US3170919A - A-nor derivatives of the pregnane series and intermediates in the production thereof - Google Patents

A-nor derivatives of the pregnane series and intermediates in the production thereof Download PDF

Info

Publication number
US3170919A
US3170919A US212154A US21215462A US3170919A US 3170919 A US3170919 A US 3170919A US 212154 A US212154 A US 212154A US 21215462 A US21215462 A US 21215462A US 3170919 A US3170919 A US 3170919A
Authority
US
United States
Prior art keywords
methyl
compounds
carboxylate
acid
androstane
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.)
Expired - Lifetime
Application number
US212154A
Other languages
English (en)
Inventor
Fried Josef
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Olin Corp
Original Assignee
Olin Corp
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Olin Corp filed Critical Olin Corp
Priority to US212154A priority Critical patent/US3170919A/en
Priority to FR942297A priority patent/FR1366305A/fr
Priority to FR951205A priority patent/FR4049M/fr
Application granted granted Critical
Publication of US3170919A publication Critical patent/US3170919A/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J61/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by contraction of only one ring by one or two atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J75/00—Processes for the preparation of steroids in general

Definitions

  • Z may be hydrogen, hydroxy, halogen (i.e'., chloro, fluoro, iodo or bromo) or acyloxy; R is hydrogen; R' may be hydrogen or hydroxy; or together R and R is oxo (0
  • the preferred acyloxy radicals are those of hydrocarbon carboxylic acids of less than twelve carbon atoms, as exemplified by the lower alkanoic acids (e.g., acetic,
  • Those final products of this invention which are oxygenated in the 21-position are physiologically active compounds which possess mineraloeorticoid activity and thus can be'employed instead of desoxycorticosterone, for example, in the treatment of Addisoris disease, for which purpose they can be administered in the same manner as desoxycorticosterone, for example, the dosage being adjusted for the relative potency of the particular steroid.
  • the compounds of this invention are physiologically active steroids which possess antiandrogenic activity, i.e., they inhibit the action of androgens, and they can be used in the treatment of such conditions as hyperandrogenic acne.
  • the compounds may be formulated for such administration, the concentration and/or dosage being based on the activity of the particular compound and the requirements of the patient.
  • a-triterpenoid acid it is here meant a polymethylsteroid, having a D-ring structure represented by the formula:
  • R may be the same or difierent and may be either hydrogen or alkyl and R may be the same or dilferent and may be selected from the group consist ing of hydrogen and hydroxyi
  • the triterpenoid acids which may be employed in the practice of this invention include eburicoic, polyporenic, tumulosic, pinicolic, elemolic, elemonic, dehydroeburicoic, dehydroelemolic, dehydroelemonic, and other like acids.
  • the steps of the process employing eburicoie acid.
  • eburicoic acid is converted to its S-ester derivative (Compounds A)
  • the 3-acetate of eburicoic acid is a known compound.
  • Other 3-esters can be prepared in the usual manner by reacting with the desired acylating agent (e.g., acyl chloride or acid anhydride) in the presence of a base, such as pyridine.
  • the desired acylating agent e.g., acyl chloride or acid anhydride
  • a base such as pyridine
  • the preferred esters are those with hydrocarbon carboxylic acids of less than twelve carbon atoms. These are formed by reacting with the acyl chloride or acid anhydride of a hydrocarbon carboxylic acid of less than twelve carbon atoms, such as one of the acids listed hereinbefore.
  • the 3-ester is then converted to a corresponding ester of 24-keto-A -lanostene-2l-oic acid (Compounds C).
  • This may be done by ozonolysis of Compounds A and reducing the ozonide formed by treatment with either hydrogen in the presence of a hydrogenation catalyst, such as palladium or charcoal, or an electropositive metal, such as zinc, in the presence of an acid, such as glacial acetic acid, whereby Compounds C are obtained directly.
  • a hydrogenation catalyst such as palladium or charcoal
  • an electropositive metal such as zinc
  • Compounds C can also be obtained in a two-step process by first treating Compounds A with a hydroxylating agent, such asosmium tetroxide, to yield the corresponding 3- ester of 3/3,24,-28-trihydroxy-A -eburiCene-Zl-oic acid (Compounds B) and then cleaving the glycol, as by treatment with lead tetraacetate to yield Compounds C.
  • a hydroxylating agent such asosmium tetroxide
  • Compounds C are then lactonized by treatment with an acid anhydride and a salt of a strong base and a weak acid, such as sodium acetate in acetic anhydride, to yield a mixture of the a-lactone (Compounds D) and p-lactone (Compounds E) of the corresponding 3-esters of 35- hydroxy-24-keto-A -lanostene-2l-oic acid.
  • the reaction is preferably carried out at an elevated temperature, such as the reflux temperature of the organic solvent employed and the two lactones are separated chromatographically.
  • an elevated temperature such as the reflux temperature of the organic solvent employed and the two lactones are separated chromatographically.
  • both the a-lactone and fi-lactone give the same product in the next step of the process of this invention, suchseparation is not necessaryy and a mixture of the lactones may be used directly.
  • Compounds F can then be isomerized to the corresponding 3 acetoxy-24-hydroxy-A -1anostatriene- 2l-oic acid lactone derivative (Compounds G), by treatment with hydrogen chloride in a solvent (e.g., glacial acetic acid).
  • a solvent e.g., glacial acetic acid
  • the lanostatriene 21-oic acid lactones (Compounds F and G) may then be oxidized by treatment with potassium permanganate, and the manganese dioxide formed, reduced as by treatment with sulfur dioxide, to form the A -5e-androstene-7,11 dione 17,6 carboxylates (Compounds H), which are new compounds of this invention.
  • Compounds H are then reduced as by treatment with zinc in glacial acetic acid, preferably at elevated temperatures of yield the 5u-androstane-7,l1-dione-17/3-carboxylates (Compounds I), which are also new compounds of this invention.
  • Compounds I are then converted to the ll-keto-Saandrostanes (Compounds L) by treatment first with an alkylenedithiol, such as ethanedithiol, in the presence of a Lewis acid, such as borontrifluoride etherate, to produce the dithioethylene ketals (Compounds K).
  • Compounds K may then be treated at elevated temperatures with a sponge nickel catalyst in an organic solvent (e.g., ethanol) to produce Compounds L, which are new compounds of this invention.
  • Compounds L may be obtained by treating Compounds I with hydrazine and a base, such as potassium hydroxide, at elevated temperatures.
  • a base such as potassium hydroxide
  • hydrolysis of the ester groups at C and C are reformed by treatment first with an acylating agent such as acid anhydride or acyl chloride, in the presence of a base, such as pyridine, followed by treatment with a methylating agent (e.g., ethereal diazomethane), to produce Compounds L directly.
  • a methylating agent e.g., ethereal diazomethane
  • the ll-kBtO-Sot-fllldIOStElIlfiS (Compounds L) may then be dehydrated and rearranged as by treatment with phosphorus pentachloride at reduced temperature in the absence of light, to yield the 3-alkylene-1l-keto-A-nor-Sw androstanes (Compounds M), which are also new compounds of this invention.
  • Compounds M are then treated with ozone and the ozonide formed is reduced, as by treatment with zinc and glacial acetic acid to yield the 3,11-dik6t0-A-I10f-5ocandrostanes (Compounds N) (wherein R is SaH and R is CH which are also new compounds of this invention.
  • these free acid compounds may be obtained in a stepwise process which entails first, treatment of Compounds N (wherein R is SaH and R is CH with cold alkali to produce Compounds N (wherein R is 55H and R is CH followed by treatment with hot alkali to yield Compounds N (wherein R is 551-1 and R is H)
  • Compounds N may then be treated with anacid halide, for example, oxalyl chloride, to obtain the A-nor-SB-androstane-l7fl-carboxylic acid halides (Compounds 0), which are also new compounds of the instant invention.
  • Compounds 0 are then treated with a methylating agent, for example, ethereal diazomethane to produce 2l-diazo- ZO-keto-A-nor-pregnanes (Compounds P) which are new compounds of this invention.
  • a methylating agent for example, ethereal diazomethane to produce 2l-diazo- ZO-keto-A-nor-pregnanes (Compounds P) which are new compounds of this invention.
  • Compounds P are treated at elevated temperature with a fatty acid, such as acetic, propionic or butyric acid, to yield the 2l-esters of 3,l1,20-triketo-A- nor5,B-pregnane (Compounds Q) which are also new compounds of this invention.
  • a fatty acid such as acetic, propionic or butyric acid
  • Compounds Q (wherein Z is acyloxy) may be obtained by first treating Compounds P with a hydrohalide, such as hydrochloric acid, to yield the 2l-halogenated A-norpregnanes (Compounds Q), which are also new compounds of this invention, and then acylating the 2l-halide A-norpregnanes as by treatment with potassium acetate and potassium iodide to yield the 2l-acyloxy-A-norpregnanes (Compounds Q). To obtain the 2l-hydroxy A-norpregnanes (Compounds Q), the 2l-acyloxy compounds are treated with a base, such as potassium carbonate. The 2l-hydroxy A-norpregnanes (Compounds Q) are also new compounds of this invention.
  • a hydrohalide such as hydrochloric acid
  • Compounds Q are then brominated as by treatment with bromine in an acid medium to yield the 21-oxygenated S-bromo-A-norpregnanes (Compounds R), which are also new compounds of this invention;
  • the 2l-oxygenated S-bromo-A-norpregnanes (Compounds R) are then converted to the 21-oxygenated-A-nor-M-pregnenes (Compounds S) by treatment with a base, such as co11i dine or lithium halide, e.g., lithium chloride or lithium bromide in dimethylformamide.
  • a base such as co11i dine or lithium halide, e.g., lithium chloride or lithium bromide in dimethylformamide.
  • Compounds S are new final products of this invention.
  • Compounds P are first treated with a hydrohalide, such as hydriodic acid, to yield the 21- unsubstituted A-norprcgnanes (Compounds Q), which are new compounds of this invention.
  • a hydrohalide such as hydriodic acid
  • the 21-unsubstituted pregnanes (Compounds Q) are then brominated, as by treatment with bromine in an acid medium, to yield the ill-unsubstituted S-bromo-A-norpregnanes (Compounds R), which are then converted to the 2l-unsubstituted A-nor-A -pregnenes (Compounds S) by treat ment with a base, such as collidine or a lithium halide, such as lithium chloride, in dimethylformamide.
  • a base such as collidine
  • a lithium halide such as lithium chloride
  • the final products of this invention which are halogenated in the 2l-position (i.e., wherein Z may be chlorobromo-fluoro or iodo) are obtained by first treating, at reduced temperatures, the Zl-diazoketone (Compounds P) with a hydrogen halide such as hydrogen chloride, to yield the corresponding 21-halo substituted A-norpregnanes (Compounds Q), which are also new compounds of this invention.
  • a hydrogen halide such as hydrogen chloride
  • the 3,1l-diketo-A-norandrostanes (Compounds N) are treated with an enol ester of a carbocyclic acid of less than 10 carbon atoms of an aliphatic or alicyclic ketone, such as isopropenyl acetate in the presence of a strong acid, e.g., p-toluenesulfonic acid, to produce the 11-keto-A-nor-A -androstenes (Compounds T), which are also new compounds of this invention.
  • a strong acid e.g., p-toluenesulfonic acid
  • Compounds T may then be halogenated, as by treatment with a halogenating agent, such as N-bromoacetamide, N-bromosuccinimide, dibromodimethylhydantoin, bromine, N-chloro- COZ 9 succinimide or N-iodoacetamide, to yield the -halo-'3,11- diketo-A-nor-Sfl-androstanes, (Compounds U), which are also new compounds of this invention.
  • a halogenating agent such as N-bromoacetamide, N-bromosuccinimide, dibromodimethylhydantoin, bromine, N-chloro- COZ 9 succinimide or N-iodoacetamide
  • Compounds W which first entails treating Compounds N with bromine in an acid medium, such as glacial acetic acid, to obtain the 5a-halo-A-nor-Su-andmstanes (Compounds Z) which are new compounds of this invention.
  • Compounds Z may then be dehydrohalogenated as by treatment with lithium bromide in dimethylformamide or collidine to yield the A-nor-A -androstenes (Compounds W).
  • Compound W and V may then be converted to the final A-nor-pregnene derivatives of this invention by an identical series of steps. If a compound W is employed, the final product and all the intermediates thereof contain a double bond in the 5,6position. If a Compound V is employed, the final products and all intermediates contain a double bond in the 1,2-position.
  • Compounds BB and Compounds EE are then converted to the 21-substituted final products of this invention as set forth hereinbefore in the treatment" of Compounds P to produce Compounds S and Compounds FF, which are new final products of this invention.
  • a fatty acid such as acetic, propionic or butyric acid
  • Compounds FF which are new final products of this invention.
  • the 2l-unsubstituted derivatives are obtained by treating Compounds BB and EE with hydroiodic acid, thus yielding the A-nor-A -pregnenes (Compounds S) and the A-nor-A -pregnenes (Compounds FF), which are new compounds of the instant invention.
  • saturated final products of this invention may be obtained by an alternate procedure, which may be represented by the following equations, wherein R, R and Z are as hereinbefore defined:
  • Compounds GG are then ozonized to yield the A-nor-Sa-pregnane-3,1 1,20-triketones (Compounds HH) which are also new compounds of this invention.
  • Compounds HH may then be treated with a base, such as sodium hydroxide to yield the A-nor-SB-pregnane-Iid1,20-triketones (Compounds Q, wherein Z is H), which are new compounds of this invention.
  • Compounds II are then treated in accordance with the procedures set forth hereinabove in the treatment of Compounds L and M to yield the corresponding B-keto-A- norandrostanes (Compounds KK) which are also new compounds of this invention.
  • Compounds KK are treated in exactly the same manner as set forth hereinbefore in the treatment of Compounds N through P to obtain Compounds Q.
  • Compounds KK (R H) are treated with an acid halide, converted into the diazoketones as with ethereal diazomethane and then reduced to yield the 3,ZO-diketo-A-nor-pregnanes (Compounds LL) which are new compounds of this invention.
  • Compounds KK may also be treated in accordance with the procedures set forth hereinabove in the treatment of compounds N through BB and EE to yield the saturated A-nor-A -pregnene-3,ZO-diones (Compounds MM) and the A-nor-A -pregnene-3,20-diones (Compounds NN), both of which are new final products of this invention.
  • Still more new final products of this invention may be obtained by the further processing of some of the derivative material obtained in the treatment of the original triterpenoid acid starting material.
  • the additional processing required to obtain these new final products is set forth in the following equations wherein R, R and Z are as hereinbefore defined:
  • Compounds 00 and PP may then be treated in accordance with the procedures set forth hereinabove in the production of Compounds N from Compounds L and M to yield the corresponding'A-nor-A -androstenes (Compounds RR) and 1'1,8-hydroxy-A-norandrostanes (Compounds QQ) which are also new compounds of this invention.
  • Compounds RR and QQ are then treated in the same manner as set forth hereinabove to yield Compounds Q, S and FF, thus producing respectively, the A-nor-A pregnen'es (Compounds WW), the A-nor-A -preg'nadienes (Compounds YY), the A-n'or-A -pregnadienes (Compounds ZZ) and the A-nor-A l pregnatrienes (Compounds AAA) from Compounds RR; and the 11,8- hydroxy-A-nor-pregnanes (Compounds SS), the llfi-hydroxy-A-nor-A -pregnenes (Compounds'TI), the llfi-hydroiiy-A-nor-A -p'r'egnenes (Compounds UU)'and the 115- 14 hydroxy-A-nor-A -pregnadienes (Compounds VV) from Compounds QQ. All these compounds are
  • new compounds of this invention may be produced by an alternate procedure.
  • the starting material employed in this alternate process is derived from the treatment of the original t'riterpenoid acid starting material-as described hereinbefore.
  • This alternate process may be represented by the followinge'quations wherein R, R and Z are as hereinbefore defined:
  • the mixture thus obtained may be separated into the individual compounds as by fractional crystallization or chromatographic separation.
  • the 17fi-carboxylates (Compounds BBB and CCC) may be converted into the corresponding free acid compounds (wherein R is H) by treating the 17 8-carboxylates with a base, such as potassium hydroxide, in an alcohol medium thus producing the corresponding A-nor-M-androstene 175 carboxylic acids (Compounds BBB) and the A-nor-a -androstene- 17fl-carboxylic acids (Compounds CCC).
  • a base such as potassium hydroxide
  • Compounds CCC may then be hydrolyzed by treatment with a mineral acid to yield the free acid of Compounds V.
  • Compounds BBB may be treated with an organic acid, for example acetic acid at room temperature to yield the A-nor-A -androstene-lll-diones (Compounds DDD) which are new compounds of this invention.
  • Compounds DDD may then be treated in accordance with the procedures described in the treatment of Compounds N, O and P, in order to yield the final products of this invention, Compounds S.
  • Compounds BBB are reduced as by treatment with lithium borohydride, to yield the 3-alkylenedioxy-A-nor-A -androstene-llfl-ols (Compounds GGG), which are new compounds of this invention.
  • Compounds GGG may then be treated with a base, such as pyridine, and methanesulfonyl chloride in dimethylformamide to yield the A-nor- A landrostadienes (Compounds HHH) which are also new compounds of this invention.
  • Compounds GGG and HHH may then be processed in the same manner to yield the final products of this invention, Compounds TT and Compounds ZZ, respectively.
  • treatment with an acid halide e.g., oxalyl chloride yields the corresponding acid chlorides, Compounds 1]] and Compounds KKK; reaction thereof with a methylating agent, e.g., ethereal diazomethane, yields Compounds LLL and MMM, and the reaction of these compounds as set forth hereinabove in the treatment of Compounds BB, yields the final products of this invention, Compounds TT and ZZ, respectively.
  • an acid halide e.g., oxalyl chloride
  • a methylating agent e.g., ethereal diazomethane
  • Compounds GGG and HHH may be hydrolyzed with a fatty acid, such as acetic acid, to yield the A -3-keto-A-nor-androstenes (Compounds NNN) and the A6301) 3 keto-A-nor-androstadienes (Compounds OOO).
  • Compounds NNN and Compounds 000 may then be treated with a mineral acid to yield respectively the A -3-keto-A-nor-androstenes (Compounds PPP) and the A 3 keto-A-nor-androstadienes (Compounds QQQ), all of which are new compounds of this invention.
  • Compounds PPP and QQQ may then be treated in acco dance With the procedure hereinbefore described COOR COOR
  • Compounds SSS may then be treated with a base, such as pyridine, and methanesulfonyl chloride, in dimethylformamide to yield the A-nor-A androstenes (Compounds TTT), which are also new compounds of this invention.
  • Compounds 'ITT and SSS may then be treated in the same manner to yield the final products of this invention Compounds WW and SS, respectively.
  • EXAMPLE 1 Eburicoic acid 3-pr0pi0nate (II) To a solution of 10 g. of eburicoic acid in 50 ml. of anhydrous pyridine is added 10 ml. of propionic anhydride and the mixture is allowed to remain at room temperature for 18 hours. Five grams of ice is then added and 30 minutes later the mixture is diluted slowly with 250 ml. of ice and water. The resulting precipitate is filtered, washed thoroughly with water, dried in vacuo and recrystallized from 95% alcohol yielding pure eburicoic acid 3-propionate (II).
  • EXAMPLE 2 3,8-acetoxy-24-ket0-A Janostene-Z1-0ic acid (IV) Through a solution of 15 g. of eburicoic acid 3-acetate (I) in a mixture of 150 ml. of chloroform and 150 ml. of ethyl acetate, cooled in a Dry Ice-acetone bath, is passed 26.2 1. of ozone (1 mole of ozone contained in .89 l. of oxygen). The resulting solution is allowed to warm to room temperature and then added to a suspension of 975 mg. of pre-reduced 5% palladium on charcoal catalyst in 50 ml. of ethyl acetate. 550 ml. of hydrogen is taken up rapidly, following which the solution is filtered and the filtrate evaporated to dryness in vacuo.
  • the ozonide can be decomposed with zinc in acetic acid as follows:
  • the ozonolysis mixture obtained from 50 g. of eburicoic acid S-acetate in 50 ml. of chloroform and 500 ml. of ethyl acetate, is allowed to warm up to when it is diluted with 50 ml. of glacial acetic acid. Powdered zinc is then added in portions with stirring and the temperature allowed to rise to A total of g. of zinc is required. After 2 /2 hours the reaction mixture is filtered and the zinc and zinc salts washed thoroughly with ethyl acetate. The ethyl acetatechloroform filtrate is washed thoroughly with water, dried over sodium sulfate and evaporated to dryness in vacuo. A total of about 56 g. of the crude keto acid IV is obtained.
  • the acid (IV) is obtained in pure form by chromatography on neutral alumina.
  • a solution of 14 g. of the crude acid is dissolved in 50 ml. of benzene and charged to the column containing 280 g. of alumina.
  • 50% chloroformbenzene (9 l.) elutes about 1.9 g. of pure acid melting at about 234236, which is followed by about 1.2 g. of acid when the eluant is changed to 75% chloroform in benzene (3 1.).
  • An additional 1.3 g. of pure acid is obtained with chloroform (5 1.).
  • the column is then stripped with 5% acetic acid in chloroform (2. l.) which elutes about 10.4 g. of crude material which max.
  • EXAMPLE 3 3 ,B-ace'toxy-Z4,28-dihydroxy-A -eburicene-21 -0ic acid (III) To a solution of 2 g. of eburicoic acid B-acetate (I) in 20 ml. of benzene and 2 ml. of pyridine is added dropwise a solution of 1 g. of osmium tetroxide in 10 ml. of benzene. Addition is complete in 1 hour and the reaction mixture is allowed to remain at room temperature for an additional 4 hours. The resulting dark solution is diluted with 76 ml. of dioxane and saturated with hydrogen sulfide for 15 minutes.
  • EXAMPLE 4 3,9-acet0xy-24-ket0-A -lanostene-21-oic acid (IV)
  • a solution of 1.17 g. of the 24,28-dihydroxy acid (III) in 200 ml. of .0108 molar lead tetraacetate solution in glacial acetic acid is allowed to stand at room temperature for 35 minutes.
  • a few drops of ethylene glycol are then added to reduce the excess lead tetraacetate and the solution is concentrated in vacuo and diluted with water.
  • the resulting suspension is extracted with ethyl acetate and the ethyl acetate extract washed several times with water, dried over sodium sulfate and evaporated to dryness in vacuo.
  • the resulting crude produce (about 1.07 g.) on recrystallization from acetone furnishes about 700 mg. of the pure keto acid IV possessing the following properties: M.P. about 225-227"; [04] +50 (c., .43 in chlf.).
  • the 12.05 and 1263a band are diagnostic for the oclactone and are absent in the ,B-lactone.
  • EXAMPLE 8 24-hydroxy-B-keto-A -lan0statriene-21-0ic acid lactone To a solution of 95 mg. of 3/3-24-dihydroxy-A lanostadiene-Zl-oic acid lactone (VIII) in 3 m1. of acetone is added 1 mi. of a aqueous acetone solution of 20 mg. of chromium trioxide and 32 mg. of concentrated sulfuric acid. After 10 minutes methanol is added to reduce excess chromium trioxide and the solution is diluted with water and extracted with chloroform. The chloroform extract is dried over sodium sulfate and evaporated to dryness in vacuo. The crystalline residue on recrystailization from acetonitrile produces the analytically pure 3-ketone possessing the following properties: M.P. about 230-232;
  • XI 3,8-acetoxy-24-hydroxy- 21 -lanostatriene-2l-oic acid 21,24-lactone
  • VII 3,8-acetoxy-24-hydroxy- 21 -lanostatriene-2l-oic acid 21,24-lactone
  • the potassium permanganate is added in 20 g. portions, first more rapidly, later on at greater intervals so as to maintain the proper temperature and making sure that the permanganate color is discharged prior to new additions.
  • the total time of addition is about 1 hour and 20 minutes and the reaction is allowed to proceed until all the permanganate color is discharged (approximately an additional 1 to 1 /2 hours).
  • 60 ml. of Water is added, the mixture cooled to 0 in an ice-bath and sulfur dioxide is passed through the solution until all the manganese dioxide has been transformed into colorless manganous sulfate.
  • the suspension is filtered and the filter cake washed thoroughly with hot acetone.
  • the yellow acetone solution is concentrated in vacuo to 800 ml. and
  • the precipitated acid (XI) is filtered off, Washed with water and
  • the dried material (30.8 g.) is dissolved in 200 ml. of hot absolute alcohol and allowed to crystallize.
  • 2.3 g. of lactone starting material (VII) separates and the resulting mother liquor is taken to dryness.
  • the residue is then dissolved in 75 ml. of acetonitrile and the acid (XI) allowed to crystallize.
  • the analytically pure 3B-acetoxy-4,4,14-trimethyl-A '5a-androstene-7,l1-dione-17fi-carboxylic acid (XI) obtained by recrystallization from methanol has the following properties: M.P. 252-255-, [011 +85 (c., 1.24 in chlf.);
  • EXAMPLE 12 3,8-acet0xy-4,4,14-trimethyl-A 5a-androstene-Z11 dione-J 7fl-carb0xylic acid (XI) Following the procedure set forth in Example 11 but substituting 50 g. of 3B-acetoxy-24-hydroxy-A' lanostatriene-Zl-oic acid 21,24-lactone (IX) for 3fl-acetoxy 24 hydroxy-A -lanostatriene 21 oic acid 2l,24-lactone, yields 3;? acetoxy-4,4,l4-trimethyl-A 5aandrostene-7,1l-dione-lldcarboxylic acid (XI).
  • the methyl 3fl-acetoxy 4,4,14 trimethyl-A -5a-androstene-7,11-dione-l7l3-carboxylate (XII) readily crystallizes yielding 9.2 g. of material (MP. -172") in the first crop and an additional 2 g. (M.P. 158-160) in the second crop.
  • the analytical sample, recrystallized from methanol, has the following properties: M.P. 178- 179"; [M +88 (c., 1.18 in chlf.);
  • N22, 268 my. (e 9,400); A232 5.73, 5.80 and 5.94;
  • EXAMPLE 14 M etlz yl 3,Bacct0xy-4,4,I 4-trimethy l-5 ot-androstane- 7,1 1-di0ne-17fi-carb0aylate (XV) To a refluxing solution of 17 g. of methyl 35-acetoxy- 4,4,146t trimethyl-A da-androstene-7,11-dione-17fi-carboxylate (XII) in 425 ml. of glacial acetic acid is added, over a 20 minute period, 170 g. of 20 mesh granular zinc. The yellow color lightens and complete decolorization is achieved by the portionwise addition of a total of 3 g. of zinc dust.
  • EXAMPLE 15 Methyl 3f3-acet0xy-7-ethylenedithi04,4,14-trimethyl- 5 ot-andr0stane-1 1 -0ne-1 7,8-carb0xylate (XVIII) To a mixture of 58 ml. of ethanedithiol and 47 ml. of twice distilled boron trifluoride etherate is added 14 g. of methyl 3fl-acetoxy-4,4,14-trimethyl-5:x-androstane-7, 1l-dione-17B-carboxylate (XV). All the material dissolves within 1.5 hours and after a total reaction time of 23 hours at room terneprature, 290 ml.
  • the anatlytically pure material obtained by recrystallization from methanol has the following properties: M.P. 219-220";
  • EXAMPLE 18 4,4,14-trimethyl-A -5a-andr0stezze-3/3-ol-7J 1 -dine-1 75- carboxylic acid (XIII)
  • EXAMPLE 19 4,4,14-trimethyl-a-androstane-3fi-ol-7J 1 -di0ne-1 75- carboxylic acid (WI) Following the procedure set forth in Example 17 but substituting methyl-3,8-acetoxy-4,4,14-trimethyl-5a-androstane-7,1l-dione-17B-carboxylate (XV) for methyl-3B- acetoxy 4,4,14-trimethyl-5u-androstane-11-one-17fi-carboxylate (XIX), yields 4,4,14-trimethyl-5a-androstane-3fiol-7,ll-dione-l7 3-carboxylic acid (XVI).
  • EXAMPLE 21 M ethyl-4,4,1 4-trimethy l-A -5 a-an drostene-S 8- 01-7,]1 -di0ne-1 7,8-carb0xy late (XIV) Following the procedure set forth in Example 20, but substituting 4,4,14-trimethyl-A -5a-androstene-3B-ol-7,11- dione-17B-carboxylic acid (XIII) for 4,4,14-trimethy1-5aandrostane-3B-ol-11-one-17 3-carboxylic acid (XX), yields methyl 4,4,14 trimethyl A 50c androstene 35 ol- 7, 11-dione-17fl-carboxylate (XIV).
  • the resulting material is reacetylated with /2 cc. of acetic anhydride and /2 cc. of pyridine for 18 hours at room temperature and the resulting material remethylated with diazomethane. Removal of the solvent leaves the methyl 4,4,14 trimethyl 3;? acetoxy 5a androstane- 17fi-carboxylate as a crystalline solid.
  • EXAMPLE 27 4,4,] 4 -trimetl1 yl-5 a-andrOStane-S 5,1 I fi-d i 0l- 17B-carb0xylic acid Following the procedure set forth in Example 17 but substituting methyl-4,4,l4-trirnethyl-3,B-acetoxy-Sa-androstane 11,6 ol 17;? carboxylate for methyl-3,8-acetoxy- 4,4,14 trimethyl 5a androstane-l l-one-l7l3-carboxylate (XIX). yields 4,4,14 trimethyl 5a androstane-3fi-l1fldiol-17fl-carboxylate acid.
  • EXAMPLE 28 Methyl 4,4,14-trimethyl-Swandrostarze-BBJ1(3- dz'0l-1 7fi-carb0xylate Following the procedure set forth in Example 20, but substituting 4,4,14 trimethyl-Sa-androstane-SB,1lB-diol- 17-fl-carboxylic acid for 4,4,l4trimethyl-h-androstane- 3,8-01-1l-one-17B-carboxylic acid (XX). yields methyl 28 4,4,14 trimethyl-Sot-androstane-3p,1lB-diol-17p-carboxylate.
  • EXAMPLE 29 4,4,14-trimethyl-A -5oz-andr0stene-3[3-0l- 1 7,8-carb0xylic acid Methyl 4,4,14trimethyl-A -5a-andr0stene- 3B-ol-1 7fi-carboxylate Following the procedure set forth in Example 20, but substituting 4,4,14 trimethyl-A -5a-androstene-3,B-ol- 17fi-carboxylic acid for 4,4,14-trimethyl-Sa-androstane- 35-01-1l-one-17fl-carboxylic acid (XX), yields methyl 4,4,14 trirnethyl-A -5a-androstene-3fi-ol-17fi-carboxylate.
  • EXAMPLE 33 Methyl 3-is0pr0pylidenc-14-methy l-A-n0r-5otandrostalze-l Ifl-ol-I 7/i-carb0xylate Following the procedure set forth in Example 26 but substituting methyl 4,4,14-trimethyl-1a-androstane-3/3-1lfldiol-17B-carboxylate for methyl 4,4,14-trimethyl-5u-androstane 3 8 ol 11-one-17fi-carboxylate (XXI) yields methyl 3-isopropylidene-14-methyl-A-nor-5a-androstane- 1 1 8-ol-17p-carboxylate.
  • EXAMPLE 35 Following the procedure set forth in Example 26, but substituting methyl 4,4,l4-trimethyl-5a-androstane-3fi-ol- 17B-carboxylate for methyl 4,4,14-trimethyl-5wandrostane-3fl-ol-1l-one-l7 8-carboxylate (XXI), yields methyl -3-isopropylidene 14 methyl-A-nor-Sa-anclrostane-lcarboxylate.
  • EXAMPLE 37 Following the procedure set forth in Example 36 but substituting methyl 3-isopropylidene-14-methyl-A-nor-5aandrostane-11B-ol-17fi-carboxylate for methyl 3-isopropylidene 14 methyl-A-nor-Su-androstane-1Lone-17,8- carboxylate (XXII), yields 3-isopropylidene-14-methyl- A-nor-Sa-andrOstane-I 1,8-01- 17B-carboxylic acid.
  • EXAMPLE 38 3-isopropylidene-14-m ethy l-A -nr-A -5aandrosten e-l 7fi-carb0xylic acid Following the procedure set forth in Example 36, but substituting methyl 3-isopropylidene-14-methyl A nor- A -5a-androstene-17B-carboxylate for methyl 3-isopropylidene 14 methyl-A-nor-h-androstane-1Lone-17ecarboxylate (X) yields 3-isopropylidene 14 methyl-A- mer-A -5a-androstene-17,3-carboxylic acid.
  • EXAMPLE 39 3-is0pr0pyIidene-1 4-methyl-A -n0r-5 lx-androstane- 17,6-carb0xylic acid Following the procedure set forth in Example 36, but substituting methyl 3-isopropylidene-14-methy1-A-11or-5aandrostane-l7fi-carboxylate for methyl 3-4isopropylidene- 14-methyl-A-nor-5rx-androstane 11 one 17B carboxylate (XXII) yields 3-isopropylidene-14-methyl-A-nor- 5a-androstane-17B-carboxylic acid.
  • EXAMPLE 40 M ethyl 14-methyl-A -nor-5a-andr0stane-3,1l dione-I 7, 3-carb0xylate (XXV)
  • XXV 3-carb0xylate
  • a solution of 1.5 g. of methyl 3-isopropylidene-14- methyl-A-nor-Su-androstane-1l-oue 17,6 carboxylate (XXII) in '80 ml. of ethyl acetate is ozonized at 20 until a potassium iodide trap, placed behind the reaction vessel, shows the color of iodine. This requires 3.6 liters of gas containing .714 mmole of ozone per liter.
  • the calculated amount for 1 mole of ozone per mole of substrate is 3.2 liters.
  • the ozonolysis solution is then allowed to Warm up to 0", 3.5 ml. of glacial acetic acid is added and the ozonide decomposed reductively by the portionwise addition of 12 g. of zinc dust. After stirring for a total of 1 hour at room temperature the ozonide is completely decomposed as indicated by a negative starch iodide test.
  • the mixture is then filtered, the ethyl acetate filtrate extracted with water, dried over sodium sulfate and evaporated to dryness in vacuo.
  • the crystalline residue upon recrystallization from acetone-hexane yields 590 mg.
  • EXAMPLE 49 14-methyl-A-n0r-5t3-andr0stane-3,1 1-dione-1 713- carboxylic acid (XXVII) To a mixture of .7 N KOH in methanol and 4.6 ml. of water, which has been refluxed for 10 minutes and cooled under a blanket of helium is added 460 mg. of methyl 14 methyl A nor 5a androstane 3,11 dione 17,6- carboxylate (XXV) and the resulting light yellow solution is refluxed for 7 /2 hours under a blanket of helium. The mixture is then cooled and after the addition of 5 ml. of glacial acetic acid is diluted with water.
  • EXAMPLE 50 1 4 -methyl-A -n0r-5 fi-androstane-3 ,1 1 -di0ne-] 7a carboxylic acid (XXVII)
  • EXAMPLE 51 14-methyl-A-nor-5;3-arzdr0stane-11fi-0l-3-0ne-17f3- carboxylic acid (LXXXIX)
  • LXXXIX 14-methyl-A-nor-5;3-arzdr0stane-11fi-0l-3-0ne-17f3- carboxylic acid
  • EXAMPLE 52 14-methy l-A mar-A -5/3-andr0ste1ze-3-0ne-1 7 pcarboxylic acid (XCI) Following the procedure set forth in Example 49 but substituting methyl 14-methyl-A-nor-A -5et-androstene- 3 one 17fi-carboxylate for methyl l4-methyl-A-nor-5aandrostane-3,11-dione-17fi-carboxylate (XXV) yields 14- methyl-A-nor-A -5a androstene-3-one-17 8-carboxylic acid (XCI) EXAMPLE 53 14-n zethyl-A -n0r-5;3-andr0stane-3-0ne-l 7ecarboxylic acid (LXIX) Methyl 14-methyl-3-acet0xy-A mar-A -andr0stene- 1l-0ne-17fl-carh0xylate (X
  • XXV methyl 14-methy1-A-nor-Saandrostane-3,11-dione-1718-carboxylate
  • 40 mg. of p-toluenesulfonic acid in 5 ml. of redistilled isopropenyl acetate is slowly distilled under anhydrous conditions.
  • One ml. is distiled otf rapidly and a second milliliter over a 30 minute period. After a total of 45 minutes the mixture is cooled to room temperature, taken up in chloroform and the chloroform extract washed with dilute sodium bicarbonate and water, dried over sodium sulfate and taken to dryness in vacuo. 42 mg.
  • XLV 14-methyl-3-acetoxy-A-nor-A -androstene-l1-one-17t3-carboxylate
  • EXAMPLE 56 Methyl 14-methyl-3-acet0xy-A-n0r-A -androstadiene-I 7fi-carboxylate Following the procedure set forth in Example 54 but substituting methyl 14-methyl-A-nor-A -5a-androstene 17,6-carboxylate for methyl 14-methyl-A-nor-5tx-androstane-3,11-dione-17fl-carboxylate (XXV), yields methyl 14 methyl-3-acetoxy-A-nor-A -androstadiene-lcarboxylate.
  • EXAMPLE 58 Methyl 14-methyl-3-acezoxy-A -rzor-A -andrstene- 1.1 -on 6-1 7 fl-carboxylate (XLV) Following the procedure set forth in Example 54 but substituting methyl 14-methyl-A-nor-5/3-androstane-3,11- dione-17/3-carboxylate (XXVI) for methyl 14-methyl-A- nor-Sa-androstane 3,11 dione-17/3-carboxylate (XXV) yields methyl 14-methyl 3 acetoxy-A-nor-A -androstone-1l-one-l7fi-carboxylate (XLV) EXAMPLE 59 14-methyl-3-acet0xy-A mar-A -andr0steize-]l -one- 1 7 B-carhoxylic acid (XLVI) Following the procedure set forth in Example 54, but substituting 14 methyl-A-nor-S/3-androstane-3
  • EXAMPLE 60 4-methyl-3-acetoxy-A -n0r-A -andr0stene-11 /3-0l- 17/3-carb0xylic acid Following the procedure set forth in Example 54, but substituting 14-methyl-A-nor-5fi-androstane-l 1 ,B-ol-3-one- 17,8-carboxylic acid for methyl 14-methyl-A-nor-Sa-androstane-3,11-dione-17 3-carboxylate (XXV) yields 14-meth yl 3-acetoxy-A-n0r-A -androstene-1 1 /3-ol-17,B-carboxylic acid.
  • EXAMPLE 61 14 methyl 3 acetoxy A nor A3(5)'9(11) androsiadiene 17/3 carboxylic acid Following the procedure set forth in Example 54 but substituting 14 methyl A nor A901) 5oz androstene 3 one 17/1 carboxylic acid for methyl 14- methyl A nor 5a androstane 3,11 dione 17 3 carboxylate (XXV) yields 14-methyl-3-acetoxy-A-nor- 545L901) androstadiene 17/3 carboxylic acid.
  • EXAMPLE 62 14 methyl 3 acezoxy A nor A androsteize 17/3 carboxylic acid Following the procedure set forth in Example 54 but substituting 14 methyl A -nor 5a androstane 3 one-17,8-carbcxylic acid for methyl 14-methyl-A-nor-5aandrostane 3,11 clione 17,8 carboxylate (XXV) yields 14-methyl-3-acetoxy-Au1or-A androstene 17B- carboxylic acid.
  • N-chloro compound such as N-chlorosuccinimide or an N-iodo compound such as N-iodo acetamide is used in place of N-bromoacetamide in following the procedure of Example 63, there is obtained the corresponding methyl 14 methyl 5/3 chloro A nor androstane 3,11 dione 17/? carboxylate and methyl 14 methyl 5/8 iodo A nor androstane 3,11 dioue 17 8 carboxylate.
  • EXAMPLE 64 Following the procedure set forth in Example 63 but 7 substituting methyl 14-methyl-3-acetoxy-A-nor-A -an- Methyl 14 methyl 5/? bromo A nor A901) androstene 3 one 17 8 carboxylate Following the procedure set forth in Example 63, but substituting methyl 14 methyl 3 acetoxy A nor A3(5),9(11) androstadiene 17,8 carboxylate for methyl 14 methyl 3 acetoxy A nor A345) androstene 11-one-17/i-carboxylate (XLV) and reducing the quantity of N-bromo-acetamide from mg. to 40 mg. yields methyl 14 methyl 5e bromo A nor A androstene-3-one-17fl-carboxylate.
  • EXAMPLE 66 Methyl 14 methyl 5/3 bromo A nor androstane 3 one 17/3- carboxylate Following the procedure set forth in Example 63, but substititing methyl 14 methyl 3 acetoxy A -nor A androstene 17/3 carboxylate for methyl 14- methyl 3 acetoxy A nor A androstene 11 one-17/3-carboxylate (XLV) yields methyl 14-methyl-5fibromo A nor androstane 3 one 17/3- carboxylate.
  • EXAMPLE 67 14 methyl 5/3 bromo A nor androszane 3,11 dioize 17/5 carboxylic acid (XLVHI) Following the procedure set forthin Example 63-, but substituting 14 methyl 3 acetoxy A nor A androstene 11 one 17/3 carboxylic acid (XLVI) for methyl 14 methyl 3- acetoxy A nor A androsteue 1'1 one 1 7/3 carboxylate (XLV) yields 14 methyl 5,8 bromo A nor androstane 3,11 dione-17/3-carboxylic acid (XLVIII).
  • EXAMPLE 68 Following the procedure set forth in Example 63 but substituting 14-methyl-3-acetoxy-A-nor-A -androstene- 11,8-ol-l7fl-carboxylic acid for methyl 14-methyl-3-acetoxy-A-nor-A -androstene 11 one 17/8 carboxylate (XLV) yields 14-methyl-5B-bromo-A-nor-androstane-11,8- ol-3-one-17fl-carboxylic acid.
  • EXAMPLE 69 I4-methyl-5fl-bromo-Amar-A 1)-andr0stene-3-0ne- 17,8-carboxylic acid Following the procedure set forth in Example 63, but substituting 14-methyl-3 acetoxy-A-nor- -androstadiene-17fl-carboxylic acid for methyl 14-methyl-3-acetoxy- A-nor-A -androstene-1l-one 17 ,8 carboxylate (XLV) and decreasing the amount of N-bromoacetamide from 100 mg. to 40 mg. yields 14-methyl-5fl-bromo-A-nor- A -androstene-3-one-17,8-carboxylic acid.
  • EXAMPLE 7O Following the procedure set forth in Example 63, but substituting 14-methyl-3-acetoxy-Anor-A -androstene- 17,B-carboxylic acid for methyl 14-methyl-3-acetoxy-A- nor-A -androstene 11 one 1718 carboxylate (XLV) yields 14-methyl-5/3-bromo-A-nor-androstane-3-one-17,B- carboxylic acid.
  • chloroform-dioxane extract is evaporated to dryness in vacuo and the resulting methyl 14-methyl-5fl-fiuoro-A- nor-androstane-3,11-dione-17/3-carboxylic (XLII) recrystallized from acetone.
  • EXAMPLE 72 A solution of 62.5 mg. of methyl 14-methyl-5fi-bromo- A+nor-androstane-3,1l-dione-1713 carboxylate (XLVII) and 125 mg. of lithium chloride in 4.5 ml. of dimethyl- "36 formamide is heated on the steam bath for 2 hours. The cooled mixture is diluted with water, extracted with chloroform and the chloroform extract washed thoroughly with water. The chloroform extract is dried over sodium sulfate, evaporated to dryness in vacuo and the 55 mg.
  • the ether mother liquors contained the methyl 14- methyl-Anor-A -androstene-3,ll-dione 17fl-carboxylate (L1H) which after recrystallization from methanol has the following properties: M.P. 202-203"; 39 (c., .48 in chlf.);
  • an equimolar amount of lithium bromide may be substituted for the lithium chloride employed in Example 73, without altering the results obtained.
  • Concentration of the chloroform extract to dryness furnishes a mixture of methyl 14-methyl-A-nor-A -androstene-3,11-dione-17fi-carboxylate (U11) and methyl 14- methyl-A-nor-N-5 3-androstene-3,11-dione-17fl carboxylate (XLlX), which may be separated into its individual components by fractional crystallization.
  • EXAMPLE 78 14-Me2hyl-A-nor A androstene-SJ 1 -di0ne-1 7 ,B-carboxylic acid (LIV) and 14-methyl-A-n0r-A -5fl-androstene-3,11-di0ne-17fl-carb0xylic acid (L) 14-melhyl-A-n0r-A -andr0stene 11/5 0l-3-0ne-17B-carboxylic acid and l4-methyl-A-n0r-A -5,8-andr0stene- 11,8-01-3-0ne-17B-carboxylic acid Following the procedure set forth in Example 73 but substituting 14-methyl-5,B-bromo-A-nor-androstane-11B- ol-3-one-17B-carboxylic acid for methyl 14-methyl-5flbromo-A-nor-androstane-3,11 dione 17B carboxylate (
  • EXAMPLE 8O 14-methyl-Aaim-A -andr0stadiene-3-0ne 17,8 carboxylic acid and 14-methyl-An0r-A -5fl-andr0stadiene-3-0ne-17,8-carboxylic acid Following the procedure set forth in Example 73, but substituting 14-rnethyl-5fi-bromo-A-nor-A -androstene- 3-one-17fl-carboxylic acid for methyl 14-methy1-5 B-bromc- A-nor-androstane 3,11 dione-lfli-carboxylate (XCVH) yields 14-methyl-A-nor-A -androstadiene-3-one-175- carboxylic acid and 14-methylA-nor-A -55-androstadiene-3-one-17,B-carboxylic acid.
  • the acetic acid-water filtrate from the methyl 14- methyl 5oz bromo A nor audrostane 3,11 dione- 17fi-carboxylate (Ll) is diluted further with Water, extracted with chloroform and the chloroform extract washed thoroughly with Water, bicarbonate and again with water.
  • the chloroform extract is dried over sodium sulfate, evaporated to dryness and fractionally crys tallized from methanol. There is obtained an additional 65 mg. of the methyl 14'methyl-5a-bromo-A-nor-andro stane-3,11-dione-17fi-carboxylate (L1) in the first crop, and by concentration of the mother liquors, 17 mg.
  • EXAMPLE 86 14-111 ethyl-A -nI'A -andr0stene-3,1l -di0ne-1 75- carboxylic acid (LIV)
  • the mixture is then acidified with glacial acetic acid, diluted with Water and extracted with chloroform.
  • EXAMPLE 87 14-methyl-A -n0rA -5B-andr0stene-3,1 1 -di 011e- 17,6-carboxylic acid (L) Following the procedure set forth in Example 86 but substituting methyl 14-methyl-A-nor-N-Sfi-androstene- 3,11-dione-17B-carboxylate (XLIX) for methyl 14-methyl A nor A androstene 3,11 dione 17 8 carboxylate (LIII) yields 14-methyl-A-nor-A 5,B-androstene- 3,11-dione-17B-carboxylic acid (L).
  • EXAMPLE 88 l 4-m ethyl-A -n0J"A -andr0stene-1 l 6-01-3 -0nel 7 3- carboxylic acid Following the procedure of Example 86 but substituting methyl 14-methyl-A-nor-M-androstene-11,8-01-3-one- 17,8-carboxylate for methyl 14-methyl-A-nor-A -androstem-3,11-dione-l7 3-carboxylate (LIII) yields 14-methyl- A-nor-M-androstene-l 1,8-ol-3-one-17fl-carboxylic acid.
  • EXAMPLE 90 14-mefhyl-A mar-A -androstadierze-3-one- 1 7-carb0xylic acid Following the procedure set forth in Example 86 but substituting methyl 14 methyl A nor A5301) androstadiene-3-one-17fi-carboxylate for methyl 14-methyl- A nor A androstene 3,11 dione 17,6 carboxylate yields 14 methyl A nor A5301) androstadiene 3-one-17fl-carboxy1ic acid.
  • CXXIV the pure methyl 14 methyl 3,3-etl1ylenedioxy-A-nor-A -androstene-11- one-l7fi-carboxylate

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Steroid Compounds (AREA)
US212154A 1962-07-24 1962-07-24 A-nor derivatives of the pregnane series and intermediates in the production thereof Expired - Lifetime US3170919A (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
US212154A US3170919A (en) 1962-07-24 1962-07-24 A-nor derivatives of the pregnane series and intermediates in the production thereof
FR942297A FR1366305A (fr) 1962-07-24 1963-07-23 Procédé de préparation de nouveaux stéroïdes des séries du a-nor-androstane, du a-nor-prégnane et des a-nor-prégnènes
FR951205A FR4049M (forum.php) 1962-07-24 1963-10-21

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US212154A US3170919A (en) 1962-07-24 1962-07-24 A-nor derivatives of the pregnane series and intermediates in the production thereof

Publications (1)

Publication Number Publication Date
US3170919A true US3170919A (en) 1965-02-23

Family

ID=22789772

Family Applications (1)

Application Number Title Priority Date Filing Date
US212154A Expired - Lifetime US3170919A (en) 1962-07-24 1962-07-24 A-nor derivatives of the pregnane series and intermediates in the production thereof

Country Status (2)

Country Link
US (1) US3170919A (forum.php)
FR (2) FR1366305A (forum.php)

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3274237A (en) * 1963-10-23 1966-09-20 Squibb & Sons Inc A-norpregn-3-ene derivatives
US3296300A (en) * 1965-08-30 1967-01-03 Squibb & Sons Inc 5 beta-alkanoyl-alpha-norandrostanes
US3330861A (en) * 1965-06-18 1967-07-11 Squibb & Sons Inc 11, 17-oxygenated a-norprogesterones
US3332985A (en) * 1965-05-12 1967-07-25 Squibb & Sons Inc 12-oxo-15-oxy-a-norprogesterones
US3344169A (en) * 1963-11-08 1967-09-26 American Cyanamid Co Novel 1-acyloxy-6-hydroxy-9-methyl-delta4(10)-octalins and -trans-decalins
US3367962A (en) * 1964-12-02 1968-02-06 Squibb & Sons Inc 11, 15- and 12, 15-oxygenated a-norprogesterones
US3393230A (en) * 1963-09-13 1968-07-16 Squibb & Sons Inc Alpha-norsteroids
US3413304A (en) * 1966-02-28 1968-11-26 Merck & Co Inc 13-alkyl-17beta-hydroxy-a-nor-5alpha-gonanyl-[2, 3-c]-pyrazoles
US3424787A (en) * 1964-09-28 1969-01-28 Squibb & Sons Inc Derivatives of a-norprogesterone
US3424786A (en) * 1964-09-28 1969-01-28 Squibb & Sons Inc Derivatives of a norprogesterone
US3439023A (en) * 1964-09-28 1969-04-15 Squibb & Sons Inc Derivatives of a-norprogesterone
US3723508A (en) * 1965-06-25 1973-03-27 Squibb & Sons Inc 12,17-dioxy and 12-oxo-17-oxy-a-norprogesterones

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
None *

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3393230A (en) * 1963-09-13 1968-07-16 Squibb & Sons Inc Alpha-norsteroids
US3274237A (en) * 1963-10-23 1966-09-20 Squibb & Sons Inc A-norpregn-3-ene derivatives
US3344169A (en) * 1963-11-08 1967-09-26 American Cyanamid Co Novel 1-acyloxy-6-hydroxy-9-methyl-delta4(10)-octalins and -trans-decalins
US3424787A (en) * 1964-09-28 1969-01-28 Squibb & Sons Inc Derivatives of a-norprogesterone
US3424786A (en) * 1964-09-28 1969-01-28 Squibb & Sons Inc Derivatives of a norprogesterone
US3439023A (en) * 1964-09-28 1969-04-15 Squibb & Sons Inc Derivatives of a-norprogesterone
US3367962A (en) * 1964-12-02 1968-02-06 Squibb & Sons Inc 11, 15- and 12, 15-oxygenated a-norprogesterones
US3332985A (en) * 1965-05-12 1967-07-25 Squibb & Sons Inc 12-oxo-15-oxy-a-norprogesterones
US3330861A (en) * 1965-06-18 1967-07-11 Squibb & Sons Inc 11, 17-oxygenated a-norprogesterones
US3723508A (en) * 1965-06-25 1973-03-27 Squibb & Sons Inc 12,17-dioxy and 12-oxo-17-oxy-a-norprogesterones
US3296300A (en) * 1965-08-30 1967-01-03 Squibb & Sons Inc 5 beta-alkanoyl-alpha-norandrostanes
US3413304A (en) * 1966-02-28 1968-11-26 Merck & Co Inc 13-alkyl-17beta-hydroxy-a-nor-5alpha-gonanyl-[2, 3-c]-pyrazoles

Also Published As

Publication number Publication date
FR4049M (forum.php) 1966-04-04
FR1366305A (fr) 1964-07-10

Similar Documents

Publication Publication Date Title
US3828080A (en) Androstane-17beta-carboxylic acids and processes for the preparation thereof
DE68917884T2 (de) Phosphinsäure-Derivate von Steroiden als 5-alpha-Reduktase-Inhibitoren.
NO137321B (no) Analogifremgangsm}te for fremstilling av terapeutisk aktive 3-okso-17alfa-acyloksyandrost-4-en-17beta-karboksylsyreestere
US3170919A (en) A-nor derivatives of the pregnane series and intermediates in the production thereof
CH533094A (de) Verfahren zur Herstellung neuer Steroide
DE68917885T2 (de) Phosphonsäure-Derivate von Steroiden als Hemmstoffe der 5-alpha-Reduktase.
Allen et al. Steroidal Cyclic Ketals. XI. 1 The Conversion of 11-epi-Hydrocortisone into Hydrocortisone
US2805230A (en) Esters of 17alpha-hydroxy progesterone
US2752339A (en) Preparation of cortisone
US3681410A (en) Process for preparing 17{60 -hydroxy-20-keto and 17{60 ,21-dihydroxy-20-keto pregnanes and derivatives and intermediates thereof
DE3102397A1 (de) 17(alpha)-acyloxy-5(beta)-corticoide und 17(alpha)-acyloxy-5(alpha)-corticoide
DE2715863A1 (de) Verfahren zur herstellung von steroidcarbonsaeuren und ihren estern
US3211726A (en) Process for the production of 6beta:19-oxido-steroids
US2904545A (en) 21-diazo pregnenes
CH632279A5 (en) Process for the preparation of polyhalogenated steroids
US3271390A (en) Sulfurenic acid and derivatives thereof
US2940991A (en) Method of epimerizing 11-bromo steroids
US3684674A (en) Process for preparing 18-cyano-pregnane compounds
US2783254A (en) Process for the manufacture of 17alpha-hydroxycorticosterone and intermediates obtained thereby
HU177452B (en) Process for preparing new d-homo-steroids
US2773888A (en) Process for the manufacture of 3-ketals of polyketo steroids and products obtained thereby
US2824882A (en) 16-cyano-7-oxopregnenolone and derivatives
US3140301A (en) Oxygenated triterpenoid acid derivatives
US3347854A (en) Preparation of 11beta-hydroxy-19-nor steroidal-delta1, 3, 5 (10), 6, 8-pentaenes
US3080381A (en) Optionally 6-methylated and optionally 17-alkanoyloxygenated 2-oxapregnane-3, 20-diones, a-homo compounds corresponding, and 4, 5-dehydro and 4, 5; 6, 7-bisdehydro derivatives thereof