ITMI20012099A1 - PROCESS FOR THE PRODUCTION OF (17ALF), 13-ETHYL-11METHYLENE-18.19-DINOPREGNA-4-EN-20-IN-17BETA-OLO (DESOGESTREL) - Google Patents
PROCESS FOR THE PRODUCTION OF (17ALF), 13-ETHYL-11METHYLENE-18.19-DINOPREGNA-4-EN-20-IN-17BETA-OLO (DESOGESTREL) Download PDFInfo
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- ITMI20012099A1 ITMI20012099A1 ITMI20012099A ITMI20012099A1 IT MI20012099 A1 ITMI20012099 A1 IT MI20012099A1 IT MI20012099 A ITMI20012099 A IT MI20012099A IT MI20012099 A1 ITMI20012099 A1 IT MI20012099A1
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- Prior art keywords
- methyl
- methylene
- reaction
- ene
- ester
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 42
- RPLCPCMSCLEKRS-BPIQYHPVSA-N desogestrel Chemical compound C1CC[C@@H]2[C@H]3C(=C)C[C@](CC)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 RPLCPCMSCLEKRS-BPIQYHPVSA-N 0.000 title claims description 20
- 229960004976 desogestrel Drugs 0.000 title claims description 18
- 238000004519 manufacturing process Methods 0.000 title description 2
- 238000006243 chemical reaction Methods 0.000 claims description 52
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 51
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 45
- 239000000203 mixture Substances 0.000 claims description 37
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 36
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 35
- 230000015572 biosynthetic process Effects 0.000 claims description 32
- 238000003786 synthesis reaction Methods 0.000 claims description 32
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 30
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 30
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 26
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 24
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 22
- AKEJUJNQAAGONA-UHFFFAOYSA-N sulfur trioxide Chemical compound O=S(=O)=O AKEJUJNQAAGONA-UHFFFAOYSA-N 0.000 claims description 22
- 230000003647 oxidation Effects 0.000 claims description 19
- 238000007254 oxidation reaction Methods 0.000 claims description 19
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 14
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims description 14
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 claims description 14
- 229940043265 methyl isobutyl ketone Drugs 0.000 claims description 14
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 13
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 11
- 230000001476 alcoholic effect Effects 0.000 claims description 11
- OSVMTWJCGUFAOD-KZQROQTASA-N formestane Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1O OSVMTWJCGUFAOD-KZQROQTASA-N 0.000 claims description 11
- 239000003960 organic solvent Substances 0.000 claims description 11
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 10
- 239000003153 chemical reaction reagent Substances 0.000 claims description 9
- -1 11-methylene-18-methyl-3a-methoxyestra-4-en-17β-ol Chemical compound 0.000 claims description 8
- 238000007171 acid catalysis Methods 0.000 claims description 8
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 claims description 8
- 238000003379 elimination reaction Methods 0.000 claims description 7
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 6
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- 229910052782 aluminium Inorganic materials 0.000 claims description 6
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims description 6
- SMZOGRDCAXLAAR-UHFFFAOYSA-N aluminium isopropoxide Chemical compound [Al+3].CC(C)[O-].CC(C)[O-].CC(C)[O-] SMZOGRDCAXLAAR-UHFFFAOYSA-N 0.000 claims description 6
- 230000007062 hydrolysis Effects 0.000 claims description 6
- 238000006460 hydrolysis reaction Methods 0.000 claims description 6
- 230000009466 transformation Effects 0.000 claims description 5
- FBPINGSGHKXIQA-UHFFFAOYSA-N 2-amino-3-(2-carboxyethylsulfanyl)propanoic acid Chemical compound OC(=O)C(N)CSCCC(O)=O FBPINGSGHKXIQA-UHFFFAOYSA-N 0.000 claims description 4
- 238000006646 Dess-Martin oxidation reaction Methods 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 238000007239 Wittig reaction Methods 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 150000007513 acids Chemical class 0.000 claims description 4
- XQTIWNLDFPPCIU-UHFFFAOYSA-N cerium(3+) Chemical class [Ce+3] XQTIWNLDFPPCIU-UHFFFAOYSA-N 0.000 claims description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
- 229920006395 saturated elastomer Polymers 0.000 claims description 4
- TVEXGJYMHHTVKP-UHFFFAOYSA-N 6-oxabicyclo[3.2.1]oct-3-en-7-one Chemical compound C1C2C(=O)OC1C=CC2 TVEXGJYMHHTVKP-UHFFFAOYSA-N 0.000 claims description 3
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 3
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 3
- 230000015556 catabolic process Effects 0.000 claims description 3
- 238000006731 degradation reaction Methods 0.000 claims description 3
- 230000008030 elimination Effects 0.000 claims description 3
- 229910052744 lithium Inorganic materials 0.000 claims description 3
- LSEFCHWGJNHZNT-UHFFFAOYSA-M methyl(triphenyl)phosphanium;bromide Chemical compound [Br-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(C)C1=CC=CC=C1 LSEFCHWGJNHZNT-UHFFFAOYSA-M 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- 239000001301 oxygen Substances 0.000 claims description 3
- 239000012279 sodium borohydride Substances 0.000 claims description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 3
- 239000012312 sodium hydride Substances 0.000 claims description 3
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 3
- KPZSTOVTJYRDIO-UHFFFAOYSA-K trichlorocerium;heptahydrate Chemical compound O.O.O.O.O.O.O.Cl[Ce](Cl)Cl KPZSTOVTJYRDIO-UHFFFAOYSA-K 0.000 claims description 3
- JRLTTZUODKEYDH-UHFFFAOYSA-N 8-methylquinoline Chemical group C1=CN=C2C(C)=CC=CC2=C1 JRLTTZUODKEYDH-UHFFFAOYSA-N 0.000 claims description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 2
- CIHXIRAAMAUYLZ-UHFFFAOYSA-N [K+].[K+].[C-]#[C-] Chemical group [K+].[K+].[C-]#[C-] CIHXIRAAMAUYLZ-UHFFFAOYSA-N 0.000 claims description 2
- 125000003158 alcohol group Chemical group 0.000 claims description 2
- 229910052783 alkali metal Inorganic materials 0.000 claims description 2
- 150000001340 alkali metals Chemical class 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 claims description 2
- VWWMOACCGFHMEV-UHFFFAOYSA-N dicarbide(2-) Chemical compound [C-]#[C-] VWWMOACCGFHMEV-UHFFFAOYSA-N 0.000 claims description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 2
- 239000011707 mineral Substances 0.000 claims description 2
- 238000006722 reduction reaction Methods 0.000 claims 2
- 239000003513 alkali Substances 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 19
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 12
- 239000012074 organic phase Substances 0.000 description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- 238000004809 thin layer chromatography Methods 0.000 description 11
- 238000001819 mass spectrum Methods 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000012071 phase Substances 0.000 description 9
- 238000002360 preparation method Methods 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 8
- 239000000047 product Substances 0.000 description 7
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- 230000007935 neutral effect Effects 0.000 description 6
- 235000017557 sodium bicarbonate Nutrition 0.000 description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 6
- 229910052938 sodium sulfate Inorganic materials 0.000 description 6
- 235000011152 sodium sulphate Nutrition 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- 238000002329 infrared spectrum Methods 0.000 description 5
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- JOPOVCBBYLSVDA-UHFFFAOYSA-N chromium(6+) Chemical compound [Cr+6] JOPOVCBBYLSVDA-UHFFFAOYSA-N 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- DEQYTNZJHKPYEZ-UHFFFAOYSA-N ethyl acetate;heptane Chemical compound CCOC(C)=O.CCCCCCC DEQYTNZJHKPYEZ-UHFFFAOYSA-N 0.000 description 2
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 2
- 229940011051 isopropyl acetate Drugs 0.000 description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 2
- 239000000583 progesterone congener Substances 0.000 description 2
- USBOABRFNZHTDU-QERJWTBHSA-N (8s,9s,10r,13s,14s)-13-ethyl-2,6,7,8,9,10,12,14,15,16-decahydro-1h-cyclopenta[a]phenanthrene-3,11,17-trione Chemical compound O=C1CC[C@@H]2[C@H]3C(=O)C[C@](CC)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1 USBOABRFNZHTDU-QERJWTBHSA-N 0.000 description 1
- SWJVCISGCDGPJY-SIRBJWHBSA-N (8s,9s,10r,13s,14s,17s)-13-ethyl-11-methylidene-2,3,6,7,8,9,10,12,14,15,16,17-dodecahydro-1h-cyclopenta[a]phenanthren-17-ol Chemical compound C1CC[C@@H]2[C@H]3C(=C)C[C@](CC)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 SWJVCISGCDGPJY-SIRBJWHBSA-N 0.000 description 1
- CAFOMEFFALHXPZ-UHFFFAOYSA-N 13-methyl-1,2,3,6,7,8,9,10,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthren-17-ol Chemical compound C1CCC2C3CCC(C)(C(CC4)O)C4C3CCC2=C1 CAFOMEFFALHXPZ-UHFFFAOYSA-N 0.000 description 1
- ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 2,3-dimethylbutane Chemical group CC(C)C(C)C ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 0.000 description 1
- 150000000703 Cerium Chemical class 0.000 description 1
- 239000003810 Jones reagent Substances 0.000 description 1
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical class C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 150000001298 alcohols Chemical group 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000005587 bubbling Effects 0.000 description 1
- 230000000711 cancerogenic effect Effects 0.000 description 1
- 231100000357 carcinogen Toxicity 0.000 description 1
- 239000003183 carcinogenic agent Substances 0.000 description 1
- 239000007806 chemical reaction intermediate Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- GCKFUYQCUCGESZ-BPIQYHPVSA-N etonogestrel Chemical compound O=C1CC[C@@H]2[C@H]3C(=C)C[C@](CC)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 GCKFUYQCUCGESZ-BPIQYHPVSA-N 0.000 description 1
- 229960002941 etonogestrel Drugs 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 230000000135 prohibitive effect Effects 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000003270 steroid hormone Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
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- Steroid Compounds (AREA)
Description
Descrizione dell’Invenzione Industriale dal titolo: Description of the Industrial Invention entitled:
“Processo per la produzione del (17a),13-etil-11-metilen-18,19-dinorpregna-4-en-20-in-17β-οΙο (DESOGESTREL)” "Process for the production of (17a), 13-ethyl-11-methylene-18,19-dinorpregna-4-en-20-in-17β-οΙο (DESOGESTREL)"
CAMPO DELL’INVENZIONE FIELD OF THE INVENTION
La presente invenzione riguarda un processo di sintesi del (17a),13-etil-11-metilen-18,19-dinorpregna-4-en-20-in-17β-olo (DESOGESTREL). TECNICA ANTERIORE The present invention relates to a synthesis process of (17a), 13-ethyl-11-methylene-18,19-dinorpregna-4-en-20-in-17β-ol (DESOGESTREL). FRONT TECHNIQUE
Il (17a), 13-etil-11 -metilen-18,19-dinorpregna-4-en-20-in-17β-οlο (desogestrel) è un potente ormone steroideo (progestinico) ampiamente utilizzato nella contraccezione orale. (17a), 13-ethyl-11-methylen-18,19-dinorpregna-4-en-20-in-17β-οlο (desogestrel) is a potent steroid hormone (progestin) widely used in oral contraception.
Sono ben noti nell’arte processi di sintesi del Desogestrel come quelli descritti in “Synthesis of 13-Ethyl-11-methylene-18,19-dinor-17a-pregn-4-en-20-yn-17-ol (Desogestrel) and its main metabolite 3-oxo Desogestrel", Sigfrid Schwarz et al., Tetrahedron Vol. 50, No. 36 pp. Desogestrel synthesis processes such as those described in "Synthesis of 13-Ethyl-11-methylene-18,19-dinor-17a-pregn-4-en-20-yn-17-ol (Desogestrel) are well known in the art and its main metabolite 3-oxo Desogestrel ", Sigfrid Schwarz et al., Tetrahedron Vol. 50, No. 36 pp.
10709-10720, 1994, o in “Synthesis of 13-Ethyl-11-methylene-18,19-dinor-17α-pregn-4-en-20-yn-17-ol", Hongwu Gao et al., OPPI BRIEFS Vol. 29, No. 5 pp. 572-576, 1997. 10709-10720, 1994, or in "Synthesis of 13-Ethyl-11-methylene-18,19-dinor-17α-pregn-4-en-20-yn-17-ol", Hongwu Gao et al., OPPI BRIEFS Vol. 29, No. 5 pp. 572-576, 1997.
Le condizioni descritte per l’attuazione dei processi di sintesi noti del desogestrel, si presentano per lo meno impegnative se non proibitive, secondo le normative di sicurezza vigenti in molti paesi industrializzati, Esse sono caratterizzate dall’uso di reagenti particolarmente pericolosi, quali agenti ossidanti a base di cromo esavalente, cancerogeno (reattivo di Jone’s), e agenti solforanti mercaptanici aggressivi ed altamente volatili, in pratica reagenti, la cui elevata tossicità e contestuale capacità di contaminazione degli ambienti di lavoro, ne rende difficile l’impiego a livello industriale. The conditions described for the implementation of the known synthesis processes of desogestrel, are at least demanding if not prohibitive, according to the safety regulations in force in many industrialized countries, They are characterized by the use of particularly dangerous reagents, such as oxidizing agents based on hexavalent chromium, carcinogen (Jone's reactive), and aggressive and highly volatile mercaptanic sulphurous agents, basically reagents, whose high toxicity and contextual contamination capacity of the workplace, makes it difficult to use on an industrial level.
Era dunque sentita l'esigenza di realizzare nuove vie di sintesi con reazioni caratterizzate da elevate rese, facilmente realizzabili su scala industriale, con intermedi d’elevato grado di purezza, mediante l’uso di reagenti con scarsa tossicità facilmente reperibili in commercio o facilmente sitetizzabili. The need was therefore felt to create new synthesis routes with reactions characterized by high yields, easily achievable on an industrial scale, with intermediates of a high degree of purity, through the use of reagents with low toxicity easily available on the market or easily settable. .
SOMMARIO SUMMARY
E’ stato ora scoperto un nuovo processo di sintesi del (17a),13-etil-11-metilen-18,19-dìnorpregna-4-en-20-in-17β-olo (DESOGESTREL) capace di superare gli inconvenienti propri dei processi noti nell’arte. A new synthesis process of (17a), 13-ethyl-11-methylene-18,19-dìnorpregna-4-en-20-in-17β-ol (DESOGESTREL) has now been discovered, capable of overcoming the drawbacks of processes known in the art.
La Richiedente ha inaspettatamente e sorprendentemente trovato un nuovo processo di sintesi del (17a),13-etil-11-metilen-18,19-dinorpregna-4-en-20-in-17β-olo (DESOGESTREL) caratterizzato da passaggi di facile applicabilità industriale ed alta resa, utilizzando reagenti facilmente reperibili in commercio o realizzabili in situ, più sicuri nella loro manipolazione rispetto ai reattivi indicati neH’arte nota tra cui, in particolare, il reattivo di Jone’s e/o l’etilentiochetale. The Applicant has unexpectedly and surprisingly found a new synthesis process of (17a), 13-ethyl-11-methylene-18,19-dinorpregna-4-en-20-in-17β-ol (DESOGESTREL) characterized by easy steps industrial applicability and high yield, using reagents readily available on the market or achievable in situ, safer in their handling than the reagents indicated in the known art, including, in particular, the reagent of Jone's and / or ethylentioketal.
DESCRIZIONE DELLA FIGURA DESCRIPTION OF THE FIGURE
Figura 1 : schema di sintesi del (17a),13-etil-11-metilen-18,19-dinorpregna-4-en-20-in-17β-olo (DESOGESTREL). Figure 1: Synthesis scheme of (17a), 13-ethyl-11-methylene-18,19-dinorpregna-4-en-20-in-17β-ol (DESOGESTREL).
DESCRIZIONE DETTAGLIATA DELL’INVENZIONE DETAILED DESCRIPTION OF THE INVENTION
Costituisce pertanto un oggetto della presente invenzione un processo di sintesi del (17a),13-etil-1 1-metilen-18,19-dinorpregna-4-en-20-in-17p-olo (DESOGESTREL) comprendente le fasi: Therefore, an object of the present invention is a synthesis process of (17a), 13-ethyl-1 1-methylene-18,19-dinorpregna-4-en-20-in-17p-ol (DESOGESTREL) comprising the steps:
A) Trasformazione del 3, 17-dicheto-11 -metilen-18-metil-estra-4-ene nel corrispondente 17p-idrossi-1 1 -metilen-18-metil-estra-4-ene per degradazione della funzione carbonilica in posizione 3 con eliminazione dell’ossigeno e riduzione ad alcool della funzione carbonilica in posizione 17; A) Transformation of 3, 17-diket-11-methylene-18-methyl-ester-4-ene into the corresponding 17p-hydroxy-1 1-methylen-18-methyl-ester-4-ene by degradation of the carbonyl function in position 3 with elimination of oxygen and reduction to alcohol of the carbonyl function in position 17;
B) Ossidazione del gruppo alcolico 17β a carbonile del 17p-idrossi-11 -metilen-1 8-metil-estra-4-ene a dare il corrispondente 11-metilen-1 8-metil-estra-4-ene-1 7-one; B) Oxidation of the 17β alcoholic group to carbonyl of 17p-hydroxy-11-methylen-1 8-methyl-ester-4-ene to give the corresponding 11-methylen-1 8-methyl-ester-4-ene-1 7- one;
C) Etinilazione del 11 -metilen-1 8-metil-estra-4-ene-1 7-one a dare il (17a),13-etil-11 -metilen-1 8,1 9-dinorpregna-4-en-20-in-17p-olo; in cui la fase A) è costituita da: C) Ethinylation of 11-methylen-1 8-methyl-ester-4-ene-1 7-one to give (17a), 13-ethyl-11-methylen-1 8,1 9-dinorpregna-4-en- 20-in-17p-ol; in which phase A) consists of:
1 ) reazione del 11 -metilen-1 8-metil-estra-4-en-3,17-dione con boroidruri alcalini, in presenza di sali di cerio(lll), in miscele, anidre o acquose, di solventi organici scelti dal gruppo consistente di: metanolo, etanolo, isopropanolo, tetraidrofurano, o loro miscele, detti solventi organici in combinazione con metanolo, a temperatura tra -20°C e 60°C a dare una miscela di 1 1 -metilen-18-metil-estra-4-en-3a,17p-diolo e 11 -metilen-1 8-metil-estra-4-en-3p,17p-diolo; 1) reaction of 11-methylen-1 8-methyl-extra-4-en-3,17-dione with alkaline borohydrides, in the presence of cerium (III) salts, in anhydrous or aqueous mixtures of organic solvents selected by group consisting of: methanol, ethanol, isopropanol, tetrahydrofuran, or their mixtures, said organic solvents in combination with methanol, at a temperature between -20 ° C and 60 ° C to give a mixture of 1 1 -methylene-18-methyl-extract -4-en-3a, 17p-diol and 11-methylen-1 8-methyl-estro-4-en-3p, 17p-diol;
2) reazione di una miscela di 1 1 -metilen-18-metil-estra-4-en-3a,17p-diolo e 11 -metilen-1 8-metil-estra-4-en-3p-17p-diolo con metanolo in presenza di catalisi acida a dare una miscela di 11-metilen-1 8-metil-3α-metossi-estra-4-en-1 7β-οΙο e 11 -metilen-18-metil-3β-metossi-estra-4-en-1 7β-οΙο; 2) reaction of a mixture of 1 1 -methylen-18-methyl-ester-4-en-3a, 17p-diol and 11 -methylen-1 8-methyl-ester-4-en-3p-17p-diol with methanol in the presence of acid catalysis to give a mixture of 11-methylene-1 8-methyl-3α-methoxy-estrus-4-en-1 7β-οΙο and 11-methylene-18-methyl-3β-methoxy-extra-4- en-1 7β-οΙο;
3) reazione di una miscela di 11 -metilen-1 8-metil-3a-metossiestra-4-en-17β-οlο e 11 -metilen-1 8-metil-3β -metossi-estra-4-en-17β-οlο con litio ed etilammina in solvente etereo a temperature tra -80°C e 0°C a dare 11 -metilen-18-metil -estra-4-en-17β-οlo. Preferibilmente nel processo oggetto della presente invenzione nella reazione di riduzione contemporanea dei due gruppi carbonilici in posizione 3 (coniugato al doppio legame) e in posizione 17 (saturo) ad alcool del 11 -metilen-1 8-metil-estra-4-en-3,17-dione con boroidruri alcalini, in presenza di sali di cerio(lll), il solvente è metanolo. 3) reaction of a mixture of 11-methylen-1 8-methyl-3a-methoxyestra-4-en-17β-οlο and 11-methylen-1 8-methyl-3β-methoxy-estrus-4-en-17β-οlο with lithium and ethylamine in ethereal solvent at temperatures between -80 ° C and 0 ° C to give 11-methylen-18-methyl-esters-4-en-17β-οlo. Preferably in the process object of the present invention in the reaction of simultaneous reduction of the two carbonyl groups in position 3 (conjugated to the double bond) and in position 17 (saturated) to alcohol of 11-methylene-1 8-methyl-extra-4-en- 3,17-dione with alkaline borohydrides, in the presence of cerium salts (III), the solvent is methanol.
Nella reazione di conversione del 11 -metilen-18-metil-estra-4-en-3, 17-dione in una miscela di 11 -metilen-18-metil-estra-4-en-3α,17β -diolo e 11- preferibilmente il boroidruro alcalino è sodio boroidruro, preferibilmente il sale di cerio (III) è il cerio tricloruro eptaidrato, preferibilmente la temperature è compresa tra 0°C e 10°C. In the reaction of converting 11-methylen-18-methyl-ester-4-en-3, 17-dione into a mixture of 11-methylene-18-methyl-ester-4-en-3α, 17β-diol and 11- preferably the alkaline borohydride is sodium borohydride, preferably the cerium (III) salt is the cerium trichloride heptahydrate, preferably the temperature is between 0 ° C and 10 ° C.
Nella reazione di trasformazione della miscela di 11-metilen-18-metil- e In the transformation reaction of the mixture of 11-methylene-18-methyl- e
con metanolo in presenza di catalisi acida a dare una miscela di 11-metilen-18-metil-3a-metossi-estra-4-en -olo e 1 1 -metilen-18-metil- la catalisi acida è ottenuta con acidi scelti dal gruppo consistente di: acido paratoluensolfonico, acido cloridrico, acido solforico, preferibilmente la catalisi acida è ottenuta con acido paratoluensolfonico. with methanol in the presence of acid catalysis to give a mixture of 11-methylene-18-methyl-3a-methoxy-estra-4-en -ol and 1 1 -methylene-18-methyl- acid catalysis is obtained with acids selected from group consisting of: paratoluenesulfonic acid, hydrochloric acid, sulfuric acid, preferably the acid catalysis is obtained with paratoluenesulfonic acid.
Nella reazione di eliminazione del gruppo metossi in posizione 3 nella miscela di 11-metilen-18-metil-3α-metossi-estra-4-en-17β-olo e 11-metilen-18-metil-3β-metossi-estra-4-en-17β-olo il solvente etereo è preferibilmente scelto dal gruppo consistente di: etere dietilico, diisopropilico, metilterbutilico, tetraidrofurano o loro miscele, più preferibilmente il solvente è il tetraidrofurano. Preferibilmente detta reazione di eliminazione del gruppo metossi avviene ad una temperatura tra -65°C e -55°C. In the elimination reaction of the methoxy group in position 3 in the mixture of 11-methylene-18-methyl-3α-methoxy-estrus-4-en-17β-ol and 11-methylene-18-methyl-3β-methoxy-extr-4 -en-17β-ol the ethereal solvent is preferably selected from the group consisting of: diethyl, diisopropyl, methylterbutyl ether, tetrahydrofuran or mixtures thereof, more preferably the solvent is tetrahydrofuran. Preferably, said elimination reaction of the methoxy group takes place at a temperature between -65 ° C and -55 ° C.
Nello sviluppo del nuovo processo di sintesi del progestinico desogestrel secondo la presente invenzione, la Richiedente ha trovato che la fase B) di ossidazione, generalmente condotta mediante reattivo di Jones caratterizzato dall’uso di cromo esavalente, è inaspettatamente attuabile mediante una delle reazioni scelte dal gruppo consistente di: reazione del 17p-idrossi-1 1-metilen-18-metil-estra-4-ene con metilisobutilchetone e alluminio isopropilato in toluene, reazione del 17β-idrossi-1 1-metilen-18-metil-estra-4-ene con il complesso piridina.zolfo triossido in dimetilsolfossido e trietilammina, reazione del 17β-idrossi-11-metilen-18-metil-estra-4-ene con il reattivo di Dess-Martin (periodinano), reattivo quest’ultimo facilmente sintetizzabile come descritto in J. Org. Chem. In the development of the new synthesis process of the desogestrel progestogen according to the present invention, the Applicant has found that the oxidation step B), generally carried out by means of a Jones reagent characterized by the use of hexavalent chromium, is unexpectedly feasible by means of one of the reactions chosen by the group consisting of: reaction of 17p-hydroxy-1 1-methylene-18-methyl-estra-4-ene with methyl isobutyl ketone and aluminum isopropylate in toluene, reaction of 17β-hydroxy-1 1-methylene-18-methyl-extractor-4 -ene with the pyridine complex, sulfur trioxide in dimethylsulfoxide and triethylamine, reaction of 17β-hydroxy-11-methylene-18-methyl-estra-4-ene with Dess-Martin's reagent (periodinan), which is easily synthesized as described in J. Org. Chem.
1983, 48, 4155-4156, J. Am. Chem. Soc. 1991 , 113, 7277-7287, J. Org. Chem. 1993, 58, 2899 e in “Practical tips on thè preparation of thè Dess-Martin Periodinane'’, William B. Geiss, Technical report, voi. 1 , No. 11 della Albany Molecular Research. 1983, 48, 4155-4156, J. Am. Chem. Soc. 1991, 113, 7277-7287, J. Org. Chem. 1993, 58, 2899 and in "Practical tips on the preparation of the Dess-Martin Periodinane '', William B. Geiss, Technical report, vol. 1, No. 11 from Albany Molecular Research.
Costituisce pertanto un ulteriore oggetto della presente invenzione il processo di sintesi del (17a),13-etil-1 1 -metilen-1 8,19-dinorpregna-4-en-20-in-17β-οlο (DESOGESTREL) in cui l'ossidazione del 17p-idrossi-1 1 -metilen-1 8-metil-estra-4-ene a 11-metilen-18-metil-estra-4-ene-17-one, seguita da etinilazione a dare il desogestrel, è scelta dal gruppo consistente di: reazione del 17β-idrossi-1 1 -metilen-18-metil-estra-4-ene con metilisobutilchetone e alluminio isopropilato in toluene, reazione del 17β-idrossi-1 1 -metilen-18-metil-estra-4-ene con il complesso piridina.zolfo triossido in dimetilsolfossido e trietilammina, reazione del 17β-idrossi-1 1 -metilen-18-metil-estra-4-ene con il reattivo di Dess-Martin (periodinano). Therefore, a further object of the present invention is the synthesis process of (17a), 13-ethyl-1 1 -methylen-1 8,19-dinorpregna-4-en-20-in-17β-οlο (DESOGESTREL) in which the Oxidation of 17p-hydroxy-1 1 -methylen-1 8-methyl-ester-4-ene to 11-methylene-18-methyl-ester-4-ene-17-one, followed by ethinylation to give desogestrel, is selected from the group consisting of: reaction of 17β-hydroxy-1 1 -methylen-18-methyl-ester-4-ene with methylisobutylketone and aluminum isopropylated in toluene, reaction of 17β-hydroxy-1 1 -methylene-18-methyl-extract -4-ene with the pyridine-sulfur trioxide complex in dimethylsulfoxide and triethylamine, reaction of 17β-hydroxy-1 1-methylen-18-methyl-estra-4-ene with Dess-Martin's reagent (periodinan).
In particolare secondo il processo oggetto della presente invenzione la fase C) di etinilazione del 11 -metilen-1 8-metil-estra-4-en-17-one consiste nella reazione di 11 -metilen-1 8-metil-estra-4-en-17-one con acetiluri di metalli alcalini in tetraidrofurano a temperature tra -40°C e 40°C a dare (17a),13-etil-1 1 -metilen-18-1 9-dinorpregn-4-en-20-in-17β-olo. Più in particolare l'acetiluro è l’acetiluro di potassio. In particular, according to the process object of the present invention, step C) of ethinylation of 11-methylen-1 8-methyl-ester-4-en-17-one consists of the reaction of 11-methylen-1 8-methyl-extract-4 -en-17-one with alkali metal acetylides in tetrahydrofuran at temperatures between -40 ° C and 40 ° C to give (17a), 13-ethyl-1 1 -methylene-18-1 9-dinorpregn-4-en- 20-in-17β-ol. More specifically, acetylide is potassium acetylide.
Il nuovo processo di sintesi del desogestrel sviluppato dalla Richiedente nella fase A) di trasformazione del 3, 17-dicheto-11 -metilen-18-metilestra-4-ene nel corrispondente 17β-idrossi-1 1 -metilen-18-metil-estra-4-ene per degradazione della funzione carbonilica in posizione 3 con eliminazione dell’ossigeno e riduzione ad alcool della funzione carbonilica in posizione 17, porta alla sintesi di nuovi intermedi identificabili e separabili quali: 11 -metilen-18-metil-estra-4-en-3a,17βdiolo, 11 -metilen-18-metil-estra-4-en-3β-17β-diolo o loro miscele, 11-metilen- 18-metil-3a-metossi-estra-4-en- 17β-οlο e 11 -metilen- 18-metil The new desogestrel synthesis process developed by the Applicant in step A) for the transformation of 3, 17-diket-11 -methylene-18-methylestra-4-ene into the corresponding 17β-hydroxy-1 1 -methylen-18-methyl-extract -4-ene by degradation of the carbonyl function in position 3 with elimination of oxygen and reduction to alcohol of the carbonyl function in position 17, leads to the synthesis of new identifiable and separable intermediates such as: 11 -methylen-18-methyl-ester-4 -en-3a, 17βdiol, 11-methylen-18-methyl-estrus-4-en-3β-17β-diol or mixtures thereof, 11-methylene-18-methyl-3a-methoxy-extract-4-en- 17β- οlο and 11-methylene 18-methyl
Costituisce pertanto ulteriore oggetto della presente invenzione il composto di formula: Therefore, a further object of the present invention is the compound of formula:
dove R è scelto dal gruppo consistente di: where R is chosen from the group consisting of:
Una forma di realizzazione preferita del processo di sintesi del (17a),13- oggetto della presente invenzione comprende, oltre alle fasi A), B) e C) di cui sopra, una fase A’) di sintesi del 3,17-dicheto-11-metilen-18-metil-estra-4-ene, in cui il 3,11,17-tricheto-18-metil-estra-5-ene 3,17-etilenchetale, mediante la reazione di Wittig è trasformato in 11 -metilen-18metilestra-5-en-3,17-dione 3,17-dietilenchetale, seguita dall'idrolisi dei due gruppi etilenchetali con acidi minerali acquosi in solvente organico ad una temperatura compresa tra -10°C e 60°C a dare 3,17-dicheto-11-metilen-18-metil-estra-4-ene. A preferred embodiment of the synthesis process of (17a), 13- object of the present invention comprises, in addition to the above steps A), B) and C), a step A ') of synthesis of the 3,17-diket -11-methylen-18-methyl-ester-4-ene, in which 3,11,17-tricheto-18-methyl-estr-5-ene 3,17-ethylenchetal, by the Wittig reaction is transformed into 11 -methylen-18methylestra-5-en-3,17-dione 3,17-diethylenchetal, followed by the hydrolysis of the two ethylenchetal groups with aqueous mineral acids in organic solvent at a temperature between -10 ° C and 60 ° C to give 3,17-diketo-11-methylene-18-methyl-ester-4-ene.
Preferibilmente la reazione di Wittig è condotta con sodio idruro, dimetilsolfossido e metiltrifenilfosfonio bromuro. Preferably the Wittig reaction is carried out with sodium hydride, dimethyl sulfoxide and methyl triphenyl phosphonium bromide.
Preferibilmente i solventi organici nell’idrolisi dei due gruppi etilenchetali sono scelti dal gruppo consistente di: acetone, tetraidrofurano, metiletilchetone, metilisobutilchetone, più preferibilmente il solvente è acetone. Preferably the organic solvents in the hydrolysis of the two ethylenchetal groups are selected from the group consisting of: acetone, tetrahydrofuran, methylethylketone, methylisobutylketone, more preferably the solvent is acetone.
Preferibilmente la temperatura di idrolisi dei due gruppi etilenchetali è compresa tra 15°C e 25°C. Preferably the hydrolysis temperature of the two ethylenchetal groups is comprised between 15 ° C and 25 ° C.
Un ulteriore forma di realizzazione ancor più preferita del processo di sintesi del (17α), 13-etil-1 1 -metilen-18-19-dinorpregn-4-en-20-in-1 7β-οΙο oggetto della presente invenzione comprende, oltre alle fasi A'), A), B) e C) di cui sopra, una fase A”) di sintesi del 3,11 ,17-tricheto-18-metil-estra-5-ene 3,17-etilenchetale, in cui il 3,11 ,17-tricheto-18-metil-estra-5-ene 3,17-etilenchetale è ottenuto dal 3-cheto-18-metil-estra-4-en-1 1α,17βdiolo per ossidazione dei gruppi alcolici in posizione 11 e 17 a carbonili mediante le condizioni operative scelte dal gruppo consistente di: reazione con metilisobutilchetone e alluminio isopropilato in toluene, reazione con il complesso piridina.zolfo triossido in dimetilsolfossido e trietilammina, reazione con il reattivo di Dess-Martin (periodinano); e i gruppi carbonili in posizione 3 e 17 sono protetti come etilenchetali a dare il 3,11 ,17-tricheto-18-metil-estra-5-ene 3,17-etilenchetale. A further still more preferred embodiment of the synthesis process of (17α), 13-ethyl-1 1-methylen-18-19-dinorpregn-4-en-20-in-1 7β-οΙο object of the present invention comprises, in addition to the phases A '), A), B) and C) above, a phase A ") of the synthesis of 3,11, 17-tricheto-18-methyl-estro-5-ene 3,17-ethylenchetal, in which 3,11, 17-tricheto-18-methyl-estrus-5-ene 3,17-ethylenchetal is obtained from 3-keto-18-methyl-estr-4-en-1 1α, 17βdiol by oxidation of the groups alcohols in position 11 and 17 to carbonyls by means of the operating conditions chosen from the group consisting of: reaction with methylisobutylketone and aluminum isopropylate in toluene, reaction with the pyridine complex, sulfur trioxide in dimethylsulfoxide and triethylamine, reaction with Dess-Martin reagent (periodinane ); and the carbonyl groups in position 3 and 17 are protected as ethylenchetals to give 3,11, 17-tricheto-18-methyl-ester-5-ene 3,17-ethylenchetal.
Preferibilmente la fase A") del processo di sintesi del (17a),13-etil-1 1-metilen-18-19-dinorpregn-4-en-20-in-17β-olo oggetto della presente invenzione consiste di: Preferably, phase A ") of the synthesis process of (17a), 13-ethyl-1 1-methylene-18-19-dinorpregn-4-en-20-in-17β-ol object of the present invention consists of:
ai) ossidazione dei gruppi alcolici in posizione 11 e 17 a carbonili ai) oxidation of alcohol groups in position 11 and 17 to carbonyls
con il complesso with the complex
piridina.zolfo triossido in dimetilsolfossido e trietillammina o con il reattivo di Dess-Martin (periodinano), a dare il 3,11 ,17-tricheto-18-metil-estra-4-ene; pyridine, sulfur trioxide in dimethylsulfoxide and triethylamine or with the Dess-Martin reagent (periodinan), to give 3,11, 17-tricheto-18-methyl-extra-4-ene;
aii ) protezione dei carbonili in posizione 3 e 17 come etilenchetali con glicole etilenico in metilene cloruro e trietilortoformiato e acido paratoluensolfonico a dare il 3,11 ,17-tricheto-18-metil-estra-5-ene 3.17-etilenchetale aii) protection of the carbonyls in position 3 and 17 as ethylenchetals with ethylene glycol in methylene chloride and triethylorthoformate and paratoluenesulfonic acid to give 3,11, 17-tricheto-18-methyl-estro-5-ene 3.17-ethylenchetal
o di: you hate:
bi) ossidazione a carbonile del solo gruppo alcolico in posizione 17 del 3-cheto-18-metil-estra-4-en-11a,17β-diolo con metilisobutilchetone e alluminio isopropilato in toluene a dare il 3.17-dicheto-1 8-metil-estra-4-en-1 1 α-olo; bi) oxidation to carbonyl of the alcoholic group only in position 17 of the 3-keto-18-methyl-estran-4-en-11a, 17β-diol with methyl isobutyl ketone and aluminum isopropylated in toluene to give 3.17-diket-1 8-methyl -estra-4-en-1 1 α-ol;
bii) protezione dei carbonili in posizione 3 e 17 come etilenchetali con glicole etilenico in metilene cloruro e trietilortoformiato e acido paratoluensolfonico a dare 3, 17-dicheto-18-metil-estra-4-en-1 1αolo 3,17-etilenchetale; bii) protection of carbonyls in position 3 and 17 as ethylenchetals with ethylene glycol in methylene chloride and triethylorthoformate and paratoluenesulfonic acid to give 3,17-diketo-18-methyl-ester-4-en-1 1αol 3,17-ethylenchetal;
bili) ossidazione a carbonile del gruppo alcolico in posizione 11 del 3.17-dicheto-18-metil-estra-4-en-11a-olo 3,17-etilenchetale con il complesso piridina.zolfo triossido in dimetilsolfossido e trietillammina o con il reattivo di Dess-Martin (periodinano). bili) oxidation to carbonyl of the alcoholic group in position 11 of 3.17-diketo-18-methyl-extractor-4-en-11a-ol 3,17-ethylenchetal with the pyridine complex, sulfur trioxide in dimethylsulfoxide and triethylamine or with the reagent of Dess-Martin (periodinano).
I prodotti e gli intermedi di reazione sono stati caratterizzati mediante tecniche di analisi IR, Massa (MS) e NMR: <1>H e <13>C. The reaction products and intermediates were characterized by IR, Mass (MS) and NMR analysis techniques: <1> H and <13> C.
Sono riportati qui di seguito alcuni esempi a scopo illustrativo ma non limitativo della presente invenzione. Some examples are reported hereinafter for illustrative but not limitative purposes of the present invention.
I dati analitici riportati qui di seguito sono stati ottenuti nelle seguenti condizioni: The analytical data reported below were obtained under the following conditions:
- spettri IR ottenuti da campioni in pastiglia di KBr - IR spectra obtained from KBr tablet samples
- spettri NMR registrati su campioni sciolti in CDCI3 - NMR spectra recorded on samples dissolved in CDCI3
- spettri di Massa (MS) ottenuti per impatto elettronico. - Mass spectra (MS) obtained by electronic impact.
Esempio 1: preparazione dei 3,11,17-tricheto-18-metil-estra-5-ene 3,17-etilenchetale Example 1: preparation of 3,11,17-tricheto-18-methyl-estro-5-ene 3,17-ethylenchetal
Via di sintesi a) Way of synthesis a)
i) In un reattore anidro ed in atmosfera inerte si carica a 20°C 50 g di 11a, 17β-diidrossi-18-metil-estra-4-en-3-one con 180 mi di dimetilsolfossido e 355 mi di trietilammina. i) In an anhydrous reactor and in an inert atmosphere, 50 g of 11a, 17β-dihydroxy-18-methyl-ester-4-en-3-one with 180 ml of dimethyl sulfoxide and 355 ml of triethylamine are charged at 20 ° C.
Si aggiunge quindi a porzioni 170 g di complesso piridina-zolfo triossido mantenendo la temperatura a circa 20°C. 170 g of pyridine-sulfur trioxide complex is then added in portions, maintaining the temperature at about 20 ° C.
Si controlla su cromatografia su strato sottile l'andamento della reazione e dopo circa 3 ore si versa la miscela di reazione in 3 litri di acqua e ghiaccio, dopo 1 ora il solido sospeso viene filtrato e lavato con acqua. The progress of the reaction is checked on thin layer chromatography and after about 3 hours the reaction mixture is poured into 3 liters of water and ice, after 1 hour the suspended solid is filtered and washed with water.
Si cristallizza con 250 ml di etere isopropilico, si filtra e si secca ottenendo un solido cristallino che consiste in 44,5 g di 18-metilestra-4-en-3 ,11,17-trione . It is crystallized with 250 ml of isopropyl ether, filtered and dried to obtain a crystalline solid consisting of 44.5 g of 18-methylestra-4-en-3,11,17-trione.
Dati analitici: IR = 1738, 1701, 1662, 1608 1/cm; MS (m/z): 300 Analytical data: IR = 1738, 1701, 1662, 1608 1 / cm; MS (m / z): 300
<1> <1>
(1 H s H-4); 5=0,80 ppm (3H 1 18-CH3). (1 H s H-4); 5 = 0.80 ppm (3H 1 18-CH3).
ii) In un reattore anidro ed in atmosfera inerte si caricano a 20°C 71 g di 18-metil-estra-4-en-3, 11,17-trione proveniente dalla fase precedente con 1,5 I di cloruro di metilene, 150 ml di glicole etilenico, 450 mi di trietilortoformiato e 7,1 g di acido paratoluensolfonico. ii) In an anhydrous reactor and in an inert atmosphere, 71 g of 18-methyl-ester-4-en-3, 11,17-trione coming from the previous phase are loaded at 20 ° C with 1.5 I of methylene chloride, 150 ml of ethylene glycol, 450 ml of triethylorthoformate and 7.1 g of paratoluenesulfonic acid.
Si scalda a riflusso controllando con cromatografia su strato sottile l'andamento della reazione e dopo circa 24 ore si versa la miscela di reazione in 700 mi di sodio bicarbonato acquoso al 5%. It is heated under reflux, checking the progress of the reaction with thin layer chromatography and after about 24 hours the reaction mixture is poured into 700 ml of aqueous sodium bicarbonate at 5%.
Si separano le fasi lavando la fase organica con sodio bicarbonato acquoso al 5% e poi con acqua fino a pH neutro. The phases are separated by washing the organic phase with aqueous sodium bicarbonate at 5% and then with water until neutral pH.
Si concentra a secco la fase organica, precedentemente anidrificata da sodio solfato, e l’olio ottenuto è purificato per cromatografia su colonna di gel di silice eluendo con gradiente eptano-acetato di etile. The organic phase, previously anhydrified from sodium sulfate, is concentrated to dryness, and the oil obtained is purified by chromatography on a silica gel column, eluting with a heptane-ethyl acetate gradient.
Si ottengono, dopo evaporazione del solvente a 50°C a pressione ridotta, 58 g di 18-metil-estra-5-en-3,11 ,17-trione- 3,17-dietilenchetale e 5 g di 18-metil-estra-5-en-3,11 ,17-trione-3,11 ,17-trietilenchetale. After evaporation of the solvent at 50 ° C under reduced pressure, 58 g of 18-methyl-ester-5-en-3,11, 17-trione-3,17-diethylenchetal and 5 g of 18-methyl-extract are obtained. -5-en-3,11,17-trione-3,11,17-triethylenchetal.
Il prodotto principale mostra spettri IR, NMR e MASSA concordi con quanto descritto in SYNTHETIC COMMUNICATIONS (1995), 25(18), 2807-2811. The main product shows IR, NMR and MASS spectra in agreement with what is described in SYNTHETIC COMMUNICATIONS (1995), 25 (18), 2807-2811.
Via di sintesi b) Route of synthesis b)
i) In un reattore anidro ed in atmosfera inerte si caricano a 20°C 170 mi di toluene e 170 mi di metilisobutilchetone, si scalda e si distillano 40 mi di teste. Si aggiunge 10 g di alluminio isopropilato e 5 g di 1 1 a, 17β-diidrossi-18-metil-estra-4-en-3-one. i) 170 ml of toluene and 170 ml of methyl isobutyl ketone are charged to 20 ° C in an anhydrous reactor and in an inert atmosphere, 40 ml of heads are heated and distilled. 10 g of isopropylated aluminum and 5 g of 1 1 a, 17β-dihydroxy-18-methyl-ester-4-en-3-one are added.
Si scalda a riflusso per 4 ore controllando il fine reazione con cromatografia su strato sottile, si raffredda a 20°C e si aggiunge una soluzione di 10 g di sodio idrossido in 300 mi di acqua, si estrae nuovamente la fase acquosa con 100 mi di toluene e le fasi organiche riunite si lavano con acqua fino a pH neutro, si evapora sino ad ottenere un residuo oleoso che viene purificato per cromatografia su gel di silice. The mixture is refluxed for 4 hours, checking the end of the reaction with thin layer chromatography, it is cooled to 20 ° C and a solution of 10 g of sodium hydroxide in 300 ml of water is added, the aqueous phase is extracted again with 100 ml of Toluene and the combined organic phases are washed with water up to neutral pH, evaporated until an oily residue is obtained which is purified by chromatography on silica gel.
Si ottengono, dopo cristallizzazione con etere isopropilico, 3,5 g di 11 a-idrossi-1 8-metil-estra-4-en-3, 17-dione. After crystallization with isopropyl ether, 3.5 g of 11 a-hydroxy-1 8-methyl-ester-4-en-3,17-dione are obtained.
Dati analitici: IR = 3437, 1732, 1645, 1605 1/cm; MS (m/z): 302 Analytical data: IR = 3437, 1732, 1645, 1605 1 / cm; MS (m / z): 302
ii) In un reattore anidro ed in atmosfera inerte si caricano a 20°C 2,5 g di 11 a-idrossi-1 8-metil-estra-4-en-3,1 7-dione, provenienti dalla fase precedente, con 50 ml di cloruro di metilene, 25 ml di glicole etilenico, 20 mi di trietilortoformiato e 0,5 g di acido paratoluensolfonico. ii) In an anhydrous reactor and in an inert atmosphere, 2.5 g of 11 a-hydroxy-1 8-methyl-ester-4-en-3,1 7-dione, coming from the previous phase, are charged at 20 ° C with 50 ml of methylene chloride, 25 ml of ethylene glycol, 20 ml of triethylorthoformate and 0.5 g of paratoluenesulfonic acid.
Si scalda a riflusso controllando con cromatografia su strato sottile l'andamento della reazione e dopo circa 24 ore si versa la miscela di reazione in 100 mi di sodio bicarbonato acquoso al 5%. It is heated under reflux, checking the progress of the reaction with thin layer chromatography and after about 24 hours the reaction mixture is poured into 100 ml of aqueous sodium bicarbonate at 5%.
Si separano le fasi lavando la fase organica con sodio bicarbonato acquoso al 5% e poi con acqua fino a pH neutro. The phases are separated by washing the organic phase with aqueous sodium bicarbonate at 5% and then with water until neutral pH.
Si concentra a secco la fase organica, precedentemente anidrificata da sodio solfato, e l'olio ottenuto è cristallizzato in etere etilico. The organic phase, previously anhydrified by sodium sulphate, is concentrated to dryness and the oil obtained is crystallized in ethyl ether.
Si ottengono 3 g di 11 a-idrossi-1 8-metil-estra-5-en-3, 17-dione-3,17-dietilenchetale che passa tal quale alla reazione seguente. Un campione è purificato per cromatografia su gel di silice e ricristallizato da etere etilico. 3 g of 11 a-hydroxy-1 8-methyl-ester-5-en-3,17-dione-3,17-diethylenchetal are obtained which passes as such to the following reaction. A sample is purified by silica gel chromatography and recrystallized from ethyl ether.
Il prodotto mostra spettri IR, NMR e MASSA concordi con quanto descritto in SYNTHETIC COMMUNICATIONS (1997), 27(11), 1981-87. The product shows IR, NMR and MASS spectra in agreement with what is described in SYNTHETIC COMMUNICATIONS (1997), 27 (11), 1981-87.
ii) In un reattore anidro ed in atmosfera inerte si caricano a 20°C 2,5 g di 11a-idrossi-18-metil-estra-5-en-3,17-dione- 3,17-dietilenchetale, provenienti dalla fase precedente, con 10 mi di dimetilsolfossido e 20 mi di trietilammina. ii) In an anhydrous reactor and in an inert atmosphere, 2.5 g of 11a-hydroxy-18-methyl-ester-5-en-3,17-dione-3,17-diethylenchetal, coming from phase above, with 10 ml of dimethyl sulfoxide and 20 ml of triethylamine.
Si aggiunge quindi a porzioni 8 g di complesso piridina.zolfo triossido mantenendo la temperatura a circa 20°C. 8 g of pyridine sulfur trioxide complex is then added in portions while maintaining the temperature at about 20 ° C.
Si controlla su cromatografia su strato sottile l’andamento della reazione e dopo circa 3 ore si versa la miscela di reazione in 150 mi di sodio bicarbonato, soluzione acquosa satura, dopo 1 ora il solido sospeso viene filtrato, lavato con acqua e cristalizzato con etere isopropilico. Si ottengono 2 g di 18-metil-estra-5-en-3, 11,17-trione- 3,17-dietilenchetale. Il prodotto mostra spettro IR, NMR, MASSA concordi con quanto descritto in SYNTHETIC COMMUNICATIONS (1995), 25(18), 2807-2811. The reaction trend is checked on thin layer chromatography and after about 3 hours the reaction mixture is poured into 150 ml of sodium bicarbonate, a saturated aqueous solution, after 1 hour the suspended solid is filtered, washed with water and crystallized with ether isopropyl. 2 g of 18-methyl-ester-5-en-3,11-trione-3,17-diethylenchetal are obtained. The product shows IR, NMR, MASS spectrum in agreement with what is described in SYNTHETIC COMMUNICATIONS (1995), 25 (18), 2807-2811.
Esempio 2: preparazione del 11-metilen-18-metil-estra-5-en-3,17-dione- 3,17-dietilenchetale Example 2: preparation of 11-methylene-18-methyl-ester-5-en-3,17-dione- 3,17-diethylenchetal
In un reattore anidro ed in atmosfera inerte si caricano a 20°C 6 g di sodio idruro, 180 mi di dimetilsolfossido e si agita la sospensione per 30 minuti. In an anhydrous reactor and in an inert atmosphere, 6 g of sodium hydride, 180 ml of dimethyl sulfoxide are charged at 20 ° C and the suspension is stirred for 30 minutes.
Si aggiungono 90 g di metiltrifenilfosfonio bromuro e si scalda a 80°C per 2 ore. 90 g of methyl triphenylphosphonium bromide are added and the mixture is heated at 80 ° C for 2 hours.
Si aggiunge una soluzione preparata con 26 g di 18-metil-estra-5-en-3,11,17-trione 3,17-dietilenchetale, ottenuto nell’esempio 1, e 70 mi di toluene. A solution prepared with 26 g of 18-methyl-ester-5-en-3,11,17-trione 3,17-diethylenchetal, obtained in example 1, and 70 ml of toluene is added.
Si scalda a 105°C controllando l’andamento della reazione con cromatografia su strato sottile. It is heated to 105 ° C, checking the progress of the reaction with thin layer chromatography.
Al termine si versa la miscela di reazione in 1 litro di acqua e si estrae per tre volte con 500 mi di toluene, le fasi organiche riunite si lavano con soluzione acquosa satura di sodio cloruro quindi con acqua. At the end the reaction mixture is poured into 1 liter of water and extracted three times with 500 ml of toluene, the combined organic phases are washed with saturated aqueous sodium chloride solution and then with water.
L’olio ottenuto dalla concentrazione del solvente è purificato per cromatografìa su colonna eluendo con gradiente eptano-acetato di etile ottenendo 23 g di 11-metilen-18-metilestra-5-en-3,17-dione- 3,17-dietilenchetale, dopo cristallizzazione in eptano, idoneo al proseguimento della sintesi. The oil obtained from the concentration of the solvent is purified by column chromatography eluting with heptane-ethyl acetate gradient obtaining 23 g of 11-methylene-18-methylestra-5-en-3,17-dione- 3,17-diethylenchetal, after crystallization in heptane, suitable for the continuation of the synthesis.
Dati analitici: Analytical data:
MASSA (m/z): 386 [M<+>] picco molecolare MASS (m / z): 386 [M <+>] molecular peak
<1>H-NMR (300 MHz) in ppm: 5=5,46 ppm (d allargato 1H H-6); 5=4,84 ppm (d 2H 11-metilene); 5=3,90 ppm (m 8H 3,17-etilenchetale); 5=0,98 ppm (t 3H 18-CH3). <1> H-NMR (300 MHz) in ppm: 5 = 5.46 ppm (d expanded 1H H-6); 5 = 4.84 ppm (d 2H 11-methylene); 5 = 3.90 ppm (m 8H 3.17-ethylenchetal); 5 = 0.98 ppm (t 3H 18-CH3).
Esempio 3: preparazione del 11-metilen-18-metil-estra-4-en-3,17-dione Example 3: preparation of 11-methylene-18-methyl-ester-4-en-3,17-dione
In un reattore in atmosfera inerte si caricano a 20°C 50 g di 11-metilen-18-metil-estra-5-en-3,17-dione- 3,17-dietilenchetale, provenienti dall'esempio 2, con 1 litro di acetone e 5 mi di acido cloridrico acquoso 12N. In a reactor in an inert atmosphere, 50 g of 11-methylene-18-methyl-ester-5-en-3,17-dione- 3,17-diethylenchetal, coming from example 2, are charged at 20 ° C with 1 liter of acetone and 5 ml of 12N aqueous hydrochloric acid.
Si agita la soluzione a 20°C controllando l’andamento della reazione con cromatografìa su strato sottile e dopo circa 4 ore si versa la miscela di reazione in 1 l di acqua portando a pH neutro con sodio bicarbonato. Si distilla il solvente organico a pressione ridotta fino ad ottenere il prodotto sospeso nella restante fase acquosa. The solution is stirred at 20 ° C, checking the progress of the reaction with thin layer chromatography and after about 4 hours the reaction mixture is poured into 1 liter of water bringing it to neutral pH with sodium bicarbonate. The organic solvent is distilled under reduced pressure until the product suspended in the remaining aqueous phase is obtained.
Si ottengono, dopo filtrazione, lavaggio con acqua ed essiccamento a pressione ridotta, 34 g di 11-metilen-18-metil-estra-4-en-3,17-dione idonei al proseguimento della sintesi. After filtration, washing with water and drying under reduced pressure, 34 g of 11-methylene-18-methyl-extrac-4-en-3,17-dione suitable for the continuation of the synthesis are obtained.
Dati analitici: Analytical data:
IR = 1735 1/cm; 1658 1/cm IR = 1735 1 / cm; 1658 1 / cm
<1>H-NMR (300 MHz) in ppm: 5=5,88 ppm (s 1H H-4); 5=4,92 ppm (d 2H 11 -metilene); 5=0,76 ppm (t 3H 18-CH3). <1> H-NMR (300 MHz) in ppm: 5 = 5.88 ppm (s 1H H-4); 5 = 4.92 ppm (d 2H 11 -methylene); 5 = 0.76 ppm (t 3H 18-CH3).
Esempio 4: preparazione del 11-metilen-18-metil-estra-4-en-3α,17βdiolo e del 11-metilen-18-metil-estra-4-en-3β-17β-diolo Example 4: preparation of 11-methylene-18-methyl-estrus-4-en-3α, 17βdiol and 11-methylene-18-methyl-estrus-4-en-3β-17β-diol
In un reattore in atmosfera inerte si carica a 20°C 30 g di 11-metilen-18-metil-estra-4-en-3,17-dione, proveniente dall’esempio 3, con 1,2 litri di metanolo. In a reactor in an inert atmosphere, 30 g of 11-methylene-18-methyl-ester-4-en-3,17-dione, coming from example 3, is charged at 20 ° C with 1.2 liters of methanol.
A dissoluzione completa si raffredda la soluzione a 5°C e si aggiungono a porzioni 38 g di cerio tricloruro eptaidrato e 40 g di sodioboroidruro. Si mantiene a 5°C controllando l’andamento della reazione con cromatografia su strato sottile e dopo circa 1 ora si aggiunge con cautela alla soluzione di reazione 1 litro di acqua agitando a freddo ancora per 1 ora. When completely dissolved, the solution is cooled to 5 ° C and 38 g of cerium trichloride heptahydrate and 40 g of sodium borohydride are added in portions. It is maintained at 5 ° C by controlling the progress of the reaction with thin layer chromatography and after about 1 hour, 1 liter of water is carefully added to the reaction solution, stirring cold for another hour.
Si distilla il solvente organico a pressione ridotta e si estrae la restante fase acquosa con 1 ,5 litri di isopropil acetato. The organic solvent is distilled under reduced pressure and the remaining aqueous phase is extracted with 1.5 liters of isopropyl acetate.
Si lava la fase organica con acqua, si anidrifica con sodio solfato e, dopo filtrazione, si concentra a residuo oleoso a pressione ridotta a 50°C. The organic phase is washed with water, anhydrified with sodium sulphate and, after filtration, concentrated to an oily residue at reduced pressure at 50 ° C.
Si ottengono 30 g di una miscela di 11 -metilen-18-metil-estra-4-en- e 11 -metilen-18-metil-estra-4-en-3β-17β-diolo che non necessita di ulteriore purificazione e che risulta idonea al proseguimento della sintesi. 30 g of a mixture of 11 -methylene-18-methyl-estrus-4-en- and 11 -methylen-18-methyl-estrus-4-en-3β-17β-diol are obtained which does not require further purification and which it is suitable for the continuation of the synthesis.
Dati analitici: Analytical data:
MASSA (m/z): 302 [M<+>] picco molecolare MASS (m / z): 302 [M <+>] molecular peak
<1>H-NMR (300 MHz) in ppm: sono stati separati i due isomeri che presentano i seguenti gruppi di segnali: <1> H-NMR (300 MHz) in ppm: the two isomers presenting the following signal groups have been separated:
Esempio 5: preparazione di 11 -metilen-18-metil-3a-metossi-estra-4-en-17β-οlο e 11 -metilen-18-metil-3β-metossi-estra-4-en-17β-olo In un reattore anidro ed in atmosfera inerte si carica a 20°C 30 g della miscela di 11 -metilen-18-metil-estra-4-estra-4-en-3α,17β-diolo e 11-metilen-18-metil-estra-4-en-3β,17β-diolo, ottenuta nell’esempio 4, con 300 mi di metanolo e 300 mg di acido paratoluensolfonico. Example 5: Preparation of 11-methylen-18-methyl-3a-methoxy-extra-4-en-17β-οlο and 11-methylen-18-methyl-3β-methoxy-extra-4-en-17β-ol In a anhydrous reactor and in an inert atmosphere, 30 g of the mixture of 11-methylene-18-methyl-ester-4-estr-4-en-3α, 17β-diol and 11-methylene-18-methyl-extract is charged at 20 ° C -4-en-3β, 17β-diol, obtained in example 4, with 300 ml of methanol and 300 mg of paratoluenesulfonic acid.
Si agita a 20°C controllando l’andamento della reazione con cromatografia su strato sottile e dopo circa 24 ore si aggiunge con cautela alla soluzione di reazione 1 litro di acqua agitando a freddo per 1 ora. It is stirred at 20 ° C, checking the progress of the reaction with thin layer chromatography and after about 24 hours, 1 liter of water is carefully added to the reaction solution, stirring cold for 1 hour.
Si aggiusta il pH alla neutralità con sodio bicarbonato quindi si distilla il solvente organico a pressione ridotta estraendo la restante fase acquosa con 1,5 litri di isopropil acetato. The pH is adjusted to neutrality with sodium bicarbonate then the organic solvent is distilled at reduced pressure by extracting the remaining aqueous phase with 1.5 liters of isopropyl acetate.
Si lava la fase organica con acqua, si anidrifica con sodio solfato e, dopo filtrazione, si concentra a residuo oleoso a pressione ridotta a 50°C. The organic phase is washed with water, anhydrified with sodium sulphate and, after filtration, concentrated to an oily residue at reduced pressure at 50 ° C.
Dopo purificazione per filtrazione su gel di silice si ottengono 28 g di una miscela di 11-metilen-18-metil-3a-metossi-estra-4-en-17β-olo e 11-metilen-18-metil-3β-metossi-estra-4-en-17β-olo che non necessita di ulteriore purificazione e che risulta idonea al proseguimento della sintesi. Dati analitici: After purification by filtration on silica gel, 28 g of a mixture of 11-methylene-18-methyl-3a-methoxy-ester-4-en-17β-ol and 11-methylene-18-methyl-3β-methoxy are obtained estr-4-en-17β-ol which does not require further purification and which is suitable for the continuation of the synthesis. Analytical data:
MASSA (m/z): 316 [M<+>] picco molecolare MASS (m / z): 316 [M <+>] molecular peak
<1>H-NMR (300 MHz) in ppm: sono stati separati i due isomeri che presentano i seguenti gruppi di segnali: <1> H-NMR (300 MHz) in ppm: the two isomers presenting the following signal groups have been separated:
Esempio 6: preparazione del 11-metilen-18-metil-estra-4-en-17β-olo In un reattore anidro ed in atmosfera inerte si caricano a 20°C 150 mi di tetraidrofurano, quindi si regola la temperatura a - 60°C e si aggiunge 200 g di etilammina. Example 6: preparation of 11-methylene-18-methyl-ester-4-en-17β-ol In an anhydrous reactor and in an inert atmosphere, 150 ml of tetrahydrofuran are charged at 20 ° C, then the temperature is adjusted to - 60 ° C and 200 g of ethylamine is added.
Agitando si aggiungono 5 g di litio in granuli e si agita per 30 minuti fino ad ottenere una soluzione blu. By stirring, 5 g of lithium in granules are added and the mixture is stirred for 30 minutes until a blue solution is obtained.
Si aggiunge una soluzione preparata con 25 g di una miscela di 11-metilen-18-metil-3α-metossi-estra-4-en-17β-olo e 11-metilen-18-metil-3β-metossi-estra-4-en-17β-olo, proveniente dall’esempio 5, e 100 mi di tetraidrofurano agitando vigorosamente a -60°C e controllando l’andamento della reazione con cromatografia su strato sottile. A solution prepared with 25 g of a mixture of 11-methylene-18-methyl-3α-methoxy-estrus-4-en-17β-ol and 11-methylene-18-methyl-3β-methoxy-extr-4- is added. en-17β-ol, coming from example 5, and 100 ml of tetrahydrofuran, stirring vigorously at -60 ° C and checking the progress of the reaction with thin layer chromatography.
A reazione terminata si aggiunge 100 g di ammonio cloruro e si agita, lasciando salire la temperatura, per 2 ore quindi si aggiunge 500 mi di toluene ed 1 litro di sodio idrossido acquoso al 5%. At the end of the reaction, 100 g of ammonium chloride is added and the mixture is stirred, allowing the temperature to rise, for 2 hours, then 500 ml of toluene and 1 liter of 5% aqueous sodium hydroxide are added.
Si separa la fase organica che si lava con acqua fino a neutralità. The organic phase is separated and washed with water until neutral.
Si concentra a pressione ridotta la fase organica ottenendo un residuo che, cristallizzato da acetonitrile, fornisce 16 g di 11-metilen-18-metilestra-4-en-17β-olo, idonei al proseguimento della sintesi. The organic phase is concentrated under reduced pressure to obtain a residue which, crystallized from acetonitrile, gives 16 g of 11-methylene-18-methylestra-4-en-17β-ol, suitable for the continuation of the synthesis.
Dati analitici: Analytical data:
IR = 1726 1/cm IR = 1726 1 / cm
MASSA (m/z): 286 [M<+>] picco molecolare MASS (m / z): 286 [M <+>] molecular peak
<1>H-NMR (300 MHz) in ppm: 5=5,44 ppm (1H s H-4); 5=4,84 ppm (2H d 11 -metilene); 5=3,80 ppm (1 H t H-17); 5=1 ,04 ppm (3H t I8-CH3). <1> H-NMR (300 MHz) in ppm: 5 = 5.44 ppm (1H s H-4); 5 = 4.84 ppm (2H d 11 -methylene); 5 = 3.80 ppm (1 H t H-17); 5 = 1.04 ppm (3H t I8-CH3).
Esempio 7: preparazione del 11-metilen-18metil-estra-4-en-17-one In un reattore anidro ed in atmosfera inerte si caricano a 20°C 300 mi di toluene e 300 mi di metilisobutilchetone, si scalda la miscela a riflusso scartando i primi 100 mi di distillato. Example 7: preparation of 11-methylene-18methyl-extrac-4-en-17-one In an anhydrous reactor and in an inert atmosphere, 300 ml of toluene and 300 ml of methyl isobutyl ketone are charged at 20 ° C, the mixture is heated under reflux discarding the first 100 ml of distillate.
Si raffredda a 90°C e si carica 14 g di alluminio isopropilato e 7 g di 11-metilen-18-metil-estra-4-en-17β-olo, proveniente dall’esempio 6, proseguendo il riflusso e controllando l’andamento della reazione con cromatografia su strato sottile. The mixture is cooled to 90 ° C and 14 g of isopropylated aluminum and 7 g of 11-methylene-18-methyl-ester-4-en-17β-ol, coming from example 6, are charged, continuing the reflux and checking the trend of the reaction with thin layer chromatography.
A reazione terminata si raffredda a 25°C e si versa la miscela di reazione in 1 litro di sodio idrossido acquoso al 5%, si aggiunge 200 mi di toluene, si separa la fase organica, si lava con acqua fino a neutralità, si anidrifica con sodio solfato, si filtra e si concentra a 50°C a pressione ridotta fino ad ottenere un olio incolore che spontaneamente solidifica. At the end of the reaction it is cooled to 25 ° C and the reaction mixture is poured into 1 liter of aqueous 5% sodium hydroxide, 200 ml of toluene is added, the organic phase is separated, washed with water until neutral, anhydrified. with sodium sulphate, it is filtered and concentrated at 50 ° C under reduced pressure until a colorless oil is obtained which spontaneously solidifies.
Dopo ulteriore essiccamento a pressione ridotta si ottengono 6 gr di 11-metilen-18-metil-estra-4-en-17-one, idonei per il proseguimento della sintesi. After further drying under reduced pressure, 6 g of 11-methylene-18-methyl-extra-4-en-17-one are obtained, suitable for the continuation of the synthesis.
Dati analitici: Analytical data:
Il prodotto mostra spettri IR, MASSA e NMR concordi con quanto descritto in TETRAHEDRON 50 (36) 10709-10720 (1994). The product shows IR, MASS and NMR spectra in agreement with what is described in TETRAHEDRON 50 (36) 10709-10720 (1994).
Esempio 8: preparazione del (17α), 13-etil-11-metilen-18-19-dinorpregn-4-en-20-in-17β-οlο (Desogestrel) Example 8: preparation of (17α), 13-ethyl-11-methylene-18-19-dinorpregn-4-en-20-in-17β-οlο (Desogestrel)
In un reattore anidro ed in atmosfera inerte si carica a 20°C 300 ml di tetra idrofura no, si raffredda a 0°C, si aggiunge 30 g di potassio terbutilato e si gorgoglia acetilene per almeno 3 ore. In an anhydrous reactor and in an inert atmosphere, 300 ml of tetrahydrophide are charged at 20 ° C, cooled to 0 ° C, add 30 g of potassium terbutylate and acetylene bubbled for at least 3 hours.
Si raffredda a -20°C e si carica una soluzione di 15 g di 11-metilen-18-metil-estra-4-en-17-one, proveniente dall’esempio 7, con 100 ml di tetraidrofurano e si prosegue il gorgogliamento di acetilene per altre 2 ore a -20°C. The mixture is cooled to -20 ° C and a solution of 15 g of 11-methylene-18-methyl-ester-4-en-17-one, coming from example 7, is charged with 100 ml of tetrahydrofuran and the bubbling is continued of acetylene for another 2 hours at -20 ° C.
Si segue l’andamento della reazione per cromatografia liquida ad alta pressione ed alla fine si versa la miscela di reazione in una soluzione, precedentemente preparata e raffreddata a 0°C, di 150 g di ammonio cloruro in 1 ,5 litri di acqua. The reaction trend is followed by high pressure liquid chromatography and at the end the reaction mixture is poured into a solution, previously prepared and cooled to 0 ° C, of 150 g of ammonium chloride in 1.5 liters of water.
Si estrae con 1 ,75 litri di metilene cloruro, la fase organica separata si lava con acqua, si anidrifica con sodio solfato, si filtra e si concentra a secco a pressione ridotta. It is extracted with 1.75 liters of methylene chloride, the separated organic phase is washed with water, anhydrified with sodium sulphate, filtered and concentrated to dryness at reduced pressure.
Il prodotto grezzo così ottenuto si purifica per cromatografia su colonna di gel di silice eluendo con eptano/etile acetato. The crude product thus obtained is purified by chromatography on a silica gel column eluting with heptane / ethyl acetate.
Le frazione contenenti il prodotto puro si concentrano a secco a pressione ridotta ed il residuo si cristallizza da metilene cloruro/eptano ottenendo 11 g di (17a),13-etil-1 1-metilen-18,19-dinorpregna-4-en-20-in-17β-οlο (desogestrel). The fractions containing the pure product are concentrated to dryness at reduced pressure and the residue crystallizes from methylene chloride / heptane obtaining 11 g of (17a), 13-ethyl-1 1-methylene-18,19-dinorpregna-4-en- 20-in-17β-οlο (desogestrel).
Dati analitici: Analytical data:
Il prodotto mostra spettri IR, MASSA e NMR concordi con quanto descritto in TETRAHEDRON 50(36) 10709-10729 (1994). The product shows IR, MASS and NMR spectra in agreement with what is described in TETRAHEDRON 50 (36) 10709-10729 (1994).
Claims (24)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ITMI20012099 ITMI20012099A1 (en) | 2001-10-11 | 2001-10-11 | PROCESS FOR THE PRODUCTION OF (17ALF), 13-ETHYL-11METHYLENE-18.19-DINOPREGNA-4-EN-20-IN-17BETA-OLO (DESOGESTREL) |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ITMI20012099 ITMI20012099A1 (en) | 2001-10-11 | 2001-10-11 | PROCESS FOR THE PRODUCTION OF (17ALF), 13-ETHYL-11METHYLENE-18.19-DINOPREGNA-4-EN-20-IN-17BETA-OLO (DESOGESTREL) |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ITMI20012099A1 true ITMI20012099A1 (en) | 2003-04-11 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ITMI20012099 ITMI20012099A1 (en) | 2001-10-11 | 2001-10-11 | PROCESS FOR THE PRODUCTION OF (17ALF), 13-ETHYL-11METHYLENE-18.19-DINOPREGNA-4-EN-20-IN-17BETA-OLO (DESOGESTREL) |
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| Country | Link |
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| IT (1) | ITMI20012099A1 (en) |
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2001
- 2001-10-11 IT ITMI20012099 patent/ITMI20012099A1/en unknown
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