60282-87-3

Usage

Uses

Used in Pharmaceutical Industry:
Gestodene is used as an orally active gestogen with a progesterone-like profile of activity for the development of oral contraceptives. It is combined with estrogen to create a contraceptive that helps regulate the menstrual cycle and prevent pregnancy.
Used in Hormonal Regulation:
Gestodene is used as a progestogen hormonal agent to help regulate the menstrual cycle during the childbearing years. Estrogens and progestins, including gestodene, are female hormones that are necessary for the normal sexual development of the female and for the regulation of the menstrual cycle.

InChI:InChI=1/C21H26O2/c1-3-20-11-9-17-16-8-6-15(22)13-14(16)5-7-18(17)19(20)10-12-21(20,23)4-2/h2,10,12-13,16-19,23H,3,5-9,11H2,1H3/t16-,17+,18+,19-,20-,21-/m0/s1

Synthetic route

3,3-(2',2'-dimethyl-1',3'-propylenedioxy)-17α-ethnyl-17β-hydroxy-18-methyl-5,15-estradiene → gestodene (60282-87-3)

Conditions	Yield
With hydrogenchloride In acetone at 20℃; for 0.75h;	90%

17α-ethynyl-18-methyl-3,3-(2',2'-dimethyl-1',3'-propylenedioxy)-5,15-estradien-17β-ol (64133-14-8) + 3,3-(2',2'-dimethyl-1',3'-propylenedioxy)-17α-ethnyl-17β-hydroxy-18-methyl-10,15-estradiene → gestodene (60282-87-3)

Conditions	Yield
Stage #1: 17α-ethynyl-18-methyl-3,3-(2',2'-dimethyl-1',3'-propylenedioxy)-5,15-estradien-17β-ol; 3,3-(2',2'-dimethyl-1',3'-propylenedioxy)-17α-ethnyl-17β-hydroxy-18-methyl-10,15-estradiene With water; hydrogenchloride In acetone at 20℃; for 0.75h; Stage #2: With sodium hydrogencarbonate In water; acetone pH=7; Product distribution / selectivity;	90%

3-ethoxy-18-methyl-estra-3,5,15-trien-17-one (1323980-05-7) + acetylenemagnesium bromide (4301-14-8) → gestodene (60282-87-3)

Conditions	Yield
Stage #1: 3-ethoxy-18-methyl-estra-3,5,15-trien-17-one; acetylenemagnesium bromide In tetrahydrofuran; 2-MeTHF at 20 - 25℃; for 2h; Stage #2: With hydrogenchloride In ethanol; water at 7 - 10℃; for 2h;	80%

17α-Ethinyl-3,3-ethylendithio-18-methyl-4,15-estradien-17β-ol (74177-02-9) → gestodene (60282-87-3)

Conditions	Yield
With calcium carbonate; methyl iodide In methanol; water for 20h; Heating;	68%

ethylene glycol (107-21-1) + 15α-Acetoxy-18-methyl-4-estren-3,17-dion (104933-97-3) + acetylene (74-86-2) → gestodene (60282-87-3)

Conditions	Yield
Yield given. Multistep reaction;

18-Methyl-4,15-estradien-3,17-dion (77410-09-4) + acetylene (74-86-2) → gestodene (60282-87-3)

Conditions	Yield
With n-butyllithium 1.) THF/hexane, -70 deg C, 10 min, 2.) -70 deg C, 1 h; Yield given. Multistep reaction;

15α-Acetoxy-3-methoxy-18-methyl-3,5-estradien-17-on (104934-00-1) + acetylene (74-86-2) → gestodene (60282-87-3)

Conditions	Yield
Yield given. Multistep reaction;

13β-ethyl-gon-4-en-3,17-dione (21800-83-9) → gestodene (60282-87-3)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: 90 percent / triethyl orthoformate; p-TsOH / CH2Cl2 / 3 h / 10 °C 2.1: t-BuOK / tetrahydrofuran / 0.17 h / 20 °C 2.2: tetrahydrofuran / 2 h / 20 °C 3.1: Et3N / xylene / 2.5 h / 140 °C 4.1: 94 percent / tetrahydrofuran / 2 h / 0 °C 5.1: 90 percent / aq. HCl / acetone / 0.75 h / 20 °C View Scheme
Multi-step reaction with 6 steps 1: 90 percent / triethyl orthoformate; p-TsOH / CH2Cl2 / 3 h / 10 °C 2: LDA / tetrahydrofuran; hexamethylphosphoric acid triamide / 2 h / -78 - 20 °C 3: MCPBA / CH2Cl2 / 0.5 h / -78 °C 4: Et3N / xylene / 2.5 h / 140 °C 5: 94 percent / tetrahydrofuran / 2 h / 0 °C 6: 90 percent / aq. HCl / acetone / 0.75 h / 20 °C View Scheme
Multi-step reaction with 3 steps 1: 77.2 percent / mushroom Penicillium raistrickii (ATCC 10490) / H2O; various solvent(s) / 70 h / 30 °C 2: 96 percent / pyridine / 1 h View Scheme

3,3-(2',2'-dimethyl-1',3'-propylenedioxy)-18-methyl-5,15-estradien-17-one → gestodene (60282-87-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: 94 percent / tetrahydrofuran / 2 h / 0 °C 2: 90 percent / aq. HCl / acetone / 0.75 h / 20 °C View Scheme

18-methyl-3,3-(2',2'-dimethyl-1',3'-propylenedioxy)-5-estern-17-one → gestodene (60282-87-3)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: t-BuOK / tetrahydrofuran / 0.17 h / 20 °C 1.2: tetrahydrofuran / 2 h / 20 °C 2.1: Et3N / xylene / 2.5 h / 140 °C 3.1: 94 percent / tetrahydrofuran / 2 h / 0 °C 4.1: 90 percent / aq. HCl / acetone / 0.75 h / 20 °C View Scheme
Multi-step reaction with 5 steps 1: LDA / tetrahydrofuran; hexamethylphosphoric acid triamide / 2 h / -78 - 20 °C 2: MCPBA / CH2Cl2 / 0.5 h / -78 °C 3: Et3N / xylene / 2.5 h / 140 °C 4: 94 percent / tetrahydrofuran / 2 h / 0 °C 5: 90 percent / aq. HCl / acetone / 0.75 h / 20 °C View Scheme

C30H40O3S → gestodene (60282-87-3)

Conditions	Yield
Multi-step reaction with 4 steps 1: MCPBA / CH2Cl2 / 0.5 h / -78 °C 2: Et3N / xylene / 2.5 h / 140 °C 3: 94 percent / tetrahydrofuran / 2 h / 0 °C 4: 90 percent / aq. HCl / acetone / 0.75 h / 20 °C View Scheme

3,3-(2',2'-dimethyl-1',3'-propylenedioxy)-18-methyl-16ξ-phenylsulfoxide-5-estren-17-one → gestodene (60282-87-3)

Conditions	Yield
Multi-step reaction with 3 steps 1: Et3N / xylene / 2.5 h / 140 °C 2: 94 percent / tetrahydrofuran / 2 h / 0 °C 3: 90 percent / aq. HCl / acetone / 0.75 h / 20 °C View Scheme

15α-Hydroxy-18-methyl-4-estren-3,17-dion (60919-46-2) → gestodene (60282-87-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: 96 percent / pyridine / 1 h View Scheme
Multi-step reaction with 3 steps 1: 96 percent / pyridine / 1 h 2: 84 percent / 4-CH3-C6H6-SO3H*C5H5N / 6 h / Heating View Scheme
Multi-step reaction with 5 steps 1: 98 percent / BF3*Et2O / methanol / Ambient temperature 2: pyridine / 3.5 h / 0 °C 3: NaOAc / pyridine; dimethylformamide / 20 h / Ambient temperature 4: 1.) 15 percent BuLi / 1.) hexane, THF, 0 deg C, 2.) 30 min 5: 68 percent / CH3I, CaCO3 / methanol; H2O / 20 h / Heating View Scheme
Multi-step reaction with 3 steps 1: pyridine / 3.5 h / 0 °C 2: NaOAc / pyridine; dimethylformamide / 20 h / Ambient temperature 3: 1.) 15 percent BuLi / 1.) THF/hexane, -70 deg C, 10 min, 2.) -70 deg C, 1 h View Scheme

3,3-Ethylendithio-18-methyl-4,15-estradien-17-on (74177-01-8) → gestodene (60282-87-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: 1.) 15 percent BuLi / 1.) hexane, THF, 0 deg C, 2.) 30 min 2: 68 percent / CH3I, CaCO3 / methanol; H2O / 20 h / Heating View Scheme

3,3-Ethylendithio-15α-hydroxy-18-methyl-4-estren-17-on (74177-00-7) → gestodene (60282-87-3)

Conditions	Yield
Multi-step reaction with 4 steps 1: pyridine / 3.5 h / 0 °C 2: NaOAc / pyridine; dimethylformamide / 20 h / Ambient temperature 3: 1.) 15 percent BuLi / 1.) hexane, THF, 0 deg C, 2.) 30 min 4: 68 percent / CH3I, CaCO3 / methanol; H2O / 20 h / Heating View Scheme

15α-Acetoxy-18-methyl-4-estren-3,17-dion (104933-97-3) → gestodene (60282-87-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: 84 percent / 4-CH3-C6H6-SO3H*C5H5N / 6 h / Heating View Scheme
Multi-step reaction with 3 steps 1.1: toluene-4-sulfonic acid / ethanol / 1 h / 20 °C 2.1: toluene-4-sulfonic acid; orthoformic acid triethyl ester / 1 h / 20 °C 2.2: 2 h / 40 °C 3.1: tetrahydrofuran; 2-MeTHF / 2 h / 20 - 25 °C 3.2: 2 h / 7 - 10 °C View Scheme

Methanesulfonic acid (8R,9S,10R,13S,14S,15S)-13-ethyl-3,17-dioxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-15-yl ester (104934-02-3) → gestodene (60282-87-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: NaOAc / pyridine; dimethylformamide / 20 h / Ambient temperature 2: 1.) 15 percent BuLi / 1.) THF/hexane, -70 deg C, 10 min, 2.) -70 deg C, 1 h View Scheme

C22H32O4S3 (104934-03-4) → gestodene (60282-87-3)

Conditions	Yield
Multi-step reaction with 3 steps 1: NaOAc / pyridine; dimethylformamide / 20 h / Ambient temperature 2: 1.) 15 percent BuLi / 1.) hexane, THF, 0 deg C, 2.) 30 min 3: 68 percent / CH3I, CaCO3 / methanol; H2O / 20 h / Heating View Scheme

15α-Acetoxy-3-methoxy-18-methyl-3,5-estradien-17-on (104934-00-1) → gestodene (60282-87-3)

Conditions	Yield
Product distribution / selectivity;

ethyl bromide (74-96-4) + acetylene (74-86-2) → gestodene (60282-87-3)

Conditions	Yield
With oxalic acid; magnesium In tetrahydrofuran; methanol; water

15α-acetoxy-3-ethoxy-18-methyl-estra-3,5-dien-17-one (106620-51-3) → gestodene (60282-87-3)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: toluene-4-sulfonic acid; orthoformic acid triethyl ester / 1 h / 20 °C 1.2: 2 h / 40 °C 2.1: tetrahydrofuran; 2-MeTHF / 2 h / 20 - 25 °C 2.2: 2 h / 7 - 10 °C View Scheme

15α-Acetoxy-18-methyl-4-estren-3,17-dion (104933-97-3) + acetylene (74-86-2) → gestodene (60282-87-3)

Conditions	Yield
Stage #1: 15α-Acetoxy-18-methyl-4-estren-3,17-dion With hydrogenchloride; propylene glycol In 1,4-dioxane; 1,2-dimethoxyethane at -20℃; for 4h; Stage #2: With toluene-4-sulfonic acid; trimethyl orthoformate In methanol at 20℃; for 3h; Stage #3: acetylene Further stages;	8.17 g

gestodene (60282-87-3) → 17α-Bromethinyl-17β-hydroxy-18-methyl-4,15-oestradien-3-on (91781-31-6)

Conditions	Yield
With N-Bromosuccinimide; silver nitrate In acetone for 0.25h; Ambient temperature;	82%

gestodene (60282-87-3) → 17β-Hydroxy-17α-iodethinyl-18-methyl-4,15-oestradien-3-on (91798-46-8)

Conditions	Yield
With N-iodo-succinimide; silver nitrate In acetone for 0.25h; Ambient temperature;	77%

gestodene (60282-87-3) → 13-β-ethyl-18,19-dinorpregna-4,14,16-trien-3,20-dione

Conditions	Yield
With hydrogenchloride at 80℃; for 2h;	1.55 g

gestodene (60282-87-3) → gestodene propionate

Conditions	Yield
With 4-pyrrolidin-1-ylpyridine In pyridine; (2S)-N-methyl-1-phenylpropan-2-amine hydrate; dichloromethane; propionic acid anhydride

pentanoic anhydride (2082-59-9) + gestodene (60282-87-3) → gestodene valerate

Conditions	Yield
With 4-pyrrolidin-1-ylpyridine In pyridine; water

gestodene (60282-87-3) + 1-hexadecylcarboxylic acid (57-10-3) + trifluoroacetic anhydride (407-25-0) → 17α-ethynyl-17β-hexadecanoyloxy-18-methyl-4,15-estradien-3-one

Conditions	Yield
With sodium hydroxide In dichloromethane; acetone; benzene

undecylenic acid (112-37-8) + gestodene (60282-87-3) + trifluoroacetic anhydride (407-25-0) → 17α-ethynyl-18-methyl-17β-undecanoyloxy-4,15-estradien-3-one

Conditions	Yield
In benzene

gestodene (60282-87-3) + trifluoroacetic anhydride (407-25-0) → 17α-ethynyl-18-methyl-17β-octanoyloxy-4,15-estradien-3-one

Conditions	Yield
In dichloromethane; acetone; benzene

gestodene (60282-87-3) → 17β-acetoxy-17α-ethynyl-18-methyl-4,15-estradien-3-one

Conditions	Yield
With acetic anhydride In 2,3,5-trimethyl-pyridine; hydrogenchloride

Upstream product

• 107-21-1 ethylene glycol 
• 104933-97-3 15α-Acetoxy-18-methyl-4-estren-3,17-dion 
• 74-86-2 acetylene 
• 74177-02-9 17α-Ethinyl-3,3-ethylendithio-18-methyl-4,15-estradien-17β-ol 
• 77410-09-4 18-Methyl-4,15-estradien-3,17-dion 
• 104934-00-1 15α-Acetoxy-3-methoxy-18-methyl-3,5-estradien-17-on 
• 106620-51-3 15α-acetoxy-3-ethoxy-18-methyl-estra-3,5-dien-17-one 
• 1323980-05-7 3-ethoxy-18-methyl-estra-3,5,15-trien-17-one 
• 4301-14-8 acetylenemagnesium bromide 
• 74-96-4 ethyl bromide 
• 64133-14-8 17α-ethynyl-18-methyl-3,3-(2',2'-dimethyl-1',3'-propylenedioxy)-5,15-estradien-17β-ol 
• 104934-03-4 C₂₂H₃₂O₄S₃ 
• 104934-02-3 Methanesulfonic acid (8R,9S,10R,13S,14S,15S)-13-ethyl-3,17-dioxo-2,3,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-15-yl ester 
• 74177-00-7 3,3-Ethylendithio-15α-hydroxy-18-methyl-4-estren-17-on 

Downstream Products

• 932388-88-0 13-β-ethyl-18,19-dinorpregna-4,14,16-trien-3,20-dione 

Relevant academic research and scientific papers

A simple synthesis of gestodene from 18-methyl-4-estren-3,17-dione

A simple synthesis enables us to obtain the progestin, gestodene, in five steps and satisfactory yields from 18-methyl-4-estren-3,17-dione. This was accomplished through the selective protection of the C-3 carbonyl group as a cyclic ketal and the installation of a phenylsulfoxide group at the C-16 position.

One kind is used in the midbody of dienone the synthesis is pregnant and its preparation method and application (by machine translation)

This invention relates to a kind of the dienone the synthesis is pregnant intermediates for preparation method and application thereof. The intermediate has the following chemical structure of formula: R in the general formula is selected from the following group of substituents: or wherein: R 1 to C 1-C 3 of the straight-chain alkane, R 2 to C 4-C 6 of the straight-chain alkane. The dihydric alcohol preparation is through intermediate of the 13 β-ethyl -15 α-acetoxy-gonanes-4-ene -3, 17-dione for 3-carbonyl selective protection reaction to obtain the. Gestodene intermediate synthesis using the method, comprising the following reaction route: Intermediates provided by the invention, not only can improve the quality of gestodene, but also can reduce the production cost of gestodene, and mild reaction conditions, selectivity of raw materials and more flexible, and the raw materials is simple and easy to obtain, is apt to meet the requirement of mass production. (by machine translation)

Process for the preparation of gestodene

The invention relates to a process for the preparation of a compound of formula (I) : wherein R1 and R2 are as defined in the description, by reaction of a compound of formula (II) with a base. Compound (I) is an intermediate useful in the preparation of gestodene.

Process for the preparation of delta(15-16)-17-ketosteroids and use thereof in the synthesis of pharmacologically active compounds

A process is described for the preparation of Δ15-16-17-ketosteroids of the formula in which the substituents have the meaning stated in the description, which process comprises a) the reaction of a 17-ketosteroid of the formula with diphenyl disulfide in the presence of a strong base, b) the subsequent oxidation reaction of the intermediate 16-phenyl sulfide to the sulfoxide and c) the sulfoxide elimination reaction to yield the Δ15-16―17-ketosteroid compound of the formula (6). Said process is preferably applied to the synthesis of gestodene.

Pharmaceutical combined preparation, kit and method for hormonal contraception

PCT No. PCT/DE96/01192 Sec. 371 Date Jun. 3, 1998 Sec. 102(e) Date Jun. 3, 1998 PCT Filed Jun. 27, 1996 PCT Pub. No. WO97/01342 PCT Pub. Date Jan. 16, 1997The present invention describes a two-stage pharmaceutical combined preparation for hormonal contraception containing at least 30 daily unit doses, which preparation, in its first stage, comprises as hormonal active ingredient a combination of an oestrogen preparation and, in a dose that is at least sufficient to inhibit ovulation, a gestagen preparation, in single stage form and, in the second stage comprises as hormonal active ingredient an oestrogen preparation only, wherein the first stage comprises a minimum of 25 and a maximum of 77 daily discrete or continuous unit doses and the second stage comprises 5, 6 or 7 daily discrete or continuous unit doses, and wherein the total number of daily units is equal to the total number of days of the desired cycle of a minimum of 30 and a maximum of 84 days. This combined preparation, in the form of a monthly pack, which is used for female fertility control, permits as low as possible an oestrogen content in each individual unit dose and also has a low total hormone content per cycle of administration, with high contraceptive reliability, low incidence of follicle development, and satisfactory cycle control with reliable avoidance of intermediate bleeding as well as undesired side effects.

Pharmaceutical combination preparation for hormonal contraception

The invention provides a pharmaceutical combination preparation with two hormone components in a packaging unit and intended for time-sequential oral administration, comprising a number of daily dosage units physically separate and individually removable in the packaging unit, whereby as a hormonal active ingredient a first hormone component contains in combination an estrogen preparation and in at least a dosage that is sufficient to inhibit ovulation a gestagen preparation, and as a hormonal active ingredient the second hormone component contains only an estrogen preparation, whereby the first hormone component comprises 23 or 24 daily units and the second hormone component comprises 4, 3 or 2 daily units, and between these two hormone components, 2 or 1 active ingredient-free daily units are present or 2 or 1 blank pill days are indicated, and the total number of hormone daily units and the active ingredient-free daily units or the blank pill days is equal to the total number of days of the desired cycle, but at least 28 days in length. This combination preparation is useful for female birth control, and allows for an estrogen content that is as low as possible in each individual dosage unit and also has a low total hormone content per administration cycle, with high contraceptive reliability, low incidence of follicular development, and satisfactory cycle control, with reliable avoidance of intracyclic menstrual bleeding as well as of undesirable side-effects.

Process for the preparation of gestodene

Disclosed is a process for the preparation of Gestodene (formula I) from (-)estra-1,3,5(10),8-tetraen-3-methoxy-18-methyl-17β-hydroxy. STR1

Pharmaceutical combination preparation for hormonal contraception

A pharmaceutical combination preparation with two hormone components that are manufactured physically separately in a packaging unit and that are intended for time-sequential oral administration, which in each case consist of a number of daily dosage units that are placed physically separately and are individually removable in the packaging unit. As a hormonal active ingredient, a first hormone component contains in combination an estrogen preparation and, in at least a dosage that is sufficient to inhibit ovulation, a gestagen preparation, and as a hormonal active ingredient the second hormone component contains only an estrogen preparation. The first hormone component comprises 23 or 24 daily units and the second hormone component comprises 4 to 10 daily units. The total number of hormone daily units is equal to the total number of days of the desired cycle, but at least 28 days in length. This combination preparation is used for female birth control, and allows for an estrogen content that is as low as possible in each individual dosage unit and also has a low total hormone content per administration cycle, with high contraceptive reliability, low incidence of follicular development, and satisfactory cycle control, with reliable avoidance of intracyclic menstrual bleeding as well as of undesirable side-effects.

Process for the preparation of gestodene

Process for preparing Gestodene from (-)estra-1,3,5(10),8-tetraen-3-methoxy-18-methyl-17β-hydroxy, comprising the following steps: a) hydrogenation of the double bond in 8(Li in liquid NH3 in presence of aniline); b) hydrogenation of a double bond of the aromatic ring (Li in liquid NH3 in presence of ter.butanol); c) hydrolysis of the methoxyl in 3 with introduction of a ketonic group and transposition of the double bond from 5-10 to 4-5; d) conversion of the ketonic group in 3 to acetalic group and transposition of the double bond from 4-5 to 5-6 (or 5-10); e) oxydation of the hydroxyl in 17 to a ketonic group; f) formation of a double bond in 15-16 by oxidation with Pd(II) acetate after transformation to sililenolether; g) ethynylation in position 17 with Li acetilide; h) hydrolysis of the acetalic group of position 3.