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Патент USA US3086048

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United States Patent 0 "’
3,086,029
Patented Apr. 16, 1963
1
2
3,086,029
160a,17ot-METHYLENE-6-SUBSTITUTED PROGES
TERONES AND PROCESS THEREFOR
J Allan Campbell, John C. Babcock, and William J.
‘Wechter, Kalamazoo, Mich., assignors to The Upjohn
‘Company, Kalamazoo, Mich., a corporation of Dela
for the production thereof. It is particularly ‘concerned
with 16a, 17 a-methylene-6a~methyl-4~pregnene-3,ZO-dione,
16:1,17 a - methylene-6a-?uoro-4-pregnene-3,20-dione, 16a,
17a-methy1ene-6a-chloro-4~pregnene-3,ZO-dione and the
corresponding A6, A1 and Abs-derivatives thereof. The
present invention also relates to the corresponding com
ware
pounds possessing 11(0: and ?)-hydroxy ‘and ll-keto sub
No Drawing. Filed Jan. 12, 1962, Ser. No. 165,954
20 Claims. (Cl. 260-3973)
stituents. The 9oc-?1101‘0 analogues of all of the aforesaid
compounds and intermediates therefor are ‘also embraced
within the scope of this invention.
The compounds of this invention and a process of pro
This invention relates to V16a,17u-methy1ene-6-substi~
tuted progesterones, intermediates therefor and processes
duction thereof are illustratively represented by the fol
lowing sequence of formulae:
ca,
CH3
5 0
i=0
as \
H3
H3
-————-—>
H
L
“reg
- “2
3
I
II
\
H
\
H3
“3
CH3
H3
i=0
-0
H3
H3
__
\
H3
9 H2
H3
VI
I
él'ig
III
Ac
H3
CH3
as '
XIII, XIV, 'XVI and
XVII
to XVIII, XIX, XX and XXI
3,086,029
Ha
toV
Ha
VIII
RI
RI
HI
XII
3,086,029
com V
from XIXc
to XIXQ and
XXII
L
from XIX
XIXc (wherein .
ll-QH is a)
3,086,029
7
8.
wherein R is selected from the group consisting of hydro
gen, methyl, ?uorine and chlorine; R’ is selected tom the
group consisting of hydrogen and the acyl radical of an
organic carboxylic acid, preferably a hydrocarbon car
boxylic acid containing from one to twelve carbon atoms,
inclusive; R" is hydrogen or lower-alkyl; n is ‘an integer
selected from the group consisting of one and two; X is
the u-hydroxymethylene radical
\ 'on
chosen from the group consisting of ?uorine and chlorine;
X’ is a halogen chosen from the group having an atomic
weight from 35 to 127, inclusive, i.e., chlorine, bromine 10
n
and iodine; X" is a halogen chosen from the group having
and the carbonyl radical (>C=O), are effective progesta
an atomic weight from 19 to 127, inclusive, i.e., ?uorine,
tion-al
agents useful in the treatment of functional uterine
chlorine, bromine and iodine; Ac is the acyl radical of an
bleeding and dysmenorrhea; their use is bene?cial in the
organic carhoxylic acid, preferably a hydrocarbon car
boxylic acid containing from one to twelve carbon atoms, 15 maintenance of pregnancy and regulation of fertility in val
uable domestic animals. In addition, the compounds em
inclusive; the broken lines appearing in Formula XIX and
braced by Formula B possess marked anti-in?ammatory
in Formulae XXII to XXVI, inclusive, represent A1 and
activity and are effective in the treatment of various in?am
Ali-double bonds, which may or may not ‘be present in
matory conditions of the skin, respiratory tract, bones and
each of the formulae and represent A4, A“, A416 and
internal
organs, contact dermatitis, rheumatoid arthritis
Alfie-compounds; ~ is a generic expression denoting on 20
and allergic reactions; the latter condition is especially re
and ,8 bonds and mixtures thereof.
sponsive to topical application of the aforesaid compounds.
The novel compounds of this invention and the inter
The compounds of Formulae A and B can be prepared
mediates therefor possess valuable pharmacological prop
and administered to mammals, birds, and animals in a
erties, particularly progestational, anti-estrogenic, gonado~
tropin inhibiting, and anti-in?ammatory. The compounds 25 wide variety of ‘oral and parenteral dosage forms, singly,
or in 1admixture with other coacting compounds. They
represented by the formula
can ‘be associated with a carrier which can be a solid mate
rial or a liquid in which the compound is dissolved, dis
persed or suspended. The solid compositions can take the
OH:
CH;
(i=0
I .... “OH,
OH:
I,
ably in unit dosage forms ‘for simple administration or
precise dosage. The liquid compositions can take the
form of solutions, emulsions, suspensions, syrups or
elixirs.
The novel 16a,17oa-methylene-G-substituted-progester
35
ones (V) of the present invention are prepared by sev-eral
processes, employing the routes and methods disclosed in
(l) and (2), below.
I
O
30 form of tablets, powders, capsules, pills or the like, prefer
A
(1) (a) 3/3-hydroxy-6~methyl-5,l6-pregnadiene-20-one
i
40 (I) (prepared as in Example 11 of US. Patent 2,871,246)
R
is reacted with diazomethane after the manner of Wett
stein (Helv. Chim. Acta 27, 1803 [1944]) to produce the
wherein R is selected from the group consisting of methyl,
?uorine and chlorine and the broken lines represent A1
corresponding 16( 17 )-diazornethane adduct, 3?-hydroxy
6-methyl-16a:17w(21:31-diazacyclopent - 21-eno)-pregn
and A6-doub1e bonds which may or may not be present and
represent A4, AM, A416 and Ali‘i-?-compounds, are effective 45 5-en-20-one (II). The thus produced adduct (II) is de
composed by heating or by reaction with a strong acid,
progestational agents which are useful in the treatment of
e.g., perchloric acid or boron tri?uoride ethenate, to pro
functional uterine bleeding and 'dysmenorrhea; they are
duce 16a,l7oz - methylene-SB-hydroxy-6-methyl-5-pregnen
also advantageously employed either alone, or in combi
20-one; acylation of this compound, e.g., with the anhy
nation with an androgen (e.g., 17-methyltestosterone, tes
tosterone cyclopentylpropionate), or an estrogen (e.g., 50 dride of a hydrocarbon carboxylic acid such as acetic an
17-ethinylestradiol 3-methyl ether, estradiol cyclopentyl
hydride, yields 16a,17a-methylene-3?-hydroxy-G-methyl
propionate) in maintaining pregnancy and regulating fer
tility in valuable domestic animals. The compounds rep
resented by the formula
S-pregnen-ZO-one 3-acylate (III). The 3-acyl group of a
compound represented by III is readily converted to 3,6
hydroxy; thus, 16a,17u-methylene-3p-hydroxy-6-methyl
55 5-pregnen-20-one (IV) is prepared, e.g., by heating a com
pound of Formula III in methanol containing a strong
mineral acid. Oxidation of the 3?-hydroxy group of the
0 Hi
0 H;
compound of IV, yields 16a,17u-methylene-6a-methyl-4
pregnene-3,20-dione (V).
i: 0
0 HI/\
Y
i ____ _. C H,
,
l 'X
0_
l/
B
E
R
(b) The 6-methy1 compounds of Formula V can also be
produced from the starting material (I) by an alternative
procedure. This method comprises oxidation of the 313
hydroxy group of 3?-hydroxy-6-methyl-5,16-pregnadiene
20-one (I) to produce 6a-methyl-4,16-pregnadiene-3,20
65 dione (VI); the thus produced A4-3-keto compound (V1)
is converted to the corresponding 16(17)-diazomethane
adduct (VII) by the method of Wettstein cited in (1) (a),
above; the thus producedl6(17)-diazomethane ‘adduct of
6a-methyl-4,16-pregnadiene-3,20-dione (VII) is decom
wherein R is selected from the group consisting of hydro
-s
posed by heating or by reaction with a strong acid, such
gen, methyl, ?uorine and chlorine, the broken lines are as
in Formula A, above, X is selected fnorn the group con
as perchloric or boron tri?uoride etherate, to yield, di
rectly, l6a,l7a - methylene-6u-methy1-4-pregnene-3,20-di
sisting of hydrogen, chlorine, bromine and ?uorine and Y
is selected from the group consisting of the ?-hydroxy
dione-3,20-dione (Va).
methylene radical
one (V) and a byproduct, 6a,l6-dimethyl-4,l6-pregna
(2) (a) The compounds of Formula V, wherein R
3,086,029
.9,
Id
is ?uorine or ‘chlorine, are prepared from the known
drogenation 0f the corresponding AVA-compounds (XXI)
compounds of Formula VIII in accordance with the
by reaction with chloranil. The Abbe-compounds (XX)
method of ‘US. Patent 2,838,528. 3,B-hydroxy-5,16-preg—
can also be prepared directly from the A4-compounds of
nadiene-ZO-onev (VIII) or the corresponding 3~acylatle
Formula V by reaction with chloranil at elevated tem
thereof, is convertedto 1i6-dehydro-3B-hydroxy or 3B 5 peratures in accordance with the method also set forth
acyloxy-5a,6u.-oxidopregnan-20-one (IX) with a peracid
in J. Amer. Chem. Soc. 79, 1257 (1957). The Al-‘t
(e.g., performic, peracetic or perbenzoic); treating the
derivatives (XXI) of Formula V are produced by 1,2
compounds of Formula IX with hydrogen ?uoride; hy
dehydrogenation with selenium dioxide in the manner dis
drogen chloride or other ?uorinating and chlorinating
closed in US. Patent 2,971,886 and by dicyanodichloro
agents yield the corresponding 16-dehydro-3?,5e-dihy
benzoquinone in the manner disclosedv in British Patent
852,847; e.g., in this manner 160:,17ot-II16I1'1Y16116-6a
droxy~6B~fluoro (or chloro) pregnan-20-one (X) or the
3 ?-acylate thereof; the i3 B-acylate is used, hydrolyzing the
methyl-4-pregnene-3,20~.dione (V) is converted to 160;,
said 16-dehydro-6B-?uoro (or chloro)-3?-acyloxy-5a-hy
l7ct-methylene-6a-methyl - 1,4 - pregnadiene - 3,20-dione
droxypregnan-ZO-one (X) under acid conditions, for ex
ample ‘with boron tri?uoride or boron trichloride, yields
(XXI).
The novel manna-methylene compounds represented
by Formula'eVV, XVIII, XX and XXI (and also embraced
by Formula A, above), in addition to possessing valuable
l6-del1ydro-6[3—?uoro (or chloro) 3 5,5 a-dihydroxypregnan
ZO-one (X); treating the l6-dehydro-65-?uoro (or
chloro)-3?,5ot-dihydroxypregnan-20‘~one (X) with an oxi
dizing agent such as sodium dichromate in acetic acid
gives 16-dehydro-5a.-hydroxy-6B-?uoro (or chloro) preg
nane-3,20-dione (XI); dehydrating the thus obtained
therapeutic properties, are useful as intermediates in the
production of the corresponding ll-oxygenated com
20
pounds designated by Formulae XIX, XIXa, XXV and
16~dehydro - 5a - hydroxy-G?-?uoropregnane - 3,20-dione
XXVI and embodied in Formula B, above. For example,
a compound represented by Formulae V, XVIII, XX and
(XI) with a base, or preferably with an acid, yields
XXI can be 115- or lla-hydroxylated with one of the
6,6-?uoro (or chloro)-4,16-pregnadiene-3,20~dione (16
many species of fungi known to oxygenate in that posi
dehydro - 613 - ?uoro (or chloro) progesterone) (XII), 25 tion, e.g., one from the order of Mucorales, Aspergillus,
which is isomerized by acid (or base) to the correspond
Penicillium, such as Rhizopus nigricans, Czmvularia [name
or Cunninghamella tblakesleeana, to produce a compound
16-dehydro-6p-fluoro - 3?,50t - dihydroxypregnan - ZO-one
represented by Formula XIX.
(X) by the Oppenauer process produced '1‘6-dehydro-6
An effective method of converting an llot-hydroxy-li
?uoroprogesterone (XII) directly. The 6-halo com~ 30 pregnene compound or" Formula XIX to the correspond
pounds of Formula XII are converted to the 16(17 )-di
ing 11,8-hydroxy epimer is readily available by adapting
azomethane adducts of 6-?uoro (or chloro)-4,16-preg
the procedures disclosed in ‘US. Patent 2,968,655 for
nadiene-3,20‘-dione (XIII) by the method of Wettstein
an analogous synthesis. In a similar manner, a 16ot,170:—
cited in (1) (a), above; decomposition of the thus pro
methylene-lie-hydroxy-ll-pregnene (XIX) is converted to
duced adducts (XIII) to yield l6a,17et-methylcne-6u 35 the corresponding ll-keto compound (XIXa) by oxida
?uoro (or chloro)-4~pregnene—3,20-dione (V) is carried
tion, e.g., with chromic acid, vchromic anhydride or N
out in the manner disclosed in (1) (a) or (1) (b), above.
bromoacetamide in pyridine, according to the usual pro
([1) The compounds of Formula V, wherein R is ?uo
cedures, Well known in the steroid art; the thus produced
ing 6a-?uoro (or chloro) compound (XII). Oxidizing
rine or chlorine, can also be prepared 'by an alternative
method that does not entail the production of the 16(17)
4-pregnenes of Formula (X-IXa), e.g., 16a,17a-methyl—
ene-6-methyl-4-pregnene~3,11,20-trione (XIXa), 160:,17rx
diazomethane adduct (XIII) of (2) (a), above. This
process also utilizes the procedures of US. Patent 2,838,
528 for the substitution of a t?uoro (or chloro) atom at the
6-position of the steroid nucleus, but employs a starting
methylene-6~?uoro-4-pregnene - 3,11,20 - trione (XIXa),
16u,l7a-methylene - 6 - chloro-4-pregnene-3,l1,20-trione
(XIXa) are diketalized, e.g., with ethylene glycol and
p-toluenesulfonic acid to give, respectively, 16¢,I7a
material containing the 16a,17pt-methylene group. By 45 methylene-G-methyl - 4 - pregnene-Ii,11,20-trione 3,20-bis
following the procedures disclosed in (2) (a), above,
(ethylene ketal) (XIXb), 16a,l7ot-methylene-6-?uoro-4
16a,l7a-methylene-3f3-‘1ydroxy (or acyloXy)-5-pregnen
pregnene-3,1l,20-trione 3,20~bis(ethylene ketal) (XIXb)
20-one (XIV) (Ber. 93, 1714 [1960]) is converted to
and 1605,1705 - methylene - 6 - chIcro-4-pregnene-3,l1,20~
16a,17u-methylene - 35 ~ hydroxy (or 3p-acyloxy)-5a,6et
trione 3,20-bis(ethylene ketal) (XIXb); the compounds
oxidopregnan-ZO-one (XV); the compounds represented
50 of Formula XIXb are reduced to their corresponding
by Formula XV are transformed to IMAM-methylene
ll?-hydroxy analogues (XIXc), e.g., with lithium alumi
6/3-?uoro (or chloro)-3?-hydroxy (or acyloxy)-5alhy
num hydride; the compounds represented by Formula
droXypregnan~20-one (XVI), which in turn are converted
XIXc, such as 16a,17a-methylene~6-methyl-1l?-hydrony
to 16a,17ot-methylene-5u-hydroxy-6?-?uoro (or chloro)
4-pregnene-3,20-dione 3,20-‘bis0ethylene ketal) .(XIXc),
55
pregnane-3,20-dione (XVII); dehydration of 1604,17!!
16w,17e-methylene-6-?uoro - 11;? - hydroxy - 4-pregnene
methylene~5q-hydroxy-6B~?uoro (or chloro) pregnanc
3,2D-dione 3,20-bis(ethylene =ketal) (XIXc), and 160:,
3,20~dione (XVII) yields, respectively, 1-6ot,17a-6(a and
17a-methylene-6-chloro -’ 11,8 - hydroxy-4-pregnene-3,2=0
B)-?uoro-4-pregnene - 3,20 - dione (16u,17a-methylene-6
dione 3,204bis(ethylene ketal) (XIXc) are hydrolyzed,
(a and B)-?uoroprogesterone) (V) and 16a,17a-methyl
e.g., with a concentrated mineral acid such as sulfuric
ene-6a-chloroprogesterone (V).
60
to yield, respectively, 16a,17a-methylene-6m-methyl-l1,8
The novel 16a,1‘la-methylene-6-substituted progester
hydroxy-4-pregnene-3,20-dione (XIX), 1‘60t,170t-'methyI
ones (V) of this invention are converted to the unsat
ene-6a-iluoro-l1?-hydroxy-4-pregnene - 3,20-'dione (XIX)
and 16cc,170L-H13lhYl6Il8-6ot-Chl01‘0 - 11,6 - hydroxy-4-preg
urated derivatives thereof in accordance with the pro
cedures well known in the steroid art. The compounds
represented by Formula V when reacted with chloranil, 65
in the manner disclosed in J. Amer. Chem. Soc. 79, 1257
‘(1957), yield the corresponding 16u,17a-methylene-6
nene-3,20-dione (XIX).
\
The lla-hydroxy and ll?-hydroxy compounds repre
sented by Formula XIX can be converted to their ll-keto
counterparts (XIXa) by oxidation, e.g., with chromic
substituted-6-dehydroprogesterones (XVIII), e.g., 16cc,
\anhydride or N-bromoacetamide in pyridine, according to
17oc-methylene-6a-?uoro - 4,6 - pregnadiene _ 3,20 - dione
usual procedures.
(XVIII). The A4-6-compounds embraced by Formula
XVIII can be dehydrogenated with selenium dioxide to
,
.
Both the llot- and ll?-hydroxy compounds of Formula
XIX ‘can be converted in ‘known manner to their corre
give the corresponding Abbe-compound (XX), e.g., 16cc,
' sponding Qa-?uoro derivatives (XXV) by the series of
17m-methylene-6a-rnethyl - 1,4,6 - pregnatriene-3,20-dione
reactions disclosed in U.S. Patents 2,852,511, 2,923,722,
2,924,612 and 2,957,894. The methods described in the
(XX); preferably, they can be prepared by the 6-dehy
3,086,029
11
12
aforesaid patents involve dehydration of the ll-hydroxy
added in small portions over a period of about 20 minutes
group, e.g., with N-bromoacetamide and anhydrous sulfur
dioxide in pyridine or via the p-toluenesulfonate ester, to
'of aqueous 50% potassium hydroxide. The ether layer
to a stirred chilled mixture of 250 ml. of ether and 70 ml.
produce the corresponding MUD-compounds (XXII)
which are then treated with a hypohalous acid, e.g., N
bromoacetamide, N-chlorosuccinimide or N-iodosuccini
mide, in the presence of aqueous perchloric acid, to pro
was decanted and the water phase washed several times
with small fresh portions of ether. The combined ether
solutions of diazomethane thus prepared were diluted to
about 400 ml. with ether and 25 g. of 3?-hydroxy-6
duce the corresponding 9a-halo-11B-hydroxy compounds
methyl-5,16-pregnadien-20-one (6 - methyl - 16 - dehydro~
pregnenelone) (I) (prepared in the manner disclosed in
represented by Formula X)GII; reaction of the 1606,1706
methylene-9a-halo-1Its-hydroxy compounds (XXIII) with
10 Example 11 of US. Patent 2,871,246) added. After stir
a base, e.g., potassium acetate in acetone or sodium or
ring for a period of about 6 hours at room temperature,
the excess diazomethane of the reaction mixture was de
potassium hydroxide in methanol, yields the correspond
composed by dropwise addition of acetic acid. This solu
tion was washed successively with water, dilute hydro
chloric acid, dilute sodium bicarbonate and again with
with anhydrous or aqueous hydrogen ?uoride at below
water. After drying over magnesium sulfate, the solvent
room temperature produce the corresponding 9ot-?uoro
was removed leaving a crystalline residue. This product
ll?-hydroxy compounds represented by Formula XXV;
was triturated with acetone and then recrystallized from
the 16a,17u-methylene-9a-halo-1Iii-hydroxy compounds
acetone to yield 7.8 g. of material with a melting point of
of Formulae XXV and XXIII can be oxidized to their cor
responding ll-keto compounds (XXVI) with chromic acid 20 184 to 187° C. (with bubbling). A small amount of the
product was recrystallized to give the pure 16(17)-diazo
or chromic anhydride. By following the above proce
methane adduct of 3B-hydroxy-6-methyl-5,16-pregnadi
dures, representative 16a,17a - methylene - 11B - hydroxy
en-20-one, [3,B-hydroxy-6-methyl-l6a: 17Ot-(211 31-diazacy
compounds of Formula XIX are converted to their 9on
clcpent-21-eno)-pregn-5-en-20-one] (II) melting at 175 to
?uoro counterparts (XXV). In this manner,
25 180° C. and a rotation [04],) of +210 (chloroform).
16a,17a-methylene-11/3-hydroxy-4-pregnene-3,20-dione
ing 95,11?-epoxides embraced by Formula XXIV; reac
tion of these 16a,17u-methylene-9,B,1l?-epoxides (XXIV)
Analysis.—Calcd. for C23H34O2N2: C, 74.55; H, 9.25;
N, 7.56. Found: C, 74.31; H, 9.02; N, 7.82.
(XIX) ,
16a,17a-methylene-1 1 B-hydroxy-6u-methyl-4-pregnene
3,20-dione (XIX),
Example 2.—16a,17a-Methylene-3?-Hydroxy-6-Methyl
’16a,17a-methylene-1 1B-hydroxy-6a-?uoro-4-pregnene
3,20-dione (XIX),
16a,17ix-methylene-1 1B-hydroxy-6a-methyl-1,4-pregnadi
ene-3,20-dione (XIX),
160;,170t-In6thY16I16-1 1B-hydroxy-6a-chloro-1,4-pregnadi
ene-3,20-dione (XIX),
16u,17u-methylene-1 1 B-hydroxy-6-1nethyl-4,6-pregnadi
ene-3,20-dione (XIX),
16u,17ot-methylene-1 1,B-hydroxy-6-?uoro-4,6-pregnadiene
3,20-dione (XIX),
16,a17a-methylene-1lit-hydroxy-1,4,6-pregnatriene-3,20
dione (XIX),
S-Pregnen-ZO-One 3-Acetate (III)
1 ml. of boron tri?uoride etherate was added to a slurry
(cooled in an ice bath) of 2 g. of the diazomethane adduct
of 3?-hydroxy-6-methyl-5J6-pregnadien-20-one (II) in
10 ml. of acetone. The solution became clear in a few
35 minutes; after a period of about 30 minutes it was poured
into water and extracted with methylene chloride. The
extract was washed successively with water, dilute sodi
um hydroxide solution, again with water and dried. The
solvent was removed from the extract leaving a yellow
The residue was dissolved in 5
m1. of pyridine and 3 ml. of acetic anhydride added to
give a blood-red solution. This solution was warmed
to about 50° C. for a period of about 30 minutes, poured
into water and extracted with methylene chloride. The
extract was washed successively with dilute hydrochloric
acid, dilute sodium hydroxide and water. It was then
dried and poured onto a 150 g. column of Florisil (syn
40 non-crystalline residue.
16oz, 17a-methylene-1 1B-hydroxy-6-methyl-1,4,6-pregnatri_
ene-3,20-dione (XIX),
16u,17ot-methylene-11?-hydroxy-6-?uoro-1,4,6-pregnatri
cue-3,20-dione (XIX) and
16:1,170t-I1‘161hYl6116-1 1;8—hydroxy-6-chloro-1,4,6-pregnatri
ene-3,20-dione (XIX) yield, respectively,
16a,17ot-methylene-9a-?uoro-11?-hydroxy-4-pregneue~
thetic magnesium silicate) packed wet with Skellysolve B
(hexanes). The intense color of the methylene chloride
3,20-dione (XXV),
16a,17a-methylene-9a-?uoro-6ot-methyl-11/3-hydroxy-4
pregnene-3,20-dione (XXV),
16a,17a-methylene-6a,9a-di?uoro-11/3-hydroxy-4-preg
50 extract was absorbed in the ?rst two inches of the column.
Gradient elution with mixtures of 5 l. of 2% acetone
Skellysolve B, 5 l. of 10% acetone-Skellysolve B (400 ml.
portions) gave crystalline residues in fractions 4 and 5.
These ‘fractions were combined and recrystallized from
aqueous methanol to yield 20 mg. of 16w17tx-methylene
nene-3,20-dione (XXV),
16a,17ot-methylene-9ot-?uoro-6a-methyl-1 1?-hydroxy-1,4
pregnadiene~3,20-dione (XXV),
16a,17a-methylene-9or-?uoro-6ot-chloro-11,B-hydroxy-1,4
pregnadiene-3,20-dione (XXV),
16oz,17ot-methylene-9a-?uoro-6-methyl-1 1/8-hydroxy-4,6
pregnadiene-3,20-dione (XXV),
16a,17a-methylene-6,9a-di?uoro-11?-hydroxy-4,6-preg
nadiene-3,20-dione (XXV),
16a,17a-methylene-9a-?uoro-11?-hydroxy-1,4,6-pregnadi
3/3-hydroxy-6-methyl-5-pregnen-20-one 3 -acetate (III)
with a melting point of 136 to 141° C.
1733 and 1675 cm.-1 and (C=O) at 1240 cm.-1.
60 Neither terminal methylene nor Ans-methyl absorptions
were observed.
Analysis.—Calcd. for CZ5H3SO3: C, 78.08; H, 9.44.
Found: C, 78.74; H, 9.70.
ene-3,20-dione (XXV),
16a,17ot-methylene-9a-?uoro-6-m'ethyl-1 1B-hydroxy-1,4,6
pregnatriene-3,20-dione (XXV),
The infrared
spectrum of the compound shows absorption (C==) at
65
Example 3.-—16a,1 7a-Methylene-j’?-Hydroxy-?
M ethyl-5 -Pregnen-20-One (IV)
16a,17a-methylene-9a-?uoro-6-chloro-11B-hydroxy-1,4,6
pregnatriene-3,20-dione (XXV).
0.5 gm. of 16a,17a-methylene-3?-hydroxy-6-methyl-5
pregnen-ZO-one 3-acetate (III) in 20 ml. of methanol and
70 0.15 ml. of concentrated hydrochloric acid is re?uxed for
Example 1.—16(17)-Diaz0methane Adduct 0f 3,3-H a period of about 1 hour. About half of the methanol
dr0xy-6-Methy l-5 ,1 6-Pregnadiene-2 O-One [3?-Hydroxy
is evaporated under a stream of nitrogen. The product
6 -M ethyl-1 61x31 7a- (21:31-Diazacycl0pent-2 1-en0) -Pregn
is ?ooded out with Water, collected, dried and recrystal
5-En-20-0ne] (II)
lized from acetone to yield 1606,1705 - methylene - 3/3 - hy
25 g. of N-methyl-N-nitroso-N'-nitroguanidine was 75
droxy-6~methyl-5~pregnen-20-one (IV).
3,086,029
13
14
Example 4.—16ot,17<x - Methylene~6u-Methyl-4-Pregnene
.
Analysis.—Calod. for C23H32O2N2: C, 74.96; H, 8.75;
N, 7.60. Found: C, 75.06; H, 9.28; N, 7.88.
Following the procedure of Example 6, but substituting
4,16-pregnadiene-3,20-dione as starting material, yields
3,20-Dionie (16%] 7e-Methylene - 60¢ - Methylprogester
one) (V)
'
A solution of 5 g. of 16ml70¢methylene-3eahydroxy-6
the 16(17)-diazornethane adduct of 4,16-pregnadiene
3,20-‘dione.
methyl~5-pregnen-ZO-one (IV) in 15 m1. of cyclohexanone
‘and 35 ml. of toluene is boiled for a few minutes to re
move any traces of water and then 2.5 g. of aluminum
isopropoxide added. This solution is stirred under re?ux
for a period of about 35 minutes, cooled, diluted with a
little methylene chloride and then washed successively 10
with dilute sodium hydroxide, salt water, dilute hydro
Example 7.—] 6 (1,1 7or - Methylene-6 Ol-Methyl-4-Pregnene
3,20-Di0ne (.1 6 0a,] 7 a - Methylene-6 a-Methylprogester
one) (V) and 6a,] 6-Dimethyl-4,]6-Pregnadiene - 3,20
Diolze (611,1 6-Dimethy [-1 6 ~Dehydr0progesler0ne ) (Va)
1 g. of the 16(17)-diazomethane adduct of 6a-methyl
chloric acid and then twice with salt Water. The solution
is dried and then chromatographed on a 200 g. column
of Florisil. The product is eluted with mixtures com
4,16~pregnadiene-3,20-dione (VII) was added in portions
methyl-4-pregnene-3,20 dione (V).
methylene chloride. The extract was successively Washed
with Water, dried, ?ltered and chromato-graphed on a 200
to a solution of 0.4 ml. of 70% perchloric acid in 21 ml.
prising Skellysolve 13 containing 6 to 8% of acetone; 15 of acetone at a temperature of about 50° C. Several
minutes after the addition of the last portion, the solu
recrystallization from a mixture of hexanes and acetone
tion was cooled, poured into ice-Water and extracted with
yields light-colored, crystalline 16oc,l7ct - methylene - 6a
Example 4A .—16or,17a-Met/zylene-4-Pregnene-3,20
Dione (16%] 7a-Merhyleneprogesterone) (V)
20 g. column of Florisilpacked wet with Skellysolve B.
Gradient elution with 5 l. of 2% acetone in Skellysolve
B and 5 ‘l. of 8% acetone in Skellysolve B (400 ml. frac
tions collected) gave the desired cycloprop'ane in frac
Following the procedure of Example 4, but substituting
16a, 170a - methylene-3B-hydrcxy-S-pregnen-20-one (XIV) .
(Ber. 93, 1714 [1960]) as starting material, yields 16a,
17ot-rrrethylene-4—pregnene-3,ZO-dione (V).
tions 15 to 19. These fractions were combined and re
25 crystallized from a mixture of acetone and Skellysolve B
to yield 0.43 g. of product melting at 136 to 139.5 ° C.
Example 5 .—-6 oc-Methyl-4,] 6-Pregnadiene-3,20-Di0ne
(6 a-M’ethyl-1 6-D ehydroprogesterone) ( VI)
Another recrystallization from the same pair of solvents
gave 0.35 1g. of 16a,17a-methylene-6a-methyl-4-pregnene
3,20-‘dione (V) with a melting point of 138 to 140° C.,
A solution of 5 g. of 3,6-l1ydroxy-6-methyl-5,16-pregna
'
dien-20-one (I) in 15 ml. of cyolohexanone and 35 ml. of 30 rotation [rd]; of +188“ (chloroform),
toluene is boiled for a few minutes to remove any traces
k312i?“ 241 mp (e=16,350)
of water and then 2.5 g. of aluminum isopropoxide added.
and ‘a negative ttetranitro‘methane test.
This solution is stirred under reflux for a period of about
Analysis.—-Calcd. for C23H32O2: C, 81.13; H, 9.47.
35 minutes, cooled, diluted with a little methylene chlo 35 Found: C, 81.47; H, 9.57.
ride and then Washed scccessively with {dilute sodium hy
Fractions 21 to 26 contained the A16-16-methyl product
droxide, salt water, ‘dilute hydrochloric acid and then
and were combined and recrystallized three times from
twice with salt water. The solution is dried ‘and ten
a mixture of acetone and Ske'llysolve B to yield 30 mg.
chromatographed on a 200 g. column of Florisil.
The
of 6u,l6~dimethyl-4,16-pregnadiene—3,20~dione (Va) with
product is eluted with mixtures comprising Skellysolve B 40 a melting point of 189 to 192° C.,
containing 6 to 8% of acetone; recrystallization from a
Antonin 2435 my, (e=23,845)
mixture of hexanes and acetone yields light-colored, crys
and ‘a positive tetranitromethane test.
talline 6ix-methyl-4,l6¢pregnadiene-3,20;dione (VI).
Following the procedure of Example 5, but employing
Analysis.—-Calcd. for C23H32O2: C, 81.13; H, 9.47.
Found: C, 81.27; H, 9.45.
3,8-hydroxy-5,l6-pregnadien-20-one as starting material,
yields 4, 1 G-pregnadien-3,20-dione.
45
Example 8. - 16 - Dehydro - 3l8-Hydroxy-5a?a-Oxiclo
pregmzn - 20 - One (16 - Dehydr0-5u,6a-Oxid0preg
Example 6.-—16(17)-Diaz0methane Adduct of Get-Methyl
nenelone) (IX)
4,16 - Pregnadiene - 3,20 - Dione [6a-Methyl-16az17a
‘
(21:31 - Diazacyclopent - 2l - E110) - Pregn-4-Ene-3:20
Dione] (VIZ)
50
' .
.
A reaction mixture comprising 20 g. of the known
compound l6-dehydropregnenelone (-‘3?g-hydroxy-5,l6
pregnadiene-ZO-one) (VIII), 4 g. of anhydrous sodium
27.5 g. of N~methyl-N-nitroso-N’-nitroguanidine was
added in small portions over a period of about 20 minutes
to a stirred chilled mixture of 270 ml. of etherand 75
acetate, and 20 ml. of 40% peracetic acid in 400 ml. of
chloroform is stirred 2 hours at a temperature between
‘ml. of aqueous 50% potassium hydroxide. The ether 55 about 0° to 4° C. The reaction mixture is then washed
with water and aqueous sodium bicarbonate and evapo
layer was decanted and the water phase Washed several
rated to near dryness. The residue thus obtained is
times with small fresh portions of ether. The combined
ether solutions of diazomethane thus prepared was diluted
to about 500 ml. with ether and 20 g. of 6ot-methyl-4,16
pregnadiene~3,20-dione (owmethyl- 1 65d'ehydroprogester
one) (VI) added.
After stirring at room temperature
for about 18 hours, ‘the excess diazo‘methane was decon -
60
crystallized from a mixture of methylene chloride and
acetone to give the desired product. Recrystallization
from the same solvent pair yields crystalline 16-del1ydro
3/3-hydroxy-5a,6ot-oxidopregnan-20~one (IX).
Example 9. - 16 - Dehydro - 3?-ACEZ‘OXY-5ot,6u-O.Xid0‘—
posed by dropwise addition of acetic acid. The reaction
pregnan - 2010112 (16 - Dehydro-Sa,6a-Oxid0pregnen
mixture was washed with water and dried. After removal
elone 3?-Acetate (IX)
of the solvent, the residue was .triturated with ether and 65
16-dehydropregnenelone 3e-acetate (3{3-acetoxy-5,16
crystallized from acetone to give 12.2 g. of the product
pregnadiene-ZO-one) (VIII) is treated with peracetic acid
melting at 159 to 162° C. (decomposition). Two further
in the same manner as described in Example 8 to give
crystallizations from acetone yielded the pure product,
the l6(17)-diaZomethane adduct of 6u-methyl-4,16-preg
16-dehydro-3p-acetoxy-5u,6a-oxidopregnan~20-one (IX).
Alternatively, l6~dehydro-3B-acetoxy-5a,6a-oxidopreg
nadiene-3,20-dione [6tt-methyl-l6ml7a .- (21:31-diazacy 70 nan-20-one (IX) is obtained in nearly quantitative yield
olopent 7 21- eno)~pregn-4-ene-3:ZO-dione] (VII) with a
‘melting point 015159 to 162°_ C. (decomposition), rota
tion [ajD of +137 (chloroform) and
“1321101 239 m” (€=16,950)
by treating 16-dehydro-3B-hydroxy-5a,6a-oxidopregnan~
20-one (IX) (from Example 8) with acetic anhydride
in pyridine.
Similarly, other 3/3-esters of 16-dehydro-313-hydroxy
75 5oz,6zx-0Xid0131‘6gn?D-20-On6 (IX) are prepared by treat
3,086,029
16
ing the corresponding unesteri?ed 3?-hydroxy compound
anol and 0.1 ml. of boron tri?uoride-etherate is heated
under re?ux for about ?fteen minutes, then is concen
trated to 1 ml. and diluted with water to give 75 milli
grams of a precipitate consisting of crude l6-dehydro
in pyridine solution with the anhydride or acyl halides
of organic carboxylic acids, particularly hydrocarbon
carboxylic acids containing from one to twelve carbon
6I3-?uoro-3{3,5ot-dihydroxy-pregnan-ZO-one (X).
atoms, inclusive. Representative 3,8-esters thus prepared
include in particular, the propionate, butyrate, isobuty
rate, valerate, isovalerate, hexanoate, heptanoate, octano
Example 13.—-16 - Dehydro-o?-chlore-3,6,5a-Dihydr0r -
pregnan-ZO-One (X)
ate, benzoate, phenylacetate, phenylpropionate, propi
olate, crotonate, B-cyclopentylpropionate, tertiary butyl
A solution of 6 g. of 16-dehydro-3?-hydroxy-5m,6ot
oxidopregnan-20-one (IX) (prepared as in Example 8) in
acetate, toluate, 2-furoate, benzenesulfonate, toluene
sulfonate, and the like of 16-clehydro-3?-hydroxy-5a,6a
50 ml. of chloroform is cooled in an ice-salt bath and
saturated with gaseous hydrogen chloride. After a period
of about one hour, the reaction mixture is purged with
oxidopregnan-ZO-one (IX).
Example 10.—1 6 -D ehydr0-6,E3-Flu0r0-3 p-A cetoxy-S a
Hydroxypregnan-ZO-One (X)
In a ?fty ml. polyethylene bottle cooled with a Dry Ice
acetone mixture is placed 6.9 g. of anhydrous hydrogen
?uoride, followed by slow addition of 5 ml. of chilled
chloroform (stabilized with a trace of alcohol) and 13.24
ml. of tetrahydrofuran. To this is added 4 g. of 16
nitrogen.
The reaction mixture is then washed with
15 water, dilute sodium carbonate solution and again with
water and then dried over magnesium sulfate. The sol
vent is evaporated leaving an amorphous residue of 16
de'nydro - 65-chloro-3?,Sa-dihydroxypregnan-ZO-one (X)
which retained chloroform is a solvated form. This resi
due can be used without further puri?cation in Exam
le 15.
dehydro-3,8-acetoxy-5ot,6ot-oxidopregnan-20-one (IX) in
P If desired, by drying at 60° C. to 100° C. under reduced
pressure, the chloroform solvate of l6-dehydro-6?-ch1oro
25 ml. of chilled chloroform giving a violet solution which
was kept for two hours at ~10° C., then poured into
excess aqueous sodium bicarbonate with stirring. The
313,5a-dihydroxypregnan-ZO-one (X), described above,
is converted to 16—dehydro—6?-chloro-3?,Sa-dihydroxy
thus obtained mixture is extracted With methylene chlo
pregnan-ZO-one (X).
Example I4.—-—16-Ddhydro-5a-Hydr0xy-6/3-Flu0r0preg
name-3,20-Di0ne (XI)
ride and the methylene chloride solution was washed with
water and evaporated to dryness. The residue thus ob
tained is crystallized from methylene chloride-ethyl ace
tate mixture to yield light-colored crystalline 16-dehydro
One gram of 16-dehydro-3?,5a-dihydroxy-??-?uoro
pregnan-ZO-one (X) is added to 25 ml. of acetic acid and
immediately 1 g. of sodium dichromate dihydrate dis
solved in 10 ml. of acetic acid is added while the reaction
6/3-?uoro-3?-acetoxy-Su-hydroxypregnan-20-one (X).
Similar results are obtained using smaller amounts of
hydrogen ?uoride as shown in the following procedure.
A mixture of 0.60 g. of anhydrous hydrogen ?uoride
mixture is stirred and cooled in a cold water bath. The
and 2.80 g. of 16-dehydro-3B-acetoxy-5a,6a-oxidopreg
reaction mixture is allowed to stand about 18 hours at
35
nan-ZO-one (IX) in 24 ml. of methylene chloride is kept
room temperature, then 2 ml. of methanol is added to
for about four hours at room temperature, then 0.6 ml.
destroy excess oxidant and the reaction mixture is poured
of pyridine is added and the mixture is evaporated to
into water to give crystalline 16-dehydro-5a-hydroxy-6B
dryness. The thus obtained residue is triturated with
ether to give crystalline 16-dehydro-6B-?uoro-3/3-acetoxy
5ot-hydroxypregnan-20-one (X).
?unropregnane-3,20-dione (XI).
40
Example 15.---] 6 -Dehydro-5 a-Hydroxy-6IS-Chloro
pregnane-3,20-Di0ne (X1)
Example 11.--16-Dehydro-QB-Chl0r0-3p-Acetox1y-5u
Hydroxypregnan-ZO-One (X)
To the residue of 16-dehydro~6B-chloro-3?,Sa-dihy
droxypregnau-ZO-one (X) from Example 13, 6 g. of
sodium dichromate in 60 ml. of acetic acid is added with
A slow stream of gaseous hydrogen chloride is passed
through a solution of 4 g. of l6-dehydro-3l8-acetoxy 45 cooling in a cold water bath. The thus obtained solu
5a,6a-oxidopregnan-20-one (IX) in 50 ml. of ice-cold
tion is allowed to stand without further cooling for about
methylene chloride for a period of about 1 hour. The
2 hours and yields a precipitate. The thus formed pre
resulting solution is allowed to stand at room tempera
cipitate is collected, ?rst washed with acetic acid, then
ture for a period of about 4 hours then neutralized with
ether and dried. The thus obtained residue is recrystal
pyridine. The methylene chloride is removed by evapo
lized from ethyl acetate-acetone to yield light-colored,
ration and to the slurry thus obtained, water is added.
The mixture thus obtained is ?ltered and the solid mate
rial remaining is washed thoroughly with water. The
solid material is then recrystallized from acetone to yield
light-colored, crystalline 16~dehydro-6,o-chloro-3341cc
toxy-5u-hydroxypregnan-20-one (X).
crystalline 16 - dehydro - 5o: - hydroxy - 6,3 - chloropreg
nane-3,20-dione (XI).
xample 16.--6;3 - Fluoro - 4,16 - Pregnadiene - 3,20
55
Dione and 6ot-Flu0r0—4,16-PregnadieIze-3,20-Dione (16
Dehydr0-613-Flu0ropr0gester0ne and 16-Dehydr0-6u
Fl uoroprogesterone) (XII)
Two grams of 1‘6-dehydro-5a-hydroxy-6/S-?uoropreg
nane-3,20-dione (XI) is suspended in 200 milliliters of
A mixture of 7.3 g. of anhydrous hydrogen ?uoride 60 chloroform (containing 0.75 percent alcohol) at room
in 5 ml. of chloroform and 14 ml. of te-trahydrofuran is
temperature and anhydrous hydrogen chloride gas passed
cooled in a Dry Ice-acetone bath and a solution of 4 g.
through the mixture for about thirty minutes. After
of 16 - dehydro - 3B-hydroxy-5a,6ot-oxidopregnan-20-one
two minutes, a pale yellow solution is obtained. Follow
(IX) in 25 ml. of chloroform is added. This reaction
ing the hydrogen chloride treatment, a stream of nitro
mixture is kept at -10° C. for about 2.5 hours and is 65 gen is passed through the solution for about ?fteen min
then poured into excess aqueous sodium bicarbonate solu
utes, and the solution is then washed with cold water and
tion. The resulting mixture is extracted with methylene
with ?ve percent aqueous sodium bicarbonate. The thus
chloride and the methylene chloride extract washed with
obtained chloroform solution is evaporated and gives as
water and evaporated to give a solid residue, which is
residue a pale glass. The crude mixture is placed on
recrystallized from methanol-ethyl acetate mixture to 70 80 g. of Florisil (synthetic magnesium silicate) and
give 16 - dehydro-6B-?uoro-3?,Sa-dihydrQXy-pregnan-ZO
eluted with 250-milliliter fractions of acetone in petro
one (X).
leurn ether (thirty to sixty degrees). With four to ?ve
In an alternative method of preparation, a mixture of
percent acetone, a mixture of l6-dehydro-6u-?uoroproges
100 mg. of 16-dehydro-6/8-?uoro-3?-acetoxy-5ot-hydroxy—
terone (XII) and 16-dehydro-6,8-?uoroprogesterone
pregnan-ZO-one (X) from Example 10, 2.5 ml. of meth 75 (XII) is obtained ‘which on fractional crystallization from
3,086,029
17
a mixture of ether and Skellysolve B hexanes gives pure
Example 21.--16(‘17)-Diaz0methane Adduct of 6a
I6-dehydro-6?-?uoroprogesterone (XII), and iii-dehydro
6ot-?uoroprogesterone (XII).
Chl0r0-4,16-Pregnadiene-3,20-Dione
[6otéChl0r0-1 61x.’
17a--‘ (21:31 - ‘Diazacyclopent - 21 - Eno - Pregn - 4
Ene-3r20-Dione] (XIII )
Example 17.-—I6-Dehyclr0-6?-Flu0r0progesterone (XII)
Following the procedure of Example 20,‘ but substitut
Two grams of 1-6-dehydro-5e-hydroxy-6p~?uoropreg
ing 6a-chloro-4,16'-pregnadiene-3,‘20‘édione (XII) (pro~
name-3,20-dioi1e (XI) suspended in 400 ml. of 95 per‘
duced in the manner disclosed'in Example 19) as starting
cent ethanol containing nine drops of concentrated hy
material, yields the 16(17)-diazomethane adduct of 6a
drochloric acid is re?uxed for about ?fteen minutes, and
‘chloro-4,ll64pregnadiene-3,ZO-dione (XIII).
'
100 ml. of dioxane and six drops of concentrated hydro 10
Example 22 .}—1 6_11,1 7a-Methylene-6m-Flu0r0-4-Pregnene
chloric acid are then added and the starting material
dissolved. The solution is heated at re?ux for about two
and one-half hours, and aliquots are taken which show
by melting points that practically no dehydration occurs.
Qne ml. of concentrated hydrochloric acid is then added
to the reaction mixture‘and re?uxing is continued for
about an additional three and one-half hours. The mix
ture is then concentrated to one-half volume by evapora
tion under diminished pressure, diluted with 100 ml. of
3,20 - Dione (160a,.l7ot - Methylene - 6a - Fluoroproges
rerone) (V)
1 g. of the 16(17)-diazom'ethane adduct of '6tx-?ll0l‘0
4,16-pregriadiene-3,20-dione (XIII) is added in portions
to a solution of ‘0.4 ml. of 70% perchloric acid in 20 ml.
of acetone at a temperature of about 510° C. Several
minutes after addition of the last portion, the solution is
cooled, poured into'ice water and extracted with methyl
water, and further concentrated until crystallization oc
‘en-e vchloride. The extract is successively washed with
Water, dried, ?ltered and chromatographed on a 200 g.
curs, giving a mixture which on fractional crystallization
from a mixture of methylene chloride and methanol
column Florisil packed'wet with Skellysolve B. Gradient‘
*elution with s 1. of 2% acetone'in Skellysolve B and
Example 1 8.-—] 6-D ehydro-6ot-Flu0ropr0gester0ne (XII ) 25 5 l. of 8% acetone in'Skelly's‘olve B (400 ml. fractions
collected) ‘gives the desired cyclopropane product. The
From 1 6-D ehydro-6,8-Flu0r0pr0gester0ne (XII )
fractions containing this product. are combined and re
A solution of 16-dehydro-6,8-fluoroprogesterone (XII)
crystallized from a mixture of acetone and Skellysolve
in a mixture of ethanol and aqueous hydrogen chloride is
B to yield‘pure crystalline 16a,17a-methylene-6a-?uor0
'
heated under reflux for about thirty minutes, and the mix 3.0 ‘4-pregnene-3,20-dione (V).
ture is then poured into a large excess of water and the
Following the procedure of Example 22, but employing
precipitated material ‘collected by ?ltration and recrystal
the 16(17),-diazonrethane adduct of 6/3-?uoro-4,16-preg
lized to give pure 16~dehydro-6a-fiuoroprogesterone
nadiene-3,20-dione (XIII) (produced in'the manner dis
gives crystalline 1i6-dehydro-6/8—?uoroprogesterone (XII).
(XII).
closed in Example 20) as starting material, yields crystal
'
35 lii'ie IMAM-methylene -‘ 6/3 -' lluoro-4~pregnene-3,20-dione
1 Example 19.—-6a~Chl0r0~4,16-Pregnadiene-3,2O-Dione
(V).
(1 6-Dehydr0-6u-Ci2loroprogesterone) (X11 )
Example 23 .—-1 6 04,1 7a-Methylene-6a-Chloro-lI-Pregnene
A solution of 4 g. of 16-dehydro-5a-hydroxy-6p-chloro
pregnane~3,20i-dione (XI) (prepared in the manner dis 40
closed in Example 15) in 50 ml. of chloroform and 0.5
ml. of absolute ethanol is cooled in an ice-salt bath and
saturated with gaseous hydrogen chloride.
After a
3,20-Di0ne (1 6 0a,] 70t-Methylene - 6 0t - Chloroprogester
; one) ( V)
Following the procedure of Example 22, but substi
tuting the 16(-.1'.7)-diazomethane,adduct of dot-chloro
4,16—pregriadiene-3,ZO-dione (XIII) (from Example 21)
period of about 3 hours, the reaction mixture is removed
as starting material, yields ‘crystals of 16a,17a‘-methylene
from the cooling bath and'purged with nitrogen. The
reaction mixture iswashed with water, then dilute aque 45 ~6d-chloro-Zl-pregnene-3,20edione (V).
ous sodium bicarbonate solution, dried over magnesium
Example 24.—-16a,1 7a-ll/Iethylene - 3B - HydrOxy-Sa?u
sulfate and the solvent evaporated to give a residue.
Qxidopregnan - 20 - One (160:,170; - Methylene-Smoot
The thus obtained residue is then crystallized twice from
Oxidopregne'nelone (XV)
p a mixture of acetone and Skellysolve B to yield 16-dehy
50 . A reaction ‘mixture comprising 20 3g. of 160:,17oc
dro~6u-chloroprogesterone (XII).
methylene-3 18-hydroxy-5 -pregnen-20-one ( 1 6ot,17ot-II16II1
ylenepregnenelone) (XIV) (Ber. 93, 1714 [1960]’), 4 g.
Example 20.—16(17)-Diaz0methane Adduct of 60:
Floom-4 ,1 6 -Pregnadiene-3,2 O-Dione
[6a-Fluoro-l 6a.‘
of 'anhydrous'sodium acetate and 20 ml. of 40% per
acetic ‘acid in 400 ml. of chloroform is stirred 2 hours
17cc - (21:31 -Diazacycl0pent - 2l - Eno) - Pregn - 4 -
Ens-3:20-Dione] (XIII)
5.5 at a'temperature between about 0° to 4° C. The reac
tion- mixture is vthen washed with water and aqueous
sodium ‘bicarbonate and evaporated to near dryness. The
An ether. solution of diazomethane (prepared in the
manner described in Example ‘6) is diluted to about 500
ml. with ether and 20 g. of 6a-?uoro-4,li?-pregnadiene
thus obtained residue is crystallized from a mixture of
methylene chloride and acetone to give the desired prod
3,20 -‘ dione (16 - dehydro - 6a - ?uoroprogesterone) 60
uct. Recrystallization from the same solvent pair yields
(XII) (produced in the manner disclosed in Examples 16
16a,17a-methylene-3B-hydroxy - 501,60; - oxidopregnan
or 18) added. After stirring at room temperature for
20-one
(XV).
about 18 hours, the excess diazomethane is decomposed
by dropwise addition of acetic acid. The reaction mix
‘Example 25.—-16ot,17oc - Methylene - 3B - AC€fOXy-5ot,6ct
ture is, washed with water and dried. After removal of
the solvent, the residue is triturated with ether and crys—
tallized from acetone to give the ‘16(17)-diazomethane
6.5
Oxidopregnari- - 20 - One (160:,17a - Methylene-Smoot
Oxidopregnenelone 3B-Acetate) (XV)
adduct’ of v6a-l‘luoro-4,l6_pregnadiene~3,ZO-dione [6a
16a,17¢x-methylene - ‘3/8 - acetoxy - 5 -*pregnen-20-one
“?uoro - 16oc1l7ot - (21:3l - diazacyclopent - 21 - eno)
(16e,17or-methylenepnegnenelone 3?-acetate) (XIV) (Ber.
pregn~4-ene-3 : ZU-dione] (XIII) .
Following the proceduretof Example 20, but employ
ing 6/3-?uoro~4,l'6-pregnadiene-3,20—dione (XII) (pro
duced in the manner disclosed in Example 17) as starting
material, yields the 16(l7)-diazomethane adduct ofo?
?uoro-4,16-pregnadiene-3,20-dione (XIII).
70 93, 1714 [1960]) is treated with peracetic acid in the
same manner as described in Example 24 to give 160:,17a
rnethylene~3B-acetoxy-Su,6a~oxidopregnan-20-one (XV).
Alternatively, 16a,l7a-methylene - 35 '- acetoxy-5a,6oc
oxido'pregnan-20éone (XV) is obtained in nearly quan
75 titative yield by treating 16a,l7a-methylene~3[3-hydroxy
3,086,029
20
19
5u,6a-oxidopregnan-20-one (XV) (‘from Example 24)
gesterone (V) and l6a,l7a-methylene-6a-?uoroproges
with acetic anhydride in pyridine.
Similarly, other 3;8-esters of 16a,l7a-methylene-3?
hydroXy-Sa,6a-oxidopregnan-20-one (XV) are prepared
by treating the corresponding unesteri?ed BB-hydroxy
compound in pyridine solution with the anhydride or acyl
halides or organic carboxylic acids, particularly hydro
terone'(V).
Example 33.—I6a,1 7a-Methylene-613$luoroprogesterone
(V)
carbon carboxylic acids ‘containing from one to twelve
3,20-dione (XVII) (from Example 30) as starting mate
Following the procedure of Example 17, but substitut
ing l6a,l7a-methylene - 5a - hydroxy-6?-?uoropregnane
rial, yields crystalline, 16a,17a-methylene-6?-?uoropro
prepared include in particular, the propionate, butyrate, 10 gesterone (V).
isobutyrate, valerate, isovalerate, hexanoate, heptanoate,
Example 34.—16a,1 7a-Methylene-6a-Flu0r0pr0gester0ne
octanoate, benzoate, phenylacetate, phenylpropionate,
(V) From I 6a,] 7a-Methylene-6p-Flu0r0progester0ne
propiolate, crotonate, p-cyclopentylpropionate, tertiary
(V)
butylacetate, toluate, 2-furoate, benzenesulfonate, tolu
Following the procedure of Example 18, but substitut
enesulfonate, and the like of 16a,17a-methylene-3/3-hy 15
ing 16a,17a-methylene-6?-?uoroprogesterone (V) (from
droxy-5a,6a-oxidopregnan-20-one (XV).
carbon atoms, inclusive. Representative 3,8-esters thus
Examples 32 or 33) as stalting material, yields light
colored crystals of 16a,l7a-methylene-6cz-?uoroproges
Example 26.-—I6a,17a-Methylene-613-Fluoro-3?-Acetoxy
terone (V).
5 a-Hydroxypregnan-ZO-One (XVI)
20
Example
35 .—1 6a,] 7a-Methylene-6 a-Chl0r0-4-Pregnene
Following the procedure of Example 10, but substitut
3,20-Di0ne (I6a,I7a-Methylerze - 6a - Chloroprogester
ing 16a,l7a - methylene-3?-acetoxy-5a,6a-oxidopregnan
20-one (XV) (from Example 25) as starting material,
one (V)
yields crystalline 16a,17a-methylene-6B-fluoro-3/3—acetoxy
5a-hydrOXy-pregnan-ZO-one (XVI).
Example 27.—16a,1 7a-Methylene-6p-Chloro-S?-Aeetoxy
Following the procedure of Example 19, but substitut
25 ing 16a,l7a-methylene - 5a - hydroxy-6?-chloropregnane
3,20-dione (XVII) (from Example 31) as starting mate
rial, yields pure 16a,17a-methylene-6a-ehloroprogester
5 oc-Hydroxy pregnan-ZO-One (XVI)
(Following the procedure of Example 11, but substitut
one (V).
Example 36. — 1604,]7a-Methylene-4,6-Pregnadiene-3,20
ing 16a,17a ~ methylene-3?-acetoxy-5a,6a-oxidopregnan
20-one (XV) (from Example 25) as starting material, 30
Dione (l6a,l7a-Methylene - 6 - Dehydroprogesterone)
yields light-colored, crystalline l6a,17a-methy1ene-6?
(XVIII)
chloro-S?-acetoxy-Sa-hydroxypregnan-20-one (XVI).
A solution of 12 g. of l6a,l7a-methylene-4-pregnene
Example 28.——I6a,17a-Methylene - 613 - Fluor0-3B,5a-Di
lzydroxypregnan-ZO-One (XVI)
3,20-dione (V) (fro-m Example 4A) and 10 g. of chloranil
35 in 500 ml. of tertiary amyl alcohol is refluxed for a period
of about 4.5 hours. The tertiary amyl alcohol is then
Following the procedure of Example 12, but substitut
ing
distilled under vacuum in a nitrogen atmosphere. The
residue is dissolved in methylene chloride and then shaken
16a,17a-methylene-3B-hydroxy-5a,6a-oxidopregnan
20-one (XV) (‘from Example 24) as starting material,
yields light-colored crystals of 16a,l7a-methylene-6?
with dilute sodium hydroxide. The precipitate that forms
is separated by ?ltration through diatomaceous earth.
The organic phase of the ?ltrate is separated and washed
with dilute sodium hydroxide, water and then dried. The
solvent is distilled leaving a residue (crude and crystal
?uoro-35,5a-dihydroxypregnan-20-one (XVI).
Example Z9.—]6oc,l 7u-Methylene - 6B - Chl0r0-3l3,5a-Di
hydroxypregnan-ZO-One (XVI)
Following the procedure of Example 13, but substitut
ing
16a,17a-methylene-3B-hydroxy-5a,6a-oxidopregnan
line) which after puri?cation by chromatography through
45
20-one (XV) (from Example 24) ‘as starting material,
a Florisil column and crystallization gives l6a,17a-meth
y1ene-4,6-pregnacliene-3,20-dione (XVIII).
Example 37.-—16a,1 7a-Methylene-6-Methyl-4,6 ~ Pregna
yields 16a,l7a - methylene - 6p - chloro-3B,5a~dihydroxy
diene-3,20-Di0ne (16a,1 7a-Methylene-6-Methyl-6 - De
pregnan-ZO-one (XVI).
lzydroprogesterone) (XVIII)
Example 30.--1‘6a,1 7a-Methylene-5 a-Hydroxy-6?-Fluoro 50
pregnane-3,20-Di0ne (XVII)
Following the procedure of Example 36, but substituting
I16a,17a~methylene-6a-methyl-4-pregnene-3,20 - dione (V)
(from Example 4) as starting material, yields light-colored
Following the procedure of Example 14, but substitut
crystalline, 16a,17a-methylene-6-methyl-4,6-pregnadiene
ing 16a,17a-methylene - 618 - ?uoro-3l3,5a-dihydroxypreg
nan-20-one (XVI) (from Example 28) as starting mate 55 3,20-dione (XVIII).
rial, yields crystalline 16a,17a-methylene-5oc-hydroxy-6l3
?uoro-pregnane-3,20-dione (XVII).
Example 38.—-16a,17a-Methylene-6-Fla0ro - 4,6 - Pregna
dz'ene—3,20-Di0ne (16cc,] 7 a-Methylene-6a-Flu0r0-6-De
hydroprogesterone) (X VIII)
Example 31.—16a,17a - Methylene-5a-Hydr0xy-6?-Chl0—
r0pregnane-3,20-Di0ne (XVII)
Following the procedure of Example 15, but substitut
60
Following the procedure of Example 36, but substituting
16a,l7a-methylene-6a-?uoro-4-pregnene-3,20 - dione (V)
ing l6a,17a-methylene - 6/3 - fluoro-3/3,5a-dihydroxypreg
(‘from Example 22) as starting material, adding 20 g. of
nan-ZO-one (XVI) (from Example 29) as starting mate
calcium carbonate to the reaction mixture and re?uxing it
for about 24 hours in an oxygen~free atmosphere, yields
rial, yields light-colored, crystalline 16a,17a-methylene
5a-hydroxy-6i9-chloropregnane-3,20-dione (XVII).
Example 32 .—160c,1 7a-Metlzylene-6/3-Fla0r0-4-Pregnene
65
light-colored crystalline, 16a,17a-methylene-6-?uoro-4,6
pregnadiene-3,20~dione (XVIII).
3,20-Di0rze and 16a,1 7a-Methylene-6a-Flu0ro-4-Preg
Example 39.——I6a,17a-Methylene-6-Flaoro - 4,6 - Pregna
nene-3,20-Di0ne (1 6a,] 7a-Methylene-??-Fluoroproges
diene-3,20-Di0ne (I 604,] 7a-Methylene-6-Flu0r0-6 - De
terone and 1 6a,] 7 a-Methylene-6 a-Fluoroprogesterone)
(V)
70
hydroprogesterone) (XVIII)
Following the procedure of Example 38, but substituting
Following the procedure of Example 16, but substitut
16a,17a-methylene-6?-?uoro-4-pregnene-3,20 - dione (V)
ing 16a,17a-methylene - 50c - hydroxy-6?-?uoropregnane
(from Example 22) as starting material, yields crystalline
3,20-dione (XVII) (from Example 30) as starting mate
l6a,l7a-met-hylene'6-?uoro-4,6-prcgnadiene - 3,20 - dione
rial, yields crystalline 16a,17ot-IllCthYlCIl?-??-IIUOIOPIO 75 (XVIII).
3,086,029
21
(from Example 23) as starting material, yields pure crys
talline 160i,17a-methylene-6e-chloro-l,4-pregnadiene-3,20'
dione (XXI).
dierte-3,20-Di0ne (16a,]7a-Methylene~6-Chl0r0-6 - De
hytlroprogesterone) (X VH1 )
Following the procedure of Example 36, but substituting
Example 46._16o:,17d - Methylene - 1,4,6 - Pregnatriene
l16a,17m-n1ethylene~6oechloro-4-pregnene-3,20 - dione (V)
3,20-Dione (16%] 7a-Methylene-1 ,6 - Bisdehydroproges
(from Example 23) as starting material, yields light
terone) (XX)
colored, crystalline, 16a,17a-methylene - 6 - chloro - 4,6
A mixture containing 101 g. of 16a,l7oc-methylene-4,6
Pregnadiene-iZO-dione (XVIll) .
‘Example 41 .—16ot,17a-Metltylene~1,4-Pregnadiene - 3,20
Dione (16%] 70c - Methylene - 1 - Dehydroprogesterone)
(XXI)
pregnadiene-3,20-dione (XVIII) (from Example 36), 500
10 ml. of tertiary butyl alcohol, 5 ml. of glacial acetic acid
and 4 g. of selenium dioxide is warmed at reflux for 24
hours. An additional 4 g. portion of selenium dioxide is
A mixture containing 10 g. of 16u,17a-n1ethylene-4
added and warming is continued for another 24-hour '
period.
pregnene-3,20-dione (V) (from Example 4A), 500 ml. of
tertiary butyl alcohol, 5 ml. of glacial acetic acidand 4 g.
The reaction mixture .is cooled and ?ltered. The ?l
trate is concentrated to about 150 ml., then slowly diluted
with 850 ml. of water. The resulting precipitate is iso
‘lated by ?ltration. The precipitate is dissolved in 300
ml; ofethyl acetate, then washed with four lOO-ml. por
of selenium dioxide is warmed at re?ux for a period of
about 24 hours. An additional 45g. portion of selenium
dioxide is added and‘ warming is continued for another
24Jhour period.
The reaction mixture is cooled and ?ltered. The ?l 20 tions of freshly prepared cold ammonium sul?de, dilute
trate is concentrated to about 150 ml., then slowly diluted
ammonium hydroxide, water, dilute hydrochloric acid and
with 850 ml. of water. The resulting precipitate is isolated
water. The solution is dried over sodium sulfate and
by ?ltration. The precipitate is dissolved in 300 ml. of
evaporated to give a residue containing 16a,l7u-methyl
ethyl acetate, then Washed successively with hour 100 ml.
one-1,4,6-pregnatriene-3,ZO-dione (XX).
portions of freshly prepared cold ammonium sul?de, dilute
ammonium hydroxide, water, dilute hydrochloric acid and
, The residue is dissolved in 50 ml. of methylene chlo
ride and 100 ml. of Skellysolve'B hexanes. The solution
is then chromatographed over a column containing 400
g. of Florisil. The column is eluted with increasing pro
portions of acetone in Skellysolve B hexanes to give
I16a,‘l7a-methylene-l,4,6-pregnatriene-3,ZO-dione (XX), a
water. The solution is dried over sodium sulfate and
evaporated to give a residue containing l6a,l7ot—methyl
ene-1,4-pregnadiene-3,ZO-dione (XXI) .
The residue is dissolved in 50 ml. of methylene chloride
and 100 ml. of ‘Skellysolve B. The solution is then
chromatographed over a column containing 400 g. of
Florisil. ‘The column is eluted with Skellysolve B ‘con
taining increasing proportions of acetone to give 16a,17u~
rnethylene-1,4-pregnadiener3,‘ZO-dione (XXI), a light col
ored, crystalline solid, which can be further puri?ed by
recrystallization from acetone~Skellysolve B mixtures.
crystalline solid, which canbe further puri?ed by recrys
tallization from acetone-Skellysolve B hexanes mixtures.
‘Example147.-—]6a,17u-Methylene - 6 — Methyl-1,4,6-Preg
35
Following the procedure of Example 46, but substituting
16a,17oc - methylene~6~methyl£4,6-pregnadiene-3,20-dione
v in dry benzene with 2,3-dichloro-5,6-dicyanobenzoquinone
Patent 852,847) also yields l6a,17<x-methylene-1,4-preg
nadiene-LZO-dione (XXI).
(XVHI) (from Example 37) as starting material, yields
. pure, crystalline 160517“ - methylene-6-methyl-1,4,6-preg
. natriene~3,20-dione (XX).
Example 48.—] 6a,] 7a-Methylene‘ - 6 - Fluor0-1,4,6-Preg
Example 42.—16a,]7a-Me‘thylene-6ot-Methyl~l,4 - Pregna
diam-3,2 (ll-dione (1 6 0a,] 7 a-Methy lens-6 a-Methyl-1 ‘- De
hydroprogesterone) (XXI)
ndtrz'ene-3,20—Dione (160:,170: - Methylene-6a-Methyl
1,6-Bisa'ehydroprogeslerone) (XX)
Heating 16e,l7e-methylene-4-prcgnene~3,ZO-dione (V)
under re?uxfor a period of about 12 hours (as in British
.
natrz'ene-3,20~Di0ne (16a,17u-Methylene - 6a - Fluore
45
J ,6-Bisdehydroprogesterone) (XX)
Following the procedure of Example 46, but ‘substitut
Following the procedure of Example 41, but substituting
ing l6e,l7ec -‘ methylene - *6 - ?uoro-4,6-pregnadiene-3,20
16a,l7ot~methylene-6u-methyl-4-pregnene-3,20 - dione (V)
dione (XVIII) (from‘Example 38) as starting material,
(from Example 4) as starting material, yields light col
yields light colored, crystalline, 1600,1704 - methylene - 6
ored crystalline, Manna-methylene - 6oz - methylene - 6oz .50
lluoro-l,4,6-pregnatrieneé3,ZO-dione (XX).
‘ methyl-l,4-pregnadiene~3,ZO-dione‘ (XXI).
Example 49.——16¢x,17e-Methylene - t6 - Chl0ro-1,4,6-Preg—
, natrz'ene-3,20-Di0ne (16a,]7a-Metlzylene-6-Chloro-1,6
Example 43 .———1 6 ot,1 7oc-Methylene~6u-Flu0ro-1 ,4 - Pregna
dlene-3,20-Dione (16%] 7a-Methylene-6ct-FlMoro-1~De
hydroprogesterone) (XXI)
Following the procedure of Example 41, but substituting
55
16C(,17Ct - methylene-6-chloro-4,6-pregnadiene-3,20-dione
16a,l7c¢~methylene-6ot>?uoro-4-pregnene-3,20 - dione (V)
(XVIIE) (from Example 40) as starting material, yields
(from Example 22) as starting material, yields crystalline
crystalline 16a,17oz-methylene~6qchloro-1,4,6-pregnatriene
16a,17a—rnethylene-6e-iluoro~1,4-pregnadiene-3,2O - dione
60
(XXI).
Example 44 .—1 6 0a,] 7a-Methylene-6,B-Fluoro-J ,4 - Pregnaq
Bisdelzydroprogesterone) (XX) '
Following the procedure of Example 46, but substituting
3,20-dione (XX).
Example 50.---] 6a,] 7oz-Methylene-1,4,6-Pregnatriene-3,20
diene-3,20+Di0ne (1.6%] 7a-Methylene-6/3-Flu‘oro-1-Dw
hydroprogesterone) (XXI)
Dione (16a,17ot - Methylene - 1,6 - Bisdehydropragesv
Following the procedure of Example 41, but substituting
A solution of 12 g. of 16a,l7a-methylene-l,4-preg
16a,l7a-methylene-6r3-?uoro-4-pregnene-3,20 - dione (V)
terone) (XX)
'
'
nadiene-.3,20-dione (XXI) (from Example 41) and 10
(from Example 22) ‘as starting material, yields crystalline
g. of chloranil in 500 ml. of tertiary amyl alcohol is re.
, 16a,17oemethylene-6a-?uoro-l,4¢pregnadiene-3,20 - dione
iluxed for a period of about‘4.5 hours. The tertiary amyl
alcohol is then distilled off under vacuum in a nitrogen
atmosphere.
The residue is dissolved in methylene chlo
.70
Example 45.—16a,1 7a-Methylene~6a-Chlore-1,4 QPregnn
ride and then shaken with dilute sodium hydroxide. The
diene-3,20-Di0ne (16a,]7e-Methylene-6a-Chloro-1-De
‘ (XXI),
‘
hydroprogeslerone) (XXZ)
Following the procedure o? Example 41, but substituting
precipitate that forms is separated by ?ltration through
diatomaceous earth. The organic phase of the ?ltrate is
separated, washed ?rst with dilute sodium hydroxide solu
16a,17a-methylene-6a-chloro-4-pregnene-3JO - dione (V) 75 tion, then ‘water and dried.
The solvent is distilled off
3,086,029
23
24
leaving a residue of crystalline l6a,17u-methylene-1,4,6
tions of a two percent aqueous solution of sodium bicar
pregnatriene-3,20-dione (XX).
bonate and then with two one-tenth by volume portions
of water. After drying the methylene chloride extracts
Example 51.--—] 60a,] 7a - Methylene-6-Methyl-1,4,6-Preg
natriene-3,20-Dione (1 6a,] 7 oc-Methylene-6-Methyl-I ,6
Bisdehydroprogesterone) (XX)
U!
Following the procedure of Example 50, but substitut
with about three to ?ve grams of anhydrous sodium sul
fate per liter of solvent and ?ltering, the solvent is re
moved by distillation. The residue is dissolved in a mini
mum of methylene chloride and chromatographed over
Florisil. The product, eluted with increasing propor
tions of acetone in Skellysolve B, is recrystallized from
ing 16a,17e - methylene-Ga-methyl-1,4-pregnadiene-3,20
dione (XXI) (from Example 42) as starting material,
yields crystalline 16oz,l7oi-methylene-6-methyl-1,4,6-preg
natriene-3,20-dione (XX).
methanol to yield light colored, crystalline 16a,17a-meth
Example 52.—160t,17ot - Metlzylene-6-Fluor0-1,4,6-Preg
Example 56.-——16oc,17oc - Methylene - 11a - Hydr0xy-6a
natrz'ene-3,20-Di0ne (160a,]7a-Methylene-6-Flu0r0-I,6
Bisdelzydroprogesterone (XX)
Methyl-4-Pregnene-3,20-Dione (16¢,17a - Methylene
Following the procedure of Example 50, but substitut
ylene-l la-hydroxy-4-pregnene-3,20-dione (XIX) .
15
(V) (from Example 4) as starting material, yields crystal
dione (XXI) (from Example 43) as starting material,
line
20
l6a,l7ot - methylene-1 1ot-hydroxy-éa-methyl-4-preg
nene-3,20-dione (XIX).
Example 5 7.—-I 6a,] 7 or - Methylene-I I a-Hydr0xy-6 ac-Flu
oro-4-Pregnene-3,20-Di0ne (16ot,17oc - Methylene-11a
triene-3,20-Di0ne (16e,I7a-Methylene - 6 - Flu0r0-1,6
Hydroxy-6a-Flu0r0progester0ne) (XIX)
Bisdehydroprogesterone) (XX)
Following the procedure of Example 50, but substitut
Following the procedure of Example 55, but substitut
ing 1606,1706 - methylene-6e-methyl-4-pregnene-3,20-dione
ing l6a,l7a-methylene - ‘6oz - ?uoro-1,4-pregnadiene~3,20
yields crystalline ‘16a,17e-methylene-6-?uoro-1,4,6-pregna
triene-3,20-dione (XX).
Example 53.-—16a,1 7u-Methylene-6-Flu0r0-I ,4,6-Pregna
1Ia-Hydr0xy-6a-Methylprogesterone) (XIX)
25
Following the procedure of Example 55, but substitut
ing 160:,l7oc-l‘l16ihYl6l'l6 - 6,8 - ?uoro-l,4-pregnadiene-3,20
ing
dione (XXI) (from Example 44) as starting material,
yields crystalline 16a,l7ot-n1ethylene-6-?uoro-1,4,6-pregna
triene-3,20-dione (XX).
(V) (from Example 22) as starting material, yields light
colored crystals of 1606,170c-?'ll6ll1Yl6116-110t-hydI‘OXy-6m
?uoro-4-pregnene-3,ZO-dione (XIX).
Example 54.—--16a,]Zia-Methylene-6-Chl0ro-1,4,6-Pregna- a
Example 58.--—-16oc,1 7a - Methylene-1 I a-Hydr0xy-6B-Flu
triene~3,20-Di0ne (160a,! 7a-Methylene - 6 - Chime-1,6
oro-4-Pregnene-3,20-Dione
(1611,] 7a - Methylene-1 1 a
Hydroxy-ti?-Flaoroprogesterone) (XIX)
Following the procedure of Example 55, but substitut
Bisdehydroprogesterone) (XX)
Following the procedure of Example 50, but substitut
ing 16a,17u-methylene—6a-cl1loro - 1,4 - pregnadiene-3,20
l6a,l7a - methylene-6a-?uoro-4-pregnene-3,20-dione
35
dione (XXI) (from Example 45) as starting material,
yields light colored, crystalline 160:,170: - methylene - 6
chloro-1,4,6-pregnatriene-3,20-dione (XX).
Example 55.—16a,17a - Methylene-11 ot-Hydr0xy-4-Preg 4d)
nene-3,2O-Di0ne (16a,1 7a-Methylene-I I a-Hydroxypro
gesterone) (XIX)
ing
16a,l7<x - methylene-6,8-?uoro-4-pregnene-3,ZO-dione
(V) (‘from Example 22) as starting material, yields crys
talline 16a,17a~methylcne-l loc-hydroxye6?-?uoro-4-preg
nene-3,20-dione (XIX).
Example 59.-—16a,17a - Methylene — 11cc - Hydroxy - 60¢
Chl0ro-4-Pregnene-3,20 - Dione (16a,17a - M ethylene
11 a-Hydr0xy-6a-ChIoroprogesterone) (XIX)
Following the procedure of Example 55, but substitut
A medium is prepared containing 10 g. of Cerelose dex
trose technical grade and 20 g. of corn steep liquor (60%
ing l6e,l7a - methylene-6a-chloro-4-pregnene-3,ZO-dione
solids) in sufficient tap water to make up one liter of
solution. One hundred liters of such a medium is ad
talline 16a, 17a-methylene-l let-hydroxy-6a-chloro~4-preg
nene-3,20-dione (XIX).
justed by the addition of 25 percent sodium hydroxide
(V) (from Example 23) as starting material, yields crys
solution to a pH of 5. Thereto is then added 400 ml. of
lard oil and lard-oil octadecanol as an anti-foaming agent.
This medium is sterilized for 45 minutes at 20 lbs. pres
sure and inoculated with Rhizopus nigricans minus strain,
Example 60.--1 604,71 a-Methylene - 4 - Pregame-3,11,20
American Type Culture Collection No. 6227b, and in
methylene-1la-hydroxyprogesterone (XIX) (from Exam
cubated for 24 hours at a temperature of 28° C. using a
rate ‘of aeration and stirring such that the oxygen uptake
ple 55) in 50 ml. of acetic acid at room temperature.
Thereto is added dropwise a solution of 2 g. of chromium
trioxide in 50 ml. of acetic acid and 0.5 ml. of water.
is 6.3 to seven millimoles per hour per ml. of sodium‘
sul?te according to the method of Cooper, Fernstrom and
Miller, Ind. Eng. Chem. 36,504 (1944). To this medium
containing a 24 hour growth of Rhizopus nigricans minus
strain is added 6 g. of 16a,l7a-methylene-4-pregnene
3,20-dione (V) (from Example 4A) in 150 milliliters of 60
Trione
(I6a,17a - Methylene - II - Ketoprogesterone)
(XIXa)
A solution is prepared containing 3.5 g. of 160:,l7oc
During the addition, the temperature is maintained be
tween 20 to 23° C. and thereafter for another period of
1.5 hours. The reaction mixture is then diluted with 1 l.
of water and extracted with six 150-milliliter portions of
methylene chloride. The extracts are combined, washed
with dilute sodium bicarbonate ‘solution and water, dried
over anhydrous sodium sulfate and evaporated to dry
ness under reduced pressure. The thus obtained solid is
acetone to provide a suspension of the steroid in the
culture. After an additional 24 hour period of incubation
under the same conditions of temperature and aeration,
the beer and mycelium are extracted. The mycelium is
recrystallized from methanol to yield light colored, crys
?ltered, washed twice each time with a volume of acetone 65 talline, 160:,17a - methylene - 4 - pregnene-3,11,20-trione
approximately equal to the volume of the mycelium, and
(XIXa).
extracted twice, each time with a volume of methylene
Example 61 .-—-—16oc,1 7a-Methylene-6oi-Methyl-4-Pregnene
chloride approximately equal to the volume of the my
3,11,20 - Trione (160:,170: - Methylene - 6u-Methyl-1I
celiurn. The acetone and methylene chloride extracts
Ketoprogesterone) (XIXa)
including solvents are added to the beer ?ltrate. The 70
Following
the procedure of Example 60, but substitut
mixed extracts and beer ?ltrate are extracted successively
with two one-half by volume portions of methylene chlo
ride and then with two one-fourth by volume portions
of methylene chloride. The combined methylene chloride
extracts are washed with two one-tenth by volume por
ing
l6a,17a - methylene - 11u-hydroxy-6a-methyl-4-preg
nene-3,20-dione (XIX) (from Example 57) as starting
material, crystalline l6e,l7a-methylene'Ga-rnethyl-Il-preg
nene-3,11,20-trione (XlXa).
3,086,029
Example
26
.
25
62.——16a,17a - Methylene - 6o: - F lzwr0-4-Preg
methylene - 11m - hydroxy - 6 - ?uoro-4,6-pregnadiene—
nene-3,1l,20-Trione (1666,170l-Melhylé‘l’l€~6t!-FlllOl‘O-1 1
3,20-dione (XIX) (‘from Example 68), and 1604,17“
' Ketqprogesterone) ‘(X1Xn )
methylene - l‘la ~hydroxy - 6 - chloro - 4,6-pregnadiene
3,20-dione (XIX) (from Example 70), yields, respec
tively, light colored, crystalline, l6a,l7a-methylen'e-4,6
pregnadiene-3,l1,20-trlone (XIXn), Manna-methylene
6-methyl-4,6-pregnadiene-3,l1,20-trione (XIXa), 16oz,
Following the procedure of vExample 60, but substitut
ing 16a, 17a~methylene-l 1 whydroxy-6a-?uoro-4-pregnene
3,20-dione (XIX) (from Example 58) as starting mate
rial, yields pure, crystalline 16a,l7a-rnethylene-6-a-riuoro
17amethylene-6-?uoro-4,G-pregnadiene - 3,11,20 - trione
4-pregnene-3,~l 1,20-trione (XIXa) .
Example 63.—~16ot,17a-Methylene-6?-Fln0r0-4-Pregnene
3,11,20 - Trz'one
(XIXa) and 16a,l7oc-methylene-6-chloro-4,G-pregnadiene
10
(16a,17a - Methylene - 6/8-Fln0r0~1 J -
3,11,20-trione (XiXa).
Example ,70.—¢16oc,17a-Methylene-11a-HydrOxy-JA-Preg- '
Ketoprogesterone) (XlXa)
nadiene-3,20-Di0ne (16%] 7ot-Methylene-11 a-Hytlroxy
Following the procedure of Example 60, but substitut
l -Dehydroprogester0ne) (XIX)
Following the procedure of Example 55, but substitut
ing l6a,17u - methylene - 11a -'hydroxy-6B-?uoro-4-preg
nene-3,20-dione (XIX) (from Example 59) as starting 15 ing l6a,l7a-methylene-l,4-pregnadiene-3,20adione (XXI)
(fro-m" Example 41) as starting material, yields pure,
4-pregnene-3,1 1,20-trione (XIXa) .
material, yields crystalline, 16a,17ot-rnethylene-6?-?uoro
crystalline,
- Example 64 .—1 6 (1,1 7a-Methylene-6et~Chl0r0-4-Pregnene
3,11,20 - Trione
(16a,17a - Methylene - 6 Ot-ChlOl’O-Z 1 -
Ketoprogesterone) (XIXa)
a
20v
nene-3,2G-dione prepared by the method of Example 55,
to give 16u,17e-rnethylene-11a-hydroxy-1,4-pregnadiene
16¢,17ot - methylene - 11why-(1rOXY-Goc-ChlOI‘O-4-pl‘6g
3,20-dione (XIX).
nene-3,20-dione (XIX) (from Example 59) as starting
material, yields crystalline l6oz,l'l'ot-ell'l?lh??IlB-?Ot-ChlOl‘O
‘
Alternatively, 160:,17a - methylene-l la-hydroxy-ll-preg
can be l-dehydrogenated by the method of Example 41
Following the procedure of Example 60,,but substitut
ing
160:, 17a » methylene-1la-hydroxy-lA-pregna
dicne~3,20‘-dione (XIX).
25 Example 71.—-16Ct,17ct -
ethylene - 11a - Hydroxy - 66t
4-pregnene-3, l 1,20-trione (-Xl‘Xa) .
Methyl-1 ,4 -Pregnadiene-3,2 Q-Dione (1611,] 70c - Methyl
Example 65 .~—'-] 6 0a,] 7Ot-Methylene-1 1 a-Hydr0xy-4,6-Preg
ene-1 1 0e - Hydroxy - 6ct-Methyl-1-D ehydroprogesterone)
nadiene-3,20-Di0ne (16ml 7a-Methylene-1 1 a-Hydroxy
6-D ehydroprogesterone) (XIX)
Following the procedure of Example 55, but substitut
Following the procedure of Example 55, but substituting
ing
(XIX)
16¢,l7a - methylene-6o<~methyl-1,4-pregnadiene-3,ZO-dione
(XXI) (from Example 42) ‘as starting material, yields
l6rx,l7ot - methylene - 4,6 - pregnadiene - 3,20 - dione
crystalline 16a,17a-methylene-lla5hydroxy-6a-methyl-1,4~
(XVIII) “(from Example 36) as starting material, yields
crystalline
pregnadiene-3,20-dione (XIX).
160a, 170a - methylene-.11a-hydroxy-4,6-pregna
diene-3,20‘-dione (XIX).
Alternatively, 1604,170: - methylene - 11cc - hydroxy-éu
'
methyl-4*»pregnene-3,ZO-dione, prepared by the method of ,
Example 66.-t-—16ot,17ot- Methylene - 11a - Hydroxy - 6—
M ethyl-4,6-Pregnadiene-3,20-Dione , (160:,170: - M ethyl
Example 56, can he l-dehydrogenated by the method
of'Example 41 to give 16a,17u-methylene-llot-hydroxy
ene - 11oz - Hydroxy-6~Methyl-6-Dehydroprogesterone)
'
(XIX)
6oc~methyl—1,4-pregnadiene-3,20-dione (XIX).
.
Example
Following the procedure of Example 55, but substituting
Example '67.——16a,17ot-Methylene-1lw-Hydroxy-ti-Flnoro
(16a,17a-Methylene
11 ct-Hydr0xy-6a-Fln0r0-1-Dehydr0pr0gesterone) (XIX)
dione (XVIII) (from ‘Example 37) as starting material,
yields pure, crystalline l6a,l7u-methylene-1lot-hydroxy
6~methyl-4,6-pregnadiene-3,20-dione (XIX). ,
72 .-—1 6 ct,] 7o:-Methylene-l 1 oz-Hydr0xy-6oz-Flu
are - I,4-Pregnadiene-3‘,20-Dione
16ix,17oc - methylene - 6 - methyl - 4,6 - pregnadiene-S,20
Following the procedure of Example 55,.but'substitut
ing 160:,17oc ~ methylene - 6a - ?uoro-1,4-pregnadiene-3,20-t
45 dione (XXI) (from Example \43) as starting material,
yields crystalline,
4,6-Pregnadiene-3,20-Dione (16n,17ot - M ethylene-1 1 o:
Hydr0xy-6-Fluoro-6-Dehydroprogesterone) (XIX)
Example 7s.-_16a,17¢ - Methylene-J1a-Hy1dr0xy-6B-Flu
Following the procedure of Example 55, but substitut
ing 16a,l7ca - methylene - 6-methyl-4,6-pregnadiene-3,20
50
oro - 1,4-Pregnndiene-3‘,20~Dione
(16a,17a-Methylene
11a - Hydroxy - 6,8 ~ Flnoro - 1 - Dehyd‘roprogesterone) ~
dione (XVIII) (from Example 38) as starting material,
yields light colored, crystalline l6a,l7ot-methy-lene-lla
hydroxy-6-?uoro-4,6-pregnadiene-3,20‘-dione (XIX).
(XIX)
Following the procedure of Example 55, but substitut
ing
Example 68.——16ot,17oc - Methylene - 11a - Hydroxy-6
1606,1706 - methylene - 6,8-?uoro-1,4-pregnadiene-3,20
dione (XXI) (from Example 44) ‘as starting material,
Chlore-4,6-Pregnttdiene-3J0-Dione (16a,]7a - Methyl
yields light colored, crystalline 1606,1705-11’l6tl'1YlB1'l6‘11d
hydroxy-6?-?uoro-1,4-pregnadiene-3,ZO-dione (XIX).
ene - 11a - Hydroxy - 6-Chl0-r0-6-Dehydroprogesterone)
(XIX)
Example
Following the procedure of Example 55, but substitut
ing 160t,170t - methylene - 6-ch-loro-4,6-pregnadiene-3,20
l6ot,l7a-methylene-llot-hydroxy-6ot
?-uoro-l,4-pregnadiene-3,ZO-dione (XIX).
74.——16ot,17cz - Methylene - 110a - Hydroxy - 60c
‘Chlore-1,4-Pregnadiene-3,20-Dione (160:,170; - Methyl
60
dione (XVIII) (from Example 40) ‘as starting material,
ene - 11o; - Hyclmxy~6 a-Chl0r0-1 -Dehydr0pr0gester0ne)
(XIX)
yield-s crystalline 16oc,170t - methylene - l1a-hydroxy~6
I
Following the procedure of Example 55, but substitut
chloro-4,6-pregnadiene-3,20-dione (XIX).
ing '16oc,17oc - methylene-6ot-chloroal,,4Lpregnadiene73,20
Example
dione (XXI) (from Example 45) as starting material,
69. -- 160:,170: - Methylene - 4,6 - Pregna‘zliene
yields crystalline 16oc,17ot - methylene - llot-hydroxy-6ca
3,11,20-Tri0ne (XIXa) ,, 16a,]7ct-Methylene-6-Methyl
4,6-Pregnadiene~3,11,ZO-Trione (XIXa), 1606,170t-M2th
chloro-l,4-pregnadiene-3,ZO-dione (XIX).
ylene-6-Flu0ro-4,6-Pregnethane-3,11,20-trione (XIXa) ,
Example 75.—~-16u,17ot ? Methylene-1,4-Pregnadiene-3J1,
and
16e,17'd - Methylene - Chloro - 4,6 - Pregnadiene
3,11,20-Tri0ne (XIXa)
Following the procedure of Example 60, but substitut
ing as starting materials, 16ioc,17a:-methyl6n6-llot-hYdl‘OXY
ZO-Trione (XIXa), 1 6a,] 7a-Methylene-6ot-Methyl-1 ,4
70
Pregne'a‘iene-SJ 1 ,ZO-Trione ( XIXa ) , 1 6 11,1 7a-Methyl
6716-666-Flll07‘0-1 ,4-Pregnndiene-3 ,1 1 ,‘ZO-Trione ( XIXa) ,
'4,6-pregnadiene-3,20-dione (XIX) (from Example 66),
diene-3,20-dione (XIX) (from ‘Example 67), l6u,l7a- ‘
Following'the procedure of Example 60, but substitut
3,086,029
28
27
16a,l7a - methylene - 11oz - hydroxy - 60c - methyl - 1,4
natriene-3,20-dione (XIX) (from Example 79), yields,
respectively, light colored, crystalline, 16a,17a-methyl
ene-'l,4,6-pregnatriene-3,11,20~tri0ne (XIXa), 1611,1711
pregnadiene-3,20-dione (XIX) (from Example 71), 16a,
methylene-6-methyl-1,4,6-pregnatriene - 3,11,20 - trione
ing as starting materials, 16a,17a-methylene-1lot-hydroxy
1,4-pregnadiene-3,20-dione (XIX) (from Example 70),
17a - methylene - 11a - hydroxy - 6oz - ?uoro - 1,4 - preg
(XIXa), 16a,l7a - methylene-6-‘luoro-1,4,6-pregnatriene
nadiene-3,20-dione (XIX) (from Example 72), 16a,17ot
3,11,20-trione (XIXa), and l6a,l7a-rnethylene-6-chloro
1,4,6-pregnatriene-3,11,20-trione (XIXa).
methylene - 110a - hydroxy - 613 - ?uoro - 1,4 - pregnadiene
3,20-dione (XIX) (from Example 73) and 16oc,17a
Example
methylene - 11a - hydroxy - 60c - chloro - 1,4 - preg
nadiene-3,20-dione (XIX) (from Example 74), yields,
respectively, light colored, crystalline, 16a,17<x-methylene
1,4-pregnadiene-3,11,20-trione (XIXa), 16a,17a-methy1
10
(16a,17tx-Methylene - 115 - Hydroxy
progesterone) (XIX)
A seed culture of Curzninghamella blakesleeana
(ATCC 8688b), obtained from spores grown on a 2%
‘agar, 5% malt extract solids at a pH of 6.0 is prepared
ene - 6a - methyl - 1,4 - pregnadiene - 3,11,20 - trione
(XIXa), 16a,l7oc—methylene-6a-?uoro-1,4-pregnadiene
3,11,20-trione (XIXa), 16oz,l70t-Il'16ihYl?IlB-6l3-?l10l‘0-1,4
pregnadiene-3,l1,20-trione (XIXa) and 16a,17a-methyl
81 . —— 16a,]7a-Methylene-I1?-Hydr0xy-4-Preg
nene-3,20-Di0ne
15 by growth in a medium containing, per liter of tap water,
10 g. of dextrose (Cerelose) and 20 g. of liquid corn
steep liquor (containing about 1.2 g. solids) adjusted to
a pH of about 5 with 25% aqueous sodium hydroxide.
ene - 6a - chloro - 1,4 - pregnadiene - 3,11,20 - trione
(XIXa).
Five one-liter portions of the above medium are inocu
Pregnatriene - 3,20-Di0ne (16a,17a-Methylene-11a-Hy 20 lated with the seed culture and growth with aeration and
shaking was continued for 48 hours. Then 0.2 g. of
droxy-I ,6-Bisdehydroprogester0ne) (XIX)
Example 76.--—16a,17ot - Methylene - 11a - Hydr0xy-1,4,6
16a,17ot-methylene-4—pregnene-3,20-dione (V) (from Ex
Following the procedure of Example 55, but substitut
ample 4A) in 30 ml. of alcohol is added to each ?ask
and fermentation continued 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
ing 16a,l7a-methylene-1,4,6-pregnatriene-3,20-dione (XX)
(from Example 46)
crystalline
as starting material,
yields
l6a,17<x - methylene-11a-hydroxy-1,4,6-preg
natriene-3,20-dione (XIX).
Alternatively, 160:,1704 - methylene - 11a - hydroxy - 4,
of methylene chloride containing 25% ethyl acetate.
6-pregnadiene-3,20-dione, prepared by the method of
The extracts are evaporated to dryness. The residue thus
obtained is redissolved in 150 ml. of methylene chloride
and chromatographed on a column of magnesium silicate.
Example 55, can be l-dehydrogenated by the method of
Example 41, to give 16a,l7o¢-methylene-l1a-hydroxy-1,4,
6-pregnatriene-3,20-dione (XIX).
The column is developed with hexanes containing in
creasing proportions of acetone to elute a mixture con
Example 7 7.—] '6 0a,] 7 (Z-M ethylene-1 1 a-Hydr0xy-6-Methyl
taining the desired 11/3-hydroxy-product. The crude
product is crystallized from a mixture of hexanes and
1,4,6 - Pregnatriene - 3*,20 - Dione (16a,17a-Methylene
11a - Hydroxy - 6-Methyl-1,6-Bisdehydroprogesterone)
acetone and recrystallized from the same solvent pair to
(XIX)
yield light colored, crystalline 16a,17a-methylene-1lp-hy
Following the procedure of Example 55, but substituting
droxy-4-pregnene-3,20-dione (XIX).
16a,17ot - methylene - 6 - methyl - 1,4,6 - pregnatriene - 3,
20-dione (XX) (from Example 47) as starting material,
Example 82.——16a,17a - Methylene - 11p - Hydroxy - 60:
yields light colored, crystalline, 16a,17a-methylene-11a
M ethyl-4-Pregnene - 3,20 - Dione
ihydroxy-6-methyl-1,4,6-pregnatriene-3,20-dione (XIX).
Example 78.-—16a,17u-Methylene-1lot-Hydroxy-o-Fluora
11?-Hydroxy-6ot-Methylpr0gester0ne) (XIX)
Following the procedure of Example 81, but substitut
ing 160.,17a - methylene-6oc-methyl-4-prcgnene-3,20-dione
J ,4,6-Pregnatriene-3,ZO-Dione (160:,1 7a-Methylene-11a
(V) (from Example 4) as starting material yields crys
Hydroxy-6-Fluor0-1,6-Bisalehydroprogesterone) (XIX)
talline 16a,l7a-methylene-1 l?-hydroxy-6a-methyl-4-preg
nene-3,20-dione (XIX).
Following the procedure of Exam-pleS 5 but substituting
16a,17a - methylene - 6 - ?uoro - 1,4,6 - pregnatriene - 3,
20-dione (XX) (from Example 48) as starting material,
yields crystalline 16a,17a-methylene-1 1a-hydroxy-6-?uoro
1,4,6-pregnatriene-3,20-dione (XIX).
Example 79.—-16OC,17C4-M€?1yl€nE-11 a-Hydroxy-ti-Chloro
50
Following the procedure of Example 55, but substituting
I1,B-Hydroxy-6a-Flu0r0pr0gester0ne) (XIX)
in g 16a,17wmethylene-6a-?uoro-4-pregnene - 3,20 - dione
(V) (from Example 22) as starting material, yields pure,
55 crystalline 16e,17a-methylene-1lp-hydroxy - 6a - fluoro-4
pregnene~3,20-dione (XIX).
160:,17a - methylene - 6 - chloro - 1,4,6 - pregnatriene - 3,
20-dione (XX) (from Example 49) as starting material,
yields pure, crystalline 16a,17a-methylene-1lot-hydroxy-?
chloro-1,4,6-pregnatriene-3,20-dione (XIX).
Example 83.-—16a,17a - Methylene - 11p - Hydroxy - 6a
Fluoro - 4 - Pregnene-3,20-Di0ne (I6u,17u-Methylene
Following the procedure of Example 81, but substitut
J ,4,6-Pregnatriene-3,20-Di0ne (1 6 00,1 7oc-Methylene-I1ot
Hydr0xy-6-Chl0r0-1 ,6-Bisdehydroprogesterone) (XIX)
(16a,17a-Methylene
Example 84.—16ot,17a - Methylene - 11B - Hydroxy - 6,6’
F luoro-4-nregnene - 3,20 - Dione (16a,17u-Methylene
60
I1p-Hydroxy-ti?-Flnoroprogesterone) (XIX)
Following the procedure of Example 81, but substitut
Example 80.—] 6 12,1 70: - Methylene-1 ,4,6-Pregnatriene-3 ,
11,20-Tri0ne (XIXa) , 16:1,] Zia-Methylene - 6 - .Methyl
ing l6a,17a-methylene-6?-?uoro-4-pregnene - 3,20 - dione
1,4,6-Pregnatriene - 3,11,20 - Trz'one (XlXa), 161x170:
M ethylene-6-F luoro - 1,4,6 - Pregnatriene-3,1I,ZO-Tri
one (XIXa), and 16a,17a - Methylene-6-Chl0r0-1,4,6
colored, crystalline 16a,17et-methylene-11p-hydroxy-6B
?uoro-4-pregnene-3,20-dione (XIX).
Pregnatriene-3,11,20-Tri0ne (XIXa)
Example 85.-—16e,17a - Methylene - 11p - Hydroxy ' 6a
(V) (from Example 22) as starting material, yields light
Following the procedure of Example 60, but substitut
ing as starting materials, 16a,17a-methylene-1lot-hy
Chl0r0-4-Pregnene - 3,20 - Dione
droxy-1,4,6-pregnatriene-3,ZO-dione (XIX) (from Ex 70
ample 76), 1'6a,*17a-methylene — 11cc - hydroxy-6-methyl
77),
l6a,l7a - methylene-6a-chloro-4-pregnene-3,20-dione
(V) (from Example 23) as starting material, yields crys~
talline l6a,17a~methylene-1l?-hydroxy-6a-chloro-4-preg
16a,17a - methylene-1 lu-hydroxy - 6 - ?uoro - l,4,6~
pregnatriene-3,20~dione (XIX) (from Example 78), and
1611,1711 - methylene-11a-hydroxy-6-chloro - 1,4,6 - preg
Following the procedure of Example 81, but substitut
ing
1,4,6-pregnatriene-3,20-dione (XIX) (from Example
(16a,17a-Methylene
I I p-Hydr0xy-6a-Chloroprogesterone) (XIX)
75
nene~3,20-dionc (XIX).
3,086,029
29
Example 86.-—16a,17a-1\/1ethylene - 4 - Pregnene-3,11,20
Example
F lu0r0-4,6-Pregnadiene-3,20-Di0ne - (16%170: - M ethyl
ene -' 1'15 - Hydroxy - 6-Flu0r0-6-Dehydroprogesterone)
T rione (161,170; - Methylene - 11 '- Ketoprogesterone)
(XZXa)
Following the procedure of Example 60, but substitut
ing
(XIX)
dione (XIX) (from Example 81) as starting material,
yields pure, crystalline 16a,l7ot-methylene-4-pregnene-3,
11,20-trione (XIXa).
ing
10
hydroxy-6-?uoro-4,6-pregnadinene-3,20-dione (XIX).
161x, l7a-methylene-1 ll?-hydroxy - 6a - methyl-4-preg
nene-3,20-dione (XIX), (from Example 82) as starting
Example
material, yields crystalline 16a,17a-methylene-6a-methyl
prdgesterone) (XIX )
Example 88.—] 6 05,1 7 Oc-Methylene-6a-Fluor0-4-Pregnene
20
Ketoprogesterone) (XIXa)
Following the procedure of'Example 6'0, but substitut
rial, yields crystalline l6ot,17a-methylene-1l?-hydroxy-G
material, yields pure, crystalline 16a,l7a-methy1ene-6a
chloro-4,6-pregnadiene-3,ZO-dione (XIX). ,
Alternatively, l6a,17a - methylene - 11p‘ - hydroxy - 60c
ch1oro-4-pregnene-3,ZO-dione (XIX), prepared by the
?noro-4-pregnene-3,l 1,20-trione (XIXa) .
method of Example 85, can be o-dehydrogenated by the
method of Example 40 to give» looelh-methylene-ll?
Example v89.~—16a,]7ot-Methylene-6,8-Flu0r0-4-Pregnene
hydroxy-G-chloro-4,6-pregnadiene-3,20-dione (XIX).
(160:,1704 - Methylene - 65 - Fluoro - 11
Ketoprogesterone) (XIXa)
Example 95.—160a,17ct - Methylene - 4,6 - Pregnadiene
3,11,20 - Trione (XlXa), 1604,17ot - ll/lethylene - 6
Following the procedure of Example 60, but substitut
Methyl-4,6-Pregnadiene-3,11,ZO-Trione (XlXa), 16a
16oz,17u - methylene-l le-hydroxy-6B-fluoro - 4 - preg
1704 - Methylene - 6 - Fluoro - 4,6 - Pregnadiene - 3,11,
nene-3,20-dione (XIX) (from Example 84) as starting
35
,4-pregnene-3,1 1,20-trione (XIXa) .
ZO-Trione (XlXa), and 16a,]7ot-Methylene-64Chl0v'0
4,6-Pregnadiene-3,1l ,ZO-Trione (XIXa)
Following the procedure of Example 60, but substitut
ing as starting materials, l6a,l7ot-rnethylene-1l?-hydroxy
Example 90.—16u,1 7a-Methylene-6a-Chl0r0-4-Pregnene
3,11,20-Tri0ne (160:,1704 - Methylene - 6a - Chloro — 11
40
' Ketoprogesterone) (XIXa)
16a,l7<x - methylene - 6i - chloro - 4,6 - pregnadiene
3,20-dione (XVIII) (from Example 40) as starting mate
160:,170: - methylene-1 l?-hydroxy - 6oz - ?uoro-4-preg
material, yields crystalline 16a,l7a-methylene-6?-?uoro
Following the procedure of Example 81, but substitut
ing
nene-3,20-dione (XIX) (from Example 83) as starting 25
ing
94.—~16q,170t - Methylene - 115 - Hydroxy - 6
Chloro - 4,6 - Pregnadiene - 3,20 - Dione - (115M170:
Methylene - 115 - Hyd‘roxy - 6 - Chloro - 6 - Dehydra
4-pregnene-3,l1,20-trione (XIXa) .
' 3,11,20-Tri0ne
Alternatively, 160:,170t - methylene - 115 - hydroxy - 60t
method of Example 83, can be 6-dehydrogenated by the
method of Example 38 to give l6ot,l7ct-methylene-llf3
Following the procedure of Example 60, but substitut
ing
yields light colored, crystalline 16e,17ot-methylene-llp
hydroxy-6~?uoro-4,6-pregnadiene-3,20-dione (XIX).
tluoro-4-pregnene-3,ZO-dione ()GX), prepared by the
Ketoprogesterone) (XIXa)
3,11,20-Tri0ne (160:,17a - Methylene - 6oz - Fluoro .- 11
16a,l7e-methylene-6¢?uoro - 4,6 - pregnadiene - 3,20
dione (XVIII) (fromExample 38) as-starting material,
3,11,20-Trione (16a,17a — Methylene - 60c - Methyl - 11
ing
‘
Following the procedure of vExamplerti‘l, but substitut
16u,17ot-methylene-1l?-hydroxy ~ 4 - pregnene - 3,20
Example 87.~—16a,1 7a-Methylene-6u-1l/Iethyl-4-Pregnene
1
30
93.-——16u,17ot - Methylene - 11B - Hydroxy - 6
4,6-pregnadiene~3,20-dione (XIX) (from Example 91),
160417“ - methylene - 11B - hydroxy .- 6 - methyl - 4,6
pregnadiene-3,20-dione (XIX) (from Example 92), 160:,
Following the procedure of Example 60, but substitut
ing 16u,l7a - methylene-l1,8-hydroxy-6ot-chlor0'- 4 ¢ preg
1711 ~ methylene ll {3 - hydroxy ~ 6 - ?uoro - 4,6 - pregna
nene-3,20-dione (XIX) (from Example 85) as starting
diene-3,20-dione (XIX) (from Example 93), 16a,l7ot
material, yields crystalline, 16a,17e-methylene~6ot-chloro
methylene - 11B - hydroxy - 6 - ehlo-ro - 4,6 _ pregnadiene
45
4-pregnene-3,l 1,20-trione (XIXa) .
nadiene-3,l1,20-trione
Example 91.-—-—16Dt,1705‘- Methylene - 11B - Hydroxy - 4,6
dr0xy-6-Dehya'roprogesterone) (XIX)
‘
Example 96.——‘160t,17ot - Methylene - 11B - Hydroxy - 1,4
Pregnadiene - 3,20 - Dione
(1611,] 7st - Methylene
light colored, crystalline '16u,l7c¢-methylene-ll?-hy
55
none-3,20-dione (XIX), prepared by the method of Ex
11 ti-Hydnoxynl -Dehydr0pr0gester0ne-) (XIX)
Following the procedure of Example 81, but substituting
16a,17ot-methylene-1,47pregnadiene - 3,20 - dione
ample 81, can be G-dehydrogenated by the method of Ex
(XXI)
(from Example 41) as starting material, yields light
colored, crystals of l6a,l7a-methylene-llp-hydroxy-IA
ample 36 to -give 16a,l7a-methylene-1l [3-hydroxy-4,6
pregnadiene-3,20-dione (XIX).
pregnadiene-LZO-dione (XIX).
-
Alternatively, l6ct,17a-methylene-l lB-hydroxy-4-preg
Example 92. -- 160a,] 7a-Mez‘hylene-11?-Hydr0xy-6-Meth
yl-4,6-Pregnadiene - 3,20 - Dione
(XlXa), and 16a,l7a-methy1ene-6-chloro-4,6-pregnadi
ene-3,11,20-trione (XIXa).
(XVIII) (from Example 36) as starting material, yields
Alternatively, 160e,17ot - methylene-l 1B-hydroxy-4-preg
16ce,170c - methylene-6
methylene - 6 - ?uoro - 4,6 - pregnadiene - 3,11,20 - trione
50
ing 16:4,17a - methylene - 4,6 - pregnadiene - 3,20 - dione
, droxy-4,6-pregnadiene-3,ZO-dione (XIX).
(XlXa),
methy1-4,G-pregnadiene-S,11,20-trione (XIXa), 160L,17OL
Pregnadiene-3,20—Di0ne (16a,17a - Methylene-1 1 B-Hy
Following the procedure of Example 81, but substitut
3,20-dione (XIX) (from Example 94), yields, respective
ly, light colored, crystalline 16m,I7e-methylene-4,6-preg
nene-l3,20-dione (XIX), prepared by the method of Ex
(16a,17a-Methylene
ample 81, can be l-dehydrogenated by the method of Ex
ample 41 to give 16a,17e-methylene-1,4-pregnadiene-3,
11,8 - Hycli'oxy - 6 - Methyl - 6- Dehydroprogesterone)
(XIX)
Following the procedure of Example 81, but substitut
ZO-dione (XIX).
Example 97.—16<x,17a-Methylene - 11B - Hydroxy - 6o:
Methyl - 1,4 - Pregnadiene - 3,20 - Dione (1604,1770:
ing 16e,l7a - methylene-6-methyl '~ 4,6 - pregnadiene-3,20
dione (XVIII) (from ‘Example 37) as starting material,
yields light colored, crystalline 1’6a,l7a-methylene-11B
hydroxy-6-rnethyl-4,6-pregnadiene-3,ZO-dione (XIX).
70
Alternatively, 1604,1702 — methylene - 11,8 - hydroxy ~ 6;»
Methylene- 11/3 - Hydroxyv - 6a - Methyl - 1 - Dehydra
progesterone) ' (XIX)
Following the procedure of Example 81, but substituting
methyl-4-pregnene-3,ZO-dione (XIX), prepared by the
16¢,l7ot - methylene - 6a - methyl - 1,4 - pregnadiene-3,20
method of Example 82, can be 6-dehydrogenated by the
method of Example .37. to give 16a,l7a-methylene-ll,8
yields crystalline
hydroxy-6-methyl-3,20¢dione (XIX).
dione (XXI) (from Example 42) as starting material,
75
16a,17e-methylene~1'1,8 - hydroxy - 6a
methyl-1,4-pre'gnadiene-3,20-dione (XIX).
8,088,029
32
31
methyl-4-pregnene-3,20-dione (XIX), prepared by the
Example 102. — 16a,]7a-Metlzylene-II?-Hydr0xy-1,4,6
Pregnatriene - 3,20-Di0ne ( 1 604,1 7 a-Methylene - 11B
method of Example 82, can be l-dehydrogenated by the
method of Example 42 to give 16a,17a-methylene-l l?-hy
Following the procedure of Example 81, but substitut
Alternatively, 160:,170: - methylene - 11p - hydroxy - 6o:
Hydroxy-1,6-Bisa'ehydroprogesterone) (XIX)
droxy-6a-methyl-‘l,4-pregnadiene-3,20-dione (XIX).
ing
Fluoro - 1,4 - Pregnadiene - 3,20 - Dione (16oz,17ot Methylene - JIB-Hydroxy - 6a ~ Fluoro - 1 - Dehyclro~
progesterone) (XIX)
Alternatively,
Following the procedure of Example 81, but substitut
ing
10
1,4,6-pregnatriene-3,20-dione (XIX).
yields crystalline l6a,l7oc-methylene - 11p - hydroxy - 60c
?uoro-1,4-pregnadiene-3,ZO-dione (XIX).
15
Alternatively, 160:,170: - methylene - 11,8 - hydroxy - 6n
?uoro-4-pregnene-3,ZO-dione (XIX), prepared by the
terone) (XIX)
20
ing 16a,17a-methylene-6-methy1-1,4,6-pregnatriene-3,20
dione (XX) (from Example 47) as starting material,
yields pure, crystalline 16a,l7a-methylene-ll?-hydroxy
Fluoro - 1,4 - Pregnadiene - 3,20 - Dione
(1604,1704
Methylene - II?-Hydroxy - 6/3 - Floaro - 1 - Dehydra
Following the procedure of Example 81, but substituting
103. - 1601,17“ - Methylene-115 - Hydroxy -
Methyl-1,4,6-Pregnatriene-3,20-Dione (16a,1 7a-Meth
Following the procedure of Example 81, but substitut
Example 99.—16oc,17ot - Methylene - 11/3 - Hydroxy - 613
progesterone) (XIX)
Example
ylene-Il?-Hydroxy - 6-Methyl - 1,6-Bisdehydropr0ges
method of Example 83 can be ‘l-dehydrogenated by the
method of Example 43 to give 16u,17e-methylene-l1?
hydroxy-6a-?uoro-l,4-pregnadiene-3,20-dione (XIX).
l6a,l7e-methylene - ll?-hydroxy - 4,6
pregnadiene-3,20-dione (XIX) prepared by the method
of Example 91, can be l-dehydrogenated by the method
of Example 46 to give l6a,17a-methylene-1lit-hydroxy
16a,17a-methylene-6a-?uoro-1,4—pregnadiene - 3,20
dione (XXI) (from Example 43) as starting material,
6-methyl-1,4,6-pregnatriene-3,20-dione (XIX).
25
Alternatively 160:,17ot-I1'16thYl6H6-1 1 B-hydroxy-6-rnethyl
4,6-pregnadiene-3,20-dione (XIX), prepared by the
method of Example 92, can be l-dehydrogenated by the
method of Example 47 to give 16a,17a-methylene-ll?
16c:,17oc - methylene - 618 - ?uoro - 1,4 - pregnadiene
3,20idione (XXI) (from Example 44) as starting mate
rial, yields pure crystalline l6a,l7a-methylene-ll?-hy
hydroxy-?-methyl-1,4,6-pregnatriene-3,20-dione (XIX).
droxy-6?-?uoro-1,4-pregnadiene-3,20~dione (XIX).
Alternatively,
16a,17<x~methylene - 1,4,6-pregnatriene - 3,20-dione
(XX) (from Example 46) as starting material, yields
crystalline 16a, l7a-methylene-1 1 ?-hydroxy-l,4,6-pregna
triene-3,20-di0ne (XIX).
Example 98.——16a,17a - Methylene - 11/3 - Hydroxy - 6a
Example 104. -— 160:,170: - Methylene - 1113 - Hydroxy-6
Fluoro-I ,4,6-Pregnatriene-3,20-di0ne (1 6 04,1 7cz-Methyl
16oc,17oz - methylene - 11B - hydroxy
6,8-?noro-4-pregnene-3,ZO-dione (XIX), prepared by the
ene-J1?-Hya'roxy-6-Flu0ro - 1,o-Bisdehydroprogesler
method of Example 84, can be l-dehydrogenated ‘by the
method of Example 44 to give l6a,17a-methylene-11,8~
one) (XIX)
hydroxy-GB-?uoro-l,4-pregnadiene-3,20-di0ne (XIX).
Example
Following the procedure of Example 81, but substitut
35
(1 601,1 7u-I‘Jethyl'
_ ?uoro-l,4,6-pregnatriene~3,20-dione (XIX).
ene - 11,3 - Hydroxy - 60c - Chloro _ 1 - Dehydraproges
terone) (XIX)
Following the procedure of Example 84, but substituting
40
hydroxy-6-?uoro-l,4,6-pregnatriene-3,204lione (XIX).
rial, yields crystalline 16u,17a-methylene-11?l-hydroxy-6a
chloro-1,4-pregnadiene-3,20-dione (XIX).
16a,17a-methylene - 11/3 - hydroxy - 6a
Alternatively, 16a,17a-methylene-l l?-hydroxy-G-?uoro
4,6-pregnadiene-3,ZO-dione (XIX), prepared by the
method of Example 93, can be l-dehydrogenated by the
method of Example 48 to give 16a,17a-methylene-1 1B
16u,17a - methylene - 6oz - chloro - 1,4 - pregnadiene
3,20-dione (XXI) (from Example 45) as starting mate
Alternatively,
16a,l7a-methylene-6-?uoro-1,4,6-pregnatriene~3,20
dione (XX) (from Example 48) as starting material,
yields crystalline 16oz, 17OL-I1'1?thYl6Il6-I 1 ?-hydroxy-G
100.'—160t,170t-M€[hyl6ll€ - 11p - Hydroxy - 6a
ChloroJ ,4-Pregnadiene-3,20-Dione
ing
Example 105. —- 16a,17a - Methylene - 11f3-Hydroxy-6
45
Chloro-l,4,6-Pregltatriene-3,20-Di0ne (16u,17oc-Metll
chloro-4-pregnene-3,20-dione (XIX), prepared by the
ylene - 11 ,?-Hydroxy-ti-Chloro - 1,6-Bisdelzydropr0ges
method of Example 85, can ‘be l-dehydrogenated by the
method of Example 45 to give 160:,17oc-metl1Yl6I16-1119
Following the procedure of Example 84, but substitut
terone) (XIX)
hydroxy-?a-ehloro-l,4-pregnadiene-3,20-dione (XIX).
Example 101 .——16a,]7a-Methylene-1,4-Pregnadiene-3,11,
ZO-Trione (XIXa), 16a,17a-Methylene-6a-Methyl-1,4
50
(XIXa),
Alternatively,
Trione
1611,]7a-Methylene-6?-Flu0r0-1,4-Pregnaa'i
ene-3,11,20-Tri0ne (XIXa) and 16a,17u-Metlzylene~6a
55
Chloro-I,4-Pregnadiene-3,11,20-Tri0ne (XIXa)
diene-3,20-di0ne (XIX) (from Example 97), 160:,17a
Trione (XIXa), and 1604,]7a-Methylene-6-Chl0r0
dione (XIX) (from Example 98), 16oz, l7a-methylene~
16a,17a-methlyene ~ 6a-methyl - 1,4-pregnadiene-3,11,20
trione (XIXa), 16a,17a-methylene-6a-?u0ro-1,4-pregna
diene-3,1 1,20-trione (XIXa),16a17a-methylene-6/8-?uoro
1,4-pregnadiene-3,l1,20-trione (XIXa) and 16ot,17oc
methylene - 6a-chloro - 1,4-pregnadiene - 3,11,20 - trione
(XIXa).
3,11,20-Tri0ne (XIXa), 16%]7oc-Methylene-6u-Methyl
1,4,6-Pregnatriene-3,11,ZO-Trione (XIXa), 160:,17a
Methylene - 6 - Fluoro - 1,4,6 - pregnalrl'ene - 3,11,20
methylene-ll?-hydroxy - Got-?uoro-1,4-pregnadiene-3,20~
17a-methylene-1,4-pregnadiene - 3,11,20-trione (XIXa),
the method of Example 94, can be l-dehydrogenated by
the method of Example 49 to give 16a,17a-methy1ene-11/3
Example 106.—16a,17a-Methylene - 1,4,6-Pregnatriene
60
16a,l7a-methylene-llB-hydroxy - Got-methyl - 1,4-pregna
11/3-hydroxy-6B-?uoro-1,4-pregnadiene-3,20-dione (XIX)
(from Example 99), 16a,17a-methylene-1l/3-hydroxy-6a
chloro-l,4-pregnadiene-3,20-dione (XIX) (from Example
100), yields, respectively, light colored, crystalline 16a,
16a,l7a - methylene - ll?-hydroxy - 6
chloro-4,6-pregnadiene-3,20-dione (XIX), prepared by
hydroxy-6-chloro-1,4,6-pregnatriene-3,20~dione (XIX).
Following the procedure of Example 60, but substitut
ing as starting materials, 16a,Not-methylene-ll?-hydroxy
1,4-pregnadiene-3,20-dione (XIX) (from Example 96),
16a,l7a-methylene-6-chloro-1,4,6~pregnatriene-3,20
dione (XX) (from Example 50) as starting material,
yields light colored crystals of 16a,17a-methylene-llf3
hydroxy-6-chloro-1,4,6-pregnatriene-3,ZO-dione (XIX).
Pregnadiene-3,11,20-Tri0ne (XIXa) , 1611,] 7a-Methyl
ene - 6a - FlllOJ‘O - 1,4 - Pregnadiene - 3,11,20
ing
65
1,4,6-Pregnatriene—3,11,20-Tri0ne (XIXa)
Following the procedure of Example 60, but substitut
ing as starting materials, 16a,17a-methylene-1lit-hydroxy
1,4,6-pregnatriene-3,20-dione (XIX)
(from Example
102), 16¢,17a - methylene - 11/3-hydroxy-6-methyl-1,4,6
70 pregnatriene-3,20~dione (XIX) (from Example 103),
160:,17a - methylene - 11p - hydroxy-6-?oro-1,4,6-pregna
triene-3,20-dione (XIX) (from Example 104), l6ot,l7oc
methylene - 11?-hydroxy-6-chloro-4,6-pregnatriene-3,20
dione (XIX) (from Example 105), yields, respectively,
75 light colored, crystalline 16a,Not-methylene-1,4,6-pregna
3,086,029
34
33
triene-3,1 1,20-trione
(XIXa ) ,
ketal) (XIXb) (from Example 107) dissolved in 500‘ m1.
16a,17a-methylene-6
methyl-1,4,6-pregnatriene-3,11,20-trione
(XIXa),
of ether. This mixture is stirred for about 45 minutes at
room temperature after which time it is refluxed for about
one hour and then cooled and hydrolyzed with water. The
precipitate and water are extracted repeatedly with ether
and the combined ether extracts are evaporated after
16¢
17a-methylene-6-?uoro - '1,4,6-pregnatr-iene-3,11,20-trionc
(XIXa), and 1611,17a»methylene46-chloro—1,4,6~pregna
triene-3,11,20-trione (XIXa) .‘
Example ' 107. -— ‘161:,17a-Methylene-5~pregnene-3,Il,20
Trione 3,20-Bis(Ethylene . Ketal) [16ot,17otMethylene
J1 - Ketoprogesterone 3,20 -Bis(Ethylenel Ket'al)]
(XIX b) 1
e
Washing with water and drying with anhydrous sodium
sulfate. The resulting crystalline residue is essentially a
quantitative yield of crude 16a,17a-methylene-1lp-hy
10 droXy-progesterone 3,20-bis-(ethylene ketal) (XIXa),
which on recrystallization gives the pure, light colored,
A mixture of 300 mg. of 16a,17a-methylene-4-pregnene
crystalline product.
3,11,20-trione (XIXa) (‘from Example‘ 60), 5 'ml.‘ of
ethylene glycol, 50mg. of para-toluenesulfonic acid mono
Example 113.—16a,17a-Methylene-6 - Methyl - 11 5 ~Hy
“ hydrate and 100 ml. of 'benzene is placedin a reaction
‘?ask equipped with a‘r'e?ux condenser and a water trap so 15
dr0xy-5-Pregnene-3,20-Diane 3,20-Bis(Ethylene Ketal)
[1 6 (1,1 7a-Methylene?-Methyl-.1 1 p - Hydroxyprogester
arranged that the condensed vapors pass‘ through the
one 3,20-Bt's(Ethylene Ketal)] (XIXc)
Following the procedure of Example 112 but sub
water trap before returning to _the reaction flask. The
mixture is heated to ‘reflux and‘ allow to re?ux for about
i 5 hours while at the same time being agitated.
_
stituting 16a,17a-methylene-6-rnethyl-5-pregnene-3,11,20
The
water of reaction formed is continuously removed by co 20 trione 3,20-bis(ethylene ketal) (XIXb) (from Example
distillation with the refluxing ‘benzene and is collected in V 108‘) ‘as starting material, yields crystalline l6oc,l7ot
the water trap. Thebenzene solution is then washed
with successive portions of a dilute sodium bicarbonate
solution and water, and then dried. The residue remain
methylene-6-methyl-ll?-hydroxy-5-pregnene-3,20 » dione
. 3,20-bis(ethylene ketal) (XIXc).
.
.
Example ]14.—16a,17a-Methylene - 6 - Flnoro - 11,8 - Hy
ing ‘after evaporation of the solvent is crude 16a,17u-meth 25;
dr0xy-5-Pregnene-3,20 Dione 3,20-Bis(Ethylene Ketal)
(XIXb) which is recrrystallized from ethyl acetate to give
one 3,20-Bis(Ethylene Ketal)] (XlXc)
_‘ylene-5-pregnene-3,11,20-trione 3,20-bis(ethylene ketal)
[160a,] 7'a-Methylene-6-Flu0r0 - 11B - Hydroxyprogester
the pure, light colored, crystalline product.
Example 108.—-16u,1 7a-Methylene-6-Methyl-j-Pregnene
3,11,20-Tri0ne .3,20-Bis(Ethylene Ketal)
[160a,] 7a
‘Following the procedure of Example 112, but substitut
30 ing 16a,17a-methylene-6-?uoro-5-pregnene-3 ,1 1,20-trione '
3,20l-bis(ethylene‘ketal) (XIXb) (from Example 109) as
startingjmaterial, yields crystalline 16a,17a-methylene-6
Methylene - 6-Methyl - -1 l-Ketoprogesterone 3,20-Bis
(Ethylene Ketal)] (XIXb)
» I?uoro- 11,6-hydroxy-5~pregnene-3 ,20-dione 3 ,20-bis (ethyl
one ketal) (XIXa).
Following the procedure of Example 107, but substitut
ing < 16a, 17OL-I'l'l?llhYl6116-60t-1'II6lLhyl-4¥PIBgIl€l16-3, 1 1,20-tri
Examplr l15.-—16a,1 ?an-Methylene - 6 - Chloro - 11,8 - Hy
1 one (XIXa) ‘(from Example 61-) as starting material,
" yields pure, ‘crystalline. 16a,17a-methylenee6amethyl-5
- [160a,] 7u-Jl4ethylene-6-Chloro - 1113 - Hydroxyprogester
dr0xy-5-Pregnene-3,20-Dione 3,20-Bis(Ethylene Ketal)
pregnene-3,11,20-trione 3,20~bis(ethylene ketal) (XIXb).
;0ne:3,20-Bis(Ethylene Ketal)] (XIXc)
Example 1095-91605] 7a-Methy lene-6-Fluoro-5-Pregnene
Following‘the procedure of Example 112, but substitut
[1602,1700
in'g" 1160;,17ot-methyIene-G-chloro-5-pregneue-3,11,20-trione
Methylene - 6 - Fluoro ‘- .l1_- Ketoprogesterone 3,2'0-Bis
f>l-3',20-bis(ethylene ketal) (XIXb) (from Example 111) as
(Ethylene Ketal)] (XIXb)
Following the procedure of Example 107, but substitut
istartingmaterial, yields light colored, crystalline l6oc,17oc
‘ 3,11 ,20_-Tri0\ne -3,'20-Bis(Ethylene Ketal)
Fmethylene?-chloro-ll?-hydroxy-S-pregnene - 3,20 - dione
_‘ ing 16a,17beinethylene-6a-?uoro-4-pregnene-3,11,20-trione 45 3,20-biS-(ethylene ketal) (XIXc).
(XIXa) (from Example v612) ‘ as starting material, yields
7' Example How-160e,] 7a-Methylene-l1? - Hydr0xy-4-Preg
crystalline 16a, 17 wmethylene-G-?uoro-S -pregnene-3,1 1,20‘
‘ , ne'ne-3,20-Di0ne (116x170: - Methylene - 115 ~ Hydroxy
‘ trione 3,20-bis(ethylene ketal) (XIXb).
I progesterone) (XIX)
To a: solution of 2 g. of 160:,l7oc-II16thYl6Il6-ll?-hy
Example ‘ 1l0.‘—-16a,17a-Methylene-6-Flu0r0-5-Pregnene
[160a,17ot 50 droxyprogesterone 3,20-bis(ethylene ketal) (XlXc) (from
- Ket0pr0gester0ne43,20-Bis~
Example 112), in 75 ml._ of acetone, is added one ml. of
‘ 3,11,20-Triqne 3,20-Bis(Ethylene" Ke‘tal)
Methylene - 6 - Fluoro - 1]
‘(Ethylene Ketal)] (XIXb)
'
- concentrated sulfuric acid in 25 ml. of water and the result
~
ing acidic mixture allowed to stand for about 15 hours.
Following ‘the procedure of Example 107, but sub
stituting “ 16a,17ot-methylene-6B-?uoro-4-pregnene-3,11,20
" trione (XIXa) (from Example 163') as starting material,
1 yields crystalline '16a,‘17a-methylener6-?uoro-5-pregnene
3,11,20-trione 3,20-bis(ethylene ketal) \(XIXb) ..
Example 111 .—16'a,17a-Methylene-6-Chlor0~5-Pregnene
3,11,20-Tri0ne 3,20-Bis(Ethylene Ketal) ‘-[16a,17a
55
(XIXb)
'
'
‘
crystallization takes place. The thus obtained 16a,17ot
imethylene-1l?-hydroxyprogesterone (XIX) is collected
, ona ?lter and puri?ed by recrystallization from ethyl
acetate to give pure ‘ lV6a,1\7a-methylene-1l?-hydroxy
’ . progesterone (XIX).
60
’ Methylene - 6 - I1 ‘- Ketoprogesterone 3,20-Bis-(Ethyl
ene Ketal)]
The solution is then concentrated and water added until
Example 117.—-16a,17oz-Methylene~6a-Methyl - 11,3 - Hy
‘dr0xy-4-Pregnene-3,20FDi0ne (1611,] 7a - M ethylene-6a
_
Methy H .1 5-Hydroxyprogesterone) (XIX)
Following the procedure of Example 116, but substitut
‘Following the‘ procedure of Example 107, but sub
stituting 16a,17qt-methylene-éa-chloroi4-pregnenel3 ,11,20
_trione (XIXa) (from Example‘ 64) as starting material,
ing 16a,l7a-rnethylene-6-methyl-1l?-hydroxy-S-pregnene
' ‘pr‘egne‘ne-S ,1 1,20‘-trione 3,'20"-bis(ethylene vketal) 1(XIXb) .
' ample 113) as start-ing material, yields crystalline 16a,17 a
3,20-dione ,3,20-bis(ethylene ketal) (XlXc) (from Ex
‘yields pure, crystalline" v'16oz,17ot-methylene-64chloro-5
Example 112.—16a,1 7a-Methylene-l Ip-HydrOxy-S-Preg .
nene-3,20-Dione 3,20-Bisi(Ethylene Ketal) [16a,17<x 70
Methylene-1lp-Hydroxyprogesterone 3,20-Bis(Ethylene
Ketal)] (XIXc)
‘-
i
‘
To a solution of 10 g. of_ lithium aluminum hydride
suspended in 800 ml. of ether is added 10 g. of 16a,17a
‘ methylene~5-pregnene - 3,11,20 - trione 3,20‘ - bis(e'thy1ene
methylene-6aamethylrl1B-hydroxy-4-pregnene-3,20 - dione
(XIX).
Example ll.8.—16a,17a-Methylene-6a — Fluoro - 11,6 - Hy
dr0xy-4-Pregnene-3,20-Di0ne (1160;,1 7a - Methylene-6a
Fluoro-llp-Hydroxyprogesterone) (XIX)
‘Following the procedure of Example 116, but substitut
75 ing ,16oz,l7r0t-TI16’tl1Yl6116-6-?1101‘0-1 1 ?-hydroxy-S-pregnene
3,086,029
35
36
3,20-dione 3,20~bis(ethylene ketal) (XIXc) (from Ex
ample 114) as starting material, yields crystalline 1600,170t
methylene-60t
?uoro-ll?
Example 121.--I6a,1700 - Methylene - 9a - Flnoro - 60L
Methyl - 11,9 - Hydroxy - 4 - Pregnene - 3,20 - Dione
(160t,1700 - Methylene - 900 - Flaoro - 6a - Methyl - 11B
hydroxy - 4 - pregnene - 3,20
Hydroxyprogesterone) (XXV)
dione (XIX).
Following the procedure of Example 120, but substitut
Example 119.—160t,170t-Methylene-6a-chloro - 11,3 - Hy
ing
droxy-4-Pregnene-3,20-Di0ne (1-60t,170t - Methylene-600
160:,1700 - methylene - 60¢ - methyl - 11p - hydroxy
4-pregnene-3,20~dione (XIX) (from Example 117) as
starting material, yields crystals of 1606,170L-1T1BthYl61'16-90L
Chloro-JJ?-Hydroxyprogesterone) (XIX)
Following the procedure of Example 116, but substitut 10
ing 16a,17ot-IIl6thYl61'16-6-Chl0l‘O-l 1B-hydroxy-5~pregnene~
3,20-dione 3,20-bis(ethylene ketal) (XIX) (from Example
?uoro - 600 - methyl - 1113 - hydroxy - 4 - pregnene - 3,20
dione (XXV).
Example 122.—160t,1700 - Methylene - 60t,900 - Di?aoro
115) as starting material, yields light, crystalline 1600,170t
11,8 - Hydroxy - 4 - Pregnene - 3,20 - Dione (1600,1700
methylene-‘600-chloro-11p-hydroxy-4-pregnene-3,20 - dione
Methylene - 600,900 - Di?a0r0-11p - Hydroxyprogester
(XIX).
15
one) (XXV)
Following the procedure of Example 120, but sub
Example 120.—-160t,1700 - Methylene - 90¢ - Fluoro - 11B
Hydroxy - 4 - Pregnene - 3,20 - Dione
(160¢,170t
stituting 1600,1700 - methylene - 6C1. - ?uoro - 115 - hydroxy
Methylene - 900 - Fluora - 1113 - Hydroxyprogesterone)
20
(XXV)
4-pregnene-3,20-dione (XIX) (from Example 118) as
starting material, yields crystalline l60t,l70t-methylene—
600,900 - di?uoro - 11p - hydroxy - 4 - pregnene - 3,20 - di
one (XXV).
(a) A mixture of 1 g. of 16a,1700-methylene-1l?-hy
droxy-4-pregnene-3,20-dione (XIX) (from Example 116),
Example 123.—-160c,170t - Methylene - 900 - Fluoro - 66t
650 mg. of N-bromoacet-amide and 6 ml. of pyridine is
stirred in the dark for a period of about 30 minutes. The 25
mixture is cooled in an ice-water bath and a stream of
sulfur dioxide is directed onto the surface of the stirred
Chloro - 11B - Hydroxy - 4 - Pregnene - 3,20 - Dione
(1600,170: - Methylene - 9a -Fla0r0 - 600 - Chloro - 11B
Hydroxyprogesterone) (XXV)
Following the procedure of Example 120, but substitut
mixture until a negative potassium iodide-starch test is
ing 160t,170t - methylene - 600 - chloro a 116 ~ hydroxy - 4
obtained. Fifty ml. of water is then added to the mix
pregnene-3,20-dione (XIX) (from Example 119) as start‘
ture and the mixture maintained at about 5° C. -for about 30 ing material, yields light colored, crystalline 160a1700~
30 minutes. The precipitated white solid is ?ltered,
methylene - 900 - ?uoro - 600 - chloro - 11,8 - hydroxy - 4*
washed with water and dried under vacuum.
After crys
pregnene-3,20-dione (XXV).
tallization from acetone there is obtained crystalline
1600,1700 - methylene - 4,9(11) - pregnadiene - 3,20 - di
one (XXII).
35
(b) 0.5 gram of 1600,17a-methylene-4,9(11)-pregnadi
ene-3,20-dione (XXII) is dissolved in 20 ml. of methyl
Example 124.-—160L,170t - Methylene - 900 - Fluoro - 11B
Hydroxy - 4,6 - Pre'gnaa‘iene - 3,20 ~ Dione (XXV),
1600,1700 '- Methylene ; 90a - Fluoro - 6 - Methyl - 115
Hydroxy ~ 4,6 - Pregnadiene - 3,20 a Dione (XXV),
1600,1700 - Methylene - 6,90t - Di?uoro _- 11,8 - Hydroxy
ene chloride and thereto is added a solution of 1 ml. of
71% perchloric acid in 10 ml. of water and 200 mg. of
N-bromoacetamide in 50 ml. of tertiary butyl alcohol. 40
4,6 - Pregnadiene - 3,20 '- Dione (XXV),- and 16a,1700
Methylene - 90: - FluorO - 6 - Chlo'ro * 11f} - Hydroxy=
4,6-Pregnadiene-3,20-Di0ne (XXV)
The solution is maintained at room temperature for about
?fteen minutes and then mixed with a solution of 0.3 of
sodium sul?te in 12 ml. of water. The mixture is distilled
at reduced pressure until the residual solution becomes
Following the procedure of Example 120, but substitut
ing as starting materials, 16a,170t-methylene-l l?-hydroxy
cloudy. The product is then precipitated by the addition 45
91),
of 100 ml. of a mixture of ice-water. The white crystal
4,6 - pregnadiene - 3,20 - dione (XIX) (from Example
160t,170t - methylene - 6 - methyl - ll? - hydroxy
4,6-pregnadiene¢3,20-dione (XIX) (from Example 92),
line precipitate is ?ltered, washed with water, and then
1600,1700 - methylene - 6 - ?uoro - ll? - hydroxy - 4,6
dried to give crystalline 1600,170t-methylene-90t-bromo
pregnadiene-3,20—dione (XIX) (from Example 93), and
1 1B-hydroxy-4-pregnene-3,20-dione (XXIII) .
1600,1700 - methylene ~ 6 - chloro - 116 - hydroxy - 4,6
(c) A mixture of 0.45 g. of 16a,170t-methylene-900— 50 pregnadiene-3,20-dione (XIX) (from Example 94) yields,
respectively, light colored, crystalline 16a,170t-methylene
bromo - 11B - hydroxy - 4 - pregnene - 3,20 - dione
(XXIII), 0.45 g. of anhydrous potassium acetate and 20
9a - ?uoro - 11,3 - hydroxy - 4,6 - pregnadiene - 3,20 - di
ml. of acetone is heated at its re?uxing temperature for
one (XXV), 160¢,170t-methylene-9a-?uoro-6-methyl-1 1,8
a period of 5 hours. The mixture is then cooled and
hydroxy-4,6-pregnadiene-3,20-dione (XXV), 160t,1700
poured into water and extracted with methylene chloride. 55 methylene - 6,90t - di?uoro - 11B - hydroxy - 4,6 - pregna
The methylene chloride extract is dried and poured over a
diene - 3,20 - dione (XXV) and 160t,170t - methylene
column of 25 grams of Florisil. The column is developed
90; -fluoro - 6 - chloro - 1113 - hydroxy - 4,6 - pregnadiene
with Skellysolve B containing increasing proportions of
acetone.
3,20-dione (XXV).
The Skellysolve B plus 10% acetone eluate con
60
Example 125.—-—160t,170t - Methylene - 90¢ - Fluoro - 11B
Hydroxy - 1,4 - Pregnadiene - 3,20 - Dione (XXV),
(d) A solution of 1 g. of 1600,1700-methylene-9/3,11,B
oxido-4-preguene-3,20-dione (XXIV) is dissolved in 50
ml. of methylene chloride and thereto is added 5 ml. of
48% hydro?uoric acid. The mixture is stirred vigorous 65
Hydroxy - 1,4 - Pregnadiene - 3,20 - Dione (XXV),
160,170: - Methylene - 60t,900 - Dt'?aoro - 1118 - Hy
droxy - 1,4 - Pregnadiene - 3,20 - Dione (XXV), 16a,
tains‘
l60t,1700 - methylene - 95,115 ~ oxido - 4 - pregnene
3,20-dione (XXIV).
1600,170: - Methylene - 900 - Fluoro - 6a - Methyl - 11p
ly for about 6 hours and then poured into an excms of
cold aqueous 5% sodium bicarbonate solution. The
1700 - Methylene - 613,90: - Di?aoro - 11,8 - Hydrvxy
methylene chloride layer is separated, dried with anhy
Methylene - 900 - Fluoro - 600 -Chl0r0 - 11,8 - Hydroxy
1,4 - Pregnadt'ene - 3,20 - Dione (XXV) and 1600,1700
1,4-Pregnadiene-3,20-Dione (XXV)
drous sodium sulfate and then poured over a column of
100 of Florisil. The column is developed with Skelly 70
solve B and acetone, the fractions containing 10% ace
tone are evaporated to dryness and recrystallized from
Following the procedure of Example 120, but substitut
ing as starting materials, 160$,170t-H16thYl6l'16-1l?-hydl‘Oxy
1,4 - pregnadiene - 3,20 - dione (XIX) (from Example
acetone and Skellysolve B to give pure crystalline 16a,
96),
1700 - methylene - 9a - ?uoro - ll? - hydroxy - 4 - preg
1,4 - pregnadiene - 3,20 - dione (XIX) (from Example
97), 160:,170; - methylene - 60¢ - ?uoro: l-l? - hydroxy-'
nene-3,20-dione (XXV).
75
1611,1700 - methylene - 6a - methyl - 11p - hydroxy
‘3,086,029
as
‘ ‘Example 130,—16a,17a-Methylene-9 -Flu0r0-6ug-Chl0r_0
1,4-pregnadiene-3,20rdione (XIX) ‘ (from Example 198),
1611,1704 - ‘methylene - 65 - fluoro - 11B - hydroxy - 1,4
4 - Pregnene - 3,11,20-Tri0ne (1611,] 7a-Methylen'e-9u
pl‘egnadiene-3,l0-dionei (XIX). tfrqmi‘Example :99.) and
Flu‘0rfa-6a-Chl‘0r0-1I-Ketoprogesterone) (XXVI)
16a,17a - methylene -. 6a - chloro - 11p - hydroxy - 1,4
pregnadiene-3,20ddione I (XIX)
Following the procedure of Example 127, but substitut
(from Example 100)
ing . 16a,17a-methylene-9a-?uoro~6a-chloro-1lp-hydroxy
yields, respectively, light colored, crystalline 16a,17a-‘
4-pregnene-‘3,20-dione (XXV) (from Example’ 123) as
starting material, yields light colored, crystalline 16a-17a
methylene - 9oc-flll01‘0 - 11B - hydroxy - 1,4 - pregnadiene
3,20 - dione (XXV), 16a,17a - methylene - 9a - ?uoro
6oz - methyl - 11/3 - hydroxy -'1,4 - pregnadiene - 3,20~
vmethylene “- ‘9a.-_?uoros?a-chloroA-pregnene-3,11,2'0-trione
‘ (XXVI).
dione (XXV), 16a,17tat-methylene-6a-,9‘a—di?uoro-1l?-hy
droxy - 1,4 -pregnadiene - 3,20 - dione
'
Example 131. — 16u,17a-Methylene-9a-Flu0r0-4,d-Preg
(XXV),
17a - methylene - 618,90‘ -, di?uoro -, 11E - hydroxy - 1,4
nadiene-3,1 1,20-Tri0ne (XXVI), 1 6 11,1 7ix-Methylene
pregnadiene-3,20-dione (XXV) and 16u,17a-methylene
9m - Fluoro - 6-Methyl-4;6=Pregnadiene;3,1J ,ZO-Trione
(XXVI), 160a,] 7a-Mez‘hylene-6,9u-Di?u0ro-4,6-Pregna
diene-3,11,20-Tri0ne (XXVI) and 16a,17a-Methylene
90c - fluoro - 6oz - chlor-o ~. 11/3 - hydroxy - 1,4 - pregna~
diene-3,20-dione (XXV).
'
'
15
90c - Fluoro - 6 - Chl0r0-4,6-Pregnadiene-3,11,20-Tri0ne
1(XX VI )
Following the procedure of Example 127 , but substitut
ing as starting materials 16a,17a-methyleneJ9a-?uoro-11,8
hydroxyd4,6-pregnadiene-3,20~dione (XXV) (from Ex
20
ample 124), 16a,17a-methylene-9a¢?uoro~6-rnethyl-l1/3
hydroxy-4,t6-pregnadiene-3,20-dione (XXV) (from Ex~
ample
Following the procedure of Example 120, but substitut
25
1,4,-6-pregnatriene-3,20-dione (XIX) "(from ',,Example
1604,17u - methylene-6,9a-di?uoro-1lB-hy
9124) yields, respectively, light colored, crystalline 16w
102), ‘1‘6a,17oc - methylene-16-methyl-11?-hydroxy-1,4',6
17a - methylene - ‘9‘a-?uoro-4,‘6-pregnadiene-3,11,20-trione
pregnatriene-3,20-dione (XIX) (from Example 103), 161x,
1704 ~ methylene - 6 - ?uoro-l-l?-hydroxy-1,4,6-pregnatri
124),
droxy-4,6-pregnadiene-3,20~dione (XXV) ‘(from Example
124) and 16a,17u-methylene-9‘a-?uoro~‘6-chloro-1l?-hy
droxy-p4,6~pregnadiene-3,20-dione (XXV) (from Example
30
nadiene-3,11,‘20-trione (XXV), '16a,l7a-methylene-9a
ene-3,20-dione (XIX) ‘(from Example 104) and 16a,17a
r?uoro - 6,90: - ‘di?uoro - 4,16 -‘pregnadiene -_ 3,11,20-trione
methylene - 6,-chloro-1l?-hydroxy-l,4,6-pregnatriene-3,20
dione (XIX) (from ‘Example 105) yields, respectively,
light color, crystalline 16a,'17a-methylene-9u-?uoro-l1B
pregnadiene-3,11,20-tri0ne (XXVI).
Example 132.--16a,1 7a-Methylene-9a-Flu0ro-1 ,4-Pregna
hydroxy~1,4,6-pregnatriene-3,20-dione (XXV), 160:,1711- . 35
methylene - 9‘a-?uoro-‘6-methyl-‘1l?-hydroxy-l,4,-6-pregna
diene-3,11,20-Trione - (XXVI), I6a,1 7m-Methylene-9a
F luoro - 6a - Methyl - 1,4 - Pregnadiene-3J1,20-Trione
triene-3,20-dione (XXV), 16a,17ot-methylene-6,'9u-di?uo
ro~1 1?-hydroxy-1,4,6-pregnatriene-3,ZQ-dione (XXV) and
16ot,17u - methylene - 9oz -'fluoro~6-chloro-l,4,‘6-pregnatri
ene-3,2:0-dione (XXV). '
nadiene-3,1 1 ,20-1"rione (XXVI), 160a,] 7a-Methylene
613,9u - Di?uoro - 1,4 - Pregnadiene - 3,11,20 - Trione
40
(XXVI) and 16:1,] 7a-Methylene~9a-Flu0ro-6a-Chl0ro
1,4-Pregnadz'ene-3,11,20-Trione '(XXVI)
, Example 127.—16,u,1‘_7a 7 Methylene- 90c _- Flu0ro-4-Preg
Following the procedure of Example ‘127, but substitut
ing as starting materials 16a,17a-methylene—9u-I?uoro
45 -1 1 ?-hydroxy-l ,4-pregnadierle-3,20-dione (XXV) (from
Example 125 ) , 16a,17a-methylene-‘9‘a-?uoro~6a-methyl
Example 120) in 4 ml. of acetic acid is added 60 mg. of
chromic anhydride,.dissolved in 1 ml. of acetic acid and
, droxy-l,4-pregnadiene-3,20-dione (XXV) (from ‘Exam
0.1 m1. of water. The mixture is allowed to stand at room
temperature for a period of, about 4 hours, then poured ,50'
into 5-0 ml. of water, neutralized with sodium bicarbonate" , 11,4ypregnadiene-3,20=dione (XXV) (from Example 125)
and extracted with three -10, m1.,portions of methylene
. ,1,4-pregnadiene-3,20-dione (XXV) (from Example 125)
chloride. The methylene chloride extracts are combined,
washed with water, dried over anhydrous sodium sulfate,
evaporated, and the thus produced residue twice recrystal-_
lized from methanol to give‘ ‘16a,17a-methylene-9‘w?uoroé
yields,‘ "respectively," light colored,“ crystalline‘- \16a,17a
methylene - ‘90c - ?uoro - 1,4 - pregnadiene-3,11,20¢trione
55
(XXVI),
160:,17av - methylene-59‘6t¥?uoro»6u-methyl-1,4
pregnadiene-3,11,2'0htrione l(XXVI), 1-6a,17a-methylene
4-pregnene-3 ,11,‘20‘-trione (XXVI) .
600,90: ~ di?uoro~1,4-pregnadiene-3,11,20-trione
1..
, Fluaro-6ay-Metlzyl-1J fKetaoprogesteroae) (XX VI )
Following the procedure of Example 127, but; substitut
(XXVI),
l'6oc,17oc - methylenee6?,9oa-di?uoro-1,4-pregnadiene-3,11,
‘ 4"- Pregame-3,11,ZO-Tribrte‘ (16a,1\7a;Methyler_te'-‘9a
'20-tri0ne (XXVI) and 16a,17a-methyIeneQa-?uOrQ-Ga
60
chloro-l,4-pregnadiene-3,1 1,20-trione (XXVI).
Example 133 .—1 60a,] 7a-Methylene-9a-Fluoro-l ,4,6-Preg~
ing 1'6a,17a-methylene=9a-?uoro-6a-methyl-1lj8-hydroxy
natriene-3,11,20-Tri0ne (XXVI), 160a,] ?an-Methylene
4-pregnene-3,20sdione :(XXV) (from Example 1121) as
starting material, yields crystalline 16u,17a-methylene-9a7
9a - Fla0r0-6-Melhyl-I,4,6~Pregnatriene—3,11,20-Tri0ne
65
'(XXVI) , 160a,] 7oc-Methyle'ne-6,9a-Di?uoro-I ,4,6—Preg~
fluoro-6u-methyl-4¢pregnene-3, 1 1,20-trione (XXVI) .
Example 129. ——,I6a,1 7a - Methylene-6a,9a-Di?uoro-4
natriene-3,1 1,20-Tri0ne (XXVI) and 16a,I7u-Methyl
ene - 9a - F luoro - 6-Chlor0-1,4,6-Pregnatriene-3,11,20
Pregnene - 3,11,20} Trione I (1600,] 7 a-Methylene-.6 cc,9u
Trione 1(XXVI)
Di?uoro-l 1 -Ketoprorgesteron‘e) (XXVI)
Following the procedure of Example 1127, but substitut
Following the procedure of ‘Example 127, but substitutl' -
ing 1‘6a,17a-methylene-‘6oa9a-di?uoro-1‘1B-hydroxy-4-preg
nene-3,20-dione l(XXV) ‘(from Example ‘122) as starting
material, yields crystalline '16a,17a-methyleneJ6a,=9a-di
?uoro-4-pregnene-3, 1 1,201-tri0ne (XXVI) .
‘1
'
as l starting I‘ materials ‘16a,177a-methylene-9‘a-?uoro
’ 1lj3-hydroxy11,4,6-pregnatriene-3,20idione (XXV) (from
"Example 1126),‘ ‘ l6a,17wmethylene-9a-?uoro-6-methyl
, l-l?-hydroxy-‘l,4,6-pregnatriene-3,20-dione (XXV) (from
‘Example 126)‘, 16a,17a4methylene-9u-?uoro-6,9a-di?uo
3,086,029
'40
39
r0 - 11B - hydroxy-1,4,‘6-pregnatriene-3,20>di0ne
12. 16a,17a - methylene-6-chloro-4,6-pregnadiene-3,20
(XXV)
(from Example 126) and l6a,'17a-methylene-9a-?uoro-6
dione.
13. Compounds of the formula
chloro-ll?-hydroxy-1,4,6-pregnatriene-3,ZO-dione (XXV)
(from Example 126) yields, respectively, light-colored,
crystalline l6oc,17oc - methylene-9a-?uoro-1,4,6-pregnatri
CH3
CH3
5
ene-3,11,20-trione (XXVI), 160:,17m-methylene-9u-?uoro~
6-methyl-1,4,‘6-pregnatriene-3,11,20-trione ()OCVI), 160:,
170: - methylene-6,9ot-dif1uoro-1,4,6-pregnatriene-3,11,20h
trione (XXVI) and 1611,17 a-methylene-9a-?uoro-6-chloro
1,4,6-pregnatriene-3,11,20-trione (XXVI) .
10
We claim:
1. Compounds of the formula
CH3
CH5
CH5 Iii-CH.
15
wherein R is selected from the group consisting of methyl,
?uorine and chlorine.
20
14. 16a,17a - methylene-6-methyl-1,4,6-pregnatriene-3,
ZO-dione.
15. 16a,17a-methy1ene-6~?uoro - 1,4,6 - pregnatriene-3,
20-dione.
O...
16. 160:,l7a - methylene-6-chloro-1,4,6-pregnatriene-3,
25 ZO-dione.
R
17. A process for the production of a compound of the
formula
wherein R is selected from the group consisting of methyl,
?uorine and chlorine.
CH:
CH;
2. 16oc,17oc - methylene - 6a - methyl-4-pregnene-3,20
dione.
3. 16a,17m-methylene-6a-?uoro-4-pregnene-3,ZO-dione.
4. 16m,17u-methylene-6a-ehloro-4~pregnene-3,20-dione.
30
OH‘
5. Compounds of the formula
CH2
(i=0
jl"" "CH:
35
0:
it
40
wherein R is selected from the group consisting of hydro
.gen, methyl, ?uorine and chlorine, which comprises react
ing a compound of the formula
45
wherein R is selected from the group consisting of methyl,
?uorine and chlorine.
6. 16a,17a-methylene - 60c - methyl-1,4-pregnadiene-3,
50
20-dione.
7. 160:,17u - methylene-6a-?uoro-1,4-pregnadiene—3,20
dione.
8. 160:,17a. - methylene»6a-ch1oro-1,4-pregnadiene-3,20
dione.
9. Compounds of the formula
55
CH:
CH,
CH:
Inn-CH:l
wherein R has the same meaning as above, with a strong
60 acid.
18. A process for the production of a compound of the
formula
CH:
CH;
/
65
O:
R
wherein R is selected from the group consisting of methyl, 70
?uorine and chlorine.
10. 16a,17a-methylene-6-methy1 - 4,6 - pregnadiene-3,
20-dione.
11. 160:,1711 - methylene-6-?uoro-4,6-pregnadiene-3,20—
dione.
.
75
on,
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