WO2013001322A1 - PROCESS FOR THE SYNTHESIS OF (5α,17β)-N-[(2,5-BIS(TRIFLUOROMETHYL)-PHENYL]-3-OXO-4-AZA-5-ANDROST-1-ENE-17-CARBOXAMIDE - Google Patents

PROCESS FOR THE SYNTHESIS OF (5α,17β)-N-[(2,5-BIS(TRIFLUOROMETHYL)-PHENYL]-3-OXO-4-AZA-5-ANDROST-1-ENE-17-CARBOXAMIDE Download PDF

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WO2013001322A1
WO2013001322A1 PCT/HU2012/000057 HU2012000057W WO2013001322A1 WO 2013001322 A1 WO2013001322 A1 WO 2013001322A1 HU 2012000057 W HU2012000057 W HU 2012000057W WO 2013001322 A1 WO2013001322 A1 WO 2013001322A1
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aza
oxo
formula
acid
ene
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PCT/HU2012/000057
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English (en)
French (fr)
Inventor
Béla SÖRÖS
Zoltán Tuba
György GÁLIK
Sándor MAHÓ
László BALOGH
Péter VINCZE
János HORVÁTH
András Kovács
Zoltán BÉNI
Frigyes VARGA
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Richter Gedeon Nyrt.
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Publication of WO2013001322A1 publication Critical patent/WO2013001322A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J75/00—Processes for the preparation of steroids in general
    • C07J75/005—Preparation of steroids by cyclization of non-steroid compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/16—Preparation of carboxylic acids or their salts, halides or anhydrides by oxidation
    • C07C51/31—Preparation of carboxylic acids or their salts, halides or anhydrides by oxidation of cyclic compounds with ring-splitting
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
    • C07J7/0005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21
    • C07J7/001—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group
    • C07J7/0015—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group not substituted in position 17 alfa
    • C07J7/002—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group not substituted in position 17 alfa not substituted in position 16
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J73/00—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms
    • C07J73/001—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom
    • C07J73/005—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom by nitrogen as hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
    • C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
    • C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
    • C07C2603/12—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings only one five-membered ring
    • C07C2603/16—Benz[e]indenes; Hydrogenated benz[e]indenes

Definitions

  • the present invention relates to a process for the synthesis of the known (5a, 17 ⁇ )- ⁇ - [(2,5-bis(trifluoromethyl)-phenyl]-3-oxo-4-aza-5-androst-1 -ene-17-carboxamide of formula (I) (known as dutasteride)
  • Dutasteride belongs to the group of 5a-reductase inhibitors, inhibiting the reduction of the ⁇ 4 double bond in steroids containing the 3- ⁇ - ⁇ 4 structure in mammalian tissues.
  • type 1 and type 2 5a-reductase enzymes take part.
  • the tissue distribution of these two enzymes is different, the type 2 enzyme occurs predominantly in the urogenital system, whereas the type 1 can be found predominantly in the skin, the brain and the liver tissues. In the mentioned tissues the other type enzyme can also occur in minor quantities.
  • DHT dihydrotestosterone
  • tissues sensible to androgens e.g. prostate, skin tissue
  • the mediator responsible for the androgen activity is the DHT, which is locally synthesized from testosterone delivered by the blood circulation.
  • the increased tissue-concentration of DHT plays a main role in the development and sustaining of several androgen-dependent illnesses. Such androgen-dependent illness is e.g.
  • BPH benignus prostate hyperplasia
  • prostate carcinoma the acne, the seborrhea, a female hirsutismus and the androgen alopecia.
  • Those compounds, which inhibit the steroid 5a-reductase enzyme and this way reducing the quantity of DHT in the tissues, are suitable for the treatment of these DHT dependent illnesses.
  • the treatment of the benignus prostate hyperplasia is a particularly important task.
  • the DHT problem is relevant for 50-70% of the male population over 50 and its probability increases with the age and can reach 100% at the age of 80.
  • the inhibition of the 5a-reductase enzyme it is possible to influence selectively the pathography caused by the prostate hyperplasia without the symptoms of testosterone deficiency (gynaecomastia, impotency).
  • dutasteride of formula (I) which differ from each other firstly in the starting materials and the sequence of the reaction steps.
  • the methods applied for the introduction of the different functional groups in the individual reaction steps are usually well known for an expert in the art.
  • the goal of the first syntheses was to produce the quantity of the compound or compounds necessary for the pharmacological investigations as well as in case of advantageous biological results to insure the data necessary for the patent application. But the fulfillment of the purity requirements of the compounds necessary for the therapy made further developments necessary. The introduction of an economic industrial process can be achieved only via the further development of the original process or processes.
  • the NalO 4 KMnO 4 /K 2 CO 3 reagent, used in tert-butanol for the oxidative cleavage of the "A" ring of ⁇ , ⁇ -unsaturated ketones, e.g. the ring cleavage of 3-oxo-A 4 -steroids, into seco acids is a well known method (see e.g. the US patent No. 3,644,421 ).
  • Example 2 of the international patent WO 95/07927 the researchers of Glaxo used (5a,17p)-3-oxo-4-aza-5-androst-1-ene-17-carboxylic acid as starting material, which was made anhydrous by distillation with toluene, then the 17p-carboxylic acid was converted into its acid chloride as described above and this was amidated with 2,5-bis(trifluoromethyl)-aniline. The final product was recrystallized from methanol.
  • the unsaturated 3-oxo-4-aza-androst-5-ene-N-[2,5-bis(trifluoromethyl)-phenyl]-17- carboxamide derivative was hydrogenated in acetic acid in the presence of PtO 2 as catalyst at 60-70°C for 6 h and subsequently it was converted into dutasteride using 2,3-dichloro-5,6-dicyano-1 ,4-benzoquinone and N,O-bis(trimethylsilyl)- trifluoroacetamide in dioxane for dehydrogenation.
  • the US patent No. 5,998,427 describes a synthesis starting from 3-oxo- androst-4-ene-17 -carboxylic acid, according to which first the 17-amide substituent of the D-ring was built via the amidation of the already described activated carboxylic acid. This was followed by the oxidation of the ⁇ , ⁇ -unsaturated "A"-ring, the amidation of the obtained seco compound with ammonia and its cyclisation. The B- ring of the obtained unsaturated lactam was hydrogenated using known methods and its "A"-ring was subsequently dehydrogenated.
  • the international patent WO 2002/46207 deals mainly with the stereoselective reduction of the unsaturated lactams and uses such additives as ammonium acetate, ammonium dihydrogenphosphate and tetramethyl-ethylenediamine.
  • the hydrogenation was carried out in acetic acid at 60°C using PtO 2 as catalyst.
  • ammonium acetate instead of ammonia for the ring closure of the A-seco acid and the reaction was performed in acetic acid instead of ethylene glycol at reflux temperature. At this temperature the reaction was complete after 3 h.
  • the starting steps of the synthesis were identical with those already described.
  • the 3-oxo-androst-4-ene-17p-carboxylic acid was oxidized according to the known method using sodium metaperiodate in the presence of potassium permanganate and potassium carbonate applying tert- butanol/water as solvent, then the cyclization was carried out in ethylene glycol with ammonia at 180°C. Hydrogenation of the obtained 3-oxo-4-aza-androst-5-ene-17p- carboxylic acid was carried out in acetic acid in the presence of Pt0 2 as catalyst. The saturated 4-aza-steroid was converted into its ester and the ring "A" was dehydrogenated using phenylselenic acid anhydride in chlorobenzene.
  • the so obtained unsaturated lactam was hydrogenated in acetic acid using PtO 2 as catalyst and the free carboxylic acid was converted into its methyl ester before introduction of the ⁇ 1 double bond by phenyl-selenic acid. Thereafter the protecting group was hydrolyzed and the free carboxylic acid was treated in toluene with 2,2-dipyridyl-disulfide in the presence of triphenyl-phosphine.
  • the final step of the synthesis the amidation of the active ester with 2,5-bis(trifluoromethyl)-aniline in the presence of silver trifluoromethanesulfonate was published in J. Med. Chem. 38 3189-92 (1995).
  • the starting material was again the (5a,17p)-3-oxo-4-aza-5-androst-1- ene-17-carboxylic acid, which was first made anhydrous via an azeotropic distillation with toluene and then it was converted into the corresponding acid chloride with thionyl chloride in pyridine as described above and the latter was converted into "carboximide” with ammonia in the same mixture, then purified in a separate step.
  • the xylene solution of the obtained compound was dried in the presence of potassium carbonate with azeotropic distillation, then it was treated with 2-iodo-1 ,4- bis(trifluoromethyl)-benzene in the presence of copper powder at 140-150°C for 50- 60 h and the final compound was obtained after purification in two steps.
  • the next step of their synthesis was the activation of the 17 -carboxylic acid and the amidation of the obtained acid chloride with ammonia, resulting in the corresponding 17p-carboxamide, which was coupled with 2-iodo-1 ,4- bis(trifluoromethyl)-benzene in o-xylene in the presence of copper powder at 140- 150°C using sodium carbonate as base.
  • the US2007/0173523 A1 patent application describes the synthesis of finasteride in a different way.
  • the (5a,17p)-3-oxo-4-aza-5-androstane-17-carboxylic acid was activated with 1 ,1 '-carbonyl-diimidazole and this was reacted with tert-butyl- amine in the presence of 2-hydroxy-pyridine in a high-pressure equipment, when the 17-carboxamide was obtained in a yield of 90%.
  • the hydrogenation of the ⁇ 5 double bond could be carried out with high stereoselectivity when 3-oxo-4-aza- androst-5-ene-17 -carboxylic acid was reacted in a mixture of formic acid and a diol - e.g. ethyleneglycol - in the presence of activated zinc as catalyst, practically at 100-105°C.
  • the 5a-androstane derivative was obtained in a yield of 81 % by the authors.
  • the above mentioned mixture was applied without zinc the 5 ⁇ - derivative was obtained in a yield of 15%.
  • no diol derivative was added, the stereoselectivity further decreased and the ratio of the 5 ⁇ isomer reached 35%.
  • trialkyl-silyl-enolether was dehydrogenated with a proper benzoquinone derivative in the presence of palladium acetate. After completion of the reaction the reaction mixture was worked up and the protecting group was hydrolyzed with trifluoroacetic acid to yield finasteride.
  • Benzene selenic acid used for the introduction of the ⁇ 1 double bond, is toxic and the lithium-diisopropylamide is inflammable.
  • the DDQ used for the same purpose is toxic, the BSTFA is expensive.
  • the 2-phenyl-sulfenyl method proposed for the introduction of the A 1 -double bond in combination with the oxidation with sodium metaperiodate promote the decomposition and isomerization of the product because of the 10 hours long boiling time.
  • the updated requirements of the pharmacopoeia specify many investigation techniques, such as TLC or HPLC for the detection of the impurities and restrict and limit the number and amount of the contaminations.
  • investigation techniques such as TLC or HPLC for the detection of the impurities and restrict and limit the number and amount of the contaminations.
  • To fulfill these requirements it is important to know the contaminating components of the intermediates which make easier the purification of the final product.
  • the impurities of each intermediate on one hand because of the choice of purification methods on the other hand taking into consideration their necessity and their profitability, i.e. which synthetic steps can be drawn together or which crude product can be used in the next step without purification.
  • R is a Ci-C 4 straight or branched alkyl group, or the (5 ,17p)-3-oxo-4-aza-5-androstane-17-(phenyloxy-carbonyl)-carboxylate, . wherein the meaning of R is a phenyl group
  • R is a C C6 straight or branched alkyl group or a phenyl group
  • the process according to our invention is preferably carried out by oxidizing the 3,20-dioxo-pregn-4-ene of formula (II) with sodium metaperiodate in the presence of potassium permanganate, using aqueous potassium carbonate as a base below 60°C, then after completion of the reaction distilling off the tert-butanol under reduced pressure.
  • acidification of the aqueous solution extraction is carried out with dichloromethane and after separation of the phases the organic solution is washed with aqueous sodium pyrosulfite solution and subsequently with water, the solvent is removed by distillation and the crude product is recrystallized from ethyl acetate.
  • the "ene-lactam” of formula (V) can be synthesized the following way too: the tetrahydrofuran solution of 3-(ethoxy-carbonyl)-carboxylate or the 3-(phenyloxy- carbonyl)-carboxylate derivative of the general formula (IV) is further reacted without isolation with ammonia at -10-0°C. After completion of the reaction the excess of ammonia is removed by passing a stream of nitrogen through the solution, thereafter the tetrahydrofuran solution is acidified with hydrochloric acid at -10-(-15)°C, diluted with water, the precipitate is filtered off, washed with water to neutral and dried.
  • the "ene-lactam” of formula (V) can be synthesized the following way too: the synthesis of the 3-(ethoxy-carbonyl)-carboxylate derivative is carried out in a chlorinated solvent e.g. chloroform, then after completion of the reaction the solvent is distilled off under reduced pressure, methanolic ammonia is added to the residue and the solution is stirred at room temperature for 1 h. After completion of the reaction the ammonia was distilled off, the residue was diluted with methanol and the "seco amide" was cyciized by the addition of e.g. p-toluene sulfonic acid. The resulting product is filtered off from methanol solution, washed and dried.
  • a chlorinated solvent e.g. chloroform
  • the stereochemistry of the hydrogenation is influenced mainly by the applied hydrogen pressure, the type of catalyst, the used temperature, the solvent as well as the polarity and stereochemistry of the substituent at position 17.
  • the hydrogenation of the "ene-lactam" containing a progesterone side-chain can be carried out on industrial scale.
  • the invented process provides adequate product as far as the purity and the yield is concerned.
  • the industrial applicability of the method and the data of the procedure are supported by the examples described below.
  • the 3,20-dioxo-4-aza-pregn-5-ene of formula (V) is preferably dissolved in acetic acid in a hydrogenation equipment and under nitrogen Pd/C catalyst - preferably Heraeus or Degussa Pd/C catalyst containing 10% Pd - and in given case Pd/C catalyst and ammonium acetate or triethyl amine are added.
  • Pd/C catalyst - preferably Heraeus or Degussa Pd/C catalyst containing 10% Pd - and in given case Pd/C catalyst and ammonium acetate or triethyl amine are added.
  • the nitrogen is exchanged by hydrogen, the pressure is adjusted to 6-10 bar and the hydrogenation is continued at room temperature with stirring until the completion of the reaction, thereafter the catalyst is filtered off, the filtrate is concentrated and the residue is recrystallized from ethanol.
  • the 3,20-dioxo-4-aza-5a-pregnane of formula (VI) obtained in the previous step is dissolved in a mixture of dioxane and water and an aqueous sodium hypobromide solution, cooled previously to 2-5°C is added dropwise to the steroid solution.
  • the excess of the oxidizing agent is decomposed by the addition of a solution of sodium pyrosulfite, and after adjusting the pH of the solution to acidic the dioxane is distilled off from the aqueous solution, the residue is further diluted with water, the precipitated crystals are filtered off, washed with water till neutrality and dried.
  • the oxidation process can be carried out by adding the dioxane solution of the steroid to the sodium hypobromide solution too.
  • the reaction mixture is stirred at - 5°C for at least 1 h, thereafter the excess of the reagent is decomposed by the addition of a mixture of aqueous 20% salt solution and acetic acid, and then the formed crystalline slurry is filtered after stirring and is washed with water till neutrality.
  • the crude product is purified as described in detail in the example.
  • the advantages of the new synthesis according to our invention and the existence of the inventive steps are supported by the following facts: a) The starting material of the synthesis is progesterone which possess the best physical properties among the available steroid compounds, it is easily accessible, cheap and it has not been used so far as the starting material for the synthesis of dutasteride.
  • the two layers were separated and the dichloromethane solution was washed with 2 x 2 L of 5% sodium- pyrosulfite solution and water.
  • the dichloromethane was distilled off, the residue was dissolved in 500 mL of ethyl acetate and the stirred solution was cooled to 0°C.
  • the precipitated crystalline material was filtered off, washed with cooled (0°C) ethyl acetate and dried at 40-50°C at diminished pressure till constant weight.
  • the volume of the ammonia free methanolic mixture was diluted with methanol to 500 mL and 2 g of p-toluene-sulfonic acid was added.
  • the slurry dissolved after stirring for a few min and after about 5 min the desired compound started to precipitate and was filtered after 30 min. It was washed with 20 mL of cooled (0°C) methanol and subsequently with water till neutrality and was dried at reduced pressure below 50°C till constant weight.
  • the 3,5-seco-4-norpregn-5,20-dion-3-(ethoxycarbonyl)-carboxylate obtained according to example 2 was dissolved in 20 mL of tetrahydrofuran and 2.45 g (29.87 mmol) ammonium acetate was added to the solution. Thereafter the reaction mixture was refluxed for 1 h, cooled to 0-5°C and 2 mL of concentrated hydrochloric acid was added. The reaction mixture was stirred for 1 h and then it was diluted with 80 mL of water. After 20 min stirring the precipitate was filtered off, washed with water till neutrality and dried at reduced pressure below 50°C till constant weight.
  • the purity of the product was 98.5 % and contained 0.59% of 3,20-dioxo-4-aza-pregn-5-ene as well as 0.35 % of 3,20-dioxo-4-aza-5p-pregnane.
  • the purity of the material was 97.1 % and contained 0.34% of 3,20-dioxo-4-aza-pregn-5-ene as well as 0.28 % of 3,20-dioxo-4-aza-5p-pregnane.
  • the purity of the product was 98.3 % and contained 0.28% of 3,20-dioxo-4-aza-pregn-5-ene as well as 0.23 % of 3,20-dioxo-4-aza-5p-pregnane.
  • hypobromide was decomposed by addition of 4 g of sodium pyrosulfite dissolved in 40 mL of water. After 15 min stirring the reaction mixture was acidified with 45 mL of concentrated hydrochloric acid, the dioxane was removed by distillation at diminished pressure and the resulting aqueous slurry was diluted with 400 mL of water. The precipitated crystals were filtered off, washed with water till neutrality and dried at diminished pressure till constant weight.
  • reaction mixture was stirred at -10-(-8)°C for 4 h, when it became a homogenous yellow solution.
  • TLC dichloromethane- methanol 9:1
  • development ethanol-sulfuric acid 1 :1
  • the wet crystals were dissolved in 300 mL of dichloromethane, the aqueous layer was separated and the organic solution was concentrated at diminished pressure.
  • the product contained 1.5 % of starting material.
  • the product contained 0.63% of starting material.
  • Example 20 int. %): 514(10); 513(1 ); 51 (7); 496(10); 454(2); 440(2); 400(4); 364(2); 298(2); 285(12); 267(28); 257(72); 249(18); 239(100); 197(10); 183(15); 169(4); 155(2).
  • Example 20
  • the dried crude product was dissolved in a mixture of 35 mL of dichloromethane and 35 mL of ethanol at 25°C, treated with 1.39 g of charcoal, filtered and the charcoal was washed with 10 mL of the 1 :1 solvent mixture mentioned before.
  • the filtrate was concentrated to a volume of 20 mL, the solvent was exchanged by continuous addition and evaporation of 120 mL of ethyl acetate in such a way, that the amount of the remaining crystalline slurry should be about 42 g.
  • the slurry was stirred for 30 min at 0°C, the crystalline compound was filtered off, washed with 5 mL of cold (0°C) ethyl acetate and dried at 70°C to yield 5.66 g product.
  • the obtained crystalline product was dissolved in 35 ml of dichloromethane and concentrated to a volume of approximately 20 mL.
  • the solvent was exchanged by continuous addition and evaporation of 200 mL of ethyl acetate in such a way, that the amount of the crystalline slurry should be about 34 g. This was stirred for 30 min at 0°C, the obtained crystals were filtered off, washed with 5 mL of cold (0°C) ethyl acetate and dried at 70°C.
  • the amount of the crude crystals was 790 g
  • the dried crude material was dissolved in a mixture of 4 L of dichloromethane and 4 L of ethanol at 25°C, treated with 158 g of charcoal, filtered and the charcoal was washed with 1 .2 L of the 1 :1 mixture mentioned above.
  • the filtrate was concentrated at diminished pressure to a volume of about 2 L and the solvent was exchanged by constant addition and evaporation of 13.64 L of ethyl acetate in such a way, that the volume of the final crystalline slurry should be about 4.6 L.
  • the slurry was stirred for 30 min at 0°C, the crystals were filtered off, washed with 650 mL of cold (0°C) ethyl acetate and dried at 70°C.
  • the so obtained crystalline product was dissolved in 4.2 L of dichloromethane and concentrated to a volume of about 1.8 L.
  • the solvent was exchanged by a continuous addition and evaporation of 24 L of ethyl acetate in such a way, that the volume of the final ethyl acetate crystallibe slurry should be about 3.9 L.
  • the obtained crystalline slurry was stirred for 30 min at 0°C, the crystals were filtered off, washed with 600 mL of cold (0°C) ethyl acetate and dried at 70°C. Yield: 613 g (76%).
  • the crude product was dissolved in 50 mL of ethyl acetate at reflux temperature, cooled to 0°C, the crystals were filtered off after 1 h of stirring, washed with 5 mL of cold (0°C) ethyl acetate and dried at 70°C until constant weight.
  • the conversion was 50%, consequently the obtained material could not be completely dissolved in the given amount (100 mL) of ethyl acetate, therefore the unreacted 17p-carboxylic acid was filtered off (2.7 g after drying!) and the filtrate was extracted with 3 x 35 mL of 5% sodium hydrocarbonate solution, then with 2 x 20 mL of 0.1 N hydrochloric acid and finally with 4 x 35 mL of water. The organic solution was concentrated under diminished pressure, and the obtained residue could be dissolved completely by boiling in 92 mL of acetonitrile.
  • the purity of the crude product was 77.63 % (according to HPLC).
PCT/HU2012/000057 2011-06-30 2012-06-29 PROCESS FOR THE SYNTHESIS OF (5α,17β)-N-[(2,5-BIS(TRIFLUOROMETHYL)-PHENYL]-3-OXO-4-AZA-5-ANDROST-1-ENE-17-CARBOXAMIDE WO2013001322A1 (en)

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HU1100351A HU230730B1 (hu) 2011-06-30 2011-06-30 Eljárás (5alfa,17béta)-N-[2,5-bisz-(trifluormetil)-fenil]-3-oxo-4-aza-5-androszt-1-én-17-karbonsavamid előállítására

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CN103254268A (zh) * 2013-05-16 2013-08-21 寿光市富康化学工业有限公司 一种制备度他雄胺的工艺
CN106810594A (zh) * 2016-12-30 2017-06-09 南京生命能科技开发有限公司 一种高纯度度他雄胺的制备方法
CN108051513A (zh) * 2017-11-27 2018-05-18 重庆华邦制药有限公司 Hplc法分离测定度他雄胺起始原料sm2及其相关杂质的方法
CN113968886A (zh) * 2021-11-15 2022-01-25 湖南科瑞生物制药股份有限公司 一种17-甲酸甾体化合物的制备方法

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