ITRM960477A1 - PROCEDURE FOR THE PREPARATION OF 14-HYDROXY-15-ENE-17-KETO STEROI = DI - Google Patents
PROCEDURE FOR THE PREPARATION OF 14-HYDROXY-15-ENE-17-KETO STEROI = DI Download PDFInfo
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- ITRM960477A1 ITRM960477A1 IT96RM000477A ITRM960477A ITRM960477A1 IT RM960477 A1 ITRM960477 A1 IT RM960477A1 IT 96RM000477 A IT96RM000477 A IT 96RM000477A IT RM960477 A ITRM960477 A IT RM960477A IT RM960477 A1 ITRM960477 A1 IT RM960477A1
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- ene
- androsta
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- 238000000034 method Methods 0.000 title claims description 15
- 238000002360 preparation method Methods 0.000 title description 12
- 239000000543 intermediate Substances 0.000 claims description 7
- HETCEOQFVDFGSY-UHFFFAOYSA-N Isopropenyl acetate Chemical compound CC(=C)OC(C)=O HETCEOQFVDFGSY-UHFFFAOYSA-N 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 3
- 125000002252 acyl group Chemical group 0.000 claims description 3
- 239000007800 oxidant agent Substances 0.000 claims description 3
- 238000010992 reflux Methods 0.000 claims description 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 2
- 150000007513 acids Chemical class 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- USSBDBZGEDUBHE-UHFFFAOYSA-L magnesium;2-oxidooxycarbonylbenzoate Chemical compound [Mg+2].[O-]OC(=O)C1=CC=CC=C1C([O-])=O USSBDBZGEDUBHE-UHFFFAOYSA-L 0.000 claims description 2
- 230000001590 oxidative effect Effects 0.000 claims description 2
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- 150000001875 compounds Chemical class 0.000 description 11
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- -1 7-keto steroids Chemical class 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 150000003431 steroids Chemical class 0.000 description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 244000309464 bull Species 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 230000009466 transformation Effects 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- HAUVDKBDLCXMEG-HQEMIIEJSA-N (8r,9s,10s,13s,14s)-10,13-dimethyl-1,2,3,4,5,6,7,8,9,11,12,14-dodecahydrocyclopenta[a]phenanthren-17-one Chemical compound C1CCC[C@]2(C)[C@H]3CC[C@](C)(C(C=C4)=O)[C@@H]4[C@@H]3CCC21 HAUVDKBDLCXMEG-HQEMIIEJSA-N 0.000 description 2
- TVEXGJYMHHTVKP-UHFFFAOYSA-N 6-oxabicyclo[3.2.1]oct-3-en-7-one Chemical compound C1C2C(=O)OC1C=CC2 TVEXGJYMHHTVKP-UHFFFAOYSA-N 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- GQPLMRYTRLFLPF-UHFFFAOYSA-N nitrous oxide Inorganic materials [O-][N+]#N GQPLMRYTRLFLPF-UHFFFAOYSA-N 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- XGAZYVFYLADCPH-USOAJAOKSA-N (3s,8r,9s,10r,13s,14s)-3-hydroxy-10,13-dimethyl-1,2,3,4,7,8,9,11,12,14-decahydrocyclopenta[a]phenanthren-17-one Chemical compound C1[C@@H](O)CC[C@]2(C)[C@H]3CC[C@](C)(C(C=C4)=O)[C@@H]4[C@@H]3CC=C21 XGAZYVFYLADCPH-USOAJAOKSA-N 0.000 description 1
- CRFSKKKDUPEBBJ-FCYODTKKSA-N (8R,9S,10S,13S)-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,16,17-dodecahydro-1H-cyclopenta[a]phenanthrene Chemical class C1CC2CCCC[C@]2(C)[C@@H]2[C@@H]1C1=CCC[C@@]1(C)CC2 CRFSKKKDUPEBBJ-FCYODTKKSA-N 0.000 description 1
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- 125000000204 (C2-C4) acyl group Chemical group 0.000 description 1
- 238000007115 1,4-cycloaddition reaction Methods 0.000 description 1
- NFGXHKASABOEEW-UHFFFAOYSA-N 1-methylethyl 11-methoxy-3,7,11-trimethyl-2,4-dodecadienoate Chemical compound COC(C)(C)CCCC(C)CC=CC(C)=CC(=O)OC(C)C NFGXHKASABOEEW-UHFFFAOYSA-N 0.000 description 1
- BGWKBVGZEVFQFU-UHFFFAOYSA-N 2-carbonoperoxoylbenzoic acid hexahydrate Chemical compound O.O.O.O.O.O.OOC(=O)C1=CC=CC=C1C(O)=O BGWKBVGZEVFQFU-UHFFFAOYSA-N 0.000 description 1
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- 101100011750 Mus musculus Hsp90b1 gene Proteins 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- KXAJABNDLZOYRG-UHFFFAOYSA-N benzyl n-oxocarbamate Chemical compound O=NC(=O)OCC1=CC=CC=C1 KXAJABNDLZOYRG-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000001738 cardenolides Chemical class 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- OCLXJTCGWSSVOE-UHFFFAOYSA-N ethanol etoh Chemical compound CCO.CCO OCLXJTCGWSSVOE-UHFFFAOYSA-N 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 150000002432 hydroperoxides Chemical class 0.000 description 1
- 150000002440 hydroxy compounds Chemical class 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 150000004965 peroxy acids Chemical class 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- JPJALAQPGMAKDF-UHFFFAOYSA-N selenium dioxide Chemical compound O=[Se]=O JPJALAQPGMAKDF-UHFFFAOYSA-N 0.000 description 1
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical class [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 231100000167 toxic agent Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- 101150117196 tra-1 gene Proteins 0.000 description 1
- 230000001131 transforming effect Effects 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
Questa invenzione riguarda un nuovo metodo chimico e i nuovi intermedi in esso prodotti. Più specificatamente, questa invenzione riguarda un nuovo e semplice metodo per introdurre un sostituente 14β-idrossi nei 17-cheto-15-ene steroidi per dare 14β-idrossi-15-ene-17-cheto steroidi (dei quali è nota l'utilità quale intermedi per la preparazione di cardenolidi, utilizzati principalmente per la loro attività sul cuore quali inotropi) e i nuovi intermedi 14, 16-dienolacetati steroidici in esso prodotti. This invention relates to a new chemical method and the new intermediates produced therein. More specifically, this invention relates to a new and simple method for introducing a 14β-hydroxy substituent into 17-keto-15-ene steroids to give 14β-hydroxy-15-ene-17-keto steroids (whose usefulness is known as intermediates for the preparation of cardenolides, mainly used for their activity on the heart such as inotropes) and the new steroid intermediates 14, 16-dienolacetates produced therein.
I composti finali dei procedimento rivendicato hanno la seguente formula generale (I): The final compounds of the claimed process have the following general formula (I):
dove: where is it:
il simbolo ha significato di configurazione α o β; the symbol has the meaning of configuration α or β;
R rappresenta idrogeno: C2-C6 alchile non sostituito; C2-C6 acile non sostituito o tert-butildimetilsilil. R represents hydrogen: C2-C6 unsubstituted alkyl; C2-C6 unsubstituted acyl or tert-butyldimethylsilyl.
Il gruppo C1-C6 alchile è preferibilmente un C1-C4 alchile. per esempio metil. etil, n-propil, isopropil, n-butil, sec-butil. The C1-C6 alkyl group is preferably a C1-C4 alkyl. for example methyl. ethyl, n-propyl, isopropyl, n-butyl, sec-butyl.
Il gruppo C2-C6 acile è preferibilmente un C2-C4 acile. per esempio acetil. propionil, butirril. The C2-C6 acyl group is preferably a C2-C4 acyl. for example acetyl. propionyl, butyryl.
Le sintesi note per la preparazione di 14β-idrossi-15-ene-17-cheto steroidi presentano notevoli inconvenienti, tali da renderle difficilmente applicabili su scala industriale. Alcune (Sondheimer, FF; Burstein, S.; Mechoulam, R. J. Am. Chem. Soc., I960, 82, 3209; Afonso, A. US Pat. 3,595,883) si basano sull'ossidazione dei derivati dell'androst-14-en-17-one: la loro utilità pratica è limitata dalla difficoltà di preparazione dei chetoni di partenza β,γ-insaturi. Poco pratica è la sequenza di reazioni per ottenere i 14β-idrossi derivati dall'androst-15-en-17-one descritta da Fetizon et al. {Beloeil, J. C.; Bertranne, M.; Fetizon, M. Tetrahedron, 1983, 23, 3937): i 14βidrossi composti si ottengono dopo ripetute sequenze di adsorbimento dei chetoni α,β-insaturi su una colonna di allumina, ossidazione mediante ossigeno, desadsorbimento e riduzione degli idroperossidi risultanti. Wicha et al. (Groszek, G.: Kabat, M. M.: Kurek, A.; Masnyk, M.; Wicha, J. Bulletin of thè Polish Academy of Sciences, 1986, 14, 313) ossidano l'androst-15-en-17-one con Se02- L'ossido di selenio è però un composto tossico. Neef et al. (Kirsch, G.; Golde. R.; Neef, G. Tetrahedron Lett. 1989, 30, 4497) descrivono la sintesi del 3β-acetossi-14β-idrossiandrost-5-en-17-one mediante una sequenza di reazioni basate su una cicloaddizione [4+2] con benzil nitroso formiato sui 14.16-dienolacetati steroidici. Questa reazione non è molto economica, visto il costo dei reattivi per preparare il benzil nitroso formiato. The known syntheses for the preparation of 14β-hydroxy-15-ene-17-keto steroids have considerable drawbacks, such as to make them difficult to apply on an industrial scale. Some (Sondheimer, FF; Burstein, S .; Mechoulam, R. J. Am. Chem. Soc., I960, 82, 3209; Afonso, A. US Pat. 3,595,883) are based on the oxidation of androst-14-en derivatives -17-one: their practical utility is limited by the difficulty of preparing the starting β, γ-unsaturated ketones. The sequence of reactions to obtain the 14β-hydroxy derived from androst-15-en-17-one described by Fetizon et al. Is not very practical. {Beloeil, J. C .; Bertranne, M .; Fetizon, M. Tetrahedron, 1983, 23, 3937): the 14β hydroxy compounds are obtained after repeated adsorption sequences of α, β-unsaturated ketones on an alumina column, oxidation by oxygen, desadsorption and reduction of the resulting hydroperoxides. Wicha et al. (Groszek, G .: Kabat, M. M .: Kurek, A .; Masnyk, M .; Wicha, J. Bulletin of the Polish Academy of Sciences, 1986, 14, 313) oxidize androst-15-en-17-one with Se02- Selenium oxide, however, is a toxic compound. Neef et al. (Kirsch, G .; Golde. R .; Neef, G. Tetrahedron Lett. 1989, 30, 4497) describe the synthesis of 3β-acetoxy-14β-hydroxyandrost-5-en-17-one by a sequence of reactions based on a [4 + 2] cycloaddition with benzyl nitroso formate on the steroid 14.16-dienolacetates. This reaction is not very economical, given the cost of the reactants to prepare benzyl nitrous formate.
Il procedimento rivendicato con la presente invenzione, riportato nello Schema 1. consiste nel trasformare i 15-ene-17-cheto steroidi di formula generale (H) nei 14,16-dienolacetati di formula generale (ΙI) che vengono successivamente ossidati, mediante ossidanti quali ad es. peracidi, oxone a 14 β-idrossi- 15-ene- 1 7 -cheto steroidi (I). The process claimed with the present invention, reported in Scheme 1. consists in transforming the 15-ene-17-keto steroids of general formula (H) into 14,16-dienolacetates of general formula (ΙI) which are subsequently oxidized, by means of oxidants such as eg. peracids, oxone to 14 β-hydroxy- 15-ene- 1 7-keto steroids (I).
Schema 1 Scheme 1
I vantaggi rispetto ai metodi di sintesi della tecnica nota sono: The advantages with respect to the synthesis methods of the known art are:
(1) trasformazione (Π) (I) senza bisogno di purificare gli intermedi (III: (1) transformation (Π) (I) without the need to purify the intermediates (III:
(2) resa e purezza dei 14β-idrossi-15-ene-17-cheto steroidi superiori a quelle realizzate con le sintesi note; (2) yield and purity of 14β-hydroxy-15-ene-17-keto steroids higher than those obtained with known syntheses;
(3) assenza di reagenti tossici, come l'ossido di selenio, o di sostanze costose, come il benzil nitroso formiato; (3) absence of toxic reagents, such as selenium oxide, or expensive substances, such as benzyl nitrous formate;
(4) possibilità' di condurre preparazioni su larga scala. (4) possibility of conducting large-scale preparations.
Esempi preferiti di composti di formula generale (I) della seguente invenzione sono: Preferred examples of compounds of general formula (I) of the following invention are:
3β, 14β-diidrossiandrost- 15-en- 17-one 3β, 14β-dihydroxyandrost- 15-en- 17-one
3β, 14β-diidrossi-5β-androst- 15-en- 17-one 3β, 14β-dihydroxy-5β-androst- 15-en-17-one
3β, 14β-diidrossiandrosta-5, 15-dien-17-one 3β, 14β-dihydroxyandrosta-5, 15-dien-17-one
3, 14β-diidrossiestr- 15-en- 1 7 -one 3,14β-dihydroxyestr- 15-en- 1 7 -one
e i corrispondenti eteri 3β-metossi , 3β-etossi, 3β-η-propossi, 3βisopropossi, 3β-tert-butildimetilsililossi dei composti riportati sopra; e i corrispondenti esteri 3β-acetossi, 3β-propionilossi. 3βbutìrrilossi dei composti riportati sopra. and the corresponding 3β-methoxy, 3β-ethoxy, 3β-η-propoxy, 3β-isopropoxy, 3β-tert-butyldimethylsilyloxy ethers of the above compounds; and the corresponding 3β-acetoxy, 3β-propionyloxy esters. 3βbutyryloxy of the compounds listed above.
Esempi preferiti di nuovi intermedi di formula generale (II) della seguente invenzione sono inoltre: Preferred examples of new intermediates of general formula (II) of the following invention are also:
3β, 17-diacetossi-5β-androsta-14, 16-diene 3β, 17-diacetoxy-5β-androsta-14, 16-diene
3, 17-diacetossi-estra- 1 ,3 ,5( 10), 15-tetraen- 17-one 3, 17-diacetoxy-extra- 1, 3, 5 (10), 15-tetraen- 17-one
3 β- tert-butildimetilsililossi- 17 -acetossi-5 β-androsta- 14,1 6-diene 3β-tert-butildimetilsililss 17-acetossiandrosta-5, 14, 16-triene 3-tert-butildimetilsililossiestra- 1 ,3,5( 10), 15-tetraen- 17-one. 3 β-tert-butyldimethylsilyloxy- 17 -acetoxy-5 β-androsta- 14,1 6-diene 3β-tert-butyldimethylsilylss 17-acetoxyandrosta-5, 14, 16-triene 3-tert-butyldimethylsilyloxyestra- 1, 3,5 ( 10), 15-tetraen- 17-one.
La trasformazione (I) — ► (II) avviene mediante trattamento con isopropenilacetato in presenza di acidi in soluzione di isopropenilacetato o di in un solvente organico inerte non acquoso, quale diossano, tetraidrofurano, cloroformio, cloruro di metilene, piridina. dimetilformammide. benzene o esano a temperature comprese tra temperatura ambiente e riflusso. Gli aerai utilizzat possono essere, ad es.. acido solforico o p-toluensolfonico. L trasformazione (ΙII ) → (I) avviene mediante trattamento con un ossidante quale acido m -cloroperbenzoico, magnesio monoperossiftalato, oxone, in un solvente organico inerte quale etanolo. etanolo/H20, diossano, diossano/H20, tetraidrofurano. cloroformio, cloruro di metilene, piridina, dimetilformammide, benzene o esano a temperature comprese tra temperatura ambiente e riflusso. The transformation (I) - ► (II) takes place by treatment with isopropenyl acetate in the presence of acids in a solution of isopropenyl acetate or in a non-aqueous inert organic solvent, such as dioxane, tetrahydrofuran, chloroform, methylene chloride, pyridine. dimethylformamide. benzene or hexane at temperatures between room temperature and reflux. The areas used can be, for example, sulfuric or p-toluenesulfonic acid. The transformation (ΙII) → (I) occurs by treatment with an oxidant such as m-chloroperbenzoic acid, magnesium monoperoxyphthalate, oxone, in an inert organic solvent such as ethanol. ethanol / H20, dioxane, dioxane / H20, tetrahydrofuran. chloroform, methylene chloride, pyridine, dimethylformamide, benzene or hexane at temperatures between room temperature and reflux.
I 15-ene-17-cheto steroidi (II), composti di partenza di questo processo, sono noti: 3β-idrossiandrost-15-en-17-one (Back. T. G. et al. Tetrahedron Lett. 1992, 33, 5685), 3β-idrossi-5β-androsa-15-en-17-one (Kabat, M. M. J. Org. Chem. 1995, 60. 1823), 3 β-tertbutildimetilsililossi-5β-androst-15-en-17-one (Balogh, V, et al. Tetrahedron 1977. 33, 1321), 3β-idrossiandrosta-5,15-dien -17-one (Reeder, A. Y. et al. Steroids 1996, 6 1, 74). 3β-tertbutildimetilsililossiandrosta-5,15-dien-17-one (Takahashi. T. et al. Tetrahedron 1985, 41, 5747), 3-idrossiestra-l,3,5(10),15-tetfaen-17-one (Suzuki. E. et al. Steroids, 1995, 60, 277). The 15-ene-17-keto steroids (II), starting compounds of this process, are known: 3β-hydroxyandrost-15-en-17-one (Back. T. G. et al. Tetrahedron Lett. 1992, 33, 5685) , 3β-hydroxy-5β-androse-15-en-17-one (Kabat, M. M. J. Org. Chem. 1995, 60. 1823), 3β-tertbutyl dimethylsilyloxy-5β-androst-15-en-17-one (Balogh, V, et al. Tetrahedron 1977. 33, 1321), 3β-hydroxyandrosta-5,15-dien-17-one (Reeder, A. Y. et al. Steroids 1996, 6 1, 74). ( Suzuki, E. et al. Steroids, 1995, 60, 277).
Sono pure noti alcuni dienolacetati (UT): 3β, 17-diacetossiamdrosta-14,16-diene (Nambara, T. et al. Chem. Pharm. BulL 1977, 29. 2650), 3β,17-diacetossiandrosta-5,14,16-triene (Kirsch, G. et al. Tetrahedron Lett. 1989, 30, 4497), 3. 17-diacetossiestra- 1,3,5(10), 14. 16-pentaen-17-one (Bull, J. R. et al. Tetrahedron 1994, 50, 6347). Some dienolacetates (UT) are also known: 3β, 17-diacetoxiamdrosta-14,16-diene (Nambara, T. et al. Chem. Pharm. BulL 1977, 29. 2650), 3β, 17-diacetoxiandrosta-5,14, 16-triene (Kirsch, G. et al. Tetrahedron Lett. 1989, 30, 4497), 3. 17-diacetoxyestra- 1,3,5 (10), 14. 16-pentaen-17-one (Bull, J. R. et al. Tetrahedron 1994, 50, 6347).
Il procedimento della presente invenzione viene ulteriormente illustrato, ma non limitato, dai seguenti esempi. The process of the present invention is further illustrated, but not limited, by the following examples.
Esemplo 1 Example 1
3β-Acetossi-14β-idrossi-5β-androst-1 5-en- 17-one (I-a) 3β-Acetoxy-14β-hydroxy-5β-androst-1 5-en- 17-one (I-a)
Ad una soluzione di 25 g (67 mmoli) di 3β,17-diacetossi-5β“ androsta-14. 16-diene (IIΙ-a. Prep. 1) in 1.9 L di diossano e 0.38 L di acqua sono stati aggiunti 46.8 g (80.6 mmoli) di sale di magnesio dell' acido monoperossiftalico esaidrato all’ 85% · Dopo 2.5 ore a temperatura ambiente, è stata aggiunta una soluzione satura di sodio solfito fino a reazione negativa alla cartina amido iodurata. Il diossano è stato evaporato e la miscela risultante è stata estratta due volte con etile acetato. Le fasi organiche riunite sono state lavate con acqua, anldrificate su sodio solfato ed evaporate a pressione ridotta. Il grezzo di reazione è stato purificato mediante colonna di Si02 flash usando come eluente cicloesano : etile acetato 9 : 1 a dare 16.9 g di 3β-acetossi-14β-idrossi-5βandrost-15-en-17-one (I-a) come solido bianco (Wicha, J. et al. BulL PoL Acad. Sci 1986, 34, 313). To a solution of 25 g (67 mmol) of 3β, 17-diacetoxy-5β “androsta-14. 16-diene (IIΙ-a. Prep. 1) in 1.9 L of dioxane and 0.38 L of water were added 46.8 g (80.6 mmoles) of magnesium salt of 85% monoperoxyphthalic acid hexahydrate · After 2.5 hours at temperature environment, a saturated sodium sulphite solution was added to the iodinated starch paper until a negative reaction. The dioxane was evaporated and the resulting mixture was extracted twice with ethyl acetate. The combined organic phases were washed with water, anhydrified on sodium sulphate and evaporated under reduced pressure. The reaction crude was purified by a flash Si02 column using cyclohexane: ethyl acetate 9: 1 as eluent to give 16.9 g of 3β-acetoxy-14β-hydroxy-5βandrost-15-en-17-one (I-a) as a white solid (Wicha, J. et al. BulL PoL Acad. Sci 1986, 34, 313).
Esempio 2 Example 2
3β-tert-Butildimetilsillossi-14β-idrossi-5β-androst-15-en-17-one (I-b) 3β-tert-Butyldimethylsyloxy-14β-hydroxy-5β-androst-15-en-17-one (I-b)
Il composto (I-b) (16.5 g) è stato ottenuto come solido bianco partendo dal 3β-tert-butildimetilsililossi-17-acetossi-5β -androsta-14,16-diene (ΙI-b, Prep. 2) (25 g) usando la stessa procedura descritta nell' Esempio 1. Compound (I-b) (16.5 g) was obtained as a white solid starting from 3β-tert-butyldimethylsilyloxy-17-acetoxy-5β -androsta-14,16-diene (ΙI-b, Prep. 2) (25 g) using the same procedure described in Example 1.
Esempio 3 Example 3
3β-Acetoasi-14β-idrossiandrost-15-en-17-one (l-c) 3β-Acetoase-14β-hydroxyandrost-15-en-17-one (l-c)
Il composto (I-c) (19.2 g) è stato ottenuto come solido bianco partendo dal 3β, 17-diacetossiandrosta-14,16-diene (28 g) (Nambara, T. et al. Chem. Pharm. BulL 1977, 25, 2650) usando la stessa procedura descritta nell' Esempio 1. Compound (I-c) (19.2 g) was obtained as a white solid starting from 3β, 17-diacetoxiandrosta-14,16-diene (28 g) (Nambara, T. et al. Chem. Pharm. BulL 1977, 25, 2650 ) using the same procedure described in Example 1.
Esempio 4 Example 4
3β-Acetossi-14β-idrossiandrosta-5. 15-dien-17-one (I-d) 3β-Acetoxy-14β-hydroxyandrosta-5. 15-dien-17-one (I-d)
Il composto (I-d) (12.2 g) è stato ottenuto come solido bianco partendo dal 33,17-diacetossiandrosta-5,14, 16-triene (21 g) (Kirsch, G. et al. Tetrahedron Lett. 1989, 30, 4497) usando la stessa procedura descritta nell' Esempio 1. Compound (I-d) (12.2 g) was obtained as a white solid starting from 33,17-diacetoxiandrosta-5,14, 16-triene (21 g) (Kirsch, G. et al. Tetrahedron Lett. 1989, 30, 4497 ) using the same procedure described in Example 1.
Esempio 5 Example 5
3β-tert-Butildimetilsililossi-14β-idrossiandrosta-5.15-dien-17- 3β-tert-Butyldimethylsilyloxy-14β-hydroxyandrosta-5.15-dien-17-
Il composto (I-e) (14.1 g) è stato ottenuto come solido bianco partendo dal 3 β - tert-butildimetilsililossi- 17 -acetossiandrosta-5, 14, 16-triene (III- c Prep. 3) (25 g), usando la stessa procedura descritta nell' Esempio 1. Compound (I-e) (14.1 g) was obtained as a white solid starting from 3 β - tert-butyldimethylsilyloxy- 17 -acetoxyandrosta-5, 14, 16-triene (III- c Prep. 3) (25 g), using same procedure described in Example 1.
Esempio 6 Example 6
3- tert-Butildimetilsililossi- 14B-idrossiestra- 1. 3. 5( 10) , 15-tetraen-17-one (l-f) 3- tert-Butyldimethylsilyloxy- 14B-hydroxyester- 1. 3. 5 (10), 15-tetraen-17-one (1-f)
Il composto (I-f) (20.4 g) é stato ottenuto come solido bianco partendo dal 3-tert-butildimetilsililossi-17-acetossi-estra-1,3,5{10). Compound (I-f) (20.4 g) was obtained as a white solid starting from 3-tert-butyldimethylsilyloxy-17-acetoxy-extrac-1,3,5 {10).
14,16-pentaen-17-one (ΙΙΙ-d, Prep. 4) (31 g), usando la stessa procedura descrìtta nell' Esempio 1 . 14,16-pentaen-17-one (ΙΙΙ-d, Prep. 4) (31 g), using the same procedure described in Example 1.
Preparazione degli intermedi Preparation of intermediates
Preparazione 1 Preparation 1
3β. 17-Diacetossi-5β-androsta-14, 1 6-diene (III-a) 3β. 17-Diacetoxy-5β-androsta-14, 1 6-diene (III-a)
Ad una soluzione di 20 g (69 mmoli) di 3β-idrossi-5β-androst-15-en-17-one (Kabat. M. M. J. Org. Chem. 1995, 60. 1823), in 200 ml di ìsopropenil acetato sono stati aggiunti, in atmosfera di azoto. 2 mi (37.4 mmoli) di acido solforico 97%. Dopo una notte a temperatura ambiente sono stati aggiunti 500 mi di etile acetato e 400 mi di una soluzione satura di sodio bicarbonato. La fase acquosa è stata estratta due volte con etile acetato. Le fasi organiche riunite sono state anidrificate su sodio solfato anidro ed evaporate a pressione ridotta a dare 25 g di 36,17-diacetossi-5βandrosta-14,16-diene (Ia ). To a solution of 20 g (69 mmol) of 3β-hydroxy-5β-androst-15-en-17-one (Kabat. M. M. J. Org. Chem. 1995, 60. 1823), in 200 ml of ìsopropenyl acetate was added , in a nitrogen atmosphere. 2 ml (37.4 mmol) of 97% sulfuric acid. After one night at room temperature, 500 ml of ethyl acetate and 400 ml of a saturated sodium bicarbonate solution were added. The aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulphate and evaporated under reduced pressure to give 25 g of 36,17-diacetoxy-5βandrosta-14,16-diene (Ia).
Preparazione 2 Preparation 2
3β- tert-Butildoimetilsililossi 17-acetossi-5β -androsta- 14,16-diene (Ib ) 3β- tert-Butildoimethylsilyloxy 17-acetoxy-5β -androsta- 14,16-diene (Ib)
Il composto (Ib ) (33.9 g) è stato ottenuto dal 3β-tertbutildimetilsililossi-5β-androst-15-en-17-one (31 g. 77 mmoli) (Balogh, V. et al. Tetrahedron 1977, 33, 1321) usando la stessa procedura descritta nella Preparazione 1. Compound (Ib) (33.9 g) was obtained from 3β-tertbutyl dimethylsilyloxy-5β-androst-15-en-17-one (31 g. 77 mmol) (Balogh, V. et al. Tetrahedron 1977, 33, 1321) using the same procedure as described in Preparation 1.
Preparazione 3 Preparation 3
3β-tert-Butlldimetilsililossi-17-acetossiandrosta -5, 14. 16-triene (Ic ) 3β-tert-Butlldimethylsilyloxy-17-acetoxyandroste -5,14.16-triene (Ic)
Il composto (III-c) (29.5 g) è stato ottenuto dal 3β -tertbutildimetilsililossiandrosta-5,15-dien-17-one (27 g, 67.4 mmoli} (Takahashi, T. et al. Tetrahedron 1985, 41 , 5747) usando la stessa procedura descrìtta nella Preparazione 1. Compound (III-c) (29.5 g) was obtained from 3β-tertbutyl dimethylsiloxyandrosta-5,15-dien-17-one (27 g, 67.4 mmol} (Takahashi, T. et al. Tetrahedron 1985, 41, 5747) using the same procedure described in Preparation 1.
Preparazione 4 Preparation 4
3- tert-Butildimetilsililossi- 1 7-acetossiestra- 1.3.5(1 0). 14.16-pentaen-17-one (Id ) 3- tert-Butyldimethylsilyloxy- 1 7-acetoxyestra- 1.3.5 (1 0). 14.16-pentaen-17-one (Id)
Ad una soluzione di 3-idrossiestra-1,3,5(10),15-tetraen-17-one (35g, 123.2 mmoli) (Suzuki. E. et al. Steroids , 1995, 60, 277) in 350 ml di dimetilformammide a 0 °C sono stati aggiunti 64.9 g (430.5 mmoli) di tert-butildimetilclorosilano e 60 ml (430.5 mmoli) di trietilammina. Dopo 3 ore sótto agitazione a temperatura ambiente è stata aggiunta acqua: il precipitato è stato filtrato, lavato con 70 ml di etile acetato ed infine essiccato in stufa a pressione ridotta a 50 °C. Sono stati così ottenuti 44.3 g di 3-tertbutildimetilsililossies tra- 1 , 3 , 5( 10), 15-tetraen- 1 7-one . To a solution of 3-hydroxyestra-1,3,5 (10), 15-tetraen-17-one (35g, 123.2 mmol) (Suzuki. E. et al. Steroids, 1995, 60, 277) in 350 ml of dimethylformamide at 0 ° C 64.9 g (430.5 mmoles) of tert-butyldimethylchlorosilane and 60 ml (430.5 mmoles) of triethylamine were added. After 3 hours under stirring at room temperature, water was added: the precipitate was filtered, washed with 70 ml of ethyl acetate and finally dried in an oven under reduced pressure at 50 ° C. 44.3 g of 3-tertbuthyldimethylsilyloxies tra- 1, 3, 5 (10), 15-tetraen- 1 7-one were thus obtained.
3-tert-butildimetilsililossiestra-1,3,5(10).15-tetraen-17-one (37 g, 93 mmoli) è stato trattato come descritto nella Preparazione 1 per ottenere 36 g di 3-tert-butildimetilsililossi-17-acetossiestra-1,3,5(10), 14,16-pentaen-17-one (Id ). 3-tert-butyldimethylsilyloxyestra-1,3,5 (10) .15-tetraen-17-one (37 g, 93 mmol) was treated as described in Preparation 1 to obtain 36 g of 3-tert-butyldimethylsilyloxy-17- acetoxyestra-1,3,5 (10), 14,16-pentaen-17-one (Id).
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