DE1234713B - Process for the preparation of 2-en-3-olaethers of 2-hydroxymethyl-3-oxo-5alpha-steroids of the androstane and pregnane series - Google Patents

Description

UNDESREPUBLIC OF GERMANY

EUCHES

PATENT OFFICE

EDITORIAL

Int. Cl .:

Number:
File number:
Registration day:
Display day:

CQ7c

O 7 y

German class: 12 ο -

B 70470 IV b / 12 ο
January 24, 1963
February 23, 1967

The invention relates to a process for the preparation of 2-en-3-ol ethers of 2-hydroxymethyl-3-oxo-5'-steroids the androstane and pregnane series. These new compounds have and can be of therapeutic and veterinary importance can also be used as intermediate products. So have the corresponding derivatives of 17 /} - hydroxy-5 «-androstane claudogenic, especially ovulation-inhibiting properties. The corresponding Derivatives of na ^ l-dihydroxy-Sn-pregnan-11,20-dione and corresponding 21- and 17,21-esters show claudogenic activity. The derivatives des 17a-acyloxy-5a-pregnan-20-one have progestational Activity on. The products of the process can also be used as intermediates. she can be aeylated, halogenated and oxidized afterwards; their hydrogenation gives 2-methylated steroids, which among other things to 2a-methyl-3-oxosteroids can be hydrolyzed, of which z. B. the 2α, 17α-dimethyl-17 / i-hydroxyl-5α-androstan-3-one is known as a biologically valuable substance.

The 2-en-3-ol ethers of the 2-hydroxymethyl-3-oxo-5 «steroids the androstane and pregnane series of the general formula I.

HIGH ₂

(0

in which R is an O-alkyl, O-hydroxyalkyl, O-cycloalkyl or O-aralkyl group, are according to the process of the invention prepared by the fact that the corresponding 2-en-3-olether one 2-formyl-3-oxo-5a-steroids of the androstane or pregnane series of the general formula II

CH ₃

(Ii)

in which R has the meaning given, under not acidic conditions reduced by methods known per se.

Process for the preparation of 2-en-3-ol ethers
of 2-hydroxymethyl-3-oxo-5a-steroids der
Androstane and Pregnane series

Applicant:

The British Drug Houses Limited, London

Representative:

Dipl.-Ing. F. Weickmann,

Dr.-Ing. A. Weickmann,

Dipl.-Ing. H. Weickmann

and Dipl.-Phys. Dr. K. Fincke, patent attorneys,

Munich 27, Möhlstr. 22nd

Named as inventor:

Bernard Ellis,

Derek Burn,

Vladimir Petrow, London

Claimed priority:
Great Britain January 26, 1962 (3001),
dated January 14, 1963

According to the process, the reducing agents must not have an acidic character, nor must they be in an acidic medium, since the reaction products of the formula T towards acids are extremely sensitive. They are converted into dimerc materials by acids.

A 2 - formyl derivative of the formula TI which has substituents which are sensitive to both reduction and alkaline hydrolysis, e.g. B. the substituent - COCH ₂ OAc, is catalytically reduced according to the process, using Raney nickel as a catalyst. Normally produced Raney nickel is strongly alkaline. It is therefore advisable to free the Raney nickel before use of alkali, if not to a hydrolysis ■ / .. as the aeylierten Ketolsystcms occur. The alkali liberation can be carried out in the usual way, for. B. by treatment with ethyl acetate.

Platinum on carbon in the presence of a sodium acetate buffer is another useful catalyst

709 510/580

for the hydrogenation according to the process. Said catalyst can be used to hydrogenate the 2-formyl group in compounds such as 21-acetoxy-2-formyl-17a-hydroxy-3-methoxy-5a-pregn-2-en-ll, 20-dione, be used.

Complex metal or organometallic hydrides, ζ. B. lithium, sodium, magnesium or calcium borohydrides, Lithium aluminum hydride or tri-tert-butoxy-aluminum hydride, are representatives of those Reducing agents which reduce the 2-formyl group in na-acyloxy-Sa-pregnan ^ O-one derivatives are suitable. Lithium cyanoborohydride can also be used in certain cases.

The Ponndorf reduction method can be used to reduce such 2-formyl derivatives, which do not contain any additional carbonyl groups.

In the reduction according to the method, the double bond of the parent steroids becomes surprisingly not attacked.

The 2-formyl derivative (II) used as starting material for the process according to the invention is prepared by a process described elsewhere. According to this process, for which no protection is sought within the scope of the present invention, a 2-en-3-olether of 3-oxo-5a-steroids or a 3,3-dialkoxy-5a-steroid is treated with a Vilsmeier reagent ( see Houben-Weyl, Methods of Organic Chemistry, 4th Edition, 1954, Vol. 7 [1], p. 29 ff.), preferably at about ⁰ ° C., in a solvent such as ethylene dichloride. The complex obtained is decomposed, for example, with aqueous-methanolic sodium acetate in order to obtain the 2-formyl derivative (II) in this way.

The starting materials used in the process according to the invention can be the corresponding Steroids carry the usual substituents, provided that these carry out the reduction carried out according to the method do not bother.

The following examples explain the process according to the invention.

example 1

17 / i-acetoxy-2-hydroxymethyl-3-methoxy-5a-androst-2-ene

Example 2

17 ₍ ? -Hydroxy-2-hydroxymethyl-3-methoxy-17 "-methvl-5ra-androst-2-en

vT- CH ₃

_T0 HIGH ₂

H ₃ CO

A solution of nfi-acetoxy ^ -formyl-na-methyl-3-methoxy-5a-androst-2-ene (4.25 g) in dry tetrahydrofuran (100 ml) is treated with lithium aluminum hydride (3.5 g). The mixture is refluxed for 2 hours and then cooled in ice. For the purpose of decomposing the reducing agent, water is added. The product is isolated with ether. The product named in the example heading is obtained in the form of microcrystals with a melting point of 137 to 141 ^° C .; [α] ΐ - - (33 ° (c = 1.06, in

25th

30 chloroform). Yield: 80%.

Example 3

Ua-acetoxy ^ -hydroxymcthyW-methoxy-5u-pregn-2-en-20-one

COCHa

H ₃ C

r-OAc

OAc

H ₃ C

2

H ₃ CO

35

4 ° 20-one (2 g) is added to a suspension of lithium borohydride (0.3 g) in anhydrous tetrahydrofuran (40 ml). It is stirred for 5 minutes and poured into water. The product is isolated with ether. The crystallization takes place from aqueous methanol which contains traces of pyridine. The product obtained corresponds to that in the example heading

so-called ' ν ™ t' ^ 3400, 1724 and 1700 cm- ¹ . Yield: 75%.

Example 4

55

A solution of ß
oxy-5u-androst-2-ene (1 g) in methanol (25 ml) is treated with sodium borohydride (0.2 g) for 15 minutes at room temperature. After adding water, a solid is obtained which is crystallized from aqueous methanol which contains traces of pyridine. The substance named in the heading is separated off in the form of needles with a melting point of 120 to 122 ^° C .; [α)? = 1-41 ° (c - 0.98, in dioxane). Yield: 90%.

21-acetoxy-17α-hydroxy-2-hydroxymethyl-3-methoxy-5a-pregn-2-en-ll, 20-dione

CH ₂ OAc

-OH

21-acetoxy-2-formyl-17α-hydroxy-3-methoxy-5a-pregn-2-cn-ll, 20-dione (2 g) is poured over a pre-reduced 5% platinum-carbon catalyst (0.25 g) hydrogenated in 100 ml of methanol containing 0.3 g of sodium acetate. The absorption of hydrogen is ended after taking up the equivalent amount. The catalyst is then removed by filtration; the filtrate is concentrated, water is added and the product is isolated with dichloromethane. It is purified from aqueous, traces of pyridine-containing ι ο the ethanol to produce the desired substance to obtain. > ΊΤ '- 3400. Yield: 75%.

Example 5

17 ^ -Acetoxy-2-hydroxymethyl-3-methoxy-19-nor-5a-androst-2-ene

'5

OAc

H ₃ C

Example 6

17 /} - Hydroxy-2-hydroxymethyl-3-methoxyl7a-methyl-19-nor-5a-androst-2-cn

OH

HOCHj

H ₃ CO

ν- CH ₃

hydrofuran (25 ml) is treated with lithium aluminum hydride (0.75 g). The mixture is stirred under reflux for IV2 hours. After cooling, it is treated with water. The product is isolated with ether. After crystallization, the product named in the example heading is obtained, / ^ i ⁰ '= 3400 and cm- ¹ . Yield: 75%.

Claims (2)

Patent claims: 1. Process for the preparation of 2-en-3-ol ethers of 2-hydroxymethyl-3-oxo-5a-steroids the androstane and pregnane series of the general formula I. CH ₃ A solution of n ^ yy oxy-19-nor-5a-androst-2-ene (1 g) in dry tetrahydrofuran (10 ml) is added to lithium borohydride (200 mg) in dry tetrahydrofuran (10 ml) at room temperature. It is stirred for 10 minutes. After adding water, the product is isolated with ether. After crystallization, the product named in the example heading, having a melting point of 133 to 135 ° C; [a] V = -f 92 ° (c = 1.0, in chloroform). Yield: 80%. 40 45 1 liter - acetoxy - 2 - formyl -1 Ta - methyl - 3 - methoxy-19-nor-5a-androst-2-en (1 g) in dry tetra- in which R is an O-alkyl, O-hydroxyalkyl, O-cycloalkyl or O-aralkyl group means d a through characterized in that the corresponding 2-en-3-olether of a 2-formyl-3-oxo-5a-steroid is used the androstane or pregnane series of the general formula 11 CH ₃ (II) in which R has the meaning given, under non-acidic conditions according to known per se Methods reduced. 2. The method according to claim 1, characterized in that the reduction with a Metal borohydride or with lithium aluminum hydride or by catalytic hydrogenation under Use of platinum on charcoal, especially charcoal, in the presence of a sodium acetate buffer undertakes. Considered publications:
Chemical Reports, Vol. 85 (1952), pp. 635 to 640. 709 510/510 2nd Sl O Bundesdruckerei Berlin