts vWith about 3 to .5 g. ofianhydrouls
. ( 60¢,1 6 ot-Dimethyl-l l .?-Hydroxyprogesterone) (l [e] )
‘ " To v‘a solution of ‘2 g. of \6,-l6a~methyl-ll?-hydroxy
‘progesterone 3,ZO-biS-(ethyIenelketal) (e) in 75' ml. of ace- ,
sodium sulfate per liter of solvent'and ?ltering, thesol- '. ‘tone, is added oneml. of concentrated sulfuric acid in 25
vent is removed by distillation. The residue is dissolved 75 ml. of water and the resulting acidic mixture allowed to
stand for about‘15 hours. The solution is then concen:
as starting material, ‘gives 6m,l6ot-dimethyl-9a-bromo-11,8
trated and water added until crystallization takes place.
The thus obtained 6a,]oa-dimethyl-llp-hydroxypro
hydroxy-4-pregnene-3,20-dione (III).
gesterone (I) is collected on a ?lter and purified by re
6a-Methyl-9B-l1B-Oxido-4-Pregnene—3,2G-Dione (IV )
crystallization from ethyl acetate to give pure 611,160:
dimethyl-l 1 ?-hydroxyprogesterone (I) .
A solution of 4.9 g. of crude 6a-methyl-9a-bromo-11,8
hydroxy-4-pregnene-3,20-dione (III), as obtained in Prep
aration 2, in 168 ml. of acetone, was stirred and re?uxed
‘with 5.8 g. of anhydrous potassium acetate for a period
10 of 201/2 hours. The yellow mixture was concentrated in
A solution of 5.0 g. of 6oc-11'18’tl1Yl-1 J p-hydroxyprogester
vacuo to 75 ml. in volume and poured thereupon into one
one (I) in 58 ml. of dry pyridine (distilled overib‘arium
liter of water. After extracting the reaction mixture with
oxide), was treated with 3.0 -g.. ofrN-bromoacetamide.
three 250-m1. .portions of methylene‘ chloride, drying the
The mixture was stirred for about 15. minutes and cooled
extracts overanhydrous sodium sulfate and evaporating
to 0° C. Gaseous, sulfur dioxide ‘was slowly passed over 15 to ‘dryness in vacuo, 3.57 g. of oil was obtained. The
the surface of the reaction mixture ‘for aperiod of about
oil‘was dissolved in 300 ml. of methylene chloride and
6ot-Methyl-4,9(11 )-Pregnadien-3,20 (II)
‘ one-‘half hour at 12° C. until the reaction mixture gave a
poured over a column of 300 g. of Florisil (magnesium
negative reaction with potassium iodide-starch paper. The
silicate). The column was developed with 16 portions
reaction mixture was then poured into, 150 ml. of ice water
of 8% acetone-92% Skellysolve B, and one portion of
and stirred. A yellowish-white gummy material was col 20 10%—90% Skellysolve B. Each solvent portion was 375
lected on ?lter paper; the ?ltrate was extracted with three
‘ml. Fractions 6 through 16 were combined, dried and
?fty-milliliter portions of methylene chloride, and the gum
evaporated to give 3.1 g. of semicrystalline material which
was dissolved in the combined extracts of methylene chlo
was recrystallized from methanol to give 2.35 g. of product
ride. The thus-obtained methylene chloride solution was
as needles of melting point 119 to 122° C. The yield was
washed several times with water, then dried over an 25 therefore 61% of theory. An analytical sample of 6a
hydrous sodium sulfate and evaporated to dryness at 60°
methyl-9;8,1l?-oxido-4-pregnene-3,ZO-dione (IV) was pre
C. in vacuo to yield a residue of 4.62 g. This residue
was chromatographed over 350 g. of Florisil. ‘For the -
pared which melted at‘120.5 to 122° C. and had a rota
tion of [111D of +69° in acetone.
chromatography the 4.62 g. of residue was redissolved in
Analysis.—_Calcd. for C22H30O3: C, 77.15; H, 8.83.
350 ml. of methylene chloride and poured over the Florisil 30 Found: C, 75.84; H, 8.73.
charged column. The ?rst three fractions of 375 ml. each
Following the procedure of Preparation 3 but substitut
of a solvent consisting of 5% acetone and 95% Skelly
ing 6a,16a - dimethyl-9a-brom'o-1l?i-hydroxy-Ll-pregnene
solve B (hexanes) were collected and discarded; There
‘3,20-dione (III) . as starting material, yields 6a,l6oc-di- '
upon 15 fractions of 375 ml. each, consisting of 8% ace
methyl-9,6,1 1{3-oxido-4-pregnene-3,20-dione (IV) .
tone and 92% Skellysolve B were collectedjcombined, 35
dried and evaporated to give 3.27 g. of yellowish crystals.
These crystals were recrystallized from methanol to give
2.18 g. of product melting between 115 to 118°C. Yield,
46.3% of theory. An analytical sampleof 6a-rnethyl
4-9(11)-pregnadiene-3,20-dione (II) was prepared which
melted at 117 to 119.5 ° C. and had a rotation [0th, at
7 22° C. of +114° C. in acetone.
‘(6u-Methyl-9a-Fluoro-l1B-Hydroxyprogesterone) (V)
A solution of 2.03 g. of 6a¢methyl-9r8,llp-oxido-ll-preg40' nene-3,20-dione
(IV) in 30 m1. of methylene chloride and
Aizalysis.-Calc‘d. for CLQZHmOZ: ‘C, ‘ 80.94; H, 9.26.
Found: C, 80.80; H,'9.19.
16.8 g. of tetrahydrofuran was cooled in Dry-Ice bath for
‘10 minutes.» This solution was added portionwise in a
‘ 10-minute period with agitation to 9.6 g. of hydro?uoric
Following the‘ procedure of Preparation 1 but substitut-‘ 45 acid, cooled in a Dry-Ice bath, in a polyethylene bottle.
After standing in the bath for 20 minutes and thereafter
ing 6u,16u-dimethyl-1l?-hydroxyprogesterone (I) as start
in a refrigerator for 17 hours, the light colored solution
ing material,‘ yields 6a,16a-dimethyl-4,9(11)-pregnadiene
3,20-dione (II).
was poured into a solution of 46 g. of sodium bicarbonate
in 920ml. of water and stirred until gas evolution ceased.
50 The mixture was then separated and the aqueous layer.
6u-Methyl-9a-BromodB-Hydr0xy-4-Pregrtene> \ ‘
3,20-Dicne ‘ (III)
was extracted with methylene chloride. The combined
extracts and organic layer were washed with water, dried
‘ over anhydrous sodium sulfate and evaporated to dryness
in vacuo at 60° C. The thus-obtained oily residue of 3.15
A solution of 3.68 g. of 6a-methyl-4,9(11)-pregnadiene
3,20—dione (II) in 68 ml. of methylene chloride and 132 55 g. weight was redissolved in 300 ml. of methylene chloride _
and poured through. a column, charged'with 315 g. of
ml. of tertiary butanol was prepared. To this solution
Florisil magnesium silicate. This column was developed
was added at room temperature (about 23° C.) a solution
as follows: Fractions 1 through 6 with solutions of 8%
of 10.45 ml. of 72% perchloric acid in 78.8 ml. of water
acetone and 92% Skellysolve B hexanes; fractions 7'
and a solution of 1.92 g, of N-bromoacetamide in 33.5
through 12, 12% acetone and 88% Skellysolve B.‘ All
ml. of tertiary~butanol. The mixture'was stirredyfor 15
fractions were 630ml. portions. Fractions 9 through 12
minutes and thereupon a solution, of 1.92“ g. of sodium
sul?te in 104.5 ml. of water ‘was added.
The ‘mixture ‘
was then concentrated in vacuo until crystals appeared.
were combined and evpaorated to give 1.46 g. of semi~
crystalline material. i ‘ This material was recrystallized from
methanol to give 1.23 g. of product as white crystals of
The reaction‘ mixture was thereupon cooled to 5° C. and’
diluted wtih‘stirring with 350 ml. of ice cold water. A 65 melting point 170 to 172.5". An analytical sample of 60a
methy1-9a-?uoro-11B-hydroxy-4-pregnene-3,20-di0ne (V)
solid of an off-white color was collected on ?lter paper,
was prepared ‘by additional crystallization from methanol
washed with water until’ neutral and dried in a vacuum
melted at 172 to 172.5 ° and had a rotation of [ab plus
desiccator at room temperature. The material obtained,
1711 in acetone.
.6wmethyl-9a-bromo-l1Brhydroxy-4—pregnene-3,20 - dione
Analysis.—Calcd. for czzmooar; C, 72.90;; H, 8.62; F,
(III), weighed 4.9 g. (102% of theory) ‘and possessed a
5.24. . Found: C, 72.72; H, 8.98; F, 5.30.
melting point of 144.5 to 145.5 ° C. This material was
Following the procedure of Preparationlt but substitut
used in the next step without further puri?cation.
' Following the procedure of Preparation 2, but substitut
ing 6a,l6oa-dimethyl-4,9(11)-pregnadiene-3,20-dione (II)
ing 6m,16a-dimethyl-9,8,1l?eoxido-4-pregnene-3 ,ZO-dione
(IV) as starting material, yields 6a,16a-dimethyl-9a
75 ?uoro-l 1,8-hydroxy-4-pregnene-3,20-dione (V) .
6ct-MethyZ-9a-Flu0r0-11p-Hydroxy-4-Pregnene- ~
oat-Methyl - 9a - Fluoro ‘J15 - Hydroxy - 4 - Pregnadiene
3,20-Di0ne (1-Dehydr0-6oc-Methyl - 9oz - Fluoro - 11,8
' 3,20-Di0ne (V)
Alternatively, 6a-met-hyl-9a-fluoro-1 1 ?-hydroxy-4-preg
. -nene-3,20-dione (V) can conveniently be prepared from
(VII) _
Five IOO-ml. portions of a medium in 2501-rn1. Erlen
‘5st, l1owdihydroxya6?-methyipregnaneéi ,ZO-dione [Spero
~ettal., J. Am. Chem.‘Soc. 78, 6213 (1956)] by making the
meyer ?asks containing>>1%»Cerelose corn sugar, 2% corn.
llct-toluenesulfonate in knownmanner with 1011131163111‘,
ifonyl chloride, dehydrating‘the toluenesulfonate by heat
ing in aqueous solution to.obtainSwhydroxyb?-xhethyl
9(1‘1)-pregnene-3,20idione, dehydrating thereafter ‘with
pH of 4.95. This medium is sterilized for one hour at
20 lbs. per square inch pressure and 120° C. and inocu
lated with a one to two day growth of Septomyxa a?’mis
The Erlenmeyer ?asks are shaken at
‘sodium hydroxide 5 solution to obtain 16a-methyl-'4',9.(:1l)~
‘room-temperature (about 24° -C.) for a-p'eriod of three
-pregnadiene-3,20-di0ne (II).
steep liquor (60% solids) and tap water is adjusted to a
This compound "is then ,
vsubmitted'toithe:steps-shownin Preparations 2 to 4, inclu
sive, to give’ the desired product 6ot=methyl-9ot.~?uoro
days. ‘At the'end of this period, this vSOD-ml. volume is
‘15 used'as an inoculum for 10 1. of the same glucose-corn
vsteep ‘liquorrnedium which-in addition contains 10ml.
111BéhydrOXyQ4-Pregnene-3,ZO-dione (V) .
ofv an antifoarn (a mixture tof'lard oil and *octadecanol). ,
The fermentor is ‘PlEICCd‘III‘IhGjWHEI' bath, adjusted to
28° 'C., and the contents vare stirred (3100 rpm.) and
16a - ‘M ethyl -‘ 90c - Fluoro-4-Preenene-3,11,20-‘Tri0ne
(-6a-MethyZ-9a-Flu'0r0-lZ-Ketoprogesterone) (VI)
20 aerated (0.5 v1. air per 101. beer per minute). After about
19 hours of incubation, when 1a good growth develops,
’hydroxyprogesterone (V) in 10 ml. of aceticacid ‘is
added 1510 mg. of chromicanhydride, dissolved vin '3' ml.
2 g. of 6a-methyl-9or-?uoro-l l?-hydroxyprogesterone (V),
‘dissolved in 50 ml. of acetone, and 1 g; of 11¢},21-dihy
'droxy-4,17(20)~pregnadiene~3-one as promoter'is added
10f acetic acid and 0.2 m1. of water. The mixture is allowed
to stand atroom temperature (24° C_.) for a period of
about four hours,'then ‘poured’ into _50 ml. of water, neu
temperature and aeration for 19 hours. The rnycelium is
‘filtered andthe steroidal material extracted with‘ four
tralized-with'sodium bicarbonate and extracted with three
' ‘threediter portions of methylene ,lchloride'. ' The myceliurn
To a solution of 0.5 grams of ,6a-methyl-9ot-?uoroal1p
fZS-rnl. portions of methylene chloride.
and the: incubation (conversion) carried out 'at the same ‘
'is extracted with 'two SOO-ml. ‘portions of acetone and
7 '
The methylene
two 'SOO-ml. portions of methylene chloride.
‘chloride extracts are'combined,‘ washed’twice with water,
dried over anhydrous sodium sulfate, evaporated and'the
. residue twice‘ recrystallized from methanol to give 600
methyl-9a1?uoro-4-pregnene-3,11,20 - trione ‘(6a - methyl- "
Followingthe procedure of Preparation 5 but sub
droxyprogesterone (VII), ‘the compound also produced
by the method of :Preparation 6, above. . i .' " '
one (V) as starting material, yields 5d,l6oc-dlm6tl1Y1'-:9_oc?
?uoro-ll-ketoprogesterone (VI).
The‘ ex
tractsare ‘combined, evaporated and the residue chroma
‘tographed ‘over Florisil. The‘ fractions obtained with 5 to
i15%:acetone-Skellysolve'B are combined, evaporated and
'theresiduetwice recrystallizedfrom methanol‘to give
iwhitegcrystals of 1-dehydro-6a-methyl-9w?uoro-1Its-hy
‘9ct-?uor'0-1'l-ketoprogesterone) (VI).
‘Following the procedure of Preparation v8 but sub;
sti'tuting ‘6a, 1 6a§dimethy1-9¢x-?uoro-1 1 ,bféhydroxyprogester
"40 one .(V) ' as starting material,‘ yields 1-dehydro-,6ot,16a-di
‘methyl-9o5-?uoro-1l'?hydroxyprogesterone (VII). .
I In the samem'annengivenin‘Preparation 8 submitting
Lfe’rmentationby .Sleptomyxa ajr?nis'ATCC. '6737 results
g. -of"6e-methyl59w?uoro;1i?éhydroxyprogesterone
the ‘production of 1~dehydro-6a-methyl¥9a~?uoroé11- 7.
, )(V) ‘is, dissolved in.'of tertiary butyl-alcohol‘and
:ketoprogesterone‘ > (.VIII) .
‘thereto is added, 5 ‘ml; ‘ofacetic acid and 250 ‘mg. ‘of
Alternatively, lrdehydr'oa604-"v
' methyl-9a-?uo‘ro-1llketoprogesterone (VIII) is obtained ;
selenium dioxide. The mixture is'heated' to "75° CQand
jstirred for a periodao-fiabout‘24 hours. 'Ihereafter another
by oxidizing l-dehydro-6a-methyl-9ozr?uoro-l l?-hy‘droxy- ,
progesterone (VII) as shown in Preparation . .
.50 ' _ Likewise, submitting 6a,l6a7dimethyl-9ot-?uoro-4-preg
1 at 75°C. and stirring continued for about 24 hours. > :The
.poition of Y250 mg. of selenium dioxide vis added, heated
nene’l3,1‘1,20‘-trione (VI) to fermentation by Sepromyxa
mixture" is cooled,‘ ?ltered to remove the excessjselenium
:dioxide and evaporated. The thusaobtained residue is re- >
crystallized four. times‘ from acetone-Skellysolve B’hexane
hydrocarbons to give‘pure 1-dehydro-6a-methyl-9a-?uoro
af?m's A.T.C.C. 6737 ‘results in the‘ production of l-de
_hydro-6W16a-dimethyl-9a - ?uoro - 11 -°ketoprogesterone
:(VIII)- lAlternatively, 1, -, dehydro - 60¢,160t - dimethyl-9a
I -?uoro-1l-ketoprogesterone(WII) is obtained by oxidiz
, 1 1 ?-hydroxypro'gestero-ne - (VII) .
ing l-dehydro-?ot,16rx-dimethyl¥9ot,1 1 ?-hydroxyprogester
Followingtheprocedure of Preparation 6 bite-1b
vone (VII) as shownv in Preparation 5. '
stituting 60:,16ci-dimethylf9u-?uorod 1 ?-hydroxyprogesterr
Instead of using 'Septomyxrt-a?inis in the l-dehydro
‘one _(V) as starting material, yields 6a,16,a‘-dimethyl-9,a
'?uor'o-ll?-hydroxy-1‘,‘4'pregnadiene~3,20-dione (VII).
~ genation of Preparation ‘8, 11-‘dehydro~6a-methyl-9a-?uoro
.ll?-hydroxyprogesterone (VII) and l-dehydro-oct-methyl
90c -.?uoro -;11 - ketoprogesterone (VIII) can be prepared
aa - Methyl - 9oz - Fluoro - 1,4 - Pregnadiene - 3,11,20- '
Trioize (1—Dehydro-t?a-Methyl-9ot-Flu0r0-I1 - 'Ketoprm
gesterone) (VIII)
terone (VI) respectively, with other species of the genus
In the same manner given in Preparation 5, oxidizing
Septomyxa or species selectedhfrom the microorganisms»
of the genera: Calonectria, Alternaria, .Colrletotrichum,
with chromic anhydride in acetic acid l-dehydro - 60c
methyl-9otl?uoro'd l‘B-hydroxyprogesterone ' (VII), ‘yields
rl-dehydro-dufmethyl- 9a - ?uoro - 11 - ketoprogesterone
(6ot~methyl'-9oc-?uoro - 1,4- - pregnadiene - 3,11,20 - trione
Following the procedure of Preparation 7 butssubsti
cylindrocarpon, Ophiobolus, Listera, Corynebacterium,
'Erysipelothrix species .Of the family Tuberculariaceae,
'Nocandia, Cucurbitaria, -Leptosphaeriae, Tric'othecium,
iMycobacterium, -Fusarium, Didymella and the like.
Likewise, instead of- employing Septomyxa \aj?nis
tuting 1~dehydro-6a,16a-dimethyl-9ot-?uoroall?rhydroxyi ‘ ' utlizied in the l-dehydrogenation of Preparation 8, l-de-V
‘progesterone (VII) as starting material, gives »1-dehydro
6a,16a-dimethyl-1l-ketoprogesterone (VIII).
hydro - 60:,160: - dimethyl - 9a-?uoro-1l?-hydroxyproges
75 terone (VII) and 1- dehydro-6ot,16ot-dimethyl-9a-?uoro
Analysis.—-Calcd. for C22H27O3F: C, 73.71;. H, 7:59;
F, 5.30. Found: C, 73.50; H, 7.48; F, 4.89.
ll-ketoprogesterone (VIII) can be prepared by the fer
mentation of 6a,16u-dimethyl-9a-?uoro-1IB-hydroxypro
'Following the procedure of Example 2 but substituting
gesterone (V)v and 6a,l6a-dimethyl-9a-?uoro-1l-keto
progesterone (VI) with other species of the genus Sep
tomyxa or species selected from ‘the microorganisms of
the genera disclosed in the immediately preceding para;
nadiene-3,20-dione (PIX) as starting material, yields 6,16oz
6,160‘ - dimethyl - 90c - fluoro - 1113 - hydroxy - 4,6 - preg
dimethyl - 9a - ?uoro - 4,6 - pregnadiene - 3,11,20 - tr-ione
6 - Methyl -, 9a‘ - Fluoro - 4,6 - Pregnadiene »- 3,11,20
6 - Methyl - 9a - Fluoro - 1113 - Hydroxy - 4,6 - Pregnadi
ene - 3,20-Di0ne
Trione (6 - Dehydro - 6 -Methyl-9oc-Flu0r0-1 1 -Ket0pr0
gesterone) (X)
Hydroxyprogesterone) (IX)
‘Following the procedure of Example 1 but substituting
A solution of 9.25 g. of 6a-methyl-9a-?uoro-l1/3-hy
60c - methyl - 9oz - ?uoro - 4 - pregnene - 3,11,20 - trione
droxy-4-pregnene-3,20-dione (V) and 13.87 g. of chlor
(VI) as starting material, yields 6amethyl-9a-fluoro-4,6
anil (2,3,5,6-tetrachloro-1,4-benzoquinone) in 550 ml.
pregnadiene-3,l l,20~trione (X) .
of teamyl alcohol was stirred and heated at reflux for a
period of about 3 hours. .The solvent was removed un
Following the procedure of Example 1 but substituting
6a,16rx - dimethyl - 9a - ?uoro - 4 - pregnene - 3,11,20
der reduced pressure at steam bath temperature and the
dark muddy residue dissolved in 1 l. of methylene chlo
ride. The methylene chloride solution was washed ?rst
with 800 ml. of 2.5% sodium hydroxide solution (in 3
trione (VI) as starting material, yields 6,16oc-dimethyl
9a-?uoro-4,6-pregnadiene-3,11,20-trione (X) .
portions) then with water, dried with anhydrous sodium
6 - Methyl - 9a - Fluoro - 11B - Hydr'oxy - 1,4,6-Pregna
sulfate and poured over a 500 g. column of Florisil. The
column was eluted with 6 l. of a mixture of acetone and
Skellysolve B (1:9) and with 4 l. of a mixture of acetone
triene-3,20-Di0ne (1,6-Bisdehydro~6-ll/lethyl-9a-Flu0ra
11,B-Hydroxyprogesterone) (Xl)
A solution of 12 g. of i6a-methyl-9a-?uoro-1l?-hy
and ‘Skellysolve B (2:8). Evaporation of the eluates to
dryness gave 5.526 g. of crude crystalline product which
droxy-1,4-pregnadiene-3,20-dione (VII) (from Prepara
tion 6) and 10 g. of chloranil in 500 ml. of tertiary amyl
alcohol is re?uxed for a period of ‘about 4.5 hours. The
tertiary amyl alcohol is then distilled off under vacuum in
a nitrogen atomsphere. The residue is dissolved in meth
ylene chloride and then shaken with dilute sodium hy
was dissolved in 250 ml. of methanol, decolorized with
Darco G~60 (activated carbon) and the solution ‘concen
trated to about 75 ml. to give 4.163 g. of product with a
melting point of 240 to 244° C. An analytical sample
of the product, 6-methyl-9a-?uoro-1l?-hydroxy-4,6-preg
droxide. The precipitate that forms is separated by ?ltra
tion through diatomaceous earth. The organic phase of
nadiene-3,20-dione (IX), was recrystallized from metha
nol and melted at 245 to 247° C.; [ab +167“ C. (di
the ?ltrate is separated, washed ?rst with dilute sodium
hydroxide solution, then water and dried. The solvent
is distilled off leaving a residue of crystalline é-methyl
mg, 286, e = 22,150
9a - ?uoro - 11p - hydroxy - 1,4,6 - pregnatriene - 3,20
Analysis.—Calcd. ror'czznggogF; c, 73.30; H, 8.11;
F, 5.27. Found: C, 73.10; H, 8.23; F, 5.17.
Following the procedure of Example 1 but substituting
as starting material, 6a,16a-dimethyl-9a-?uoro-1l?-hy
droxy-4-pregnene-3,20-dione (V) for the corresponding
dione (XI).
Following the procedure of Example 4 but substituting
‘ 60¢,l6a - dimethyl - 91x - fluoro - 11B - hydroxy - 1,4 - preg
nadiene-3,20-dione (VII) as starting material, yields
l6a-desrnethyl compound (V), yields 6,16u-dimethyl-9d
6,161: - dimethyl - 90c - ?uoro - 115 - hydroxy-1,4,,6-preg
?uoro-l 1p-hydroxy-4,6-pregnadiene~3,20-dione (IX) .
natriene-3,20-dione (XI).
i‘ I
6 - Methyl - 9a - Fluoro - 1,4,6 - Pregnatriene - 3,111,20
6 - ‘Methyl - 9a - Fluoro . 4,6 - Pregnadiene _ ‘3,11,20
Trz'one (1,6 - Bisa'ehydro-6-Methyl-9a-Flu0r0-1l-Keto
Trione (6-Dehydr0-6-Methyl-9u-Flu0ro-1l-Ketoproges
To a solution of 0.2 g. of 6-methyl-9u-?uoro-1lp-hy
To a solution of 0.5 g. of 6-methyl-9a-?uoro-1lp-hy
droxy-4,6-pregnadiene-3,20-dione (IX) in 100 ml. of ace
tone at about 3° C. ‘was added 1 ml. of oxidizing reagent i .
(composed of 26.73 g. chromium trioxide, 23 ml. of 55
concentrated sulfuric acid and water to make a total vol- '
perature until about 150 ml. remained. This material
gave 435 mg. of precipitate that was isolated by ?ltration,
treated with Darco G-—60 in acetone, ?ltered, and the
solvent removed. The residue was chromatographed
over a 50 g. column of Florisil and eluted with a mix
ture of acetone and Skellysolve B (1:9) to give 397 mg.
of product. Crystallization of this material from a mix
ture of acetone and Skellysolve B gave 321 mg. of prod
uct ‘with a melting point of 140 to 144° C. An analytical
sample, prepared by recrystallizing a portion of the prod
uct twice from the same pair of solvents, yielded the
desired compound, 6-methyl-9a-?uoro-4,6-pregnadiene
3,11,20-trione '(X); it melted [at 143 to 145° C.; [r1113
mfg, 284, e=22,650
droxy-l,4,6-pregnatriene-3,20-dione (X1) in 4 ml. of ace
tic acid is added 60 mg. of chromie anhydride, dissolved
in 1 ml. of acetic acid and ‘0.1 ml. of water. The mix
ture is allowed to stand at room temperature for a period
‘of about 4 hours, then poured into 50 ml. of water, neu
tralized with sodium bicarbonate and extracted with three
ume of 100 ml.). After stirring for a period of about
one hour at about‘ 3° C., 2 ml. of methanol was added
followed by 200 ml. of water. The mixture was concen
trated under reduced pressure at about 60° C. bath tem
progresterone) (XII)
10 ml. portions of methylene chloride. The methylene
chloride extracts are combined, washed with water, dried
60 over anhydrous sodium sulfate, evaporated, and the thus
produced residue twice recrystallized from methanol to
give 6»methyl-9oc-?uoro-1,4,6-pregnatriene-3,1l,20~trione
Following the procedure of Example 5 but substituting
6,16ot-dimethyl-9w?uoro-l l B-hydroxy 15,4,6-pregna-triene
3,20-dione (X!) as starting material, yields 6,16a-di
methyl-9oz-fluoro~1,4,6-pregnatriene-3,11,20-trione . (XII).
6 - Methyl - 9a - Fluoro - 1,4,6 - Pregnatriene - 3,11,20
Trione (1,6 - Bisdehydro - 6 - Methyl - 9o: - Fluore
11 -Ket0pr0gester0ne) (XII)
Following the procedure of Example 4 but substituting
60c - methyl - 9m - ?uoro - 1,4 - pregnadiene - 3,11,20
trione (VIII) as starting material, yields 6-methyl-9a
Following the procedure of Example 9 but substituting
?uoro-1,4,6-pregnatriene-3,1 1,20-trione (XII).
60:,160: - dimethyl - 9a, - ?uoro - 116 - hydroxy - 4 {preg
Following the procedure of Example 4 but substituting
'nene;3,20-dione (V) as starting materiaLyields ‘6,160;
606,1606 - dimethyl - 9a — ?uoro - 1,4 - pregnadiene - 3,11,
dimethyl - 90c - ?uoro 411B - hydroxy - 1,4,6 - pregna
20-trione (VIII) as starting material, yields 6,16-dimeth
triene-v3,20-‘dione (XI).
>yl-9a-?uoro-1,4,6-pregnatriene-3, 1 1,20-trione (XII) .
6 - Methyl - 90c - Fluoro - 1,4,6 - Pregnatriene L 3,11,20~
6 - Methyl - 90c - Fluoro - 11B - Hydroxy - 1,4,6 ; Preg~
Triolze (1,6 - Bisdehydro - 6 - M’ethyl - 9a - Fluoro-ll
'natriene’ - 3,20 _- Dione (1,6 - Bisdehydro - 6 - Methyl
Qa-Fluoro-l1?-Hydroxyprogesteroine) (XI) .
Following the procedure 'of *Example .9Jbut substituting
A mixture containing 10g. of 6-methy1~9a-?uoro-1l?— '
6a - methyl ~ 90: -‘ ?uoro - 4 - pregnene ~ 3,11,20 - trione
hydroxy-4,6-pregnadiene-3,20-dione (IX) ' (from‘Example
'(VI) asv startingmaterial, yields '6-methyl-9'a-?uorol1,4,6
“1), 500 ml. of tertiary butyl alcohol, 5 ml. of ‘glacial
‘pr-egnatriene-il1,20-trione (XII).
acetic acid and 4 g. of selenium dioxide is warmed at re
?ux for 24 hours. An additional 4 g. portion of vselenium
60:,1611 - dimethylv- -9oz'- ?uoro - 4 - pregnene - 3,11,20~
dioxide is added and warming is continued foranother
vtrione (-VI) as starting material, yields 6~methyl-9u-?uoro~
24-hour period.
='1,"4,6-pregnatriene-3,11,20-trione (XII).
_' _
Following the procedure‘ ofkExample '9 v‘but substituting
Thev reaction mixture, is cooled and ?ltered. The ?l
trate is concentrated to about 150 ml, then slowly diluted 20
with 850 ml. of water. The resulting precipitate is iso
lated by ?ltration." The precipitate is dissolved in 300
ml. ,of ethyl acetate, then washed with four IOG-ml. por
and evaporated to give a residue containing 6-methyl-9a
(F '
2/1\ 5/
Following the procedure of Example7 but substituting
6,1606 - dimethyl - 90c - ?uoro ‘,- ll? - hydroxy - 4,6 - preg
JV \/
nadiene.-3,20-dione (IX) as starting material, yields 6,‘
160a _ dimethyl - 90c - ?uoro - 11,67 hydroxy - 1,4,6 - preg
natriene-SJO-dione (XI).
1. A ?-methyl-9éz-fluorodlioxygenated compound of
?uorio ~ 115 - hydroxy - 1,4,6 - pregnatriene - 3,20 - dione
the formula
tions of freshly prepared cold ammonium sul?de, dilute ammonium hydroxide, water, dilute hydrochloric ’ acid 25
and water. The solution is dried over sodium sulfate
,Wherein X is- selected from the group consisting of the
?-hydroxymethylene radical
- .
6, - Methyl - 90c - Fluoro - 1,4,6 - Pregnqtrz'en'e - 3,11,20
Trione (1,6 - Bisdehydro -.6,- Methyl - 90c - Fluoro:
_ 1 1 -Ketopr0gester0ne) (XII)
Following the-procedure of Example 7 butlsubstituting
and‘ the carbonyl radical .(>C='O), ‘R is selected from
the group consisting of hydrogen. and methylnand the
linkage between carbon atoms 1 and 2'is selectemfrom
6- methyl - 90c - l?uoro - 4,6 rpregnadiene- 3,11,20‘
trione (X), as starting» material, yields 6-methyl-9a1?uor'o
1,4,6-pregnatriene43,11,20-trione (XII).
those consisting of single and double bonds.
2. 6 - methyl - 9a - ?uoro 4115 - hydroxy.‘- 4,6 j-l ‘preg-V ‘
Following the procedure of Example 7 but substituting
6,160‘ ~dimethyl - 90¢ -.?uor'o - 4,-6 - pregnadiene - 3,11,
' ,20-trione (X) as starting material, yields 6,16a-dim'ethyl
,9a-?uoro-1,4,6-pregnatriene-3,l1,20~trioner (XII) .
-6‘ - Methyl 49a -'Flu0r0'- ‘115 - Hydroxy - 1,4,6 - Preg—
4. 6,160‘ - dimethyl _ 9oz - ?uoro - 11's. hydroxy _ 4,6
pregnadiene-3',20-di0ne. ,
; 5. 6,1606 ~ dimethyl - 9a Qfluoro é 4,6 - pregnadiene
mztriene - 3,20- Dione (1,6 - Bz'sdehydro - 6 .- Methyl
Qa-Fluoro-Zl?-?ydifoxyprogesterone) (XI)
-3. -6 - methyl-19a - Home 4 4,6 - pregnadiene 13,11,720
6. 6 - methyl - ‘90c - ?uoro - 11B _ hydroxy - 1,4,6
droxy-i4-pregnene-3,2-0-dione (V), 1.5 ‘g. of chloranil and
ml. of secondary .amyl alcohol is heated at reflux te. perature for a periodof aboutS-hours. The reaction
‘mixture, is ?ltered and the ?ltrate evaporated to dryness.
The residue 'is dissolved in chloroform and the solution
washed successively several times with each of the follow
ing: qwater, 5% sodium hydroxide solution, and again
water. The solution is dried with sodium, sulfate and
' then concentrated to dryness. The residue is dissolved in
8. 6,16“ - dimethyl - 9a - ?uoro - 11/5‘ - hydroxy - 1,4,
pouring onto a 50 g. column of Florisil; elution with a 6
line 6 - methyl - 9a - ?uoro- 11,8 - hydroxy - 1,4,6 - preg
natriene-3,20-dione (XI).
9. 6,1604 - dimethyl - 90¢ --?uoro - 1,4,6 _- pregnatriene
References Citedin the ?le ofthis patent
‘50 ml. of methylene chloride and'chromatographed by
‘mixture "of acetone and Skellysolve B yields pure crystal
, 7. 6 - methyl --9a - ?uoro - 1,4,6 - pjregn-atriene - 3,
, Moreland et al ________ __ Apr. 21, 1959
Dodson et al. ________ __ June 16, 1959
R-ingold et_ a1. .,.____,___..__ Ian. 17, 1961
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