KR820000782B1 - Process for preparation of 4,5-seco-estrane 3,5,17-trione derivatives - Google Patents

Abstract

Title compds. I(R1 = C1-3 alkyl; R2 = H, C1-5 alkyl; K & K1 = ketal function), useful for prepg. medicine, were prepd. by the reaction of alkali metal enolate of compd. II with aldehyde(R2CHO) in the presence of base. Thus, a mixt. of 3,5-bis(cyclo 1,2-ethanediylacetal)4,5-secoestrane 3,5,17-trione, dimethyl formamide) sodium methylate, and ethyloxylate was stirred at 0 ± 5oC for 2hr and acetic acid added. The obtained product and K2CO3 were suspended in anhydrous MeOH and acetaldehyde added, stirred at 20oC for 16hr and recrystallized to give 3,5-bis(cyclo-1,2-ethanediyl acetal)16-ethylidene 4,5-secoestrane 3,5,17-trione(m.p. 131≰C).

Description

Method for preparing 4,5-seco estran 3,5,17-trione derivative

The present invention relates to a process for the preparation of new 4,5-seco estran 3,5,17-trione derivatives and to the use of these for the preparation of therapeutic agents.

Compounds to be dealt with in the present invention are compounds represented by the following formula (I).

In the above structure, R ₁ is an alkyl group having 1-3 carbon atoms, R ₂ is a hydrogen atom, or an alkyl group having 1-5 carbon atoms, and K and K 'are the same or different and are blocked in the form of ketal. Ketone functional group is shown.

R ₁ is usually a methyl or ethyl group. When R ₂ represents an alkyl group, it is usually a methyl, ethyl, n-propyl, iso-butyl, or ter-butyl group. K and K 'are generally cyclic alkyl ketal groups having 2-4 carbon atoms, in particular ethylene ketal or propylene ketal, or dialkyl ketals such as dimethyl ketal or diethyl ketal.

In particular, compounds such as the formula (I) to be dealt with in the present invention are compounds in which R ₁ is a methyl group, compounds in which R ₂ is a methyl group, and compounds in which K and K 'are cyclic 1,2-ethanediylacetal groups.

Among these, in this invention, 3, 5-bis (cyclic 1,2- ethanediyl acetal) 16-ethylidene 4, 5- seco ester 3, 5, 17-trione differs especially.

In addition, in the present invention, the alkali metal enolate of the compound of formula (II _A ) or the compound of formula (II _B ) is reacted with an aldehyde having a structure of R ₂ CHO in the presence of a base. A method of obtaining a compound of formula (I) as described above is addressed.

In the above, R ₁ , K, K 'are the same as before, and alkyl means an alkyl group having 1-8 carbon atoms

M represents an alkali metal atom and R ₂ in R ₂ CHO is as described above.

In a specific embodiment of the present invention, M usually represents a sodium or potassium atom, alkyl represents a methyl or ethyl group, and alkali carbonates such as sodium hydroxide, potassium hydroxide and potassium carbonate or tertiary amines such as triethylamine are usually used as a base. do.

The compounds of formulas (II _A ) and (II _B ) are new and in the present invention are compounds of the formulas (II _A ) and (II _B ) as new industrial compounds, and in particular ethyl 3,5-bis (cyclo 1,2-ethane) Diyl acetal) 3,5,17α-tetraoxo 4,5-seco estran 16β-acetate.

In the present invention, in the presence of alkali metal salt M

A compound having the structure as described above is reacted with a compound of formula (III) to obtain a compound of formula (II _B ), and then, if necessary, an acid agent to obtain a compound of formula (II _A ).

Where R ₁ , K and K´ are the same as before.

The base used is an alkali alcoholate such as potassium hydroxide, sodium hydroxide or sodium methylate, or sodium hydride, and hydrochloric acid or acetic acid is generally used as an acid.

The compounds of the above formula (III) are known and can be prepared according to the processes mentioned in, for example, French patent 1,490,590.

In the present invention, the compound represented by the following formula (I) also acts as a hydrogenating agent capable of saturating the double bond at the 16 position and then as a reducing agent capable of reducing the ketone functional group at the 17 position. A method of using a compound of formula (I) as described above to obtain a compound of formula (IV) is described.

Reaction of a compound, such as formula (IV), with a basic agent yields a corresponding compound, such as the following formula (V).

In the present invention, 3,5-bis (cyclic 1,2-ethanediyl acetal) 16-ethylidene 4,5-seco, particularly in the preparation of 16β-ethyl 17β-hydroxy-est-4-len-3-one The use of compounds of formula (I) wherein R ₂ is a methyl group, such as the use of estran 3,5,17-trione, is addressed.

The hydrogenation agent capable of hydrogenating the double bond at position 16 is hydrogen in the presence of palladium and the reducing agent capable of reducing the ketone group is generally sodium borohydride or a mixed hydride of lithium and aluminum.

Acid hydrolytic agents are usually used hydrochloric acid, sulfuric acid, acetic acid, citric acid, or paratoluenesulfonic acid.

The basic agent which causes the A ring to be cycled is used in particular an alkali alcoholate such as sodium methylate, sodium ethylate, sodium terbutylate or potassium terbutylate, or an alkali base such as calcium hydroxide or potassium hydroxide.

Compounds of formula (V) are known compounds and can be prepared according to the methods shown in the literature (US Pat. No. 3,856,929 to STEROID 1959, p599 or Hiraga et al., F. AKingl et al.). Compounds of formula (V) have interesting pharmaceutical properties, for example 16β-ethyl 17β-hydroxy est-4-ene 3-silver has very interesting anti-androgen activity and is used for the treatment of adenoma of the prostate gland.

Thus, the compounds of the present invention are new and their preparation is unknown. In particular, the preparation of the compound of the formula (I) from the compound of the formula (II _A ) or (II _B ) is original and is not known at all. In addition, the compounds of the present invention are also very interesting industrially, and according to a method which can be easily carried out industrially, the compound of the structural formula (V) can be obtained through five steps using the compound of the structural formula as a starting material. At present, these compounds of formula (III) are easily prepared by synthesis and their preparation has been industrialized for a long time because they are intermediates for the synthesis of a large number of 19-note steroids that are widely commercialized worldwide.

Therefore, using the compounds of the present invention, the compounds of formula (V) obtained by using estrone as a starting material by a process which has been difficult to industrialize until now (Z. Physio1 Chem. 1932, 208, 127 and J. Chem. Soc. , 1938, 1997, French Patent 4957M and US Pat. No. 3,856,829). The process can be obtained by a simple and easy process for industrialization.

The following examples are intended to illustrate the invention and do not limit the invention.

Example 1

[3,5-bis (cyclo 1,2-ethanediyl acetal) 16-ethylidene 4,5-seco ester 3,5,17-trione]

[Step A: Ethyl 3,5-bis (cyclo 1,2-ethanediylacetal) 3,5,17α tetraoxo 4,5-seco estran 16β-acetate]

200 g of 3,5-bis (cyclo 1,2-ethanediyl acetal) 4,5-seco estran 3,5,17-trione (prepared according to French Patent No. 1,490,590) is 600 cm ³ of dimethylform To amide. 66 g of sodium methylate is added to this solution at a temperature of -10 ° C ± 2 ° C, and 160 cm ³ of ethyloxylate is added at 0 ° ± 2 ° C. It is stirred for 2 hours at 0 ° ± 5 ° C. and 100 cm ³ of acetic acid is added. The solution thus obtained is crystallized by scraping off in a 50:50 mixture of water and ice. Vacuum filtration and washing of the resulting suspension with water followed by drying yielded 242.5 g of the product, which had a boiling point of 100 ° C. which was used as such in the next step.

[Step B: Ethyl 3,5-bis (cyclo 1,2-ethanediylacetal) 16-ethylidene 4,5-secoestran 3,5,17-trione]

Stirring while introducing nitrogen at 20 ° C., add 242.5 g of the product obtained in step A into 243 cm ³ of anhydrous methanol and add 121 g of potassium carbonate to this suspension. The resulting suspension is stirred at room temperature for 15 minutes, then brought to -5 ° ± 2 ° C and 121 cm ³ of acetaldehyde is added. The mixture was stirred at 0 ° C. for 2 hours, the temperature was raised to 20 ° C., and stirred at this temperature for 16 hours. Crystallize by scraping in a 50:50 mixture of 730 cm ³ of water and ice and a mixture of 182 g of 182 g of potassium monophosphate. The product obtained by washing the vacuum filtered water precipitate with water is dissolved in 1200 cm ³ of methylene chloride. After decanting the aqueous phase, the organic solution is dried over magnesium sulfate and vacuumed and washed with methylene chloride.

Add 242 g of aluminum hydride solution to methylene chloride solution over 30 minutes with stirring at 20 ° C ± 2 ° C. After stirring for 1 hour, vacuum filtration and washing with 240cm ³ methylene chloride and then concentrated the organic solution until the volume is 240cm ³ . It is completely dissolved by adding 1200 cm ³ of isopropyl ether while refluxing and stirring. The solution thus obtained is concentrated until the volume becomes 600 cm ³ , the resulting suspension is cooled to −10 ° C. and stirred at this temperature for 1 hour. The precipitate obtained was vacuum filtered, washed with 120 cm ³ of isopropyl ether, and the resulting product was dried to yield 156.5 g of the desired product having a melting point of 131 ° C.

Example 2

[Use of the compound obtained in Example 1 in the preparation of 16β-ethyl 17β-hydroxy estro-4-en 3-one]

[Step A: 16β-ethyl 17β-hydroxy secoestran 3,5-dione]

[Hydrogenation of a Double Bond at 16]

To 400 cm ³ methanol is added 1.250 g of activated carbon containing 50 g of the product obtained in Example 1, 0.4 cm ³ of pyridine and 10% of palladium. Pass hydrogen through, absorb 1700 cm ³ of hydrogen and dissolve completely. Stir for 2 hours after the absorption process. The catalyst is vacuum filtered, washed with methanol and combined with methanol.

[(B) Reduction of Ketone Group]

Add to 50cm (obtained in (a)) a ³ of water and sodium hydroxide in n-15cm ³ 500cm ³ of a methanol solution. Add 2.45 g sodium borohydride for 1 hour and stir the resulting solution for 15-20 hours. The solution is concentrated to a volume of 250 cm ³ . 5 cm ³ of acetic acid is gradually added while stirring at 20 ° C. and stirred at 20 ° C. for 15 minutes. The resulting solution is poured slowly into a mixture of water and ice (50:50) 2500 cm ³ and held for 30 minutes with stirring. The precipitate obtained is vacuum filtered, washed with water and then vacuum filtered again. This yields 107.5 g of product which is used directly in the next step.

[(C) Hydrolysis of Ketal Group]

107.5 g of the product obtained in (B) is added to a solution containing 150 cm ³ of acetic acid and 93 cm ³ of distilled water. The resulting suspension is brought to 40 ° C. under stirring and maintained under these conditions for 2 hours. The suspension is cooled to 20 ° C. and poured into a mixture of water and ice (50:50) of 1000 cm ³ . The suspension is stirred for 30 minutes and the precipitate obtained is washed with water and dried to afford 34.4 g of product which is recrystallized from toluene to purify. In this way, a desired product having a melting point of 113 ° C. is obtained.

[Step B: 16β-ethyl 17β-hydroxyester-4-en 3-one]

25 g of the product obtained in Step A was added to 250 cm ³ of methanol, and the obtained suspension was stirred while heating to 50 ° C., and a 9.4 cm ³ solution containing 400 g / L sodium hydroxide was added. In this way, it is a mixture of the resulting solution was allowed to stand at 50 ℃ 30 minutes of the following at 50 ℃ 79cm ³ of water and acetic acid solution of 110% 5.8cm ^3. The suspension is stirred while cooling to 0 ° + 5 ° C. and left for 30 minutes under these conditions. After vacuum filtration and washing with methanol and water, the precipitate obtained was dried and 21.4 g of crude product was obtained, which was recrystallized from ethyl acetate.

19.800g of final product is obtained, its melting point is 152˚-153 ℃

Claims (1)

Preparation of 4,5-cecoestran 3,5,17-trione derivative of the following general formula (I) characterized by reacting with an aldehyde of the following formula R ₂ CHO structural formula of the following general formula (II _A ) in the presence of a base: Way.

In the above structural formula, R ₁ represents an alkyl group having 1-3 carbon atoms, R ₂ represents an alkyl group or hydrogen having 1-5 carbon atoms, and K and K 'are the same or different and are ketal blocked ketones. It means a functional group, and alkyl represents an alkyl group having 1-8 carbon atoms.