Process and new intermediates for the preparation of 11-methylene steroids

Abstract

A process for the preparation of 11-methylene steroids from di-keto steroids involves selective olefination of the ketone at position 11 of the di-keto steroids. The resulting 11-methylene steroid products can be used as intermediates in the preparation of the synthetic steroids, Etonogestrel and Desogestrel, as well as other pharmaceutically active agents.

Claims

1. A process for the preparation of a compound of formula (I), or a solvate thereof ##STR00077## wherein X represents H or it forms together with the carbon atom to which it is bonded a ketone protecting group; Y together with the carbon atom to which it is bonded represents C═CH.sub.2 or C(OH)CH.sub.2Z, wherein Z is selected from H and SiR′.sub.3 wherein each R′ is independently selected from C.sub.1-C.sub.6 alkyl and C.sub.6-C.sub.10 aryl; R.sup.6 is selected from H, C.sub.1-C.sub.6 alkyl and halogen; R.sup.10 is selected from H, C.sub.1-C.sub.6 alkyl and halogen, or is absent when there is a double bond between C.sub.1 and C.sub.10; R.sup.13 is selected from H and C.sub.1-C.sub.6 alkyl; R.sup.16 is selected from H, C.sub.1-C.sub.6 alkyl and halogen; - - - is a single or double bond; which comprises reacting a compound of formula (II) or a solvate thereof ##STR00078## wherein X, R.sup.6, R.sup.10, R.sup.13, R.sup.16, and - - - have the meanings defined above; with a compound of formula (III) ##STR00079## wherein Z is selected from H and SiR′.sub.3 wherein each R′ is independently selected from C.sub.1-C.sub.6 alkyl and C.sub.6-C.sub.10 aryl and M is selected from Li, MgBr, MgCl and Mgl.

2. The process according to claim 1, wherein R.sup.6, R.sup.10, R.sup.16 are H; and R.sup.13 is selected from C.sub.1-C.sub.6 alkyl.

3. The process according to claim 1, wherein Z represents a SiR′.sub.3 group wherein each R′ is independently selected from C.sub.1-C.sub.6 alkyl and C.sub.6-C.sub.10 aryl.

4. The process according to claim 1, wherein Y together with the carbon atom to which it is bonded represents C═CH.sub.2.

5. The process according to claim 4, which comprises: (a) reacting a compound of formula (II), or a solvate thereof, with a compound of formula (III) to obtain a compound of formula (I), or a solvate thereof, wherein Y together with the carbon atom to which it is bonded represents a C(OH)CH.sub.2Z group, wherein Z is selected from H and SiR′.sub.3, wherein each R′ is independently selected from C.sub.1-C.sub.6 alkyl and C.sub.6-C.sub.10 aryl; and (b) treating a compound of formula (I), or a solvate thereof, wherein Y together with the carbon atom to which it is bonded represents a C(OH)CH.sub.2Z group, wherein Z is selected from H and SiR′.sub.3, wherein each R′ is independently selected from C.sub.1-C.sub.6 alkyl and C.sub.6-C.sub.10 aryl, with an acid or a base to obtain a compound of formula (I), or a solvate thereof, wherein Y together with the carbon atom to which it is bonded represents C═CH.sub.2.

6. The process according to claim 1, which further comprises ethynylating the compound of formula (I), or a solvate thereof, to obtain a compound of formula (IV), or a solvate thereof ##STR00080## wherein Y, R.sup.6, R.sup.10, R.sup.13, R.sup.16 and - - - are as defined in claim 1; X represents H or it forms together with the carbon atom to which it is bonded a ketone group or a ketone protecting group; and R.sup.1 is selected from H and SiR″.sub.3, wherein each R″ is independently selected from C.sub.1-C.sub.6 alkyl, C.sub.6-C.sub.10 aryl and halogen.

7. The process according to claim 6, which comprises: (a) reacting a compound of formula (II), or a solvate thereof, with a compound of formula (III) to obtain a compound of formula (I), or a solvate thereof, wherein Y together with the carbon atom to which it is bonded represents a C(OH)CH.sub.2Z group, wherein Z is selected from H and SiR′.sub.3 wherein each R′ is independently selected from C.sub.1-C.sub.6 alkyl and C.sub.6-C.sub.10 aryl; (b) treating a compound of formula (I), or a solvate thereof, wherein Y together with the carbon atom to which it is bonded represents a C(OH)CH.sub.2Z group, wherein Z is selected from H and SiR′.sub.3, wherein each R′ is independently selected from C.sub.1-C.sub.6 alkyl and C.sub.6-C.sub.10 aryl, with an acid or a base to obtain a compound of formula (I), or a solvate thereof, wherein Y together with the carbon atom to which it is bonded represents C═CH.sub.2; and (c) ethynylating a compound of formula (I), or a solvate thereof, wherein Y together with the carbon atom to which it is bonded represents C═CH.sub.2, to obtain a compound of formula (IV), or a solvate thereof, wherein Y together with the carbon atom to which it is bonded represents C═CH.sub.2.

8. The process according to claim 7, which comprises: (a) reacting a compound of formula (II), or a solvate thereof, with a compound of formula (III) to obtain a compound of formula (I), or a solvate thereof, wherein Y together with the carbon atom to which it is bonded represents a C(OH)CH.sub.2Z group, wherein Z is selected from H and SiR′.sub.3, wherein each R′ is independently selected from C.sub.1-C.sub.6 alkyl and C.sub.6-C.sub.10 aryl; (b) ethynylating a compound of formula (I), or a solvate thereof, wherein Y together with the carbon atom to which it is bonded represents a C(OH)CH.sub.2Z group, wherein Z is selected from H and SiR′.sub.3 wherein each R′ is independently selected from C.sub.1-C.sub.6 alkyl and C.sub.6-C.sub.10 aryl, to obtain a compound of formula (IV), or a solvate thereof, wherein Y together with the carbon atom to which it is bonded represents a C(OH)CH.sub.2Z group, wherein Z is selected from H and SiR′.sub.3 wherein each R′ is independently selected from C.sub.1-C.sub.6 alkyl and C.sub.6-C.sub.10 aryl; and (c) treating a compound of formula (IV), or a solvate thereof, wherein Y together with the carbon atom to which it is bonded represents a C(OH)CH.sub.2Z group, wherein Z is selected from H and SiR′.sub.3, wherein each R′ is independently selected from C.sub.1-C.sub.6 alkyl and C.sub.6-C.sub.10 aryl, with an acid or a base to obtain a compound of formula (IV), or a solvate thereof, wherein Y together with the carbon atom to which it is bonded represents C═CH.sub.2.

9. A process for the preparation of Desogestrel, Etonogestrel, or a solvate thereof, the process comprising: preparing a compound of formula (I) or a solvate thereof ##STR00081## wherein X represents H or it forms together with the carbon atom to which it is bonded a ketone protecting group; Y together with the carbon atom to which it is bonded represents C═CH.sub.2 or C(OH)CH.sub.2Z, wherein Z is selected from H and SiR′.sub.3 wherein each R′ is independently selected from C.sub.1-C.sub.6 alkyl and C.sub.6-C.sub.10 aryl; R.sup.6 is selected from H, C.sub.1-C.sub.6 alkyl and halogen; R.sup.10 is selected from H, C.sub.1-C.sub.6 alkyl and halogen, or is absent when there is a double bond between C.sub.1 and C.sub.10;R.sup.13 is selected from H and C.sub.1-C.sub.6 alkyl; R.sup.16 is selected from H, C.sub.1-C.sub.6 alkyl and halogen; - - - is a single or double bond; by reacting a compound of formula (II) or a solvate thereof ##STR00082## wherein X, R.sup.6, R.sup.10, R.sup.13, R.sup.16, and - - - have the meanings defined above; with a compound of formula (III) ##STR00083## wherein Z is selected from H and SiR′.sub.3 wherein each R′ is independently selected from C.sub.1-C.sub.6 alkyl and C.sub.6-C.sub.10 aryl and M is selected from Li, MgBr, MgCI and MgI; and converting the compound of formula (I), or a solvate thereof to Desogestrel, Etonogestrel, or a solvate thereof.

10. The process according to claim 9, wherein converting to Etonogestrel, or a solvate thereof, comprises the following steps: (a) reacting a compound of formula (IIa), or a solvate thereof, ##STR00084## wherein X forms together with the carbon atom to which it is bonded a ketone protecting group; and - - - is a single or double bond; with a compound of formula (III) ##STR00085## wherein M is selected from Li, MgBr, MgCl and MgI; and Z is selected from H and SiR′.sub.3 wherein each R′ is independently selected from C.sub.1-C.sub.6 alkyl and C.sub.6-C.sub.10 aryl; to afford a compound of formula (Ia-1) or a solvate thereof ##STR00086## (b) treating a compound of formula (Ia-1), or a solvate thereof, with an acid or a base to afford a compound of formula (Ia-2), or a solvate thereof, ##STR00087## (c) ethynylating a compound of formula (Ia-2), or a solvate thereof, to afford a compound of formula (IVa-1), or a solvate thereof ##STR00088## wherein X forms together with the carbon atom to which it is bonded a ketone group or a ketone protecting group R.sup.1 is selected from H and SiR″.sub.3, wherein each R″ is independently selected from C.sub.1-C.sub.6 alkyl, C.sub.6-C.sub.10 aryl and halogen; and (d) if necessary, carrying out one or both of the following steps in any order: (i) if X forms together with the carbon atom to which it is bonded a ketone protecting group, cleavage of the ketone protecting group to afford a compound of formula (IVa-1), or a solvate thereof, wherein X forms together with the carbon atom to which it is bonded a ketone group, (ii) if R.sup.1 is a SiR″.sub.3 group, removal of the SiR″.sub.3 group to afford a compound of formula (IVa-1), or a solvate thereof, wherein R.sup.1 is H.

11. The process according to claim 9, wherein converting to Etonogestrel, or a solvate thereof, comprises the following steps: (a) reacting a compound of formula (IIa), or a solvate thereof, ##STR00089## wherein X forms together with the carbon atom to which it is bonded a ketone protecting group; and - - - is a single or double bond; with a compound of formula (III) ##STR00090## wherein M is selected from Li, MgBr, MgCl and MgI; and Z is selected from H and SiR′.sub.3 wherein each R′ is independently selected from C.sub.1-C.sub.6 alkyl and C.sub.6-C.sub.10 aryl; to afford a compound of formula (Ia-1), or a solvate thereof, ##STR00091## (b) ethynylating a compound of formula (Ia-1), or a solvate thereof, to afford a compound of formula (IVa-2), or a solvate thereof ##STR00092## wherein R.sup.1 is selected from H and SiR″.sub.3, wherein each R″ is independently selected from C.sub.1-C.sub.6 alkyl, C.sub.6-C.sub.10 aryl and halogen; (c) treating a compound of formula (IVa-2), or a solvate thereof, with an acid or a base to afford a compound of formula (IVa-1), or a solvate thereof ##STR00093## wherein X forms together with the carbon atom to which it is bonded a ketone group or a ketone protecting group R.sup.1 is selected from H and SiR″.sub.3, wherein each R″ is independently selected from C.sub.1-C.sub.6 alkyl, C.sub.6-C.sub.10 aryl and halogen; and (d) if necessary, carrying out one or both of the following steps in any order: (i) if X forms together with the carbon atom to which it is bonded a ketone protecting group, cleavage of the ketone protecting group to afford a compound of formula (IVa-1), or a solvate thereof, wherein X forms together with the carbon atom to which it is bonded a ketone group, (ii) if R.sup.1 is a SiR″.sub.3 group, removal of the SiR″.sub.3 group to afford a compound of formula (IVa-1), or a solvate thereof, wherein R.sup.1 is H.

12. The process according to claim 9, wherein converting to Desogestrel, or a solvate thereof, comprises the following steps: (a) reacting compound (12), or a solvate thereof, ##STR00094## with a compound of formula (III) ##STR00095## wherein M is selected from Li, MgBr, MgCl and MgI; and Z is selected from H and SiR′.sub.3 wherein each R′ is independently selected from C.sub.1-C.sub.6 alkyl and C.sub.6-C.sub.10 aryl; to afford a compound of formula (Ib-1) or a solvate thereof ##STR00096## (b) treating a compound of formula (Ib-1), or a solvate thereof, with an acid or a base to afford a compound of formula (Ib-2), or a solvate thereof, ##STR00097## (c) ethynylating a compound of formula (Ib-2), or a solvate thereof, to afford a compound of formula (IVb-1), or a solvate thereof ##STR00098## wherein R.sup.1 is selected from H and SiR″.sub.3, wherein each R″ is independently selected from C.sub.1-C.sub.6 alkyl, C.sub.6-C.sub.10 aryl and halogen; and (d) if R.sup.1 is a SiR″.sub.3 group, removing SiR″.sub.3 group to afford Desogestrel, or a solvate thereof.

Description

EXAMPLES

Example 1

Synthesis of 18-methyl-estra-4-en-3,11,17-trione (2—Swern Oxidation)

(1) ##STR00059##

(2) Oxalyl chloride was added to 540 mL of DCM at −20° C. The solution was cooled down at −45° C. and then DMSO (63 mL) diluted in 450 mL of DCM was dropwise added keeping the temperature below −35° C. After addition was complete, the reaction mixture was stirred 20 min at −40° C. Then, 45 g of compound 1 dissolved in 450 mL of DCM were then added keeping the temperature below −35° C. The reaction mixture was kept at −40° C. for 30 min, then DIPEA (235 mL) was quickly added and the cold bath removed allowing to warm up to room temperature (1.5 h). 675 mL of 3.3% solution of acetic acid were added and the aqueous phase was separated. The organic phase was washed with 315 mL of a solution of NaHCO.sub.3 7%, separated and concentrated under vacuum to a volume of 150 mL. 150 mL of IPA were added and reduced the volume to 150 mL. The operation was repeated two more times to reach a final volume of 150 mL. The resulting suspension was stirred in an ice bath for 30 min and then filtered, the solid was washed with 45 mL of cold IPA and dried under vacuum at 40° C. 39.8 g of compound 2 were obtained as white solid (yield=89.5%).

Example 2

Synthesis of 18-methyl-estra-4-en-3,11,17-trione (2—Parikh-Doering Oxidation)

(3) 15 g of compound 1 were dissolved in 40 mL of DMSO and then 71 mL of TEA were added. The solution was heated at 30° C., and a solution of SO.sub.3Py (79 g) in 70 mL of DMSO were added. The reaction mixture was stirred at 30° C. for 3 h, and then poured over a solution of 117 mL of glacial acetic acid in 234 mL of water forming a precipitate. The suspension was cooled in an ice bath for 1 h, and filtered. The solid was suspended in 80 mL of IPA and heated to complete dissolution and then cooled down at 0° C. The resulting solid was filtered and dried under vacuum at 40° C. to yield 13 g of compound 2 (81%).

Example 3

Synthesis of Compound 3 (Ketone Protection)

(4) ##STR00060##

(5) 18 g of compound 2 were dissolved in 140 mL of THF, then 30 mL of TEOF and 900 mg of pTsOH were added. The reaction mixture was stirred at 25° C. for 3 h. Then 2 mL of TEA were added, and 90 mL of solution of NaHCO.sub.3 7%. The aqueous phase was extracted with 50 mL EtOAc. The combined organic phases were concentrated until a wet solid was obtained, 90 mL of ethanol were added and concentrated to a volume of 40 mL, cooled in an ice bath and filtered. The solid was washed with 90 mL of cold ethanol and dried under vacuum at 40° C., to yield 14.7 g of compound 3 (75%).

Example 4

Synthesis of Compound 4 (Peterson Olefination)

(6) ##STR00061##

(7) 10 g of compound 3 were dissolved in 50 mL of THF and cooled down at −40° C. Then 88 mL of trimethylsilyl methyl lithium were slowly added, keeping the temperature below −35° C., and the mixture stirred for 1 h further after addition was complete. Then 200 mL of solution of NaHCO.sub.3 7% were added, separated and the aqueous phase was extracted with 100 mL EtOAc. The combined organic phases were concentrated to 30 mL, 30 mL of ethanol were added and the solvent was evaporated to a final volume of 30 mL. The operation was repeated two more times, then the suspension was cooled in an ice bath for 1h. The solid was filtered, washed with 10 mL of cold ethanol and dried under vacuum at 40° C., to yield 10.4 g of compound 4 (83% yield).

(8) .sup.1H NMR (400 MHz, CDCl.sub.3): δ 0.09 (s, 9H); 0.82 (t, 3H); 1.17-1.39 (m, 10H); 1.63-1.66 (m, 1H); 1.68-1.72 (m, 1H); 1.84-1.87 (m, 2H); 1.92-2.12 (m, 3H); 2.21-2.35 (d, 3H); 2.39-2.51 (m, 4H); 3.69-3.79(m, 2H); 5.19 (s, 1H) 5.31 (d, 1H).

(9) .sup.13C NMR (100 MHz, CDCl.sub.3): δ 1.1; 8.4; 14.7; 18.5; 21.3; 29.2; 30.7; 31.2; 35.1; 35.6; 37.1; 38.4; 43.4; 50.7; 51.5; 53.3; 62.4; 100.1; 117.3; 137.8; 156.2; 218.8.

Example 5

Synthesis of Compound 5 (Ethynylation Reaction)

(10) ##STR00062##

(11) To a solution of hexillithium (76 mL) in heptane (100 mL) cooled at 0° C., a solution of trimethylsilyl acetylene (30 mL) in 100 ml of a mixture of THF/heptanes ⅓ was slowly added. The reaction mixture was stirred at 0° C. for 30 min, then a solution of compound 4 (10 g) in 100 mL of THF was added and the mixture stirred for 1h further. Water (200 mL) was added to quench the excess of lithium reagent and the organic phase concentrated under vacuum. The residue (containing 85% of compound 5 and 15% of compound 4, maximum level of conversion obtained) was purified on silica gel with EtOAc/heptanes 1/9, affording pure compound 5 as an oil.

(12) .sup.1H NMR (400 MHz, CDCl.sub.3): δ 0.07 (s, 9H); 0.12 (s, 9H) 0.83-0.85 (m, 1H); 1.12-1.18 (m, 5H); 1.22-1.28 (m, 6H); 1.33-1.38 (m, 3H); 1.58-1.66 (m, 4H); 1.91 (d, 1H); 1.98-2.09 (m, 3H); 2.17 (d, 1H); 2.27-2.36 (m, 4H); 3.68-3.77(m, 2H); 5.18 (s, 1H) 5.29 (d, 1H).

(13) .sup.13C (100 MHz, CDCl.sub.3): δ 1.1; 8.4; 14.7; 18.5; 21.3; 29.2; 30.7; 31.2; 35.1; 35.6; 37.1; 38.4; 43.4; 50.7; 51.5; 53.3; 62.4; 100.1; 117.3; 137.8; 156.2; 218.8.

Example 6

Synthesis of Etonogestrel (Ethynylation Reaction)

(14) ##STR00063##

(15) 1.9 g of compound 4 were dissolved in 19 mL of THF, cooled down at 0° C. and 30 mL of LaCl.sub.3*2LiCl were added, followed by slow addition of ethynylmagnesium chloride (120 mL) keeping the temperature below 10° C. After 15 h, 2.5 mL of TEA and 250 mL of solution of NaHCO.sub.3 7% were added. The aqueous phase was extracted with EtOAc 50 mL×2, and the combined organic phases were washed with brine. The solvent was evaporated under reduced pressure to a volume of 20 mL and 40 mL of methanol were added. It was concentrated to 20 mL and repeated twice. The final methanol solution was treated with 2 mL of HCl, stirred at 25° C. for 1 h, and 2 mL of solution of NaHCO.sub.3 7% were added. Addition of 1 mL of water promoted the precipitation of a solid. It was filtered, washed with 4 mL of water and dried under vacuum at 40° C., yielding 2 g of crude Etonogestrel as brown solid (hplc purity 94%).

Example 7

Synthesis of Etonogestrel (One-Pot Ethynylation/Deprotection)

(16) ##STR00064##

(17) To a solution of hexillithium (65 mL) in heptane (100 mL) cooled at −5° C., a solution of trimethylsilyl acetylene (26 mL) in 100 ml of a mixture of THF/heptanes ⅓ was slowly added. The reaction mixture was stirred at −5° C. for 30 min, then a solution of compound 4 (10 g) in 100 mL of THF/heptanes 1:1 was added and the mixture stirred for 15h further. Water (200 mL) was added to quench the excess of lithium reagent and the organic phase concentrated under vacuum. The residue (containing 90% of compound 5 and 10% of compound 4) was dissolved in 50 mL of methanol, 0.5 mL of HCl were added and stirred 1 h at 20° C., followed by addition of 3 mL of NaOH 50% and stirring for 1 h further. The solvent was evaporated under reduced pressure, the residue dissolved in 100 mL of DCM. It was washed first with a solution of glacial acetic acid 3% and then with a solution of NaHCO.sub.3 7%. The crude obtained was dissolved in 30 mL of acetone, concentrated to a volume of 12 mL and 12 mol of IPA were added with further reduction of the volume of 50%. The operation was repeated twice. The suspension was cooled in an ice bath and the solid filtered, washed with 4 mL of cold IPA and dried at 40° C. under vacuum, to yield 2.1 g of Etonogestrel.

Example 8

Synthesis of Compound 6 (Peterson Elimination/Deprotection)

(18) ##STR00065##

(19) The residue obtained following Example 5 was dissolved in 20 mL of methanol and 2 mL of solution of HCl were added. The reaction mixture was stirred at 25° C. for 1 h, the solvent was then evaporated, 50 mL of water were added and the mixture extracted with 50 mL of EtOAc. The crude product was purified on silica gel with EtOAc/heptanes 1/9, affording pure compound 6 as a white solid.

Example 9

Synthesis of Compound 7 (TMS Deprotection)

(20) ##STR00066##

(21) The residue obtained following Example 5 was dissolved in 20 mL of methanol and 2 mL of solution of NaOH 30% were added. The reaction mixture was stirred at 25° C. for 1 h, the solvent was then evaporated, 50 mL of water were added and the mixture extracted with 50 mL of EtOAc. The crude product was purified on silica gel with EtOAc/heptanes 1/9, affording pure compound 7 as an orange oil.

Example 10

Synthesis of Etonogestrel (TMS Deprotection)

(22) ##STR00067##

(23) 1 g of compound 6 was dissolved in 10 mL of acetone and then distilled up to a volume of 4 mL. 4 mL of IPA were added and concentrated up to a volume of 4 mL. The operation was repeated three times. The solution was then cooled at 0° C., filtered and washed with 2 mL of IPA. The solid was dried under vacuum to afford pure etonogestrel.

Example 11

Synthesis of Compound 8 (Ketone Protection)

(24) ##STR00068##

(25) Compound 2 (28 g) was dissolved in DCM (280 mL), then 14 mL of 1,2-ethanedithiol and 1.4 g of pTsOH were added. The reaction mixture was refluxed for 5 h, 50 mL of DCM were distilling every hour (and adding fresh solvent). 140 mL of solution of NaHCO.sub.3 7% were added and the aqueous phase extracted with 50 mL of DCM. The combined organic phases were concentrated under vacuum to a final volume of 150 mL. 150 mL of methanol were added and concentrated under reduced pressure to a final volume of 100 mL. The obtained suspension was cooled in an ice bath for 1 h. The resulting solid was filtered, washed with 25 mL of cold methanol and dried under vacuum at 40° C., to yield 30 g of compound 8.

Example 12

Synthesis of Compound 9 (Peterson Olefination)

(26) ##STR00069##

(27) Compound 8 (20 g) was dissolved in THF (100 mL) and cooled at 0° C. Then 640 mL of trimethylsilyl mehtyl lithium were slowly added, keeping the temperature below 10° C. and the mixture was stirred for 1h further after addition was complete. Then, 300 mL of solution of NaH.sub.4Cl 12% were added, separated and the aqueous phase was extracted with 100 mL of EtOAc. The combined organic phases were concentrated to a volume of 100 mL and the suspension was cooled with an ice bath for 1h. The resulting solid was filtered, washed with 30 mL of cold EtOAc and dried under vacuum at 40° C., to yield 11 g of compound 9 (43%).

Example 13

Synthesis of Compound 10 (Peterson Elimination)

(28) ##STR00070##

(29) 11 g of compound 10 were dissolved in 35 mL of methanol and 0.5 ml of HCl were added, the reaction mixture was stirred at 25° C. for 1 h. After adjusting the pH to 6 and adding TEA, the suspension was cooled in an ice bath. The resulting precipitate was filtered, washed with 10 mL of methanol and dried under vacuum at 40° C., affording 7.8 g of compound 11 (88%).

Example 14

Synthesis of Compound 11 (Ethynylation Reaction)

(30) ##STR00071##

(31) 7.0 g of compound 10 were dissolved in 35 mL of THF, cooled down at 10° C. and 46 mL of LaCl.sub.3*2LiCl were added, followed by slow addition of ethynylmagnesium chloride (159 mL) keeping the temperature below 15° C. After the addition was completed, the reaction mixture was heated for 2h at 30° C. Then cooled down at 5° C. and 150 mL of a solution 10% HCl were added. The aqueous phase was extracted with 50 mL of EtOAc, and the combined organic phases were washed with brine. The solvent was evaporated under reduced pressure to a volume of 40 mL and 40 mL of heptane were added. It was concentrated to 40 mL and repeated twice. The obtained suspension was cooled in an ice bath for 1 h. The solid was filtered, washed with 10 mL of cold heptane and dried under vacuum at 40° C., to yield 5.8 g of compound 11 (77%).

Example 15

Synthesis of Etonoqestrel (Ketone Deprotection)

(32) ##STR00072##

(33) Thioacetal was removed using periodic acid, as described in example 8A in WO 2013/135744, or using SIBX as described in example 8C in WO 2013/135744.

Example 16

Synthesis of Compound 14 (Peterson Olefination)

(34) ##STR00073##

(35) Compound 12 (10 g) was dissolved in THF (50 mL) and cooled at 0° C. Then, 330 mL of trimethylsilyl methyl lithium were slowly added, keeping the temperature below 10° C. and the mixture stirred for 1.5 h further after addition was complete. Then, 150 mL of solution of NaH.sub.4Cl 12% were added, separated and the aqueous phase was extracted with 50 mL EtOAc. The combined organic phases were concentrated to a volume of 20 mL, and the suspension was cooled with an ice bath for 1 h. The resulting solid was filtered, dissolved in 20 mL of methanol, and 0.25 ml of HCl were added. The reaction mixture was stirred at 25° C. for 1.5 h. After adjusting the pH to 6 and adding TEA, the suspension was cooled in an ice bath. The precipitate was filtered, washed with 5 mL of methanol and dried under vacuum at 40° C., affording 7.6 g of compound 14 (76%).

Example 17

Synthesis of Desogestrel (Ethynylation Reaction)

(36) ##STR00074##

(37) To a solution of hexillithium (3.0 g 2.3 M in hexane) in hexane (5 mL) cooled at −5° C., a solution of trimethylsilyl acetylene (1.32 g) in 6.8 mL of a mixture of THF/hexane 1/7 was slowly added. The reaction mixture was stirred at −5° C. for 30 min, then a solution of compound 14 (1.0 g) in 8 mL of hexane was added and the mixture stirred for 1 h at 0/5° C. Aqueous NaCl solution (8.5 mL) was added and the phases were separated. The organic phase was mixed with 5 mL of methanol, followed by addition of 1.5 mL of aqueous NaOH 30% and stirred for 4 h further. 10 mL of an aqueous solution of 3% Acetic acid was added. The phases were separated and the organic phase was washed with water (5.0 mL). The solvent was evaporated under reduced pressure and the residue dissolved in 1 mL of MeOH. The solvent was evaporated under reduced pressure and the residue dissolved in 2 mL of Hexane. The crude obtained was dissolved in 4 mL of hexane by heating at 60° C. The solution was cooled slowly in an ice bath and the resulting solid filtered, washed with 1 mL of cold hexane and dried at 40° C. under vacuum, to yield 0.89 g of Desogestrel (89%).

Example 18

Synthesis of Compound 15 (Methylation)

(38) ##STR00075##

(39) 200 mg of compound 3 were dissolved in 1.0 mL of THF. Then 1.0 mL of methyl magnesium chloride (22%) were slowly added, heating the mixture at reflux for 3h. The reaction was quenched with TEA. Then a solution of NaHCO.sub.3 7% was added and the aqueous phase was extracted with EtOAc. The crude product was purified on silica gel, affording compound 15 (75%) and the compound of di-methylation 16 (24%).

(40) .sup.13C NMR (100 MHz, CDCl.sub.3): δ 8.3; 14.6; 18.5; 21.1; 29.2; 30.4; 33.8; 34.5; 35.5; 37.2; 43.2; 50.7; 51.8; 52.9; 62.3; 73.5; 100.1; 117.0; 137.7; 156.1; 219.2.

Example 19

Synthesis of Compound 15 (Methylation)

(41) ##STR00076##

(42) 200 mg of compound 3 were dissolved in 1.0 mL of THF and cooled at 0° C. Then 2.2 mL of Methyl Lithium (3%) were slowly added and stirred the mixture for 3h at 0° C. The reaction was quenched with TEA. Then a solution of NaHCO.sub.3 7% was added, and the aqueous phase was extracted with EtOAc. The crude product was purified on silica gel, affording compound 15 (76%) and the compound of di-methylation 16 (23%).