Process for the production of estetrol intermediates

A process for the preparation of a compound of formula (I)

• or a stereoisomer, a salt, a hydrate or a solvate thereof, comprising desulfinylation of a compound of formula (II)
• to produce a compound of formula (I), wherein:
• R1 is selected from hydrogen, R3Si(R4)(R5)—, C1-6 alkyl, C6-10 aryl, C6-10 arylC1-6 alkyl, —CH2—CH═CRaRb, C1-6 alkoxy, C3-6 cycloalkyl, and R6CO—, wherein each of said C1-6 alkyl, C6-10 aryl, C6-10 arylC1-6 alkyl, and C3-6 cycloalkyl may be optionally substituted with one or more substituents each independently selected from halo, C1-6alkyl, haloC1-6 alkyl, C1-6 alkoxy, haloC1-6 alkoxy, C6-10 aryl, heterocyclyl, and nitro;
• R2 is C6-10 aryl, or heteroaryl, wherein each C6-10 aryl or heteroaryl may be optionally substituted with one or more substituents each independently selected from halo, C1-6alkyl, haloC1-6 alkyl, C1-6 alkoxy, haloC1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, heterocyclyl, heteroaryl, hydroxyl, —S(O)2R7, —S(O)R8, —CO2R9, —C(O)R10, —SR13, —C(O)SR14, NR11R12, cyano and nitro;
• R3, R4 and R5 are each independently C1-6 alkyl or C6-10 aryl, wherein each C1-6 alkyl or C6-10 aryl may be optionally substituted with one or more substituents each independently selected from halo, C1-6 alkyl, haloC1-6 alkyl, C1-6 alkoxy, and haloC1-6 alkoxy;
• R6 is C1-6 alkyl, C6-10 aryl, or C3-6 cycloalkyl, wherein each C1-6 alkyl, C6-10 aryl, or C3-6 cycloalkyl may be optionally substituted by one or more substituents independently selected from halo, C1-6 alkyl, haloC1-6 alkyl, C1-6 alkoxy, and haloC1-6 alkoxy;
• R7, R8, R9 and R10 are each independently selected from hydrogen, hydroxyl, C1-6 alkyl, C6-10aryl, and C3-6cycloalkyl, wherein each C1-6 alkyl, C6-10 aryl, or C3-6 cycloalkyl may be optionally substituted by one or more substituents independently selected from halo, C1-6 alkyl, haloC1-6 alkyl, C1-6 alkoxy, and haloC1-6 alkoxy;
• R11 and R12 are each independently selected from the group consisting of hydrogen, C1-6 alkyl, C6-12 aryl, and C3-6 cycloalkyl, wherein each C1-6 alkyl, C6-10 aryl, or C3-6 cycloalkyl may be optionally substituted by one or more substituents independently selected from halo, C1-6 alkyl, haloC1-6 alkyl, C1-6 alkoxy, and haloC1-6 alkoxy;
• R13 and R14 are each independently selected from hydrogen, C1-6alkyl, C6-10aryl, and C3-6cycloalkyl, wherein each C1-6 alkyl, C6-10 aryl, or C3-6 cycloalkyl may be optionally substituted by one or more substituents independently selected from halo, C1-6 alkyl, haloC1-6 alkyl, C1-6 alkoxy, and haloC1-6 alkoxy;
• and
• Ra and Rb are each independently hydrogen, C1-6 alkyl or C6-10 aryl;
• wherein said desulfinylation step is performed by a continuous flow process;
• and
• wherein said desulfinylation step is performed by thermolysis at a thermolysis temperature (T) of at least 140° C.

A process for preparing estra-1,3,5(10),-triene 3,15α,16α,17β-tetrol of formula (E)

• or a stereoisomer, a salt, a hydrate, an ester, an ether, or a solvate thereof, comprising:
• (I) preparing a compound of formula (I)
• by a process comprising desulfinylation of a compound of formula (II)
• to produce a compound of formula (I), wherein:
• R1 is selected from hydrogen, R3Si(R4)(R5)—, C1-6 alkyl, C6-10 aryl, C6-10 arylC1-6 alkyl, —CH2—CH═CRaRb, C1-6 alkoxy, C3-6 cycloalkyl, and R6CO—, wherein each of said C1-6 alkyl, C6-10 aryl, C6-10 arylC1-6 alkyl, and C3-6 cycloalkyl may be optionally substituted with one or more substituents each independently selected from halo, C1-6alkyl, haloC1-6 alkyl, C1-6 alkoxy, haloC1-6 alkoxy, C6-10 aryl, heterocyclyl, and nitro;
• R2 is C6-10 aryl, or heteroaryl, wherein each C6-10 aryl or heteroaryl may be optionally substituted with one or more substituents each independently selected from halo, C1-6alkyl, haloC1-6 alkyl, C1-6 alkoxy, haloC1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, heterocyclyl, heteroaryl, hydroxyl, —S(O)2R7, —S(O)R8, —CO2R9, —C(O)R10, —SR13, —C(O)SR14, NR11R12, cyano and nitro;
• R3, R4 and R5 are each independently C1-6 alkyl or C6-10 aryl, wherein each C1-6 alkyl or C6-10 aryl may be optionally substituted with one or more substituents each independently selected from halo, C1-6 alkyl, haloC1-6 alkyl, C1-6 alkoxy, and haloC1-6 alkoxy;
• R6 is C1-6 alkyl, C6-10 aryl, or C3-6 cycloalkyl, wherein each C1-6 alkyl, C6-10 aryl, or C3-6 cycloalkyl may be optionally substituted by one or more substituents independently selected from halo, C1-6 alkyl, haloC1-6 alkyl, C1-6 alkoxy, and haloC1-6 alkoxy;
• R7, R8, R9 and R10 are each independently selected from hydrogen, hydroxyl, C1-6 alkyl, C6-10aryl, and C3-6cycloalkyl, wherein each C1-6 alkyl, C6-10 aryl, or C3-6 cycloalkyl may be optionally substituted by one or more substituents independently selected from halo, C1-6 alkyl, haloC1-6 alkyl, C1-6 alkoxy, and haloC1-6 alkoxy;
• R11 and R12 are each independently selected from the group consisting of hydrogen, C1-6 alkyl, C6-12 aryl, and C3-6 cycloalkyl, wherein each C1-6 alkyl, C6-10 aryl, or C3-6 cycloalkyl may be optionally substituted by one or more substituents independently selected from halo, C1-6 alkyl, haloC1-6 alkyl, C1-6 alkoxy, and haloC1-6 alkoxy;
• R13 and R14 are each independently selected from hydrogen, C1-6alkyl, C6-10aryl, and C3-6cycloalkyl, wherein each C1-6 alkyl, C6-10 aryl, or C3-6 cycloalkyl may be optionally substituted by one or more substituents independently selected from halo, C1-6 alkyl, haloC1-6 alkyl, C1-6 alkoxy, and haloC1-6 alkoxy;
• and
• Ra and Rb are each independently hydrogen, C1-6 alkyl or C6-10 aryl;
• wherein said desulfinylation step is performed by a continuous flow process;
• and
• wherein said desulfinylation step is performed by thermolysis at a thermolysis temperature (T) of at least 140° C., and
• (II) reacting the compound of formula (I) to produce estra-1,3,5(10),-triene 3,15α,16α,17β-tetrol of formula (E), or a stereoisomer, a salt, a hydrate, an ester, an ether, or a solvate thereof.

A composition comprising a compound of formula (I) and a compound of formula (IIa)

• wherein:
• R1 is selected from hydrogen, R3Si(R4)(R5)—, C1-6 alkyl, C6-10 aryl, C6-10 arylC1-6 alkyl, —CH2—CH═CRaRb, C1-6 alkoxy, C3-6 cycloalkyl, and R6CO—, wherein each of said C1-6 alkyl, C6-10 aryl, C6-10 arylC1-6 alkyl, and C3-6 cycloalkyl may be optionally substituted with one or more substituents each independently selected from halo, C1-6alkyl, haloC1-6 alkyl, C1-6 alkoxy, haloC1-6 alkoxy, C6-10 aryl, heterocyclyl, and nitro;
• R2 is C6-10 aryl, or heteroaryl, wherein each C6-10 aryl or heteroaryl may be optionally substituted with one or more substituents each independently selected from halo, C1-6alkyl, haloC1-6 alkyl, C1-6 alkoxy, haloC1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, heterocyclyl, heteroaryl, hydroxyl, —S(O)2R7, —S(O)R8, —CO2R9, —C(O)R10, —SR13, —C(O)SR14, NR11R12 cyano and nitro;
• R3, R4 and R5 are each independently C1-6 alkyl or C6-10 aryl, wherein each C1-6 alkyl or C6-10 aryl may be optionally substituted with one or more substituents each independently selected from halo, C1-6 alkyl, haloC1-6 alkyl, C1-6 alkoxy, and haloC1-6 alkoxy;
• R6 is C1-6 alkyl, C6-10 aryl, or C3-6 cycloalkyl, wherein each C1-6 alkyl, C6-10 aryl, or C3-6 cycloalkyl may be optionally substituted by one or more substituents independently selected from halo, C1-6 alkyl, haloC1-6 alkyl, C1-6 alkoxy, and haloC1-6 alkoxy;
• R7, R8, R9 and R10 are each independently selected from hydrogen, hydroxyl, C1-6 alkyl, C6-10aryl, and C3-6cycloalkyl, wherein each C1-6 alkyl, C6-10 aryl, or C3-6 cycloalkyl may be optionally substituted by one or more substituents independently selected from halo, C1-6 alkyl, haloC1-6 alkyl, C1-6 alkoxy, and haloC1-6 alkoxy;
• R11 and R12 are each independently selected from the group consisting of hydrogen, C1-6 alkyl, C6-12 aryl, and C3-6 cycloalkyl, wherein each C1-6 alkyl, C6-10 aryl, or C3-6 cycloalkyl may be optionally substituted by one or more substituents independently selected from halo, C1-6 alkyl, haloC1-6 alkyl, C1-6 alkoxy, and haloC1-6 alkoxy;
• R13 and R14 are each independently selected from hydrogen, C1-6alkyl, C6-10aryl, and C3-6cycloalkyl, wherein each C1-6 alkyl, C6-10 aryl, or C3-6 cycloalkyl may be optionally substituted by one or more substituents independently selected from halo, C1-6 alkyl, haloC1-6 alkyl, C1-6 alkoxy, and haloC1-6 alkoxy;
• and
• Ra and Rb are each independently hydrogen, C1-6 alkyl or C6-10 aryl.