58652-20-3

Usage

Uses

Used in Hormone Replacement Therapy:
Nomegestrol 17-acetate is used as a progesterone substitute in implantable hormone replacement therapies. It helps to alleviate symptoms associated with hormonal imbalances, such as those experienced during menopause or in cases of certain medical conditions.
Used in Contraception:
Nomegestrol 17-acetate is also utilized as a contraceptive agent, where it works to prevent ovulation and thus, the possibility of pregnancy. Its progestin properties make it an effective component in various contraceptive formulations, including oral contraceptives and implantable devices.

InChI:InChI=1/C23H30O4/c1-13-11-20-18(17-6-5-16(26)12-19(13)17)7-9-22(4)21(20)8-10-23(22,14(2)24)27-15(3)25/h11-12,17-18,20-21H,5-10H2,1-4H3/t17-,18-,20-,21+,22+,23+/m1/s1

Synthetic route

17α-acetoxy-6-methylene-19-norpregn-4-ene-3,20-dione (58652-19-0) → nomegestrol acetate (58652-20-3)

Conditions	Yield
With [Rh(Binap)2]+[ClO4]- In tetrahydrofuran at 80℃; for 0.5h; Solvent; Temperature; Sealed tube; Inert atmosphere;	99%
With palladium 10% on activated carbon; acetic acid In ethanol at 72 - 75℃; for 0.166667h; Temperature; Inert atmosphere; Large scale;	90.2%
With 5%-palladium/activated carbon In tetrahydrofuran; ethanol for 0.75h; Reflux;	77%

C23H32O4 → nomegestrol acetate (58652-20-3)

Conditions	Yield
With chloranil In 1,4-dioxane at 90 - 95℃; Solvent; Temperature;	77.8%

17α-hydroxy-3-methoxy-19-norpregna-1,3,5(10)-trien-20-one (1624-58-4) → nomegestrol acetate (58652-20-3)

Conditions

Yield

Multi-step reaction with 8 steps 1: toluene-4-sulfonic acid; trimethyl orthoformate / dichloromethane / 2 h / 20 °C 2: sodium; ammonia / ethanol; water; tetrahydrofuran; tert-butyl alcohol / -60 °C / Inert atmosphere 3: hydrogenchloride / water; tetrahydrofuran / 0.33 h / 60 °C 4: toluene-4-sulfonic acid / 24 h / 20 °C 5: toluene-4-sulfonic acid / tetrahydrofuran / 24 h / 20 °C 6: trichlorophosphate / -10 °C 7: sodium tetrahydroborate / methanol / 20 °C 8: 5%-palladium/activated carbon / ethanol; tetrahydrofuran / 0.75 h / Reflux View Scheme

20,20-(ethylenedioxy)-3-methoxy-17α-hydroxy-19-norpregna-1,3,5(10)-triene (14328-46-2) → nomegestrol acetate (58652-20-3)

Conditions

Yield

Multi-step reaction with 7 steps 1: sodium; ammonia / ethanol; water; tetrahydrofuran; tert-butyl alcohol / -60 °C / Inert atmosphere 2: hydrogenchloride / water; tetrahydrofuran / 0.33 h / 60 °C 3: toluene-4-sulfonic acid / 24 h / 20 °C 4: toluene-4-sulfonic acid / tetrahydrofuran / 24 h / 20 °C 5: trichlorophosphate / -10 °C 6: sodium tetrahydroborate / methanol / 20 °C 7: 5%-palladium/activated carbon / ethanol; tetrahydrofuran / 0.75 h / Reflux View Scheme

17-alpha-Hydroxy-19-norprogesterone (2137-18-0) → nomegestrol acetate (58652-20-3)

Conditions	Yield
Multi-step reaction with 5 steps 1: toluene-4-sulfonic acid / 24 h / 20 °C 2: toluene-4-sulfonic acid / tetrahydrofuran / 24 h / 20 °C 3: trichlorophosphate / -10 °C 4: sodium tetrahydroborate / methanol / 20 °C 5: 5%-palladium/activated carbon / ethanol; tetrahydrofuran / 0.75 h / Reflux View Scheme

Estrone (53-16-7) → nomegestrol acetate (58652-20-3)

Conditions

Yield

Multi-step reaction with 12 steps 1.1: sodium hydroxide / acetone; water / 2 h / Reflux 2.1: potassium tert-butylate / tetrahydrofuran / 0 - 20 °C 3.1: triethylamine / dichloromethane / 2 h / 0 - 20 °C 4.1: sodium methylate / methanol / Reflux 4.2: 2 h / Reflux 5.1: toluene-4-sulfonic acid; trimethyl orthoformate / dichloromethane / 2 h / 20 °C 6.1: sodium; ammonia / ethanol; water; tetrahydrofuran; tert-butyl alcohol / -60 °C / Inert atmosphere 7.1: hydrogenchloride / water; tetrahydrofuran / 0.33 h / 60 °C 8.1: toluene-4-sulfonic acid / 24 h / 20 °C 9.1: toluene-4-sulfonic acid / tetrahydrofuran / 24 h / 20 °C 10.1: trichlorophosphate / -10 °C 11.1: sodium tetrahydroborate / methanol / 20 °C 12.1: 5%-palladium/activated carbon / ethanol; tetrahydrofuran / 0.75 h / Reflux View Scheme

17α-acetoxy-19-norpregna-4-ene-3,20-dione (31981-44-9) → nomegestrol acetate (58652-20-3)

Conditions	Yield
Multi-step reaction with 4 steps 1: toluene-4-sulfonic acid / tetrahydrofuran / 24 h / 20 °C 2: trichlorophosphate / -10 °C 3: sodium tetrahydroborate / methanol / 20 °C 4: 5%-palladium/activated carbon / ethanol; tetrahydrofuran / 0.75 h / Reflux View Scheme
Multi-step reaction with 4 steps 1: orthoformic acid triethyl ester; toluene-4-sulfonic acid / dichloromethane / 25 - 30 °C 2: sodium hydroxide; dihydrogen peroxide / methanol / 20 - 25 °C 3: magnesium / chloroform; diethyl ether / 30 - 55 °C 4: chloranil / 1,4-dioxane / 90 - 95 °C View Scheme
Multi-step reaction with 4 steps 1: orthoformic acid triethyl ester; toluene-4-sulfonic acid / dichloromethane / 25 - 30 °C 2: sodium hydroxide; dihydrogen peroxide / methanol / 20 - 25 °C 3: magnesium / tetrahydrofuran / 30 - 55 °C 4: chloranil / 1,4-dioxane / 90 - 95 °C View Scheme
Multi-step reaction with 4 steps 1: orthoformic acid triethyl ester; toluene-4-sulfonic acid / dichloromethane / 25 - 30 °C 2: sodium hydroxide; dihydrogen peroxide / methanol / 20 - 25 °C 3: magnesium / toluene / 30 - 55 °C 4: chloranil / 1,4-dioxane / 90 - 95 °C View Scheme

3-ethoxy-17α-acetoxy-19-norpregna-3,5-diene-20-one → nomegestrol acetate (58652-20-3)

Conditions	Yield
Multi-step reaction with 3 steps 1: trichlorophosphate / -10 °C 2: sodium tetrahydroborate / methanol / 20 °C 3: 5%-palladium/activated carbon / ethanol; tetrahydrofuran / 0.75 h / Reflux View Scheme

6-formyl-3-ethoxy-17α-acetoxy-19-norpregna-3,5-diene-20-one (147508-40-5) → nomegestrol acetate (58652-20-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium tetrahydroborate / methanol / 20 °C 2: 5%-palladium/activated carbon / ethanol; tetrahydrofuran / 0.75 h / Reflux View Scheme

estrone 3-methyl ether (1624-62-0) → nomegestrol acetate (58652-20-3)

Conditions

Yield

Multi-step reaction with 11 steps 1.1: potassium tert-butylate / tetrahydrofuran / 0 - 20 °C 2.1: triethylamine / dichloromethane / 2 h / 0 - 20 °C 3.1: sodium methylate / methanol / Reflux 3.2: 2 h / Reflux 4.1: toluene-4-sulfonic acid; trimethyl orthoformate / dichloromethane / 2 h / 20 °C 5.1: sodium; ammonia / ethanol; water; tetrahydrofuran; tert-butyl alcohol / -60 °C / Inert atmosphere 6.1: hydrogenchloride / water; tetrahydrofuran / 0.33 h / 60 °C 7.1: toluene-4-sulfonic acid / 24 h / 20 °C 8.1: toluene-4-sulfonic acid / tetrahydrofuran / 24 h / 20 °C 9.1: trichlorophosphate / -10 °C 10.1: sodium tetrahydroborate / methanol / 20 °C 11.1: 5%-palladium/activated carbon / ethanol; tetrahydrofuran / 0.75 h / Reflux View Scheme

C22H32O4 → nomegestrol acetate (58652-20-3)

Conditions	Yield
Multi-step reaction with 6 steps 1: hydrogenchloride / water; tetrahydrofuran / 0.33 h / 60 °C 2: toluene-4-sulfonic acid / 24 h / 20 °C 3: toluene-4-sulfonic acid / tetrahydrofuran / 24 h / 20 °C 4: trichlorophosphate / -10 °C 5: sodium tetrahydroborate / methanol / 20 °C 6: 5%-palladium/activated carbon / ethanol; tetrahydrofuran / 0.75 h / Reflux View Scheme

mestranol (72-33-3) → nomegestrol acetate (58652-20-3)

Conditions

Yield

Multi-step reaction with 10 steps 1.1: triethylamine / dichloromethane / 2 h / 0 - 20 °C 2.1: sodium methylate / methanol / Reflux 2.2: 2 h / Reflux 3.1: toluene-4-sulfonic acid; trimethyl orthoformate / dichloromethane / 2 h / 20 °C 4.1: sodium; ammonia / ethanol; water; tetrahydrofuran; tert-butyl alcohol / -60 °C / Inert atmosphere 5.1: hydrogenchloride / water; tetrahydrofuran / 0.33 h / 60 °C 6.1: toluene-4-sulfonic acid / 24 h / 20 °C 7.1: toluene-4-sulfonic acid / tetrahydrofuran / 24 h / 20 °C 8.1: trichlorophosphate / -10 °C 9.1: sodium tetrahydroborate / methanol / 20 °C 10.1: 5%-palladium/activated carbon / ethanol; tetrahydrofuran / 0.75 h / Reflux View Scheme

3-methoxy-21-(phenylsulfinyl)-19-norpregna-1(2),3(4),5(10),17(20),20-pentaene → nomegestrol acetate (58652-20-3)

Conditions

Yield

Multi-step reaction with 9 steps 1.1: sodium methylate / methanol / Reflux 1.2: 2 h / Reflux 2.1: toluene-4-sulfonic acid; trimethyl orthoformate / dichloromethane / 2 h / 20 °C 3.1: sodium; ammonia / ethanol; water; tetrahydrofuran; tert-butyl alcohol / -60 °C / Inert atmosphere 4.1: hydrogenchloride / water; tetrahydrofuran / 0.33 h / 60 °C 5.1: toluene-4-sulfonic acid / 24 h / 20 °C 6.1: toluene-4-sulfonic acid / tetrahydrofuran / 24 h / 20 °C 7.1: trichlorophosphate / -10 °C 8.1: sodium tetrahydroborate / methanol / 20 °C 9.1: 5%-palladium/activated carbon / ethanol; tetrahydrofuran / 0.75 h / Reflux View Scheme

C26H38O6 → nomegestrol acetate (58652-20-3)

Conditions	Yield
Multi-step reaction with 3 steps 1: sodium hydroxide; dihydrogen peroxide / methanol / 20 - 25 °C 2: magnesium / tetrahydrofuran / 30 - 55 °C 3: chloranil / 1,4-dioxane / 90 - 95 °C View Scheme
Multi-step reaction with 3 steps 1: sodium hydroxide; dihydrogen peroxide / methanol / 20 - 25 °C 2: magnesium / toluene / 30 - 55 °C 3: chloranil / 1,4-dioxane / 90 - 95 °C View Scheme
Multi-step reaction with 3 steps 1: sodium hydroxide; dihydrogen peroxide / methanol / 20 - 25 °C 2: magnesium / chloroform; diethyl ether / 30 - 55 °C 3: chloranil / 1,4-dioxane / 90 - 95 °C View Scheme

C26H38O7 → nomegestrol acetate (58652-20-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: magnesium / tetrahydrofuran / 30 - 55 °C 2: chloranil / 1,4-dioxane / 90 - 95 °C View Scheme
Multi-step reaction with 2 steps 1: magnesium / toluene / 30 - 55 °C 2: chloranil / 1,4-dioxane / 90 - 95 °C View Scheme

nomegestrol acetate (58652-20-3) → 6-α-methyl-3,20-dioxo-19-norpregna-4-en-17-yl acetate (32420-14-7)

Conditions	Yield
With palladium 10% on activated carbon In ethanol; cyclohexane for 3h; Reflux;	71%
With 5%-palladium/activated carbon; cyclohexene In ethanol for 2h; Reflux;	34%

nomegestrol acetate (58652-20-3) → (3R,3aS,5aS,5bR,8'R,8aR,9R,9'S,10'R,12aR,12bS,13'S,14'S,17'R)-3,17'-diacetyl-3a,13'-dimethyl-3',8-dioxo-1',2,2',3,3',3a,4,5,5a,5b,6,7,7',8,8',8a,9',10,10',11,11',12,12',12a,12b, 13',14',15',16',17'-triacontahydro-1H-spiro[benzo[fg]cyclopenta[a]anthracene-9,6'-cyclopenta[a]phenanthrene]-3,17'-diyl diacetate + (3R,3aS,5aS,5bR,8'R,8aR,9S,9'S,10'R,12aR,12bS,13'S,14'S,17'R)-3,17'-diacetyl-3a,13'-dimethyl-3',8-dioxo-1',2,2',3,3',3a,4,5,5a,5b,6,7,7',8,8',8a,9',10,10',11,11',12,12',12a,12b, 13',14',15',16',17'-triacontahydro-1H-spiro[benzo[fg]cyclopenta[a]anthracene-9,6'-cyclopenta[a]phenanthrene]-3,17'-diyl diacetate

Conditions	Yield
In toluene for 12h; Inert atmosphere; Reflux;	A 0.41 g B 2.5 g

Upstream product

• 1624-58-4 17α-hydroxy-3-methoxy-19-norpregna-1,3,5(10)-trien-20-one 
• 14328-46-2 20,20-(ethylenedioxy)-3-methoxy-17α-hydroxy-19-norpregna-1,3,5(10)-triene 
• 2137-18-0 17-alpha-Hydroxy-19-norprogesterone 
• 53-16-7 Estrone 
• 31981-44-9 17α-acetoxy-19-norpregna-4-ene-3,20-dione 
• 147508-40-5 6-formyl-3-ethoxy-17α-acetoxy-19-norpregna-3,5-diene-20-one 
• 58652-19-0 17α-acetoxy-6-methylene-19-norpregn-4-ene-3,20-dione 
• 1624-62-0 estrone 3-methyl ether 
• 72-33-3 mestranol 

Downstream Products

• 32420-14-7 6-α-methyl-3,20-dioxo-19-norpregna-4-en-17-yl acetate 

Relevant academic research and scientific papers

Preparation method of nomegestrol acetate

The invention relates to the field of organic synthesis, in particular to a preparation method of nomegestrol acetate. The preparation method for nomegestrol acetate comprises a step of subjecting a compound represented by a formula 5 to a reaction in the presence of a catalyst to prepare a compound represented by a formula 1, wherein the catalyst is selected from an Rh-Binap catalyst. According to the preparation method of the nomegestrol acetate, the Rh-Binap catalyst is innovatively used for preparing the nomegestrol acetate, the method is mild in reaction conditions and easy to operate, and the catalyst used in the reaction can be recycled and reused simply and repeatedly.

Preparation method of nomegestrol acetate

The invention discloses a preparation method of nomegestrol acetate. The method comprises that gestonorone acetate as a raw material is dissolved in an organic solvent and then undergoes a reaction with ethylene glycol under acid catalysis in the presence of triethyl orthoformate to produce diketal, the diketal is dissolved in an organic solvent and undergoes a reaction with hydrogen peroxide under alkali catalysis to produce an epoxy compound, the epoxy compound is dissolved in an organic solvent and undergoes a Grignard addition reaction with methylmagnesium halide, the reaction product is hydrolyzed in a strong acid solution and is subjected to dehydration deprotection so that a methyl compound is obtained, and the methyl compound is dissolved in an organic solvent and undergoes a dehydrogenation reaction with tetrachloro-p-benzoquinone to produce nomegestrol acetate. The nomegestrol acetate has HPLC content of 99.0-99. 5% and a four-step synthesis total yield of 60-62%. Compared with the traditional method, the method has the advantages of simple and convenient operation, economy, environmental friendliness, high total synthesis yield and good product quality and reduces a costby 35-40%. The solvent used by the method can be recovered and recycled and is conducive to industrial production.

INDUSTRIAL PROCESS FOR THE SYNTHESIS OF NOMEGESTROL-ACETATE

The invention relates to the last step of a synthetic process, in which Nomegestrol- acetate of formula (I) is synthesized from 17α-acetoxy-6-methylene-19-norpregn-4-ene-3,20-dione of formula (II) in the presence of Pd/C catalyst and acetic acid in hot ethanolic solution.

An improved synthesis of nomegestrol acetate

Oral contraceptives (OCs) are synthetic steroids, or progestins, which are structurally related to testosterone or to progesterone. Many progestins have been synthesized and approved for OCs, hormonal replacement therapy (HRT), or the treatment of some gynecological disorders. Nomegestrol acetate (NOMAc) is a newly approved OC and has gained rapid acceptance in many countries for OC or HRT. The synthesis of NOMAc remains challenging and costly. We have developed a novel and improved procedure for the synthesis of NOMAc with a total of 11 steps and an overall good yield without the use of hazardous reagents.

Subcutaneous implants based on normegestrol derivatives

Subcutaneous implant for preventing conception for at least one year in women comprising an amount effect to prevent conception without suppressing intermontly bleeding of a steroid compound of formula I or formula II and a physiologically-tolerable pharmaceutical carrier.

Process for crystallizing the organic substances from steroidal origin and the thus obtained compounds

A process for crystallizing a pharmaceutically active steroidal product, without mechanical procedure, to obtain a homogeneous granulometric class which may be prepared beforehand, wherein the product which is desired to be crystallized is dissolved in a ternary mixture made of a lipophilic solvent, a hydrophilic solvent and a surface active agent at a temperature close to the boiling point of the mixture of solvents and wherein the mixture of solvents is allowed to revert to a temperature where the crystallization initiates, then, the thus-formed crystals are recovered.