5,304,29 1

1 2
steroids could be performed with a considerably higher
METHOD OF PREPARING 9BETA, yield if an antimony lamp was used as the light source
10ALPHA-S,7-DIENE STEROIDS instead of a conventional medium-pressure mercury
lamp. If desired, the irradiation can be camed out by
The invention relates to a method of preparing a 5 using two different lamps in succession, first a conven-
9beta,lOalpha-5,7-dienesteroid by irradiating the corre- tional light source producing UY-radiation, e.g. a medi-
sponding galpha,lobeta-5,7-diene steroid or seco- um-pressure mercury lamp, and then an antimony lamp,
steroid with filtered ultraviolet light. to produce comparable results as with an one-lamp
9Beta,lOalpha-5,7-diene steroids generally are inter- irradiation. In this manner 9beta,lOalpha-3,2@bis(e-
mediates in the synthesis of pharmacologically interest- 10 thy1enedioxy)-pregna-5,7-diene could be prepared by
ing compounds which can perform a useful function in conversion of the corresponding 9alpha,lObeta com-
the human body. The hormone analogue ddehydro- pound in a yield of approx. 30%, calculated on starting
9beta,lOaIpha-progesterone (9beta,lOalpha-pregna-4,6- material, or of approx. 75%, calculated on converted
diene-3,20-dione) or dydrogesterone is an orally active material, in a reaction time of 6 to 7 hours (Examples I
progestative hormone and is generally used to correct 15 and VII of EP 0,152,138).
deficiencies of progesterone in the body. The above known process, however, is still unsatis-
Therefore, a good possibility for synthesizing this factory in some respects. First, the production capacity,
substance and other 9beta,lOalpha-steroidsfrom avail- i.e. the conversion per time unit (per hour), does not
able or readily accessible raw materials is of great im- fully come up to the producer's expectations. The in-
portance. Various 9alpha,lObeta-steroids, for example, 20 trinsic capacity of irradiation processes is always rela-
ergosterol, pregnenolone and progesterone, are avail- tively small due to the required dilution of the solution
able as raw materials for the preparation of gbeta, 10al- to be irradiated. Therefore, an improved conversion per
pha-5,7-diene steroids. The preparation of dydrogester- time unit is very important for effecting a commercially
one from pregnenolone is described by Rappoldt et al. and technically attractive process. Further, an anti-
in Recueil trav. chim. 1961, 80, 43, and 1971, 90, 27. 25 mony lamp is expensive to operate compared to a medi-
Important intermediates in the synthesis of dydrogester- um-pressure mercury lamp.
one are lumisterolz, 3-(ethy1enedioxy)-9beta,IOalpha- It is the objective of the invention to considerably
pregna-5,7-diene-20-one and 3,20-bis(ethy1enedioxy)- improve the capacity of producing 9beta,IOalpha-5,7-
9beta,IOalpha-pregna-5,7-diene.These intermediates diene steroids by irradiating the corresponding 9al-
can be prepared by irradiating the corresponding gal- 30 pha,lObeta-5,7-diene steroids or seco-steroids, and, at
pha,lObeta isomers, namely ergosterol, 9alpha,lObeta-3- the same time, to reduce the operating costs.
(ethy1enedioxy)-pregna-5,7-diene-20-oneand 9alpha,l- This objective can be achieved, according to the
Obeta-3,20-bis(ethy1enedioxy)-pregna-5,7respec- present invention, by irradiating the above starting gal-
tively, with ultraviolet light. This irradiation is prefera- pha,lObeta-5,7-diene-steroid or seco-steroid with fil-
bly camed out with filtered ultraviolet light. A medi- 35 tered ultraviolet light from an indium lamp. An indium
um-pressure or high-pressure mercury lamp has so far lamp is a medium-pressure or high-pressure mercury
been used for this purpose. In the above-mentioned lamp endowed with indium. By using this light source
publications, the desired 9beta,lOalpha-5,7-diene ste- in the method of the present invention, the operating
roids were formed during this photochemical isomerisa- techniques and facilities are much easier and simpler
tion in yields of only 20% calculated on converted 40 than by using an antimony lamp. As will become appar-
9alpha,lOkta-isomer. When the W-irradiation was ent from the appendant Example, the production capac-
carried out in two steps, namely first by means of short- ity, i.e. the desired conversion per time unit, can be
wave UV-radiation and then by means of long-wave improved with a factor of approximately two by using
W-radiation as described in NL 112,521, the desired an indium lamp compared to the known antimony lamp
9beta,lOalpha-5,7-diene steroid could also be isolated in 45 as a radiation source.
a yield of not yet 20% calculated on converted starting The above indium lamp can be used according to the
material. Obviously, a considerable part of the expen- method of the invention by passing the steroid-solution
sive starting material is lost in this photochemical through a reservoir surrounding the lamp or by immers-
isomerisation, probably due to the formation of unde- ing the lamp in the solution to be irradiated. It will be
sired side products. It therefore stands to reason that an 50 obvious that in the former method of irradiating a num-
improvement of the yield in this photochemical conver- ber of indium lamps can be used to improve the produc-
sion is of great importance. tion capacity, around which lamps the solution to be
Dauben and Phillips (J. Am. Chem. Soc. 1982, 104, irradiated can be passed in a continuous flow (annular
355 and 5780) state that the desired formation of 9be- flow reactor). In the latter method immersion lamps can
&loalpha-5,7diene steroids can be improved by the 55 be used, which are immersed in the solution accommo-
application of laser photolysis. The results of Dauben dated in a reaction vessel (immersion photochemical
and Phillips, however, are not in conformity with those reactor). Such a reaction vessel can be dimensioned in a
of Malatesta et al.: J. Am. Chem. Soc. 1981, 103, 6781. suitable manner, allowing the use of high-power indium
Apart from these questionable results, for a practical lamps, viz. up to 100 k W .
industrial production the use of lasers is not very attrac- 60 Preferably the irradiation with the indium lamp is
tive in view of the high costs of acquisition and the high preceded by an irradiation procedure with a conven-
energy consumption. Irradiation with a lamp is there- tional light source producing W-radiation, generally a
fore to be preferred by far to laser irradiation for pro- normal medium-pressure or high-pressure mercury
ducing a certain photochemical conversion. lamp, to achieve optimum results.
It was found by Rappoldt and Mos (EP 0,152,138), 65 In principle, all 9alpha,lObeta-5,7-diene steroids or
that the photochemical conversion of 9alpha,lObeta- seco-steroids may be used as starting materials for the
5,7-diene steroids or suitable seco-steroids (seco- photochemical conversion of the invention, provided
steroids) into the corresponding gbeta, loalpha-5,7-diene photosensitive substituents in the molecule are prefera-