DD147669A1 - PROCESS FOR THE PREPARATION OF 17 ALPHA-HYDROXY-17 BETA CYANOSTEROIDES - Google Patents

Abstract

It will be a new process. z. Production of 17 alpha-hydroxy-17 beta-cyano steroids d. Androstan- u. 19-Norandrostanreihe described. These are important intermediates f. the syntheses of progestagens and glucocorticoids. According to the new process androstane and 19-norandrostane-17-ketones with alkanone cyanohydrins with the addition of bases at pH values from 7.3 to 10.5 in aqueous alcohol, preferably 80 to 90% methanol or ethanol, under reaction conditions that reacted to a delayed crystallization of the unified reaction products 17 alpha-hydroxy-17 beta-cyanosteroids. The reaction products are isolated by crystallization from the reaction mixture in high purity.

Description

Title of the invention

Process for the preparation of 17oC-hydroxy ^ ß-cyanosteroiden

Field of application of the invention

The invention relates to a process for the preparation of intermediates for the synthesis of 19-n-pregnans and pregnanes from the corresponding 17-ketosteroids The new process makes an economically favorable method for the construction of the steroid side chain to pregnanes b53W _ö ccrticoids on the Based on the readily available 17 ™ Eetosteroids · developed.

Cftjaqakt ^

For the steroid side chain construction for the synthesis of pregnanes such as 25'B. Progesterone and glucocorticoids various methods "have been described in the literature." Thus, according to DMS 22 30.286; 21 40 291 and 20 23 122; DD-AP 99.163 17oC "-Atrd.r ^ 7-l - 17ß" h.hydroxy These compounds, which are easily accessible by etherification from 17 ketosteroids, are converted via the stages of bissulfite com- pound, catalytically, by means of mercury ointments and isomerization to the lyaC-hydroxy-20-ketosteroids Method x ^ erden in DE-AS 26 25 506 cited j that although on a laboratory scale good yields to be achieved

 i'i 7 μ no. · ", ·

However, they are not realized in the technical implementation. In addition, it should be noted that the individual reaction steps for a technical process are too expensive and considerable amounts of by-products are formed in the isomerization step (17ß ~ - ester-17 © £ ~ A. cetyl compound).

An improved process variant is disclosed in BE ~ U3 26 25 306 which substitutes for the sulphite esters (55 "to 60% yield) the nitrate esters (75 to 80% yield) and the same reaction scheme However, this process also requires as a crucial Kealdbionsschritt the isomerization stage j which, as already mentioned above, not always uniform.

ft ^T oh 1973 a published method DE-AS 22 ^ S of Pregnanseitenkettenaufbau durohgeführt is via the reaction of the 17-ketosteroid with a oC lithium alkyl vinyl ether. The resulting i7ß ~ hydroxy-17oC-vinyl-alkylätborverbindung is converted into a Sulfinsäurθderivat that is converted to the Λ ¹⁷ ^ ²⁰ ) -2i-sulfone on heating «

Epoxide scavenging, epoxide cleavage, and subsequent reaction with aluminum, as well as others, give rise to the 17 <> £ ~ hydroxy ~ 20-one steroid. "Disadvantages of this synthesis are the large number of required reaction steps (6 steps) and the use of butyllithium in the eonaensation reaction at temperatures from -60 to ⁰ C.

A common advantage of the processes cited is that the first stage of these processes always involves the production of 17% hyaroxysteroids, which must be converted by means of complex operations into the requisite hydroxy compounds.

Egg 1938-von Bütenandt (Ber _e 71, 1487 (1938); Bex% .72, 182, 1112 (1939) "-transferred the 17-keto.

steroids into the isomeric cyanohydrins, which are converted into the pregnane derivatives via the Λ .- compounds and Grignarda tion ·

Indian Autogen. Like P. de Ruggieri u. a, J. Im. Chem. Soo. 81, 5725 (1959) and J. Mm. Chem. Soc. 75, 650 (1955), L. Miraxnontes u. &. <T _e lsi, Chem. Soo * 82, .6155 (1960) HJ Ringold J * / in. Chem. Soo. .82, 961 (I960) and H. Kühl u. a, Steroids Vol. 28, p. 89 (1976) have a separation of those in cyanohydrin synthesis. carried out resulting from Androstanes 17oC ~ hydroxy ~ 17ß "hydroxy steroids and have the separated 17-cyano-17o (-Bo ^r droxysteroid used for Pregnansynthesen.

For the synthesis of 19-pregnanes, JoIy describes in 1966 in DE-AS 17 95 705 a cyanohydrin synthesis in which from 500 g of 17-ketosteroid 259.5 g of 17cC-hydroxy ~ 17ß ~ cyano compound by. Isomer segregation. The i7ß ~ hydroxy-17oC-cyano steroid formed in this reaction must be split back into the 17 "Eetoverbindung and can be used again in the reaction.

The cyanohydrin syn-thymides described up to this point always lead to the isomeric cyanohydrins in both the androstane and norandane series.

Significant improvement in the steroid side chain construction is described by Bucourt DIHLP 89 401. with a novel synthesis in which the 1pβ and Cp 1 "-methyl groups are introduced into a 19-norsteroid with a reaction step T. The formation of the side chain is mainly by cyanohydrin synthesis initiated in which a 5-Hkeaaio ^ ~ estra- * 5 (10), 9 (1i) ~ dien-17-one in an acidic medium with a .Alkalioyanid in anhydrous methanol on the reaction is brought to.

The formed reaction product. is isolated by 'extraction *. Crystallization from methanol, methylene chloride and isopropyl ether, the 5-ethylenedioxy - * - 17c ^ -hydroxy-17.ß ~ cyano "-stra ™ 5 (1ö) _s 9 (" | '|) -diene with a yield of 90 ^c / o received. Subsequent silylation and Grignard! Erung lead

to the I70C-Ilydroxy ~ 20 ™ ketosteroid. , ,

In the description of the claim, the application of this reaction to certain derivatives such as 3-ajkendioxy- and 5 _S 5 (lower) Diali / lo: xy ~ östra-5C10), 9 (11) -diene ~ * 17- -on limited

Giel the invention

The aim of the invention is a new, generally applicable method for the Pregnanseitenkettenaufbau, according to the technologically and "economically favorable manner from lorandrostan- and Ändrostanderivaten the corresponding 19-Iiorpreg ~ nan or pregnanes can be produced.

the invention

It is the object of the invention to provide a process for preparing 19-norpregnanes and pregnanes or intermediates for the synthesis of 19-ioropregnanes and pregnanes, which provides the essential parts of the known processes, in particular the performance of isomerization reactions and isomerization avoids certain reactions and the complicated separation of isomers,

According to the invention, this object is achieved in that 17 ~ ketosteroids of the androstane and liorandrostanreihe the general formula I in the

E ₁ : -H or .-- CH ₃ ...

B ^ i = O, -O-Aoetyl, -H, Diraethoxyketal B ₅ : = 0

mean "and double bonds between the carbon atoms C ^ / cc; Cn / Cg and Cc / C ^ q may be present, which is preferably suspended in 80 to 90 i $ aqueous llkohol a lower alcohol such as methanol or ethanol darstelltj _und.mit? .eiacro llkanon- or Cyoloalkanoncyanhydrin addition von.Basen at a pH value of 7 3 des.Beaktionsgesnisches ^_bis-;? 1O, _5} Torzugsweise 8.5 to 9.0 with stirring au ~ 17oC Hydrox5 ^r -17ß-

Cyanosteroiden of the general formula I.

^{in the} E ₁ .- -H or -CH ₃ - ...

E ₂ * ^{= 0} > * -G-lcetyl, -H, dimethylketal

E ₅ ; ζ

and double bonds between the C atoms Ca / CcJ and Cc / C ^ q may be present.

As alkanone or Cycloalksnoncyanhydrin lcetoncyanhydrin, butanone cyanohydrin or cyclohexanone cyanohydrin be used, the bases that can be used for this reaction those that promote the Cyanhydrinaustausohreaktion · They are used in concentrations that no dissolution or de-fission of the precipitated from the reaction mixture poorly soluble 17oC-Iiyi Preference is given to using inorganic bases such as sodium hydroxide, potassium hydroxide, sodium or iraliufficarbonates and the corresponding bicarbonates, imidones or organic bases such as pyridine, triethylamine, triethanolamine, which are used as combinations with one another in the form of buffering agents can become «.

The concentration of the reaction mixture is adjusted so that an overlap of the dissolution and crystallization process is avoided .... , The use of aqueous alcohols causes the storoid ketone to be present as a suspension. The low starting concentration thus obtained achieves a slower rate of precipitation which promotes the formation of the sparingly soluble 17 C-hydroxy-cyanosteroid from the present equilibrium and, moreover, a thickened crystallization caused _o

Überrasohanderwoise be in this'Verfahrenweise · the reaction of steroid C-.iy-ketone to cyanohydrin at reaction temperatures of 15 ⁰ C to 60 ⁰ C, preferably at 30 to 4-0 ⁰ C and the under the conditions found

The onset of crystallization in both the Androstanals also delayed, in the Norandrοstanreihe the corresponding 17oC-Hydrox7 "17ß ~ * received cyanosteroids in high purity.

In this reaction, it can not be ruled out that first isomer mixtures are also formed. From this isogenic genesis, the sparingly soluble 17oG-hydroxy-17β-oyanosteroid then crystallizes out under the conditions found for the delayed crystallization. The 17oC-cyanoproduct remaining in solution undergoes a new equilibration and subsequent crystallization under the reaction conditions found, so that the almost quantitative yields of the 17oC ~ Bydroxy-17ß-oyano compounds can be explained in high purity »

This result is surprising and could not be foreseen by the methods previously known from the literature. With this result, cyanohydrin synthesis as a generally applicable method for the side chain construction in the androstane and norandrostan series is tapped, which is superior to other synthetic methods, since the substituents and functional groups required for the Steroidsei ™ tenkettenaufbau necessary already in the first step of the synthesis in the configuration required for a corticoid side chain be attached to the steroid molecule «,

The examples given below are intended to explain the process according to the invention in more detail without restricting it in any way.

Ausführungsbeisoiele

3,3 ~ dimethoxy-17oC-hydroxy-17.beta. ~ oyano-5 (1O) -Ostren

Are estrene-17 ~ on 4 offset 1 of methanol and 0.5 1 of water .. The suspension is under Eühren to a temperature of 35 C.eingestellt ^-: '(LO) "500, 3 ~ 5 g dimethoxy-3'. To the mixture are added with stirring 5Ö0 ml of acetone cyanohydrin and

the pH value of the solution to 8.7 "to 8.9" a Realst ionsgemisch The stirring is continued at 35 ⁰ C, wherein the ketone used within 1 hour is completely dissolved wax a reaction time of 1.2 to. t, 5 hours at 35 ⁰ C is the crystallization of the reaction product in. after a Gssamtreaktionszeit of 2 to 2.5 hours (0.5 to 1 hour after, the onset of crystallization) is added dropwise over 0.5 h further 0.5 1 vessel to the reaction mixture is stirred for 1 to 2 hours at 35 ⁰ C and then allowed to stand overnight at room temperature.The reaction mixture is then added with 1 1 of water, cooled to +15 ⁰ C and then filtered with suction.

The crystals are then washed with 5% potassium dihydrogen phosphate solution, then washed with water and sucked dry.

Yield: 98 <fo . D. Th.

The DC test showed ': no by-products,

Starting material £ 1 fo

Mp: 95 to 98 ^° C.

.2.2.

122.5 ° (C = 1, CECl ₅ )

Example 2

17ß ~ cyano ~ 4-androstene-3-one

100 g of 4-indendione are suspended in 800 ml of methanol with the addition of 50 ml of water and 100 ml of sodium acetone cyanohydrin. The mixture is adjusted to a temperature of 35 to 40 ° C. with stirring. By addition of a base mixture, the pH of the reaction mixture is adjusted to pH 8.7 to 9.0 "After addition of the base mixture is slow dissolution.der Steroidketons and after a total reaction side of 1.5 to 2 _? The crystallization process lasted for a further two hours, and then another 150 ml of water were added dropwise, then stirred for a further hour, and then left to stand overnight. , Further work-up is carried out as described in Example 1

Yield: 98.5 g = 91.5 $> d. th

Mp: 222 ms 226 ⁰ C

ι + 141.5 ° CC = 1, CHCl ₃ )

Example 5

~ Oyano-5-androsten-hydroxy-17oC 17i3 - 3.beta.-Acetoxy

100 g of 3J3-acetoxy-5-androstene-t7-on_ are suspended in 600 ml of methanol and 50 ml of water with the addition of - 100 ml of acetone anhydride. The mixture is. heated auf..eine temperature of 35 ⁰ C and adjusted by adding 1N NaOH solution to pH 8.7 "to 8.8. After addition of the base mixture was slowly dissolving the Steroidketons, after about 45 'set the crystallization of the reaction product After a reaction time of 3 hours, an additional 100 ml of water were added dropwise. The reaction mixture was allowed to stand overnight, then treated with a further 500 ml of water, stirred for a further 2 hours, cooled to 20 ° C., then filtered off with suction, washed and dried, yield : 106.0 g = 98 <$> dth Th

 Mp: 200 to 207 ° C

& C7 ^2Z t -34 ° (C = 1, dioxane)

Literature mp: 210 to 211 ⁰ C for the 17ß-cyano-17 ^ T- (Heusser) / ρζ / -53 (dioxane) hydroxysteroid

Mp: 195 to 205 ⁰ C for 17 © C ~ cyano-17ß-

/ oC7 -121 CDioxane) hydroxysteroid D.

3β ~ Ac and oxy-17oC ~ hydroxy ~ 17β ~ cyano-5-andr ó it

50 g of 3β-oo- oxy-5 "-estesten -17-one / earth in 500 ml of ethanol and 50 ml of water with the addition of 75 ml CycJohexanonoyanhydrin

78 6 9

suspended. The mixture is heated to a temperature of 40 ° C. and adjusted to pH 9 with a "base mixture." After the base mixture has been added, slow dissolution of the starting ketone takes place while drilling, the crystallization takes place after 1.5 hours of total reaction time For a total reaction time of above 4 hours, a further 100 ml of water are added dropwise, the mixture is stirred at room temperature and then left to stand over Hach.t Further work-up is carried out as described in Example 3. Yield: 49.5 g = 91.5 $ dth Th.

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Claims (2)

invention claim 1. Process for the preparation of 17 <7C "* hydroxy-17i3-cyanosteroids of the general formula 1 (1) in the B ₁ : -H or -CH ^ · E2: = 0; -O-ilcetyl, -H, dimethoxy ketal  CN and represent double bonds between C-Ätomen C4 / C5J ^ c / ^sow Cg ^ ^e C ^ / C ^ Q may be present, DA. characterized in that 17-keto steroids of the androstane and Norandrostanreihe the general formula (I) in the R, rH or -CH ₅ . , , Έ ^ ι = O, -O-acetyl, -H, dimethoxy ketal K ₅ : = 0 and double bonds can be present between the carbon atoms C 1 -C 3 C 3 C 3 C 3 C 3 C 3 C 3 / C 2 O in aqueous alcohol, which is preferably a lower alcohol such as methanol or ethanol an alkancn ™ or cycloalkanone cyanohydrin with the addition of bases at a pH of the reaction mixture of 7j3 to 10> 5, preferably 8.5 to 9iO reacted with stirring. 2 _e Process for the preparation of 17oC ~ hydroxy-17ß- "ojano steroids naoh Punlct 1, characterized in that j as alkanone or Cycloalkanonoyanhydrin, Auetonoyanhydrin, Butanone cyanohydrin, or Cyclolaexanoncyanhydrin is used. 5. Process for the preparation of Steroids according to item 1, characterized in that as bases inorganic bases such as' alkali metal hydroxides. Alkali carbonates, AlkanihydrogencarlDonate, alkali metal cyanides, ammonia or organic bases? / Ie pyridine, triethylamine, triethanolamine, which are also used as combinations with each other in the form of buffer mixtures.