Process for the production of progesterone derivatives

Details Process for the production of progesterone derivatives Process for the production of progesterone derivatives

1991-07-15

1992-07-21

Cintins, Marianne

Organic compounds -- part of the class 532-570 series

Organic compounds

Cyclopentanohydrophenanthrene ring system containing

552597, 552598, C07J 700

Patent

active

051324407

DESCRIPTION:

BRIEF SUMMARY
The invention relates to a process for the production of progesterone derivatives of general formula I ##STR2## in which symbolizes a single bond or a double bond, vinylidene group, which is characterized in that a nitrile of the general formula II ##STR3## in which X and V have the above-mentioned meaning and in which Y and Z together are an alkylenedioxy group with 2 to 6 carbon atoms and W represents a hydrogen atom or in which an acyloxy group with 2 to 8 carbon atoms, and Z and W represent two hydrogen atoms or together mean a carbon-carbon bond, the intermediate products formed are hydrolyzed by acids.
By an alkylenedioxy group Y and Z of the nitriles of the general formula II is to be understood, for example, a 1,2-ethylenedioxy group, a 1,3-propylenedioxy group, a 2,2-dimethyl-1,3-propylenedioxy group or a 2,3-butylenedioxy group.
Suitable alkoxy groups Z are, for example, the methoxy group, the ethoxy group, the isopropyloxy group or the tertbutyloxy group.
Suitable acyloxy groups are, among others, the acetoxy group, the propionyloxy group, the dimethylacetoxy group, the trimethylacetoxy group and the benzoyloxy group.
The Grignard reagent necessary for carrying out the process according to the invention can be produced in the usual way, for example by methyl chloride or methyl bromide in an either such as diethyl ether, diisopropyl ether, dibutyl ether, 1,2-dimethoxyethane or tetrahydrofuran being reacted with magnesium chips. Because of its relatively low boiling point and its not too low flash point, tetrahydrofuran is especially suitable. These Grignard reagents can be used directly for the reaction with the nitriles of general formula II. But the ether suitably is largely removed by distillation before the reaction and replaced by toluene. (It is noted that in comparison with benzene, toluene has the advantage of substantially lower toxicity, and in comparison with xylenes, toluene has the advantage of a low boiling point). It not has only the advantage that a large part of the ether can be recovered problem-free but also that the reaction can be performed under mile conditions and the working up of the reaction mixture is greatly facilitated.
To carry out the reaction, at least 4 moles of Grignard reagent is necessary to reach high yields in the process product. The reaction is performed at a temperature of -20.degree. C. to +10.degree. C.--preferably at -5.degree. to +5.degree. C. Under these conditions, the reaction time is about 30 to 180 minutes.
After the reaction has been completed, the reaction mixture, as in the case of Grignard reactions, is usually decomposed. This decomposition can take place, for example, with an aqueous solution of tetrasodium salt of ethylenediaminetetraacetic acid; however, this reagent is somewhat expensive. The decomposition of the reaction mixture with aqueous ammonium chloride solution has been proven quite suitable and problem-free.
After the decomposition has been completed, the toluene can be removed by steam distillation and an intermediate product is obtained which consists of a mixture of the progesterone derivative of the general formula I and the imino compounds of formulas IV and V ##STR4## (in these formulas, , X, Y, Z, W and V have the above-mentioned meaning).
This product can be hydrolyzed problem-free by acids to the progesterone derivatives of the general formula I.
This hydrolysis can be performed, for example, so that the intermediate product dissolves in a lower alcohol--such as methanol, ethanol or isopropanol, mixed with an acid, such as hydrochloric acid, sulfuric acid or p-toluenesulfonic acid and heated. After the reaction has been completed, the reaction product can, for example, be precipitated with water, and suitably, care is taken that the acid is neutralized.
According to tests so far available, the yield of process product is about 90% of theory. It can be possibly be further increased by optimizing the process parameters.
It is very surprising for one skilled in the art that the progesterone derivatives of the general formul

REFERENCES:
patent: 4585590 (1986-04-01), Van Rheenen
patent: 4831131 (1989-05-01), Van Rheemen
Gasc, J. C. and L. Nedelec, "A New Approach to Corticoid Total Synthesis", Tetrahedron Letters, No. 22, pp. 2005-2008 (1971).
Ruggieri et al., "17-Hydroxypregnanes from Androstane Compounds," J. Amer. Chem. Soc., Band. 81 (Nov. 1959).

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