US2297367A - Method of producing steroid ketones from steroid alcohols - Google Patents

Description

Patented Sept. 29, 1942 METHOD OF PRODUCING STEROID KE- TONESVFROM STEROID ALCOHOLS Ebenezer Emmet Reid, Baltimore, Md., assignor to The Chemical Foundation, Incorporated, as trustee, a corporation of Delaware No Drawing.

Application May 3, 1939,

Serial No. 271,605

17 Claims. (o1. zoo-297.3)

production of unsaturated steroid ketones from secondary steroid alcohols, as for example the production of progesterone from pregnandiol.

As a result of considerable experimentation it has been discovered that saturated steroid alcohols of the type of pregnandiol may directly be converted in a single operation or stage into the corresponding unsaturated diketone. The discovery also embraces the concept that such alcohols can be catalytically dehydrogenated at such a low temperature that the starting material is not decomposed and hence can be recycled or otherwise reemployed in the process so as to secure very high conversions.

As is known, progesterone is a very valuable therapeutic product. Although this compound has been detected in certain source material such as the placenta and pregnancy urine, the amounts recoverable are extremely small and the cost of the product has been commensurately high. These circumstances induced the workers in the art to search for a more abundant source of starting material from which the desired product could be produced. As a result of such endeavors it was discovered that pregna-ndiol occurred in reasonably large amounts in cheap source material, such as pregnancy urine and that it offered a starting point for the synthesis of progesterone.

The synthesis of progesterone from such starting material as pregnandiol in the past has been complicated and costly. In one prior method suggested, the final product, progesterone, was produced only after a whole series of intermediate reactions. For example, such suggestion comprises the e'sterification of the pregnandiol to produce a di-ester; the selective saponification of the di-ester to produce a mono-ester; the oxidation of the mono-ester to the corresponding keto-ester; the saponification of the ketoester to the keto-alcohol. This product, pregnanolone, then had to be treated as by halogenation, oxidation and .dehalogenation in order to produce the desired end product, progesterone.

Other suggestions involve the direct dehydrogenation of the secondary alcohol, pregnendiol, or the keto-alcohol, pregnenolone to the corresponding di-ketone, progesterone. Such processes present the apparent advantage of a direct 55 gested, high temperatures, of the order of from 200 C. to 300 C. Were employed. Thus one earlier suggested method comprised heating pregnendiol at a temperature of 230 C. for a period of a half hour and under a pressure of 20 mm. in contact with Baker precipitated copper. In another suggested method pregnenolene was heated at 200 C. in contact with copper powder.

It will be observed that such prior methods involved a simple dehydrogenation in which the secondary alcohol group or groups only were involved. The resent method is fundamentally distinguished from such earlier suggestions in that a double dehydrogenation takes place, namely the dehydrogenation of a secondary group or groups and the removal of hydrogen from adjacent carbon atoms of the ring to establish a double bond. Thus the present invention provides a method of directly catalytically converting a saturated alcohol to an unsaturated ketone.

As will be seen more fully hereinafter, the process as applied to pregnandiol involves essentially a double dehydrogenation in'that the secondary alcohol group, on the third carbon atom of the nucleus, is converted to the ketone: CO, and simultaneously or coincidentally two atoms of hydrogen are removed from adjacent carbon atoms (4 and 5) in the ring to form a double bond. As applied to certain other materials the process may involve only dehydrogenation of ad- J'acent carbon atoms.

A major feature of the present process of direct catalytic conversion with optimum yields is the utilization of a catalyst which is efiective for such selective double dehydrogenation at temperatures which will not destroy the starting material. It has been found that special nickel catalyst in a state of high porosity serves effectively. Thus operations have been conducted using Raney nickel as the dehydrogenation catalyst. This product, as is known, is a porous or interstitial mass produced by selectively dissolving the aluminum of an aluminum-nickel alloy with a suitable solvent, such as sodium hydroxide.

In carrying out the process it is desirable to remove the hydrogen which is liberated as a result of the dehydrogenation. This may be done by utilizing a hydrogen acceptor such as diisobutylene in the reaction zone, or by any other suitable method such as pulling out the hydrogen with a vacuum.

It has been found further that the catalytic activity of the nickel or equivalent catalyst is greatly enhanced by utilizing small amounts of promoters of the type of copper chromite and alumina.

The following operation is illustrative of the method of eifectuating the invention.

A quantity of pregnandiol together with 60 parts of diisobutylene was admitted to a tube containing a quantity of Raney nickel catalyst. The tube was sealed and the reaction mass was heated to a temperature of 140 C. and was maintained as this temperature, with constant agitation, for a period of eight hours. Analysis of the reaction products showed 17 per cent of diketone on the basis of the pregnandiol.

Such operation was repeated using as the catalyst, nickel mixed with a small proportion of copper chromite. Under the conditions of the process, 1. e. heating the described mixture of pregnandiol and diisobutylene in a sealed tube at a temperature of 140 C. with constant agitation for a period of eight hours, there was effected a 40 per cent conversion of the saturated alcohol to the corresponding di-ketone.

A series of similar conversions was made utilizing mixtures of Raney nickel and copper chromite and Raney nickel and alumina as the catalysts. In these conversions the reactions were carried out in the presence of diisobutylene for a period of substantially eight hours and with constant agitation. The effects of variation in temperature and use of the different catalytic mixtures are indicated in the following table.

It will be observed that mixtures of the nickel catalyst with promoters are especially effective and that optimum conversions are secured at temperatures up to 185 C. While as indicated temperatures of approximately 185 C. are optimum, satisfactory yields may be secured by operating at temperatures between 100 C. and 185 C.

The products produced by this novel treatment, specifically the products of Examples 6 and 7 were tested clinically and were found to give the highly specific progesterone activity.

It was also found that the reaction products could be separated and the unconverted pregnandiol recovered. In accordance with the invention, therefore, the unconverted pregnandiol may be catalytically retreated.

It will be understood that while the described method presents striking efiiciency for the direct catalytic conversion of pregnandiol to progesterone because of the coincidental removal of hydrogen from the two alcohol groups and from adjacent carbon atoms (4 and it is not limited to use with this particular starting material.

Again the process may be utilized to convert androstandiol to androstendione or to convert androstandiol to androstandione. Similarly, the principles of the present invention may be utilized to convert pregnandione to pregnendione, i. e. to convert a saturated steroid ketone to an unsaturated steroid ketone.

While the invention has been described with respect to its utilization with particular compounds, it will be understood that the broad principle of the invention comprehends the treatment of certain type compounds to produce desired derivatives thereof.

I claim:

1. A process of producing valuable compounds from steroids which comprises subjecting a steroid to single stage catalytic dehydrogenation with a catalyst of Raney nickel under conditions regulated to establish a double bond.

2. A process of producing valuable compounds from steroids which comprises subjecting a steroid to catalytic dehydrogenation with a porous nickel catalyst to directly produce dehydrogenated steroid derivatives in high yields and with substantially no destruction of the unconverted starting material.

3. A process of producing unsaturated ketonic compounds which comprises, subjecting a saturated steriod alcohol to catalytic dehydrogenation with a catalytic mass consisting of porous nickel which is efiective to directly form the corresponding unsaturated ketone.

4. A process of producing therapeutically valuable compounds which comprises subjecting a saturated mono-secondary alcoholic steroid to catalytic dehydrogenation with a catalyst of the type of Raney nickel to directly form an unsaturated mono-ketonic steroid.

5. A process of producing therapeutically valuable compounds which comprises subjecting a saturated di-secondary alcoholic steroid to catalytic dehydrogenation with a catalyst of the type of Raney nickel to directly form an unsaturated di-ketonic steroid.

6. A process of producing therapeutically valuable compounds which comprises subjecting a. saturated poly secondary alcoholic steroid to catalytic dehydrogenation with a catalyst of the type of Raney nickel to directly form an unsaturated poly ketonic steroid.

'7. A process of producing therapeutically valuable compounds which comprises subjecting a saturated mono-secondary alcoholic steroid to catalytic dehydrogenation with a catalyst of the type of Raney nickel to directly form a saturated mono ketonic steroid.

8. A process of producing valuable compounds which comprises subjecting a saturated di-secondary alcoholic steroid to catalytic dehydrogenation with a catalyst of the type of Raney nickel to form a secondary di-ketonic steroid.

9. A process of directly producing steroid ketones from steroid alcohols which comprises, subjecting a steroid alcohol to dehydrogenation in the presence of a nickel catalyst and at elevated temperatures maintained above C. and below C.

10. A process of producing steroid ketones from steroid alcohols which comprises, subjecting a steroid alcohol to catalytic dehydrogenation at temperatures between substantially 100 C. and 180 C. in contact with a catalyst comprised preponderantly of Raney nickel.

11. A process of producing unsaturated steroid ketones directly from saturated secondary steroid alcohols which comprises, subjecting a steroid alcohol to catalytic dehydrogenation in contact with a catalyst consisting of porous nickel and copper chromite.

12. A process of producing ketonic compounds from steroid alcohols which comprises, subjecting a steroid alcohol to catalytic dehydrogenation at an elevated temperature above 100 C. but below 180 C. in contact with a catalyst consisting of Raney nickel and a promoter, separating the formed ketone from the unconverted alcohol and retreating the separated alcohol at the said temperature range.

13. A process of producing progesterone which comprises subjecting pregnandiol to catalytic dehydrogenation in the presence of a catalyst consisting essentially of Raney nickel While maintaining the material at an elevated temperature above 100 C. but below substantially 180 C.

14. A process of producing progesterone which comprises contacting pregnandiol, in the presence 15.- A method of producing progesterone which comprises contacting pregnandiol, in the presence of diisobutylene, with a catalyst consisting of Raney nickel and copper chromite at a temperature of between C. and C. for a period of time sufiiciently prolonged to insure the formation of a substantial quantity of progesterone, and separating the progesterone from the unconverted pregnandiol.

16. A method of producing progesterone which comprises contacting pregnandiol, in the presence of diisobutylene, with a catalyst consisting of Raney nickel and alumina at a temperature between substantially 100" C. and 180 C. for a period of time sufficiently prolonged to insure the formation of a substantial quantity of progesterone.

17. A method of producing progesterone which comprises contacting pregnandiol, in the presence of diisobutylene, with a catalyst consisting of Raney nickel and alumina at a temperature of substantially 100 C. and 180 C. for a period of time sufficiently prolonged to insure the formation of a substantial quantity of progesterone, separating the formed progesterone from the unconverted pregnandiol and subjecting the separated pregnandiol to the same catalytic treatment.

EBENEZER EMMET REID.