Process for the preparation of 11β-hydroxy-18-alkyl-estrane compounds

Claim 2

Process for the preparation of an 11β-hydroxy-18-alkyl steroid of the estrane series, the alkyl having 1 to 4 carbon atoms, which steroid may be substituted in the 3- and/or 17-position by an oxo group or a functional derivative thereof, in the 1, 2, 3, 4, 5, 6, 7, 15 and/or 16-position by hydroxy, acyloxy derived from an organic carboxylic acid having 1-18 carbon atoms, alkoxy having 1-2 carbon atoms, tetrahydropyranyloxy or trimethylsilyloxy in the 1, 6, 7, 9, 11α and/or 16-position with alkyl having 1-2 carbon atoms and in the 17α-position with saturated or unsaturated alkyl having 1-4 carbon atoms next to hydroxy, acyloxy derived from an organic carboxylic acid having 1-18 carbon atoms, alkoxy having 1-2 carbon atoms, tetrahydropyranyloxy or trimethylsilyloxy in 17β-position, and which may have a double bond in the 4,5-, 5,6-, or 5,10-position, which comprises reacting the corresponding 11β-hydroxy-13-methyl-gonane compound with an excess of an acyl hypoiodite and reacting the thus-obtained estrano-18, 11β-lactone with a compound RX, in which R = alkyl and X = MgBr or Li and thereafter reducing the thus-obtained 11β-hydroxy-18-alkyl-18-ketone to the 11β-hydroxy-18-alkyl-steroid of the estrane series.

Claim 3

Process according to claim 1, in which the starting 11β-hydroxy-13-methyl-gonane compound has the formula ##STR4##wherein R 1 = H 2 , H(OR 3 ), O or ketalised O; R 2 = o, ketalised O, H(OR 4 ) or (α-alkyl)(βOR 4 ), the alkyl group having 1-4 C-atoms and R 3 and R 4 being H or a protecting group such as acyl or alkyl; and a double bond is present in the 4,5- or 5,6-position.

Claim 4

Process according to claim 2, in which in the formula R 1 = h 2 , h(oacetyl) or ethylenedioxy; R 2 = ethylenedioxy, αH(βOacetyl) or (α-alkyl 1-4 C) (βOacetyl); and a double bond is present in the 4,5- or 5,6-position.

Claim 5

Process according to claim 1 in which the acylhypoiodite is formed in situ from iodine and an acylate of a heavy metal of Group IB, Group IIB and Group IVB of the Periodic System.

Claim 6

Process according to claim 4, in which lead tetra acetate is used as acylate of said heavy metal.

Claim 7

Process according to claim 4, in which per gmol steroid 1.5-3.0 gmol iodine are used and at least an equivalent amount of lead tetra-acylate.

Claim 8

Process according to claim 6, in which per gmol iodine 1.5-5 gmol of lead tetra-acylate are used.

Claim 9

Process according to claim 1, in which in the first step a cyclic hydrocarbon is used as solvent.

Claim 10

Process according to claim 8, in which cyclohexane is used as solvent.

Claim 11

Process according to claim 1, in which in the first step the reaction is performed in the presence of a radical initiator.

Claim 12

Process according to claim 10, in which azoisobutyrodinitril is used as radical initiator.

Claim 13

Process according to claim 10, in which 0.1-0.25 gmol radical initiator is used per gmol steroid.

Claim 14

Process according to claim 1, in which in the compound RX the alkyl group has 1-4 carbon atoms.

Claim 15

Process according to claim 1, in which the reaction of the estrano-18,11β-lactone with the compound RX is performed in an indifferent solvent under anhydrous conditions.

Claim 16

Process according to claim 1, in which the reaction of the alkyl lithium compound with the 11β-hydroxy-13-carboxylic acid is performed in an indifferent solvent under anhydrous conditions and at low temperatures.

Claim 17

Process according to claim 1, in which the 18-oxo group in the 11β-hydroxy-18-alkyl-18-ketone is reduced by reacting the 18-ketone with a hydrazine or a semicarbazide and decomposing the hydrazone or semicarbazone thus obtained with the aid of potassium hydroxide or an alkoxide.

Claim 18

Process according to claim 16, in which the reduction is performed in boiling diethylene glycol, whereby the water formed during the reaction is distilled off.

Claim 19

A compound having the formula ##STR5##wherein R 1 = H 2 , H(OR 3 ), O or ketalised O; R 2 = o, ketalised O, H(OR 4 ) or (α-alkyl)(βOR 4 ) the alkyl group having 1-4 carbon atoms and R 3 and R 4 being H or a protecting group such as acyl or alkyl; R 5 = oh, acyloxy derived from an organic carboxylic acid having 1-18 carbon atoms, alkoxy having 1-2 carbon atoms, tetrahydropyranyloxy or trimethylsilyloxy; R 6 = alkyl having 1-4 carbon atoms or R 5 and R 6 together form epoxy; and a double bond is present in the 4,5- or 5,6-position.

Claim 20

A compound having the formula ##STR5##wherein R 1 = H 2 , H(OR 3 ), O or ketalised O; R 2 = o, ketalised O, H(OR 4 ) or (α-alkyl)(βOR 4 ) the alkyl group having 1-4 carbon atoms and R 3 and R 4 being H or a protecting group such as acyl or alkyl; R 5 = oh, acyloxy derived from an organic carboxylic acid having 1-18 carbon atoms, alkoxy having 1-2 carbon atoms, tetrahydropyranyloxy or trimethylsilyloxy; R 6 = alkyl having 1-4 carbon atoms or R 5 and R 6 together form epoxy; and a double bond is present in the 4,5- or 5,6-position.

Claim 21

A compound according to claim 18, wherein R 1 = h 2 or ethylenedioxy; R 2 = ethylenedioxy or αH(βOacetyl); R 5 = oh; r 6 = methyl or R 5 and R 6 together form epoxy; and a double bond is present in the 4,5- or 5,6-position.

Claim 22

Process for the preparation of an 11β-hydroxy-18-alkyl steroid of the estrane series, the alkyl having 1 to 4 carbon atoms, which steroid may be substituted in the 3- and/or 17-position by an oxo group or a functional derivative thereof, in the 1, 2, 3, 4, 5, 6, 7, 15 and/or 16-position by hydroxy, acyloxy derived from an organic carboxylic acid having 1-18 carbon atoms, alkoxy having 1-2 carbon atoms, tetrahydropyranyloxy or trimethylsilyloxy in the 1, 6, 7, 9, 11α and/or 16-position with alkyl having 1-2 carbon atoms and in the 17α-position with saturated or unsaturated alkyl having 1-4 carbon atoms next to hydroxy, acyloxy derived from an organic carboxylic acid having 1-18 carbon atoms, alkoxy having 1-2 carbon atoms, tetrahydropyranyloxy or trimethylsilyloxy in 17β-position, and which may have a double bond in the 4,5-, 5,6-, or 5,10-position, which comprises reacting the corresponding 11β-hydroxy-13-methyl-gonane compound with an excess of an acyl hypoiodite, hydrolyzing the thus-obtained estrano-18, 11β-lactone to the corresponding 11β-hydroxy-13-carboxylic acid, then reacting said carboxylic acid with an alkyl lithium compound, and thereafter reducing the thus-obtained 11β-hydroxy-18-alkyl-18-ketone to the 11β-hydroxy-18-alkyl-steroid of the estrane series.

Claim 23

Process for the preparation of an 11β-hydroxy-18-alkyl steroid of the estrane series, the alkyl having 1 to 4 carbon atoms, which steroid may be substituted in the 3- and/or 17-position by an oxo group or a functional derivative thereof, in the 1, 2, 3, 4, 5, 6, 7, 15 and/or 16-position by hydroxy, acyloxy derived from an organic carboxylic acid having 1-18 carbon atoms, alkoxy having 1-2 carbon atoms, tetrahydropyranyloxy or trimethylsilyloxy in the 1, 6, 7, 9, 11α and/or 16-position with alkyl having 1-2 carbon atoms and in the 17α-position with saturated or unsaturated alkyl having 1-4 carbon atoms next to hydroxy, acyloxy derived from an organic carboxylic acid having 1-18 carbon atoms, alkoxy having 1-2 carbon atoms, tetrahydropyranyloxy or trimethylsilyloxy in 17β-position, and which may have a double bond in the 4,5-, 5,6-, or 5,10-position, which comprises reacting the corresponding 11β-hydroxy-13-methyl-gonane compound with an excess of an acyl hypoiodite, hydrolyzing the thus-obtained estrano-18, 11β-lactone to the corresponding 11β-hydroxy-13-carboxylic acid, then reacting said carboxylic acid with an alkyl lithium compound, and thereafter reducing the thus-obtained 11β-hydroxy-18-alkyl-18-ketone to the 11β-hydroxy-18-alkyl-steroid of the estrane series.

Claim 24

Process according to claim 20 in which the starting 11β-hydroxy-13-methyl-gonane compound has the formula ##STR6## wherein R 1 = H 2 , H(OR 3 ), O or ketalised O; R 2 = o, ketalised O, H(OR 4 ) or (α-alkyl) (βOR 4 ), the alkyl group having 1-4 C-atoms and R 3 and R 4 being H or a protecting group such as acyl or alkyl; and a double bond is present in the 4,5- or 5,6-position.

Claim 25

Process according to claim 21 in which in the formula R 1 = h 2 , h(oacetyl) or ethylenedioxy; R 2 = ethylenedioxy, αH(βOacetyl) or (α-alkyl 1-4 C) (βOacetyl); and a double bond is present in the 4,5- or 5,6-position.

Claim 26

Process according to claim 20 in which the acyl hypoiodite is formed in situ from iodine and an acylate or a heavy metal of Group IB, Group IIB and Group IVB of the Periodic System.

Claim 27

Process according to claim 23 in which lead tetra acetate is used as acylate of said heavy metal.

Claim 28

Process according to claim 23, in which per g mol steroid 1.5-3.0 g mol iodine are used and at least an equivalent amount of lead tetra-acylate.

Claim 29

Process according to claim 25, in which per g mol iodine 1.5-5 g mol of lead tetra-acylate are used.

Claim 30

Process according to claim 20, in which in the first step a cyclic hydrocarbon is used as solvent.

Claim 31

Process according to claim 27, in which cyclohexane is used as solvent.

Claim 32

Process according to claim 20, in which in the first step the reaction is performed in the presence of a radical initiator.

Claim 33

Process according to claim 29, in which azoisobutyrodinitrile is used as radical initiator.

Claim 34

Process according to claim 29, in which 0.1-0.25 g mol radical initiator is used per g mol steroid.

Claim 35

Process according to claim 20, in which in said alkyl lithium compound the alkyl group has 1-4 carbon atoms.

Claim 36

Process according to claim 20, in which the 18-oxo group in the 11β-hydroxyl-18-alkyl-18-ketone is reduced by reacting the 18-ketone with a hydrazine or a semicarbazide and decomposing the hydrazone or semicarbazone thus obtained with the aid of potassium hydroxide or an alkoxide.

Claim 37

Process according to claim 33, in which the reduction is performed in boiling diethylene glycol. whereby the water formed during the reaction is distilled off.