EP1501858A2 - Weitere verfahren zur herstellung von cyproteron azetat - Google Patents

Weitere verfahren zur herstellung von cyproteron azetat

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Publication number
EP1501858A2
EP1501858A2 EP03720460A EP03720460A EP1501858A2 EP 1501858 A2 EP1501858 A2 EP 1501858A2 EP 03720460 A EP03720460 A EP 03720460A EP 03720460 A EP03720460 A EP 03720460A EP 1501858 A2 EP1501858 A2 EP 1501858A2
Authority
EP
European Patent Office
Prior art keywords
acetate
yield
solasodine
solution
process according
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP03720460A
Other languages
English (en)
French (fr)
Inventor
Aranya Manosroi
Jiradej Manosroi
Duang Buddhasukh
Pattana Sripalakit
Roland Maier
Rolf Werner
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Boehringer Ingelheim International GmbH
Original Assignee
Boehringer Ingelheim International GmbH
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Priority to EP03720460A priority Critical patent/EP1501858A2/de
Publication of EP1501858A2 publication Critical patent/EP1501858A2/de
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J53/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by condensation with a carbocyclic rings or by formation of an additional ring by means of a direct link between two ring carbon atoms, including carboxyclic rings fused to the cyclopenta(a)hydrophenanthrene skeleton are included in this class
    • C07J53/002—Carbocyclic rings fused
    • C07J53/004—3 membered carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/26—Androgens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/28—Antiandrogens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/34—Gestagens

Definitions

  • the present invention relates to improved methods for synthesising cyproterone acetate (17 ⁇ -Acetoxy-6-chloro-1 ⁇ , 2 ⁇ -methylene-4,6-pregnadiene-3,20-dione).
  • the present invention now provides improved synthetic methods for this valuable compound which are both faster and more cost-effective.
  • the present invention it is possible to synthesise cyproterone acetate from solasodine in 14 or 16 steps as opposed to the conventional 18 step synthesis.
  • the present invention provides some reaction steps which are of particular advantage. Therefore, in one embodiment it relates to a process for the production of cyproterone acetate (M) , comprising
  • step (a) is carried out by passing anhydrous hydrogen chloride gas through a reaction mixture containing 6,7 ⁇ -oxido-4-pregnene-17 ⁇ -ol-3,20-dione- 17-acetate (J 2 ).
  • a reaction mixture containing 6,7 ⁇ -oxido-4-pregnene-17 ⁇ -ol-3,20-dione- 17-acetate (J 2 ).
  • step (a) is carried out by passing anhydrous hydrogen chloride gas through a reaction mixture containing 6,7 ⁇ -oxido-4-pregnene-17 ⁇ -ol-3,20-dione- 17-acetate (J 2 ).
  • step (a) is carried out by passing anhydrous hydrogen chloride gas through a reaction mixture containing 6,7 ⁇ -oxido-4-pregnene-17 ⁇ -ol-3,20-dione- 17-acetate (J 2 ).
  • hydrochloric acid in aqueous dioxane yields the intermediate chlorohydrin which can be dehydrated to chlormadinone a
  • step (b) is carried out by the use the dehydrogenation agent 2,3-dichloro-5,6-dicyano-1 ,4-benzoquinone (DDQ, CAS 84-58-2).
  • Dioxane may be used as a sovent.
  • selenium dioxide may be used, e.g. with pyridine and t-butanol as solvent (US Patent 3,485,852), or according to the method of Ringold et al., J. Amer. Soc, 81 , 1959, 3485).
  • a further way to carry out that step is with Pb(OAc ) 4 in acetic acid (Abe, T ., Amer. Chem.
  • DDQ may be used together with 4-nitro-phenol in benzene (Abe T ., Kambegawa, A., Chem. Pharm. Bull., 22, 1974, 2824-2829).
  • step (c) is carried out using the Ci reagent precursor trimethyl sulfoxonium iodide (TMSI, CAS 1774-47-6) and an alkali hydride.
  • TMSI trimethyl sulfoxonium iodide
  • DMSO may be used as a solvent
  • this step may be achieved with diazomethane and treatment with acid (Krakower and Van Dine, J. Org. Chem, 31 , 3467 (1966).
  • a further way would be employing diazomethane and hydrolysis according to Wiechert and Kaspar, Chem. Ber., 93,1710 (1960).
  • the present invention relates to a process for the production of cyproterone actetate (M), comprising reacting delmadinone acetate (L 2 ) with trimethyl sulfoxonium iodide (TMSI) and an alkali hydride, preferably sodium hydride.
  • TMSI trimethyl sulfoxonium iodide
  • alkali hydride preferably sodium hydride.
  • DMSO dimethylsulfoxide
  • 6,7 ⁇ -oxido-4-pregnene-17 ⁇ -ol-3,20-dione-17-acetate (J 2 ) is obtained by a process comprising
  • Step (d) may advantageously be performed with chloranil (tetrachloro-p- benzoquinone, CAS 118-75-2), either alone or in combination with selenium dioxide (Lednicer D, Mitscher LA, The organic chemistry of drug synthesis, Vol. 2, A Wiley-lnterscience Publication, 1980, pp. 182.).
  • chloranil in t-butanol or xylene may be used (L.F. Fieser and M. Fieser, Reagents for organic synthesis, Vol. 1 , John Wiley and Sons, Inc., New York, 1967).
  • a further alternative is DDQ and TsOH as catalyst (L.F. Fieser and M. Fieser, Reagents for Organic synthesis, Vol. 2, John Wiley and Sons, Inc., New York,1969.)
  • Step (e) can be done with m-chloro-perbenzoic acid or monoperoxyphthalic acid.
  • perbenzoic acid with ethylene chloride as solvent could be used (US Patent 3,234,093), or perbenzoic acid according to the method of Lednicer and Mitscher, The Organic chemistry of drug synthesis, Vol.2, A Wiley-lnterscience Publication, 1980, pp. 166.
  • the 17 ⁇ -acetoxyprogesterone (H) can be prepared conveniently from solasodine by methods known in the art.
  • Solasodine may be obtained e.g. by alcoholic extraction of dried leaves or fresh or dried green berries of Solarium laciniatum, Ait, using e.g. 2-propanol or methanol as extraction agent, and subsequent hydrolysis of the thus obtained glycoside solasonine.
  • the plant material is dried and ground into a powder before extraction.
  • the extraction agent is 65 - 85 % (v/v) 2-propanol in water, more preferably 70 - 80 % (v/v).
  • the primary extraction product solasonine may be precipitated from the extract e.g.
  • the crude precipitate is further purified by washing and recrystallization steps, as exemplified in example 1 , before acid hydrolysis e.g. with hydrochloric acid, which gives solasodine hydrochloride. Hydrolysation is preferably carried out in 1 N hydrochloric acid in 2-propanol. Free solasodine may then be obtained by recrystallization from a basic alcoholic solution. Solasodine may then be converted to 16-dehydropregnenolone acetate (16-DPA) by refluxing it in acetic acid/acetic anhydride e.g.
  • 16-DPA 16-dehydropregnenolone acetate
  • TsOH catalytic p-toluene sulfonic acid
  • oxidising e.g. with chromic anhydride, chromium trioxide, or sodium dichromate, and refluxing again with acetic anhydride.
  • the present invention relates to a process for the production of 16- dehydropregnenolone actetate (B), comprising
  • acetylation of solasodine may be achieved reacting it with acetic anhydride in the presence of a base and/or p-toluenesulfonic acid in catalytic amounts.
  • the base may be pyridine.
  • Isomerisation may be obtained with acetic acid,.
  • the phase transfer catalyst in the oxidation step is tetraethylammonium iodide or tetrabutylammonium hydrogen sulfate, preferably the latter.
  • oxidising agent potassium dichromate, sodium dichromate, or potassium permanganate may be used, potassium dichromate being preferred.
  • Methylene chloride may be used as a solvent.
  • Oxidation is carried out in at an acid pH which may be achieved e.g. with sulfuric acid. Hydrolysis of the oxidative product produces 16-DPA. It is of particular advantage to convert the 16-DPA (B) to 16,17 ⁇ - epoxypregnenolone (C) in a single-step procedure. This may be achieved by reacting (B) with peroxide, preferably hydrogen peroxide, in a basic solution, preferably an alkaline alcoholic solution. Methanol may be employed as a solvent in this reaction, and sodium hydroxide as a base.
  • peroxide preferably hydrogen peroxide
  • (C) may then be converted to 16-bromo-17 ⁇ -hydroxy-pregnenolone e.g. by addition of HBr, e.g. in glacial acectic acid, which gives a mixture of the bromohydrin (D-i) and the bromohydrin actetate (D 2 ) (cf. Figures 3A, 4A).
  • the bromohydrin may then be reduced to 17 ⁇ -hydroxypregnenolone (E 2 , in mixture with the acetate E-i, ⁇ 5 -pregnene-3 ⁇ , 17 ⁇ -diol-20-one-3-acetate) using a catalyst like Raney-Nickel and, converted to the 3-formate ester (F) by reaction with formic acid.
  • the present invention provides a process for the production of cyproterone acetate (M) , comprising
  • a preferred agent for step (f) is the dehydrogenation agent 2,3-dichloro-5,6- dicyano-1 ,4-benzoquinone (DDQ, CAS 84-58-2; Muller, M., et al., Helvetica Chemica Acta, 63, 1878, 1980).
  • DDQ dehydrogenation agent 2,3-dichloro-5,6- dicyano-1 ,4-benzoquinone
  • step (g) is carried out using the Ci reagent precursor trimethyl sulfoxonium iodide (TMSI, CAS 1774-47-6) and an alkali hydride.
  • TMSI trimethyl sulfoxonium iodide
  • this step may be achieved with diazomethane and treatment with acid (Krakower and Van Dine, J. Org. Chem, 31 , 3467 (1966).
  • a further way would be employing diazomethane and hydrolysis according to Wiechert and Kaspar, Chem. Ber., 93,1710 (1960).
  • Another agent would be diazomethane and pyrolysis by loss of nitrogen (Lednicer D and Mitscher LA, The organic chemistry of drug synthesis, Volume 2, A Wiley-lnterscience Publication, 1980, pp. 166).
  • Multistep embodiments are described by Tolf et al., Tetrahedron Lett, 25,43, 1984, 4855- 4858).
  • Step (h) may be carried out using m-chloroperbenzoic acid (CAS 937-14-4).
  • ethylene chloride is used as solvent (US 3,234,093).
  • m-CPBA m-chloroperoxybenzoic acid
  • step (i) trifluoromethanesulfonyl choride (CAS 421-83-0) is an agent of choice, preferably in combination with lithium chloride.
  • N,N-dimethyl acetamide hydrochloride in DMSO at 75°C can be used.
  • step (j) can be achieved employing an alkali acetate like sodium acetate.
  • the present invention relates to a process for the production of cyproterone actetate (M), comprising reacting compound (K-i) of formula
  • the 17 ⁇ -acetoxyprogesterone (H) can be prepared conveniently from solasodine by methods known in the art as described above.
  • the present invention relates to a process of production of delmadinone acetate (L 2 ) comprising adding chlormadinone acetate (K 2 ) to a culture of a microorganism capable of converting (K 2 ) into (L 2 ), and isolating the resulting delmadinone actetate from the culture.
  • the organism is preferably Arthrobacter simplex or Bacillus sphaericus, more preferably the strains ATCC 6946 or ATCC 13805 which may be obtained from the American Type Culture Collection (ATCC), P.O.Box 1549, Manassas, VA 20108, USA.
  • an exogenous electron carrier is added to the culture, e.g.
  • menadione (2-Methyl-1 ,4- naphthoquinone) at a concentration of 0.1 to 1.0 mmol/l, preferably 0.2 to 0.4 mmol/l.
  • the yield may be improved by addition of a steroid to the culture, preferably hydrocortisone at a concentration of 0.01 to 0.55 mmol/l, more preferably 0.3 to 0.5 mmol/l. Good results were obtained when the media contained 5 % dimethylformamide (DMF) to improve the solubility of the steroid.
  • DMF dimethylformamide
  • the yield may be further improved by addition of a surfactant, preferably a non- ionic detergent, more preferably polyoxyethylenesorbitan monooleate (Tween 80TM) at a concentration of 0.25 to 1.0 % (w/v), more preferably 0.5 to 1.0 %.
  • a surfactant preferably a non- ionic detergent, more preferably polyoxyethylenesorbitan monooleate (Tween 80TM) at a concentration of 0.25 to 1.0 % (w/v), more preferably 0.5 to 1.0 %.
  • a surfactant preferably a non- ionic detergent, more preferably polyoxyethylenesorbitan monooleate (Tween 80TM) at a concentration of 0.25 to 1.0 % (w/v), more preferably 0.5 to 1.0 %.
  • Tween 80TM polyoxyethylenesorbitan monooleate
  • reaction mixture comprises both homogeneous solutions as well as heterogenous mixtures composed of liquid and/or solid components, like suspensions, slurries, and the like.
  • Figure 1 outlines the conventional 18 step synthesis of cyproterone acetate from solasodine. 5
  • Figure 2 gives an overview of the experimental outline of the synthesis routes according to the present invention.
  • Figure 3 outlines cyproterone acetate synthesis from solasodine according to o Route A of the present invention.
  • Figure 4 outlines cyproterone acetate synthesis from solasodine according to Route B of the present invention.
  • Figure 5 outlines cyproterone acetate synthesis from solasodine according to Route C of the present invention.
  • Example 1 Extraction of Solasodine from Leaves of Solanum laciniatum, Ait
  • the crude alkaloid was purified by solution in dilute acetic acid and reprecipitation with ammonia, followed by repeated crystallisation from 60-80 % alcohol and 80 % dioxan-water (crystallisation from higher concentrations of alcohol or dioxan produces a jelly) to give colourless pointed plates, m. p. 284-285 °C (decomp.). 0
  • solasonine hydrochloride in contrast to solasonine hydrochloride, is only slightly soluble in the cold and is precipitated in a crystalline condition even from the hot solution.
  • the hydrochloride 5 was collected, recystallised twice from 80% alcohol, suspended in hot water, basified with ammonia, and heated at 100°C for ⁇ A hour.
  • the solasodine was collected after cooling and repeatedly crystallised from 80 % alcohol, forming hexagonal plates, m. p. 197.5-198.5°C.
  • the fruit of huapag is picked in the pinton stage. One kg of fruit is used. Each fruit is divided into quarters by two mutually perpendicular cuts along the axis of the fruit. The fruit is then dried in an oven at 60 °C until brittle enough to 0 grind easily. The fruit is then ground in a simple grooved-disc mill set so as to barely avoid fracturing the seeds. The weight of the ground fruit is 270 g. The solids content of the ground fruit is 94 % based on weight loss at 100 °C.
  • the ground fruit is placed in a two litre Erlenmeyer flask and 810 ml of aqueous isopropanol (77 % isopropanol by volume) is added.
  • the flask is stoppered and the extraction is carried out at room temperature for 2 hours with alternating 5 minute periods of vigorous manual agitation and rest.
  • the extraction mixture is drained on filter paper in a conical funnel and the solids are returned to the Erlenmeyer flask.
  • a further portion (540 ml) of aqueous isopropanol is added and the alternate agitation and rest is repeated except that the period is one hour instead of two.
  • the liquids are again drained as before.
  • a third extraction identical to the second, is carried out. All three filtrates are combined.
  • the combined liquids are fed slowly into a one-litre rotary evaporator heated with a water bath at 60°-70°C.
  • the initial pressure is about 150 mm of mercury, and this is gradually reduced to 50 mm by which time the distillate is essentially pure water.
  • the aqueous residue is not allowed to cool, but its weight is adjusted to 510 g by.the addition of water heated to 60-70°C.
  • the addition of the water is made over a 2 minute periods, while the mixture is being stirred. A precipitate forms immediately.
  • the mixture is then allowed to stand for 4 hours, during which time it cools to approximately room temperature.
  • the supernatant liquid is then decanted through medium filter paper and finally the precipitate (P) is transferred to the filter paper.
  • P is a finely divided but easily filtered material. Its color is olive-drab. After drying at 100 °C, P weight is 1.9 g. This material begins to melt at about 160 °C, but is not yet completely melted at 230 °C.
  • the filtrate is placed in a one litre round-bottom flask fitted with a reflux condenser and is then heated to 80°C. It is maintained at this temperature and agitated magnetically while 15 ml of 25 % aqueous ammonia is added, and agitation at 80°C is continued for one more hour.
  • the mixture is immediately filtered through medium paper and the filtrate is discarded. It has a pH between 9 and 10 and is free of glycosides.
  • the filter cake, still on the filter paper is pressed between absorbent papers to remove as much of the liquid as possible. Then, it is dried at 60°C to a final weight of 25.7 g, further drying at 100°C gives a weight loss of 27.7 %. Analysis of a sample of the 25.7 g cake shows that it contains 16.7 g of 5 glycosides and indicates a negligible loss of glycosides in the purification and isolation.
  • the mixture is swirled vigorously by hand for one to two minutes.
  • the viscosity of the mixture decreases noticeably, the colour deepens and the formation of a second liquid phase becomes apparent.
  • Addition of alkali is stopped at an pH of about 9.5 to 10, by which time a considerable separation of the liquid into o two phases and the formation of a precipitate is observable.
  • the total amount of sodium hydroxide solution added is 29 ml.
  • the mixture is allowed to stand for VA hr at room temperature and then is filtered by gravity through medium paper.
  • the precipitate is dried by pressing 5 between absorbent papers.
  • the filtrate consists of two layers.
  • the upper layer is brown and appears to contain the major portion of the isopropanol as well as a very small amount of solasodine, in addition to impurities.
  • the lower layer is dark brown and appears o to contain water, sodium chloride and impurities. The entire filtrate is discarded.
  • the damp participate is agitated with aqueous hydrochloric acid is added until the pH is between 6 and 7. It is then allowed to stand overnight. Then, the mixture is filtered by gravity through medium paper and the precipitate is pressed between absorbent papers. The precipitate is dried in an oven at 60°C for 12 hours. .
  • the dry weight of the precipitate is 14 g.
  • the precipitate is estimated to contain 97 % solasodine on the following basis: Pure solasodine is reported to melt at 200-202 °C. An early, less pure sample produced here melted 191-197 °C and contained 95% solasodine.
  • the dried leaf powder (500 g) was extracted 4-5 times by 0 to 100% v/v of 2- propanol/water (1.5 I each) at 70°C in an Erlenmeyer flask. All filtrates were pooled and 2-propanol was vacuum evaporated using the rotary evaporator (Buchi, Switzerland). The filtrate was heated to 80°C and stirred while adding 30% aqueous ammonia solution until the pH reached 9-10. The formed precipitate was collected, and then crude glycosides were hydrolyzed by 1 N hydrochloric acid in 2-propanol in a round-bottom flask for 3 h. The 20% sodium hydroxide solution was added to precipitate the crude solasodine.
  • the pure solasodine was obtained by crystallization in methanol. Yields were best with 70-80 % (v/v) 2-propanol, with 0.45 % w/w of dry leaves within that range. Particularly suitable for that method is 2-propanol at a concentration of 70 % since it was the lowest concentration giving that high yield of solasodine.
  • the dried leaf powder (1 kg) was extracted by the same procedure as in 2.4.2.1 but using distilled water instead of 2-propanol.
  • the crude glycosides were divided into four portions and hydrolyzed by four methods which were electrolysis, 1 N hydrochloric acid in water, ethanol or 2-propanol.
  • the aqueous extract (1.5 I) in 0.02 N hydrochloric acid was applied with a DC current (30 A) for 2 h using 2 pairs of aluminum plate electrodes (10 x 10 cm 2 ) in a 3 litre tank.
  • the dried fruit (60-750 g) or leaf (40-750 g) powder was dispersed in 70% 2- propanol and sonicated for 2 h before extraction.
  • the suspension was put into the thimble and the alcoholic solution (volume adjusted to 300 or 3000 ml) was added to the Soxhlet receiving flask.
  • the solution was refluxed until exhaustion and 2- propanol was vacuum evaporated using the rotary evaporator.
  • Boiling water was added to the residue while being stirred.
  • the solution was filtered and the filtrate was heated to 80°C and stirred while adding 30% aqueous ammonia solution until the pH reached 9-10.
  • the precipitate was repeatedly washed with distilled water, filtered and dried at 60°C.
  • solasodine was more than 90% (m.p. 198- 200°C). This product has sufficient purity to be use as the starting material to 5 convert to 16-DPA. All spectra (IR, MS and NMR) of the product were identical with that of the authentic sample. This indicated that solasodine can be isolated from both fruits and leaves of S. laciniatum by this method. It required no chromatographic procedure to eliminate the remaining impurities and colour materials. This method is simple, efficient and less expensive. It can also be o applicable for the production of solasodine in large scale, since it will be more convenient to harvest both fruits and leaves or the whole plant at the same time in the isolation process.
  • Example 2 Stepl/Route B
  • the reaction was cooled to room temperature and acetic acid (10 ml) and water (4 ml) were added and refluxed (160 °C) for 4 hrs.
  • the mixture was cooled to 15 °C and a solution of chromic anhydride (0.75 g) in 80 % aqueous acetic acid (3 ml) was added dropwise with stirring over a period of 20 minutes.
  • phase transfer catalyst may also be applied to increase the yield of 16-DPA, see below.
  • solasodine (2 g, 80 %) in acetic acid (12 ml) was added to a solution of p-toluene-sulphonic acid (140 mg) in acetic acid (1.2 ml) and acetic anhydride (2.2 ml). The mixture was stirred at room temperature for 1 h and then heated under reflux for 6 h. The solution was then cooled to 15-18°C and after dilution with acetic acid (14 ml). The yields of 16-DPA, based on the theoretical conversion of solasodine, ranged from 15 of 20 %.
  • the yields of 16-DPA obtained varied between 20-30 %.
  • Solasodine (2 g, 80%) was dissolved in pyridine (40 ml) and heated under reflux. Acetic anhydride (2.3 ml) was added slowly and the reflux maintained for a further 1.5 h. The pyridine and excess of acetic anhydride were distilled off under vacuum. The residue obtained was treated with acetic acid (20 ml) and heated under reflux for 15 min. With this modification, the yields of 16-DPA were improved up to 48-53 %, based on the theoretical value obtained from pure solasodine.
  • Pseudosolasodine acetate A solution of solasodine (100 g) in acetic anhydride (105 ml) and an amine solvent (650 ml) is distilled free of acetic acid and anhydride. The reaction mixture was cooled and water was added to decompose 5 excess acetic anhydride. The crude product of 0,/V-diacetate was taken in 600 ml of acetic acid and refluxed for 1 hr to give the pseudosolasodine diacetate.
  • a mixture of pyridine (40 ml, 0.05 mol) and NH CI (26.0 g, 0.50 mol) is added at o once to a stirred suspension of solasodine (210 g).
  • the mixture is heated to 125- 135 °C and kept at that temperature until TLC indicates the reaction to be complete (usually 8-9 h).
  • Acetic acid (400 ml), 1. 2-dichloroethane (400 ml), and water (54 ml) are then added, and the mixture is. cooled to 0 °C.
  • the keto ester is extracted with 1 ,2- o dichloroethane (1 x 450 ml and 3 x 60 ml), and the combined extracts are washed with water (2 x 500 ml) to remove the residual chromium salts.
  • Solid NaOAc x 3 H 2 0 70 g, 0.51 mol
  • the cooled residue is carefully treated with water (2 l) to produce a solid product, which is collected by filtration.
  • the 5 product is washed thoroughly with water until the filtrate is completely colourless. (To achieve complete removal of the residual chromium salts it may require a similar washing after 1 d).
  • Solvent removal was done in a rotary vacuum evaporator under reduced pressure (about 50 mbar). The recovered solvent was kept for recycle. After the removal of the last traces of the solvent, solid material was obtained which was confimed to be pseudosolasodine.
  • Pseudosolasodine diacetate obtained as above was dissolved in 100 ml of dichloroethane and 100 ml of glacial acetic acid and 25 ml of water.
  • the mixture was cooled to 0 -5 °C and the oxidant solution prepared as above was added to it dropwise keeping the temperature of the reaction mixture below 5 °C till the addition was over. After the addition of the oxidant solution was complete, cooling was discontinued and the temperature of the reaction medium was allowed to rise up to 15 °C and also allowed to be stirred at that temperature for a period 25 minutes. When thin layer chromatography indicated the completion of the reaction, a solution of 5 g of sodium chloride in water (200 ml) and methanol (10 ml) were added and the stirring was continued for another 20 minutes.
  • the keto ester 0,/V-diacetate was extracted from the reaction mixture with 1 , 2-dichloroethane (4 times, 200 ml).
  • the organic layer after separation was subjected to distillation under reduced pressure to recover the solvent.
  • a gummy residue of O, N- diacetate was obtained which was purified by column chromatography using petroleum ether and ethyl acetate.
  • the residue from 2.4.1 was dissolved in methylene chloride (10 ml).
  • the oxidizing agent (30 mol % excess) and phase-transfer catalyst (tetraethylammonium iodide or tetrabutylammoium hydrogen sulfate; 10 mol % of oxidizing agent) were dissolved in water (10 ml) and added to the reaction mixture dropwise.
  • the mixture was vigorously stirred while maintaining the pH at 0 to 1 by adding sulfuric acid.
  • the bath temperature was maintained at 0 to 15°C for 3 h.
  • the organic solvent phase was separated from the system and washed with water several times. Then, the solvent was removed under vacuum until gummy material was obtained.
  • the product was refluxed in glacial acetic acid ( 10 ml) for 2 h and distilled off under vacuum.
  • the gummy material of the product was packed on a column of silica gel 60 (Merck, Germany) and eluted with petroleum ether and ethyl acetate with increasing polarity. The eluent gave pure 16-DPA. Recrystallisation of 16-DPA from methanol gave a rod-like crystal.
  • the isolated solasodine was preliminary detected by thin-layer chromatography (TLC) by comparison with an authentic sample using silica gel 60 GF 25 aluminium plate (Merck, Germany) developed with a mobile phase consisting of chloroform / methanol (9:1).
  • the spots were visualized by spraying with 30% v/v sulfuric acid solution on TLC plate before heating on a hot plate.
  • 16-DPA was detected in the same manner but developed with mobile phase consisting of ethyl acetate / petroleum ether (2:8).
  • the spots were detected under UV lamp at 254 nm.
  • Solasodine was analyzed by high performance liquid chromatography (HPLC, Thermo Separation Products Inc., California, USA) at 205 nm using a Lichrosorb C-18 column (250x4.6 mm i.d.; 10 ⁇ m particle diameter, HPLC Technology, UK) and 0.01 M Tris-HCI buffer/ acetonitrile (20:80 by volume) as the mobile phase at a flow rate of 2.00 ml/min with injection volume of 20 ⁇ l.
  • HPLC high performance liquid chromatography
  • 16-DPA was analyzed by HPLC at 254 nm using a Hypersil C-18 column (250x4.6 mm i.d.; 10 ⁇ m particle diameter; 250°A average pore size, Hichrom, UK) and 100% methanol was used as the mobile phase at a flow rate of 1.00 ml/min with injection volume of 5 ⁇ l.
  • KMn0 , Cr0 3 , Na 2 Cr 2 0 7 , or K 2 Cr 2 0 may be used as oxidising agents.
  • Tetraethylammonium iodide or tetrabutylammoium hydrogen sulfate may be used as phase transfer catalysts. Best yield of 16-DPA with respect to solasodine was obtained with tetrabutylammonium hydrogen sulfate and K 2 Cr 2 0 (37.0 %).
  • Solasodine was first converted to pseudosolasodine diacetate as in two consecutive steps: i.e., acetylation of solasodine to give 0,/V-diacetylsolasodine and isomerisation of diacetate to give pseudosolasodine diacetate.
  • the resulting residue was oxidized by various oxidizing agents under PTC and conventional methods. Further hydrolysis of the oxidative product produced 16-DPA. Finally, the product was separated by column chromatography. The highest yield (37.0%, 93% purity , m.p.
  • the total crude bromohydrin was suspended in 5 I of 96% ethanol together with 400 g of Raney-Nickel. The suspension was heated to boiling, the catalyst was removed and washed thoroughly with boiling ethanol. The combined filtrates were concentrated to 500 ml, cooled in ice and the resulting precipitate was collected. This procedure produced 91.0 g of ⁇ 5 -pregnene-3 ⁇ , 17 ⁇ -diol-20-one-3-acetate.
  • a mixture of 100 g of the formate, 2.5 g of p-toluenesulfonic acid hydrate and 400 ml of acetic anhydride was heated with stirring at 80° for 30 minutes, allowed to stand at room temperature for 2 hours and finally overnight at 0°C.
  • the diester was collected, washed first with a little cold acetic anhydride and then with hot water.
  • the dried product weighed 99.5 g (89 %) and showed a m.p. of 192-196°C.
  • the analytical sample was obtained through crystallisation from acetone and exhibited m.p. 198-200°C.
  • Step 9 / Route B Synthesis of 17 ⁇ -acetoxy-6, 7 ⁇ -oxido- 4-pregnene-3, 20 -dione from 17 ⁇ - acetoxy-4,6-pregnodiene-3, 20-dione (Step 9-2/route B)
  • hydrocortisone (0-0.55 mmol/l) as a 2% ethanol solution was added to the media. After 24 hour cultivation in the presence of hydrocortisone, menadione and chlormadinone acetate in DMF were added. To optimise the effects of surfactant, menadione, chlormadinone acetate and various concentrations of Tween 80 (0-1.00% w/v) in DMF were added to the media after 24 h cultivation in the presence of hydrocortisone.
  • concentration of Tween 80 at 0.75% w/v gave the highest yield at 28.7% on A. simplex.

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CN101298465B (zh) * 2008-06-26 2011-02-16 湖北葛店人福药业有限责任公司 一种环丙孕酮醋酸酯的合成方法
CN102030793A (zh) * 2010-11-24 2011-04-27 华东理工大学 一种制备3β,16β-二羟基-5-烯-20S-甲基-21-胺基-孕甾烷的方法
CN102020694B (zh) * 2010-11-24 2012-11-14 华东理工大学 一种16β,21-环氧-20S-甲基-5-烯-3β,21β-孕甾-二醇的合成方法
CN102219825B (zh) * 2011-01-20 2012-11-07 陕西理工学院 3β-羟基-16α,17α-环氧-5-孕甾烯-20-酮的合成方法
CN102286062A (zh) * 2011-06-15 2011-12-21 陕西理工学院 16α，17α-环氧-4-孕甾烯-3，20-二酮的合成方法
CN102964411B (zh) * 2012-12-03 2015-04-22 华中药业股份有限公司 一种雄甾-4,6-二烯-17α-甲基-17β-醇-3-酮的合成方法
CN103214545A (zh) * 2013-05-08 2013-07-24 华中药业股份有限公司 3β-羟基-16α，17α-环氧-5-孕甾烯-20-酮的改进合成方法
CN103724387A (zh) * 2013-11-19 2014-04-16 华中药业股份有限公司 一种17α-羟基孕甾-4-烯-3，20-二酮的改进合成方法
CN105924487B (zh) * 2016-04-29 2018-07-24 湖北丹澳药业有限公司 17a-羟基黄体酮醋酸酯的制备工艺
CN106866767A (zh) * 2017-02-23 2017-06-20 青岛科技大学 一种醋酸甲地孕酮的制备方法
CN107698645A (zh) * 2017-10-25 2018-02-16 湖南科瑞生物制药股份有限公司 醋酸氯地孕酮的制备方法
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CN111635448B (zh) * 2020-05-25 2023-04-14 湖北葛店人福药业有限责任公司 一种醋酸环丙孕酮母液物的处理方法
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