FIELD OF THE INVENTION
The present invention relates to a method of preparing 9p,10a-5,7-diene steroids
such as dydrogesterone by irradiating the corresponding 9a, 1 Op-steroids with
filtered ultraviolet light using single illuminating lamp, while limiting the formation,
of undesirable byproducts.
BACKGROUND OF THE INVENTION
9p, 10a-5,7-diene steroids generally are intermediates in the synthesis of
pharmacologically interesting compounds which can perform a useful function in
the human body. The hormone analogue 6-dehydro-9p,10a-progesterone (9p,10apregna-
4,6-diene-3,20-dione) or dydrogesterone is an orally active progestative
hormone and is generally used to correct deficiencies of progesterone in the body.
9p, 10a-4,6-dien-3,20-dione, also known as dehydro-progesterone
(dydrogesterone), dydrogesterone, m.p. 169-170oC, at room temperature a white
crystalline powder or light yellow , insoluble in water, soluble in ethanol, acetone
and the like.
Photochemical isomerization of steroids are important in the industrial synthesis of
commercial products. For example, the photoisomerization of 7-dehydrocholesterol
(7-DHC) yields previtamin D3, which can be converted by conventional methods,
such as by thermal rearrangement, to vitamin D3. Vitamin D3 has many important
uses. For example, vitamin D3 can be used as an additive,to milk and in animal
feeds to prevent rickets.
A similar type of photoisomerization is carried out to produce 1 a,25-
dehydroxyvitamin D3. This is the actual active form of vitamin D3 that is
responsible for regulating calcium metabolism. The synthesis of dydrogesterone,
developed by Philips-Duphar, also includes a photoisomerization of a steroidal
intermediate.
Recueil des Travaux Chimiques des Pays-Bas (I960), 79: 771-783 reported an
optically sterol 2 as a starting material, which by Oppenauer oxidation,
isomerization, catalytic hydrogenation, ozonation, addition, sodium dichromate
oxidative dehydrogenation reaction provides dehydro-progesterorie. The above said
disclosure suffers from serious drawbacks such as very long synthetic route, use of
large number of environmentally harmful substances, and each step is not high
yielding, final yield is very low, hence the above said process can only be used as
a study to explore, and there is no possible industrial production.
The preparation of dydrogesterone from pregnenolone is described by Rappoldt et
al. in Recueil trav. chim. 1961, 80,43, and 1971, 90, 27. Important intermediates in
the synthesis of dydrogesterone are lumisteroh, 3-(ethylenedioxy)-9p,10a-pregna-
5,7-diene-20-one and 3,20-bis(ethylenedioxy)-9beta, 10alpha-pregna-5,7-diene.
These intermediates can be prepared by irradiating the corresponding 9a,10P
isomers, namely ergosterol, 9a,10p-3-(ethylenedioxy)-pregna-5,7-diene-20-one
and 9a,10P-3,20-bis(ethylenedioxy)-pregna-5,7-diene, respectively, with
ultraviolet light. This irradiation is preferably carried out with filtered ultraviolet
light. A medium-pressure or high-pressure mercury lamp has so far been used for
this purpose. In the above-mentioned publications, the desired 9p,10a-5,7-diene
steroids were formed during this photochemical isomerisation in yields of only 20%,
calculated on converted 9a,10p-isomer.
US 4,601,855 discloses that the photochemical conversion of 9a,10p-5,7-diene
steroids or suitable seco-steroids(seco-steroids) into the corresponding 9p,10a-5,7-
diene steroids could be performed with a considerably higher yield if an antimony
lamp was used as the light source instead of a conventional medium-pressure
mercury lamp. It further discloses that the irradiation can be carried out by using
two different Tamps in succession, first a conventional light source producing UVradiation,
e.g. a medium-pressure mercury lamp, and then an antimony lamp, to
produce comparable results as with a one-lamp irradiation. In this manner 9p,10a-
3,20-bis(ethylenedioxy)-pregna-5,7-diene could be prepared by conversion of the
J
corresponding 9a, 1 Op-compound in a yield of approx. 30%, calculated on starting
material, or of approx. 75%, calculated on converted material, in a reaction time of
6 to 7 hours as compared to the yield obtained by using high pressure mercury lamp.
The above said process has several drawbacks. First, the production capacity, i.e.
the conversion per time unit (per hour), does not fully come up to the producer's
expectations. The intrinsic capacity of irradiation processes is always"relatively
•small due to the required dilution of the solution to be irradiated. Further, an
antimony lamp is expensive to use making process un-economical.
US 5,304,291 discloses irradiating the 9a,10p-5,7-diene-steroid or seco-steroid
with filtered ultraviolet light from an indium lamp. The above indium lamp can be
used according to the method of the invention by passing the steroid-solution
through a reservoir surrounding the lamp or by immersing the lamp in the solution
to be irradiated. It further teaches that in the former method of irradiating a number
of indium lamps can be used to improve the production capacity, around which
lamps the solution to be irradiated can be passed in a continuous flow (annular flow
reactor). In the latter method immersion lamps can be used, which are immersed in
the solution accommodated in a reaction vessel (immersion photochemical
reactor). To obtain an optimum results, the irradiation with the indium lamp is
preceded by an irradiation procedure with a conventional light source producing
UV-radiation, generally a normal medium-pressure or high-pressure mercury lamp.
Although there are several processes known in the prior published references,
however they suffer from serious drawback of using multiple lamps to obtain the
desired compound in high yields.
Therefore, an improved conversion per time unit is very important for effecting a
commercially and technically attractive process. Further, there is a requirement for
development of process that utilizer single illuminating lamp in order to avoid
excess cost of production.
r: 4
The present invention is focussed to the photoconversion of steroids on solid
catalytic surfaces and more particularly to controlling the stereochemistry of the
photoconversion reaction by irradiation with filtered ultraviolet light.
OBJECT OF THE INVENTION
It is an object of the invention to provide an improved method of conducting the
photoconversion of steroids.
Another object of the invention is to provide a method of limiting the amount of
undesirable byproducts formed when photoconversions are conducted.
A further object of the invention is to provide a method of conducting the
photoconversion of steroids in a simpler manner with less waste and fewer
purification steps.
It is the objective of the invention to considerably improve the capacity of
producing 9p, 10a, 5,7-diene steroids by irradiating the corresponding 9a, 10(3-5,7-
diene steroids or seco-steroids, and, at the same time, to reduce the operating costs.
SUMMARY OF THE INVENTION
The present invention is focussed towards the development of a method of
conducting the photoconversion of steroids into desired products, while limiting the
formation of undesirable by products is provided.
Accordingly, the present invention provides process for preparation of 6-dehydro-
9p,10a-progesterone (dydrogesterone) comprising of:
a) irradiating 9a, 10p, 3,20-bis (ethylenedioxy)pregna-5,7-diene in presence of
single mercury lamp to get 9p, 10a, 3,20-bis (ethylenedioxy)pregna-5,7-diene; and
I Q l - 0 6 - 2 0 : 1 8 . 16.:. B-S5
b) converting 9p, 10a, 3,20-bis (ethylenedioxy)pregna-5,7-diene to 6-dehydro-
90, 1 Oa-progesterone.
The present invention further relates to preparation of substantially pure 6-dehydro-
9p,l Oa-progesterone (dydrogesterone) comprising of less than about 1.0% of total
impurities, wherein said process comprising of: ,
a) irradiating 9a, 1 Op, 3,20-bis (ethylenedioxy)pregna-5,7-diene in presence of
. ,single mercury lamp to get 9p, 10a, 3,20-bis (ethyleriedidxy)pregna-5,7-dierie;
b) converting 9p, 10a, 3,20-bis' (ethylenedioxy)pregna-5,7-diene to 6-dehydro-
9p,l Oa-progesterone; and
c) purifying 6-dehydro-9p, 1 Oa-progesterone to get substantially pure 6-dehydro-
9p,l Oa-progesterone with purity of 99.0% and above.
DETAILED DESCRIPTION
The present invention will now be explained in details. While the invention is
susceptible to various modifications and alternative forms, specific embodiment
thereof will be described in detail below. It should be understood, however that it
is not intended to limit the invention to the particular forms disclosed, but on the
contrary; the invention is to coyer all modifications, equivalents, and alternative
falling within the scope of the invention as defined by the appended claims.
The present invention provides a process wherein steroidal compounds can be
converted to desired products with increased stereochemical control compared to
conventional processes. This is accomplished by restricting the reaction
environment of the molecule being reacted to prevent the formation of undesirable
side products.
A low-pressure mercury vapour discharge lamp for radiation purposes having a
discharge tube made of glass with selective transmission, the tube being coated on
the inside with a luminescent layer. The discharge tube is made of glass having an
x da-,*. — n.-e*.w.-->--m,r. ft- *•&•*:." 1-5' 6
absorption edge located below 260 and 280 nm and the tube has at 300 nm a
transmission of at least 80%.
The present invention relates to a low-pressure mercury vapour discharge lamp for
radiation purposes having a discharge tube made of glass with selective
transmission, the tube being coated on the inside with a luminescent layer.
Accordingly, in one embodiment, the present'invention provides process for
preparation of 6-dehydro-90,l Oa-progesterone (dydrogesterone) comprising of:
a) irradiating 9a, lop, 3,20-bis (ethylenedioxy)pregna-5,7-diene in presence of
single mercury lamp to get 90, 10a, 3,20-bis (ethylenedioxy)pregna-5,7-diene; and
b) converting 90, 10a, 3,20-bis (ethylenedioxy)Pregna-5,7-diene to 6-dehydro-
90,1 Oa-progesterone.
In other embodiment, the present invention provides low-pressure mercury vapour
discharge lamp for radiation purposes having a discharge tube made of glass with
selective transmission, the tube being coated on the inside with a luminescent layer
and is used for selective transmission of 9a, 100, 3,20-bis (ethylenedioxy)pregna-
5,7-diene in step (a).
In another embodiment, the irradiation reaction is performed in a solvent selected
from esters such as ethyl acetate, propyl acetate, isopropyl acetate, butyf acetate, tbutyl
acetate and the like.
In further embodiment, 90,10a, 3,20-bis (ethylenedioxy)pregna-5,7-diene obtained
after irradiating 9a, 100, 3,20-bis (ethylenedioxy)pregna-5;7-diene using single
mercury lamp, can be crystallized using solvent selected from the group comprising
of methyl ethyl ketone, methyl t-butyl ketone, methyl iso-butyl ketone, acetone
ethyl acetate, isopropyl acetate, butyl acetate, n-propyl acetate, pentyl acetate,
isopentyl acetate, t-butyl acetate and mixture thereof.
"f"" *v»~-1;•- & f i ' - • "> fiV 1' 'ft- 1-- fi- *• EVE- 7
i
In further embodiment, 9p, 10a, 3, 20-bis (ethylenedioxy)pregna-5,7-diene is
converted to 6-dehydro-9p,10a-progesterone (dydrogesterone) in presence of Ci-
C5 alcoholic hydrochloric acid, ethereal hydrochloric acid wherein said solvent is
selected from the group comprising of diethyl HC1, ethanolic HC1, methanolic HC1,
butanolic HC1, isobutanolic HC1, jso-butanolic HC1, n-pentanolic HC1, isopropanolic
HC1, n-propanolic HC1 and mixture thereof.
In second embodiment, the present invention provides a process for preparation of
substantially pure 6-dehydro-9p, lOa-progesterone (dydrogesterone) comprising of
less than about 1.0% of total impurities, wherein said process comprising of:
a) irradiating 9a, 10p, 3,20-bis (ethylenedioxy)pregna-5,7-diene in presence of
single mercury lamp to get 9p, 10a, 3,20-bis (ethylene dioxy)pregna-5,7-diene;
b) converting 9p, 10a, 3,20-bis (ethylenedioxy)pregna-5,7-diene to 6-dehydro-
9p,10a-progesterone; and
c) purifying 6-dehydro-9p,10a-progesterone to get substantially pure 6-dehydro-
9P,10a-progesterone with purity of 99.0% and above.
In another embodiment, 6-dehydro-9p,10a-progesterone is purified in step (c) by
isolating from a solution comprising ester selected from ethyl acetate, propyl
acetate, isopropyl.acetate, butyl acetate, t-butyl acetate and the like.
In third embodiment, the present invention provides a process for preparation of 6-
dehydro-9P, lOa-progesterone comprising the steps of:
a) preparing 7a-bromo-3, 20-bis (ethylenedioxy)pregna ketal by treating pregna-
3,20-dione-dimethylene ketal with dibromodimethyl hydfahtoin;
b) reacting 7a-bromo-3, 20-bis (ethylenedioxy) pregna ketal with tetrabutyl
ammonium halide in ethereal solvent to get 9a, ' 10p, 3,20-bis
(ethyl enedioxy)pregna-5,7-diene;
c) irradiating 9a, 10p, 3,20-bis (ethylenedioxy)pregna-5,7-diene in presence of
single mercury lamp to get 9p, 10a, 3,20-bis (ethylene dioxy)pregna-5,7-diene;
• ' . • • » • K tt-k. IT.- «&• "tarf!" ^ » > . - "" ^^
d) converting 9p, 10a, 3,20-bis (ethylenedioxy)pregna-5,7-diene to 6-dehydro-
9p,10a-progesterone in presence of acid; and
e) isolating substantially pure 6-dehydro-9p,10ct-progesterone with purity of 99.0%
and above by way of recrystallizing from solution comprising ester solvent.
In another embodiment, the tetrabutyl ammonium halide is selected from tetrabutyl
ammonium chloride, tetrabutyl ammonium bromide and tetrabutyl ammonium
.Jluoride.
t
In further embodiment, the ethereal solvent used in step (b) is selected from diethyl
ether, tetrahydrofuran, methyl tetrahydrofuran, dioxane and the like.
In further embodiment, the 6-dehydro-9p, lOa-progesterone i.e. dydrogesterone
prepared as per the process of the present invention is characterized by purity of
99.5% and above.
In preferred embodiment, the 6-dehydro-9p, lOa-progesterone i.e. dydrogesterone
prepared as per the process of the present invention is characterized by purity of
99.9% and above.
In another embodiment, the present invention provides a composition comprising
>
dydrogesterone and at least one pharmaceutical acceptable excipients, wherein said
dydrogesterone is prepared as per the process of the present invention.
Now, the present invention will be explained in details through experimentations.
However, the examples are provided as one of the possible way to practice the
invention and should not be considered as limitation of the scope of the invention.
EXAMPLES
EXAMPLE 1
f t * e : ' i ~ " 8 c 8 , - ' 2 Q a& iS-::SS-9 gTi.:i^..- W-.A;
Q
I
K
Preparation of 7a-bromo-3, 20-bis (ethylenedioxy)pregna ketal
Charged 200ml of pet ether and 50g of pregna-3,20-dione-dimethylene ketal
followed by further addition of 100ml of pet ether. To the above solution was added
dibromodimethyl hydrantoin and the reaction mixture was heated at.reflux for 1.5
hrs. After cooling at 20°C, dimethyl hydrantoin was filtered off. Distilled the pet
ether and added ethyl acetate to the reaction mass so obtained. Re-crystallized the
reaction mass with ethyl acetate to get 32g of 7a-bromo-3, 20-bis
; (ethylenedioxy)pregna ketal.
EXAMPLE 2
Preparation of 9a, 10p, 3,20-bis (ethylenedioxy)pregna-5,7-diene
To 300ml of methyl tetrahydrofuran was added 30g of 7<500ml of water. Evaportated the solvents to get crude
compound. Re-crystallized the crude compound with ethanol to get pure 9a, 10|3,
3,20-bis (ethylenedioxy)pregna-5,7-diene (20g).
EXAMPLE 3
Preparation of 9p, 10a, 3,20-bis (ethylenedioxy)pregna-5,7-diene
20.0 g of 9a,10p-3,20-bis(ethylenedioxy)-5,7-pregnadiene were dissolved in 2
litres of ethyl acetate and the resulting solution was then irradiated with a lowpressure
mercury vapour discharge lamp while cooling and in a nitrogen
atmosphere. As glass tubes were used: a glass tube filter which absorbs all the light
below 260 nm for 1-2 hours succeeded by a glass tube filter which absorbs all the
light below, 310 nm for 3-4 hours. Finally a solution was obtained, the dissolved
substance of which according to HPLC-analysis is composed as follows: 50-54%
(10.0 g) of starting material, and 30-34% (6.0 g) of 9p,10a-3,20-bis(ethylenedioxy)-
5,7-pregnadiene. • ,
Ft, r?« »>- ki*V fiV T •-' fHt-C -- "> £>-t- ©•••• . 1-JS?- ... 5^Si 10
/ .
The reaction solution was worked up by evaporation, taking up the residue in 40 ml
of ethyl acetate, and cooling to -10°C. A crystallisate was obtained which was
filtered to get 9.0 g of starting material. Evaporated the mother liquor and added
methyl isobutyl ketone and degassed the solution so obtained. The second
crystallisate so obtained was then filtered to get 5g of desired compound, 9p, 10a,
3,20-bis (ethylenedioxy)pregna-5,7-dierie.
EXAMPLE4 ,.
Preparation of 6-dehydro-9p,10a-progesterone (dydrogesterone)
To 5g of 9p, 10a, 3,20-bis (ethylenedioxy)pregna-5,7-diene was added ethanolic
HCl in -40°C and stirred the reaction mass for 2-3 hrs. Charged dichloromethane to
above reaction mass so obtained and stirred at room temperature. Washed the
organic layer with 2* 100 ml of water and distilled the organic layer to get a residue.
Purified the residue so obtained with ethyl acetate and recrystalHzed with ethyl
acetate again to get pure compound.

WE CLAIM
1. A process for preparation of 6-dehydro-9p,l Oa-progesterone, wherein said
process comprising of:
a) irradiating 9a, 10P, 3,20-bis (ethylenedioxy)pregna-5,7-diene in presence of
single mercury lamp to get 9p, 10a, 3,20-bis (ethylenedioxy)pregna-5,7-diene;
and
.>b} converting 9p, 10a, 3,20-bis (ethyleriedi6xy)pre"gna-5,7-diene to 6-detiydro-
9p, 1 Oa-progesterone.
2. The process as claimed in claim 1, wherein said mercury lamp is a low-pressure
mercury vapour discharge lamp having a discharge tube made of glass with
selective transmission, the tube being coated on the inside with a luminescent layer
and wherein the discharge tube is made of glass having an absorption edge located
below 260 and 280 nm and the tube has at 300 nm a transmission of at least 80%.
3. The process as claimed in claim 1, wherein said irradiation reaction of step (a)
is performed in a solvent selected from ethyl acetate, propyl acetate, isopropyl
acetate, butyl acetate, and t-butyl acetate.
4. A process for preparation of substantially pure 6-dehydro-9p,l Oa-progesterone
(dydrogesterone) comprising of less than about 1.0% of total impurities, wherein
• i .-• *
% said process comprising of:
i> a) irradiating 9a, 10p, 3,20-bis (ethylenedioxy)pregna-5,7-diene in presence of
t£ single mercury lamp to get 9p, 10a, 3,20-bis.(ethylenedioxy)pregna-5,7-diene;
£ b) converting 9p, 10a, 3,20-bis (ethylenedioxy)pregna-5,7-diene to 6-dehydrog
" 9p, 1 Oa-progesterone;
o
CN
O and
5 c) purifying 6-dehydro-9p,l Oa-progesterone to get substantially pure 6-dehydro-
C! 9p, 1 Oa-progesterone with purity of 99.0% and above.
r
5. The process as claimed in claim 4, wherein said 6-dehydro-9p,10a-progesterone
purified in step (c) is performed by isolating from a solution comprising ester
selected from ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate,- t-butyl
acetate and the like.
6. The process as claimed in claim 4, wherein said process comprising the steps of:
a) preparing 7a-bromo-3, 20-bis (ethylenedioxy)pregna ketal by treating pregna-
.- •3,20-dione-dimethylerie ketal with^dibrbmodimethyl hydraritdih;
b) reacting 7a-bromo-3, 20-bis (etliylenedioxy)pregna ketal with tetrabutyl
ammonium halide in ethereal solvent to get 9a, 1 Op, 3,20-bis (ethylene
dioxy)pregna-5,7-diene;
c) irradiating 9a, 10p, 3,20-bis (ethylenedioxy)pregna-5,7-diene in presence of
single mercury lamp to get 90, 10a, 3,20-bis (ethylene dioxy)pregna-5,7-diene;
d) converting 90, 10a, 3,20-bis (ethylenedioxy)pregna-5,7-diene to 6-dehydro-
9p,10a-progesterone in presence of acid;
and
e) isolating substantially pure 6-dehydro-9p,10a-progesterone with purity of 99.0%
and above by way of recrystallizing from solution comprising ester solvent.
7. The process as claimed in claim 6, wherein said tetrabutyl ammonium halide is
selected from tetrabutyl ammonium chloride, tetrabutyl ammonium bromide and
tetrabutyl ammonium fluoride.
8. The process as claimed in claim 6, wherein said substantially pure 6-dehydro-
9p,10a-progesterone is characterized by purity of 99.5% and above.
9. The process as claimed in claim 6, wherein said ethereal solvent is selected from
diethyl ether, tetrahydrofuran, methyl tetrahydrofuran, and dioxane.
10. The process as claimed in claim 1, wherein said 6-dehydro-9p,10a-progesterone
is used for preparing composition comprising 6-dehydro-9p,10