Process for obtaining 17-spirolactones in steroids

A process for obtaining a compound of formula (III)

• wherein
• R is C1-C8 alkyl, C3-C8 cycloalkyl, aryl or benzyl;
• and
• R1 is hydrogen or a hydroxyl-protecting group;
• or a solvate thereof,
• which comprises reacting a compound of formula (IV)
• wherein R1 is that previously defined,
• with a propargyl ester of formula (V)
• H≡CO2R (V)
• wherein R is that previously defined,
• in the presence of a base.

A process for obtaining Drospirenone (I)

• which comprises
• providing a compound of formula (III)
• wherein
• R is selected from the group consisting of C1-C8 alkyl, C3-C8 cycloalkyl, aryl and benzyl;
• and
• R1 is selected from the group consisting of hydrogen and a hydroxyl-protecting group;
• or a solvate thereof, and
• subjecting said compound of formula (III) to:
• 1) optionally, deprotection of the hydroxyl group in position 3 when R1 is a protecting group, and
• 2) oxidation of the hydroxyl group in position 3 to render a compound of formula (II)
• wherein R is that previously defined, and
• subjecting said compound of formula (II) to a sequence of reactions selected from sequences A, B and C, wherein
• Sequence A comprises:
• a1) subjecting a compound of formula (II) to an elimination or an elimination/saponification reaction to yield the intermediate of formula (IIa):
• wherein R2 is H, C1-C8 alkyl, C1-C8 cycloalkyl, aryl or benzyl;
• a2) subjecting said compound of formula (IIa) to a hydrogenation reaction in the presence of a Pt or Pd catalyst to yield the intermediate of formula (IIc):
• wherein R2 is that previously defined, and
• a3) subjecting said compound of formula (IIc) to treatment in acid conditions to render Drospirenone (I),
• wherein steps a2) and a3), alternatively, take place in one-pot form;
• Sequence B comprises:
• b1) subjecting a compound of formula (II) to a hydrogenation reaction in the presence of a Pd catalyst to yield the intermediate of formula (IIb)
• and
• b2) subjecting said compound of formula (IIb) to a hydrogenation reaction in the presence of a Pt catalyst to render Drospirenone (I);
• wherein steps b1) and b2) alternatively take place in one-pot form;
• and
• Sequence C comprises:
• c1) subjecting a compound of formula (II) to a hydrogenation reaction in the presence of a Pt catalyst to yield the intermediates of formulae (IId) and/or (IIe)
• wherein R is that previously defined, and
• c2) subjecting a compound of formulae (IId) and/or (IIe) to treatment in acid conditions to render Drospirenone (I),
• wherein steps c1) and c2) alternatively take place in one-pot form;
• or alternatively,
• a) protecting a compound of formula (IVa)
• to render a compound of formula (IVb)
• wherein TBDMS is tert-butyldimethylsilyl;
• b) reacting said compound of formula (IVb) with a compound of formula (Va)
• H≡CO2Et (Va)
• to render a compound of formula (IIIb)
• wherein TBDMS is tert-butyldimethylsilyl;
• c) deprotecting the protected hydroxyl group in position 3 of said compound of formula (IIIb) to render a compound of formula (IIIc)
• d) oxidizing the hydroxyl group in position 3 of said compound of formula (IIIc) in the presence of an oxidizing reagent to yield a compound of formula (IIf)
• e) subjecting the compound of formula (IIf) to an elimination reaction to yield the intermediate of formula (IIg)
• f) subjecting the compound of formula (IIg) to a hydrogenation reaction in the presence of a Pt catalyst to yield the intermediate of formula (IIh)
• and
• g) subjecting the compound of formula (IIh) to treatment in the presence of an acid to render Drospirenone (I);
• or alternatively,
• a′) protecting a compound of formula (IVa)
• to render a compound of formula (IVb)
• wherein TBDMS is tert-butyldimethylsilyl;
• b′) reacting a compound of formula (IVb) with a compound of formula (Va)
• H≡CO2Et (Va)
• to render a compound of formula (IIIb)
• wherein TBDMS is tert-butyldimethylsilyl;
• c′) deprotecting the protected hydroxyl group in position 3 of said compound of formula (IIIb) to render a compound of formula (IIIc)
• d′) oxidizing the hydroxyl group in position 3 of said compound of formula (IIIc) in the presence of an oxidizing reagent to yield a compound of formula (IIf)
• e′) subjecting the compound of formula (IIf) to an elimination and saponification reaction to yield the intermediate of formula (IIi)
• f′) subjecting the compound of formula (IIi) to a hydrogenation reaction in the presence of a Pt or Pd catalyst to yield the intermediate of formula (IIj)
• and
• g′) subjecting the compound of formula (IIj) to treatment in the presence of an acid to render Drospirenone (I);
• or alternatively
• providing a compound of formula (III)
• wherein
• R is C1-C8 alkyl, C3-C8 cycloalkyl, aryl or benzyl;
• and
• R1 is hydrogen or a hydroxyl-protecting group;
• or a solvate thereof,
• followed by
• d1) subjecting said compound of formula (III) to a hydrogenation reaction in the presence of a metal catalyst to yield the intermediate of formula (VI)
• wherein R is that previously defined,
• d2) deprotecting the hydroxyl group in position 3 of said compound of formula (VI) when R1 is a protecting group, followed by a transesterification reaction to render the compound of formula (VII)
• d3) oxidizing the compound of formula (VII) to render the compound of formula (IId)
• and
• d4) subjecting the compound of formula (IId) to an elimination reaction to render Drospirenone (I).

A compound selected from the group consisting of:

• wherein
• R is C1-C8 alkyl, C3-C8 cycloalkyl, aryl or benzyl;
• and
• R2 is C1-C8 alkyl, C3-C8 cycloalkyl, aryl or benzyl;
• or a solvate thereof.