WO2007069039A2 - Procédé de conversion d'androsta-1,4,9(11)-triène-3-ones 17-substituées en 3-hydroxyestra-1,3,5(10),9(11)-tétraènes 17-substitués - Google Patents
Procédé de conversion d'androsta-1,4,9(11)-triène-3-ones 17-substituées en 3-hydroxyestra-1,3,5(10),9(11)-tétraènes 17-substitués Download PDFInfo
- Publication number
- WO2007069039A2 WO2007069039A2 PCT/IB2006/003580 IB2006003580W WO2007069039A2 WO 2007069039 A2 WO2007069039 A2 WO 2007069039A2 IB 2006003580 W IB2006003580 W IB 2006003580W WO 2007069039 A2 WO2007069039 A2 WO 2007069039A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- process according
- solvent
- substituted
- basic salt
- triene
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 29
- YACPILFNQXFALY-CAMMJAKZSA-N (8s,10s,13s,14s)-10,13-dimethyl-6,7,8,12,14,15,16,17-octahydrocyclopenta[a]phenanthren-3-one Chemical class C([C@H]12)CC3=CC(=O)C=C[C@]3(C)C1=CC[C@@]1(C)[C@H]2CCC1 YACPILFNQXFALY-CAMMJAKZSA-N 0.000 title abstract description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 29
- 239000002904 solvent Substances 0.000 claims description 24
- 150000001447 alkali salts Chemical class 0.000 claims description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 18
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 claims description 14
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical group [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 11
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 11
- XXJWXESWEXIICW-UHFFFAOYSA-N diethylene glycol monoethyl ether Chemical group CCOCCOCCO XXJWXESWEXIICW-UHFFFAOYSA-N 0.000 claims description 10
- 229940075557 diethylene glycol monoethyl ether Drugs 0.000 claims description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 239000011698 potassium fluoride Substances 0.000 claims description 7
- 235000003270 potassium fluoride Nutrition 0.000 claims description 7
- 229910052710 silicon Inorganic materials 0.000 claims description 7
- 239000010703 silicon Substances 0.000 claims description 7
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 235000011181 potassium carbonates Nutrition 0.000 claims description 4
- 235000011118 potassium hydroxide Nutrition 0.000 claims description 4
- PUZPDOWCWNUUKD-UHFFFAOYSA-M sodium fluoride Chemical compound [F-].[Na+] PUZPDOWCWNUUKD-UHFFFAOYSA-M 0.000 claims description 4
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical group [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 125000005210 alkyl ammonium group Chemical group 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- 239000011775 sodium fluoride Substances 0.000 claims description 2
- 235000013024 sodium fluoride Nutrition 0.000 claims description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- 238000006243 chemical reaction Methods 0.000 description 16
- 239000011541 reaction mixture Substances 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 238000004809 thin layer chromatography Methods 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 8
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 229960003399 estrone Drugs 0.000 description 6
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 5
- 238000009835 boiling Methods 0.000 description 5
- 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 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 239000011701 zinc Substances 0.000 description 5
- 229910052725 zinc Inorganic materials 0.000 description 5
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 239000011521 glass Substances 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 3
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- DNXHEGUUPJUMQT-UHFFFAOYSA-N (+)-estrone Natural products OC1=CC=C2C3CCC(C)(C(CC4)=O)C4C3CCC2=C1 DNXHEGUUPJUMQT-UHFFFAOYSA-N 0.000 description 2
- VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 description 2
- 0 C*CC(CC1C(C2(C)C=C3)=CCC4(*)*(C)(*)CCC14)C2=CC3=O Chemical compound C*CC(CC1C(C2(C)C=C3)=CCC4(*)*(C)(*)CCC14)C2=CC3=O 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 2
- DNXHEGUUPJUMQT-CBZIJGRNSA-N Estrone Chemical compound OC1=CC=C2[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1 DNXHEGUUPJUMQT-CBZIJGRNSA-N 0.000 description 2
- BFPYWIDHMRZLRN-SLHNCBLASA-N Ethinyl estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 BFPYWIDHMRZLRN-SLHNCBLASA-N 0.000 description 2
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- MWKFXSUHUHTGQN-UHFFFAOYSA-N decan-1-ol Chemical compound CCCCCCCCCCO MWKFXSUHUHTGQN-UHFFFAOYSA-N 0.000 description 2
- 229960005309 estradiol Drugs 0.000 description 2
- 229930182833 estradiol Natural products 0.000 description 2
- FRPJXPJMRWBBIH-RBRWEJTLSA-N estramustine Chemical compound ClCCN(CCCl)C(=O)OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 FRPJXPJMRWBBIH-RBRWEJTLSA-N 0.000 description 2
- 229960001842 estramustine Drugs 0.000 description 2
- 229960002568 ethinylestradiol Drugs 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 239000002798 polar solvent Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000000197 pyrolysis Methods 0.000 description 2
- -1 saturated aliphatic alcohols Chemical class 0.000 description 2
- 150000004760 silicates Chemical class 0.000 description 2
- 239000011863 silicon-based powder Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 150000003431 steroids Chemical class 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 239000010891 toxic waste Substances 0.000 description 2
- IQUXBKUKXDWZLA-VMXHOPILSA-N (8s,9s,10r,13s,14s)-10,13-dimethyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthren-3-one Chemical group C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CCC[C@@]1(C)CC2 IQUXBKUKXDWZLA-VMXHOPILSA-N 0.000 description 1
- 239000005968 1-Decanol Substances 0.000 description 1
- ZNQVEEAIQZEUHB-UHFFFAOYSA-N 2-ethoxyethanol Chemical compound CCOCCO ZNQVEEAIQZEUHB-UHFFFAOYSA-N 0.000 description 1
- 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 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- 239000004111 Potassium silicate Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical group 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 125000005587 carbonate group Chemical group 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 150000004673 fluoride salts Chemical class 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- XCOBTUNSZUJCDH-UHFFFAOYSA-B lithium magnesium sodium silicate Chemical compound [Li+].[Li+].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[Na+].[Na+].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].O1[Si](O2)([O-])O[Si]3([O-])O[Si]1([O-])O[Si]2([O-])O3.O1[Si](O2)([O-])O[Si]3([O-])O[Si]1([O-])O[Si]2([O-])O3.O1[Si](O2)([O-])O[Si]3([O-])O[Si]1([O-])O[Si]2([O-])O3.O1[Si](O2)([O-])O[Si]3([O-])O[Si]1([O-])O[Si]2([O-])O3.O1[Si](O2)([O-])O[Si]3([O-])O[Si]1([O-])O[Si]2([O-])O3.O1[Si](O2)([O-])O[Si]3([O-])O[Si]1([O-])O[Si]2([O-])O3 XCOBTUNSZUJCDH-UHFFFAOYSA-B 0.000 description 1
- 238000003760 magnetic stirring Methods 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 150000002875 norsteroids Chemical class 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- NNHHDJVEYQHLHG-UHFFFAOYSA-N potassium silicate Chemical compound [K+].[K+].[O-][Si]([O-])=O NNHHDJVEYQHLHG-UHFFFAOYSA-N 0.000 description 1
- 229910052913 potassium silicate Inorganic materials 0.000 description 1
- 235000019353 potassium silicate Nutrition 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- JUJWROOIHBZHMG-RALIUCGRSA-N pyridine-d5 Chemical compound [2H]C1=NC([2H])=C([2H])C([2H])=C1[2H] JUJWROOIHBZHMG-RALIUCGRSA-N 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- RAOIDOHSFRTOEL-UHFFFAOYSA-N tetrahydrothiophene Chemical compound C1CCSC1 RAOIDOHSFRTOEL-UHFFFAOYSA-N 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
- C07J1/0003—Androstane derivatives
- C07J1/0011—Androstane derivatives substituted in position 17 by a keto group
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
- C07J1/0003—Androstane derivatives
- C07J1/0018—Androstane derivatives substituted in position 17 beta, not substituted in position 17 alfa
- C07J1/0022—Androstane derivatives substituted in position 17 beta, not substituted in position 17 alfa the substituent being an OH group free esterified or etherified
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
- C07J1/0003—Androstane derivatives
- C07J1/0033—Androstane derivatives substituted in position 17 alfa and 17 beta
- C07J1/004—Androstane derivatives substituted in position 17 alfa and 17 beta the substituent in position 17 alfa being an unsaturated hydrocarbon group
- C07J1/0048—Alkynyl derivatives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
- C07J1/0051—Estrane derivatives
- C07J1/0059—Estrane derivatives substituted in position 17 by a keto group
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
- C07J1/0051—Estrane derivatives
- C07J1/0066—Estrane derivatives substituted in position 17 beta not substituted in position 17 alfa
- C07J1/007—Estrane derivatives substituted in position 17 beta not substituted in position 17 alfa the substituent being an OH group free esterified or etherified
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
- C07J1/0051—Estrane derivatives
- C07J1/0081—Substituted in position 17 alfa and 17 beta
- C07J1/0088—Substituted in position 17 alfa and 17 beta the substituent in position 17 alfa being an unsaturated hydrocarbon group
- C07J1/0096—Alkynyl derivatives
Definitions
- This invention relates to a method for converting 17 substituted androsta-1 ,4,9(11)- triene-3-ones to 17 substituted 3-hydroxyestra-l,3,5(10),9(l l)-tetraenes ( ⁇ 9 -estra ⁇ es).
- the 17 substituted ⁇ 9 -estranes are useful as intermediates in the synthesis of 19-nor steroids such as estradiol, estrone, estramustine, ethynylestradiol.
- Magerlein J. Am. Chem. Soc, 80, 2220 (1958) formed methyl 3-hydroxy-19-nor-l, 3,5(10), 17(20)- ⁇ regnatetraen-21-oate from methyl 3-keto-l,4,17-(20)-[cis]-pregnatriene-21-oate in 15.3% yield by a pyrolysis method in a glass vessel.
- Charpentier et al. (Steroids; 52; 1988; 609 - 621) removed the 19 methyl and aromatized the A ring of 7 ⁇ -methoxycarbonyl methyl-androsta-1 ,4,9( 11 )-triene-3, 17-dione using large excess of zinc (108 equivalents) in pyridine and water.
- Tsuda et al. removed the 19 methyl and aromatized the A ring of androsta-1 ,4, 9-(the methyl expulsion does not work in the 1,4,6 case)triene-3,17-dione using large excess of zinc (96 equivalents) in pyridine (J. Org. Chem.; 1963, 26; 783-785) Harburn et al. discuss the use of zinc in pyridine for removing the 19 methyl from molecules similar to androsta-1 ,4,9(1 l)-triene-3,17-dione (J. Chem. Research (S); 1998; 424 - 425 and J. Chem. Research (M); 1998; 1872-1884).
- elemental silicon in the presence of a basic salt, may be used to convert 17 substituted androsta-1 ,4,9(1 l)-triene-3-ones of Formula I to 17 substituted ⁇ 9 - estranes of Formula II.
- the compound of Formula ⁇ are used in the synthesis of 39- ⁇ or-methyl steroids such as estradiol, estrone, estramustine, ethynylestradiol.
- HPLC refers to high pressure liquid chromatography
- TLC refers to thin layer chromatography
- URMS refers to low resolution mass spectrum.
- NMK refers io nuclear magnetic reonance spectroscopy.
- THF refers to tetrahydroft-ran.
- DMF N,N-dimethyIformaraide
- DMA refers to N,N-dimelhylacetamide.
- DMSO diroethylsulfoxide
- sulf ⁇ lane refers to tetrahydrothiophene 1 ,3 -dioxide.
- ATTD refers lo androsta-] ,4,9(3 ])-triene-3,17-dione.
- MTBE refers to jnethyl-t-butylefher DESCRIPTION
- elemental silicon in the presence of a basic salt, may be used to convert 17 substituted androata-l ,4,9(11 )-triene-3-ones of Formula I to 17 substituted ⁇ 9 - estranes of Formula II.
- R 1 is OH
- R 2 is H or — C- ⁇ CE
- the 17 substituted androsta-3 ,4,903 >triene-3-ones of Formula I, the silicon,, and the basic salt ars mixed "* ⁇ ith a suitable solvent, and reacted at a temperature of 130 to 350 0 C.
- a polar solvent with a boiling point of 130 "C or above fhat provides appreciable solubility for the basic salt is appropriate.
- the solvent may have a boiling point well above 130 0 C, such as 1-decanol, which has a boiling point of 233 0 C, but the solvent should be a liquid at room temperature.
- the alcohols boiling above 130 0 C 5 such as n-pentanol, the C 6 to C )0 saturated aliphatic alcohols, glycols and glycol mono-ethers such as ethylene glycol, diethylene glycol, ethylene glycol mono-ethyl ether, and diethylene glycol mono-ethyl ether, and mixtures thereof are suitable solvents.
- high boiling polar aprotic solvents such as DMF, DMA, DMSO, and sulfolane may be mixed with the any of the polar solvents noted above to provide additional solubility for the basic salt.
- Diethylene glycol mono-ethyl ether and a diethylene glycol mono-ethyl ether/ethylene glycol mixture are preferred solvents.
- the solvents tend to be hygroscopic, and may contain a small percentage of water, such 1 to 2 percent water. It is not necessary to exclude water from this reaction, and it is often advantageous to add small quantities of water to enhance the reaction rate.
- the amount of water that may be added is up to 25 volume percent of the total volume of the organic solvent components. The addition of water to the solvent accelerates the reaction when the basic salt is a carbonate or bicarbonate.
- the basic salt is selected from alkali metal hydroxides, carbonates, and bicarbonates such as sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate, potassium bicarbonate, and potassium carbonate; and soluble fluoride salts such as tetra(C] to C 4 )alkyl ammonium fluorides, sodium fluoride, potassium fluoride, and ((CH 3 ⁇ N) 3 SF 2 (CH 3 ) S .
- the side products of the reaction, formed from the silicon are either silicates, or fluorosilicates. For example, when potassium hydroxide or carbonate is used as the basic salt, potassium silicate is formed, and when potassium fluoride is used as the basic salt, potassium fluorosilicate is formed during the reaction.
- a preferred basic salt is potassium fluoride.
- Two or more salts may be used in this reaction. After the 17 substituted androsta-1 ,4,9(11 )-triene-3-one, silicon, basic salt, and the appropriate solvent are mixed, the reaction mixture is heated at a temperature of 130 to 150 0 C until the reaction is complete. Depending upon the temperature, the solvent, and the basic salt, the reaction may take 2 hours or more. The reaction tends to come to completion more quickly if a soluble fluoride is selected as the basic salt. If a hydroxide, carbonate or bicarbonate is selected as the basic salt, the reaction rate may be increased by the addition of a small amount of water to the solvent.
- TLC thin layer chromatography
- the reaction mixture may be worked up, and the product isolated, by a number of methods that will be apparent to those skilled in the art.
- a typical extractive work up the reaction mixture is cooled, and poured into a dilute aqueous solution of a mineral acid.
- mineral acids include hydrochloric acid, sulfuric acid, and phosphoric acid.
- the mixture is extracted several times with a water immiscible organic solvent, such as ethyl acetate, methylene chloride, methyl-t-butylether (MTBE), or 2-methyl THF.
- Tetrahydrofuran may be used as an extracting solvent since the salts present in the water phase "salt out the THF into a separate layer.
- the organic extract is washed with water and concentrated by evaporation.
- the residue can be optionally purified by recrystaHization from solvents such as methylene chloride, benzene, or a 1:1 mixture of toluene and methylene chloride.
- the ⁇ 9 -estrane residue may also be purified by extraction from an inert organic solvent, such as toluene, into a strong aqueous base such as aqueous KOH or NaOH. Upon acidification of the aqueous layer, the ⁇ 9 -estrane precipitates.
- Androsta-],4,9(l l)-triene-3,17-dione ("ATD ; 0.5g, 1.77 mmol, 1 eq.), elemental silicon powder (325 mesh; 0.497g, 17.7 mmol, 10 eq.), K 2 CO 3 (2.45g, 17.7 mmol, 10 eq.), silica gel (as a filtration aid 0.5g) and diethylene glycol monoethyl ether (15 mL) were charged to a 50 mL, 2-necked round-bottomed flask equipped with condenser, magnetic stirring bar, nitrogen tee, and septum. The temperature of the reaction mixture was increased to 140 0 C, and was maintained for 2 hours.
- Androsta-1 ,4,9(1 l)-triene-3,17-dione ("ATD (10.0 g, 35.4 mmol, 1 eq.), elemental silicon powder (325 mesh; 4.97 g, 177 mmol, 5 eq.), potassium fluoride (10.3 g, 177 mmol, 5 eq.), diethylene glycol monoethyl ether (140 mL) and ethylene glycol (70 mL) were charged to a 500 mL, 4-necked round-bottomed flask, equipped with a condenser, nitrogen tee, thermocouple, mechanical stirrer and a glass cap. The temperature of the reaction mixture was increased to 120 0 C.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
Abstract
La présente invention a pour objet un procédé de conversion d'androsta-1,4,9(11)-triène-3-ones 17-substituées en 3-hydroxyestra-l,3,5(10),9(11)-tétraènes 17-substitués.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US74970605P | 2005-12-13 | 2005-12-13 | |
US60/749,706 | 2005-12-13 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2007069039A2 true WO2007069039A2 (fr) | 2007-06-21 |
WO2007069039A3 WO2007069039A3 (fr) | 2007-10-04 |
Family
ID=38162223
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/IB2006/003580 WO2007069039A2 (fr) | 2005-12-13 | 2006-12-12 | Procédé de conversion d'androsta-1,4,9(11)-triène-3-ones 17-substituées en 3-hydroxyestra-1,3,5(10),9(11)-tétraènes 17-substitués |
Country Status (1)
Country | Link |
---|---|
WO (1) | WO2007069039A2 (fr) |
-
2006
- 2006-12-12 WO PCT/IB2006/003580 patent/WO2007069039A2/fr active Application Filing
Non-Patent Citations (4)
Title |
---|
CHARPENTIER ET AL.: "SYNTHESIS OF 7-ALPHA- AND 7-BETA-CARBOXYMETHYL-9(11)-ENE DERIVATIVES OF ESTRONE AND ESTRADIOL" STEROID, vol. 52, no. 5-6, 1988, pages 609-621, XP002439115 cited in the application * |
LIM ET AL: "An environmentally friendly and cost effective synthesis of estradiol featuring two novel reagents: Si(0)/KF and PMHS/hexamethyldisiloxane/pTS" TETRAHEDRON LETTERS, ELSEVIER, AMSTERDAM, NL, vol. 47, no. 36, 4 September 2006 (2006-09-04), pages 6417-6420, XP005589978 ISSN: 0040-4039 * |
MAGERLEIN B J ET AL: "Preparation and Reactions of 11-Substituted 1,3,5(10)-Estratrienes. I. 11-Oxygenated Estrones and Estradiols" JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, AMERICAN CHEMICAL SOCIETY, WASHINGTON, DC, US, vol. 80, 5 May 1958 (1958-05-05), pages 2220-2225, XP002177431 ISSN: 0002-7863 cited in the application * |
TSUDA ET AL.: "AN AROMATIZATION OF A CROSS-CONJGATED DIENONE SYSTEM WITH ZINC" JOURNAL OF ORGANIC CHEMISTRY, vol. 26, 1963, pages 783-785, XP002439114 cited in the application * |
Also Published As
Publication number | Publication date |
---|---|
WO2007069039A3 (fr) | 2007-10-04 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP2774933B1 (fr) | Procédé de préparation d'acétate d'ulipristal et intermédiaire associé | |
JP5127700B2 (ja) | 3α(β)−7α(β)−ジヒドロキシ−6α(β)−アルキル−5β−コラン酸の調製方法 | |
US10000524B2 (en) | Synthesis of estetrol via estrone derived steroids | |
CN101065396B (zh) | 屈螺酮的制备方法 | |
US20020143199A1 (en) | Method of producing steroid derivatives | |
JP3984315B2 (ja) | ステロイド誘導体のケタールの製造方法 | |
US4284577A (en) | Novel vitamin D3 derivative and process for preparing the same | |
US20040024202A1 (en) | C-17 spirolactonization and 6,7 oxidation of steroids | |
EP1242444B1 (fr) | PROCEDE DE PREPARATION DE 17$g(a)-ACETOXY-11$g(b)- 4-N,N-(DIMETHYLAMINO)PHENYL]-21-METHOXY-19-NORPREGNA-4,9-DIENE-3,20-DIONE, INTERMEDIAIRES UTILISES PAR CE PROCEDE ET PROCEDES DE PREPARATION DE TELS INTERMEDIAIRES | |
EP2909224B1 (fr) | Procédé amélioré pour la préparation de fulvestrant | |
AU724696B2 (en) | Process for the preparation of 2-beta, 16-beta-diamino 3-alpha, 17-beta-diacloxy 5-alpha-androstanes, neuromuscular blocking agents with a steroidal structure | |
WO2007069039A2 (fr) | Procédé de conversion d'androsta-1,4,9(11)-triène-3-ones 17-substituées en 3-hydroxyestra-1,3,5(10),9(11)-tétraènes 17-substitués | |
JP2008521875A (ja) | 17−ヒドロキシ−6β,7β;15β,16β−ビスメチレン−3−オキソ−17α−プレグネ−4−エン−21−カルボン酸γ−ラクトンの工業的製造方法およびこの方法のための重要中間体 | |
Jin et al. | A concise synthesis of 25-hydroxycholesterol from hyodesoxycholic acid | |
JP7264569B2 (ja) | 11-メチレンステロイドの製造のための方法および新規な中間体 | |
JPH0559095A (ja) | 新規なニトロメチレン化合物及びその誘導体の製造法 | |
CA2787588A1 (fr) | Procede d'introduction d'une double liaison en positions 15, 16 d'un steroide | |
JPH036158B2 (fr) | ||
EP0071178B1 (fr) | Acyloxystéroides et procédé pour les préparer | |
JPH0822872B2 (ja) | 13α−アルキルゴナン−Δ9(11)−5,10−エポキシド及びその製法 | |
US3450697A (en) | Process for the preparation of 5(10),7-dehydro-steroids | |
WO2012032529A1 (fr) | Réduction stéréosélective de l'alpha-hydroxycétone | |
Jin et al. | A facile synthesis of 3β, 25-dihydroxy-5α-cholest-7-ene, the precursor to HMG-CoA reductase inhibitor | |
CN104829674A (zh) | 一种[3-14c]标记的类固醇雌激素的制备方法 | |
TW200831526A (en) | Novel process for diastereoselectively obtaining a chiral primary amine on a steroid |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
NENP | Non-entry into the national phase in: |
Ref country code: DE |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 06831698 Country of ref document: EP Kind code of ref document: A2 |