EP0915905A1 - PROCEDE DE PREPARATION DE DERIVES DE 16$g(a)-HYDROXY-ESTRA-1,3,5(10)-TRIENE - Google Patents
PROCEDE DE PREPARATION DE DERIVES DE 16$g(a)-HYDROXY-ESTRA-1,3,5(10)-TRIENEInfo
- Publication number
- EP0915905A1 EP0915905A1 EP97935517A EP97935517A EP0915905A1 EP 0915905 A1 EP0915905 A1 EP 0915905A1 EP 97935517 A EP97935517 A EP 97935517A EP 97935517 A EP97935517 A EP 97935517A EP 0915905 A1 EP0915905 A1 EP 0915905A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- estra
- derivative
- triene
- bromine
- hydroxy
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 238000004519 manufacturing process Methods 0.000 title 1
- 239000000243 solution Substances 0.000 claims abstract description 21
- 238000000034 method Methods 0.000 claims abstract description 13
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims abstract description 8
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 8
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 6
- 239000002253 acid Substances 0.000 claims abstract description 5
- 125000002252 acyl group Chemical group 0.000 claims abstract description 5
- 239000012062 aqueous buffer Substances 0.000 claims abstract description 5
- -1 bromine cations Chemical class 0.000 claims abstract description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims abstract description 4
- 150000007513 acids Chemical class 0.000 claims abstract description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 4
- 229910052500 inorganic mineral Inorganic materials 0.000 claims abstract description 4
- 239000011707 mineral Substances 0.000 claims abstract description 4
- 150000004965 peroxy acids Chemical class 0.000 claims abstract description 4
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 3
- 125000004043 oxo group Chemical group O=* 0.000 claims abstract description 3
- 239000012279 sodium borohydride Substances 0.000 claims description 8
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 abstract 1
- 239000011734 sodium Substances 0.000 abstract 1
- 229910052708 sodium Inorganic materials 0.000 abstract 1
- 239000000203 mixture Substances 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- 230000007935 neutral effect Effects 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 4
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- PROQIPRRNZUXQM-ZXXIGWHRSA-N estriol Chemical class OC1=CC=C2[C@H]3CC[C@](C)([C@H]([C@H](O)C4)O)[C@@H]4[C@@H]3CCC2=C1 PROQIPRRNZUXQM-ZXXIGWHRSA-N 0.000 description 4
- 239000001632 sodium acetate Substances 0.000 description 4
- 235000017281 sodium acetate Nutrition 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- PROQIPRRNZUXQM-UHFFFAOYSA-N (16alpha,17betaOH)-Estra-1,3,5(10)-triene-3,16,17-triol Natural products OC1=CC=C2C3CCC(C)(C(C(O)C4)O)C4C3CCC2=C1 PROQIPRRNZUXQM-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 239000011877 solvent mixture 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
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 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
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 2
- 239000007853 buffer solution Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- VRLDVERQJMEPIF-UHFFFAOYSA-N dbdmh Chemical compound CC1(C)N(Br)C(=O)N(Br)C1=O VRLDVERQJMEPIF-UHFFFAOYSA-N 0.000 description 2
- 229960001348 estriol Drugs 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- 239000003495 polar organic solvent Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 2
- WPOCIZJTELRQMF-UHFFFAOYSA-N 16alpha-Hydroxyestrone Natural products OC1=CC=C2C3CCC(C)(C(C(O)C4)=O)C4C3CCC2=C1 WPOCIZJTELRQMF-UHFFFAOYSA-N 0.000 description 1
- WPOCIZJTELRQMF-QFXBJFAPSA-N 16alpha-hydroxyestrone Chemical compound OC1=CC=C2[C@H]3CC[C@](C)(C([C@H](O)C4)=O)[C@@H]4[C@@H]3CCC2=C1 WPOCIZJTELRQMF-QFXBJFAPSA-N 0.000 description 1
- YNJSNEKCXVFDKW-UHFFFAOYSA-N 3-(5-amino-1h-indol-3-yl)-2-azaniumylpropanoate Chemical compound C1=C(N)C=C2C(CC(N)C(O)=O)=CNC2=C1 YNJSNEKCXVFDKW-UHFFFAOYSA-N 0.000 description 1
- HETCEOQFVDFGSY-UHFFFAOYSA-N Isopropenyl acetate Chemical compound CC(=C)OC(C)=O HETCEOQFVDFGSY-UHFFFAOYSA-N 0.000 description 1
- PKCYHELNAHVTBH-DIQFNYNJSA-N OC1C([C@]2(C)[C@@H](C1)[C@@H]1CCC=3C=CC=CC3[C@H]1CC2)=O Chemical class OC1C([C@]2(C)[C@@H](C1)[C@@H]1CCC=3C=CC=CC3[C@H]1CC2)=O PKCYHELNAHVTBH-DIQFNYNJSA-N 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 229910000318 alkali metal phosphate Inorganic materials 0.000 description 1
- 150000001541 aziridines Chemical class 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000003139 buffering effect Effects 0.000 description 1
- 150000002118 epoxides Chemical class 0.000 description 1
- 229940011871 estrogen Drugs 0.000 description 1
- 239000000262 estrogen Substances 0.000 description 1
- 229960003399 estrone Drugs 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropyl acetate Chemical compound CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- VBTQNRFWXBXZQR-UHFFFAOYSA-N n-bromoacetamide Chemical compound CC(=O)NBr VBTQNRFWXBXZQR-UHFFFAOYSA-N 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 238000006053 organic reaction Methods 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000007974 sodium acetate buffer Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- SGPDKGQGUXXQTG-UHFFFAOYSA-M sodium;sulfuric acid;acetate Chemical compound [Na+].CC([O-])=O.OS(O)(=O)=O SGPDKGQGUXXQTG-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 150000003553 thiiranes Chemical class 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000002351 wastewater Substances 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
- C07J1/0051—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
- C07J1/0059—Estrane derivatives substituted in position 17 by a keto group
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J13/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having a carbon-to-carbon double bond from or to position 17
- C07J13/005—Normal steroids containing carbon, hydrogen, halogen or oxygen having a carbon-to-carbon double bond from or to position 17 with double bond in position 16 (17)
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
- C07J71/0005—Oxygen-containing hetero ring
- C07J71/001—Oxiranes
Definitions
- the invention relates to a process for the preparation of 16 ⁇ -hydroxy-estra-l, 3,5 (10) -triene derivatives of the general formula I.
- R j represents a hydrogen atom, an alkyl group with a maximum of 4 carbon atoms, a benzyl group or an acyl group with a maximum of 8 carbon atoms,
- X and Y together symbolize an oxo group, or wherein X represents a hydroxy group and Y represents a hydrogen atom, can be prepared by using an estra-1,3,5 (10), 16-tetraene derivative of the general formula II
- Rj has the meaning given above and R 2 represents an acyl group with a maximum of 8 carbon atoms, converted into a 16 ⁇ , 17 ⁇ -epoxide by means of peracids and cleaved by means of mineral acids or by converting it into the corresponding 16 ⁇ -bromine derivative using a reagent supplying bromine cations and then rearranging the bromine and exchanging it for a hydroxyl group
- R j has the meaning given above in the presence of a strong, aqueous buffer solution of pH 5-6.5 using sodium borohydride to give the corresponding 3, 16 ⁇ , 17 ⁇ -trihydroxy-estra-1,3,5 (10) -triene derivatives of the general formula I b
- Estriol (Estra-l, 3,5 (10) -triene-3,16 ⁇ , 17ß-triol) is a naturally occurring estrogen that is also used in numerous pharmaceutical preparations.
- the invention relates to the reduction of l ⁇ -hydroxy-estra-l, 3,5 (10) -trien-17-one derivatives of the general formula I a by means of sodium borohydride to the 3,16 ⁇ , 17ß-trihydroxy-estra-l , 3,5 (10) -triene derivatives of the general formula I b.
- this reaction step can only be achieved with good yields of process product if it is carried out in the presence of a strong, aqueous buffer solution with a pH of 5 - 6.5.
- estrone cannot be reduced with sodium borohydride even in the presence of a strong, aqueous buffer solution with a pH of 5 - 6.5.
- buffer substances are used to prepare the buffer solutions, provided that the buffer substances are inert to sodium borohydride.
- buffer substances which are readily biodegradable, such as sodium acetate.
- the buffer solution should expediently be 0.5 to 15.0 mol of buffer substances (preferably
- the procedure is such that the required 16 ⁇ -hydroxy-estra-1,3,5 (10), 16-trien-17-one derivative of the formula I a is not isolated, but from an Estra-1,3,5 (10), 16-tetraene derivative of the general formula ⁇ produces a solution of the 16 ⁇ -hydroxy-estra-1,3,5 (10) -triene derivative, which by an appropriate choice of the Reaction required acids and bases and / or by adding salts to a pH value of 5 - 6.5 is buffered.
- the Estra-1, 3.5 (10), 16-tetraene derivative of the general formula ⁇ is dissolved in a polar organic solvent, such as, for example, a polar ether, and with an aqueous peracid solution such as perbenzoic acid solution or in particular peracetic acid solution.
- a polar organic solvent such as, for example, a polar ether
- an aqueous peracid solution such as perbenzoic acid solution or in particular peracetic acid solution.
- the epoxide obtained is then isolated by concentrating the reaction mixture or precipitating with water, dissolved in a polar solvent and cleaved with a dilute mineral acid such as dilute sulfuric acid.
- the reaction solution obtained can then, for example, be buffered to a pH of 5.0-6.5 by adding sodium acetate and used for further reaction.
- the Estra-1,3,5 (10), 16-tetraene derivative of the general formula II is reacted with a bromine cation-providing reagent, such as N-bromosuccinimide, N-bromoacetamide or dibromodimethylhydantoin under the conditions known per se the corresponding 16-bromo compound is converted (Gary J. Matthews et al. "Synthesis of Oxirones, Aziridines and Episulfides" in John Fried et al. "Organic Reactions in Steroid Chemistry", by Norstrand Reinhold Comp., New York et al., 1972, Vol II, p 1 ff).
- a bromine cation-providing reagent such as N-bromosuccinimide, N-bromoacetamide or dibromodimethylhydantoin
- the 16 ⁇ -bromine derivative obtained in this way is dissolved in a polar organic solvent and then rearranged with aqueous alkali metal hydroxide solution to give the 16 ⁇ -bromine compound, which is hydrolyzed to the corresponding 16 ⁇ -hydroxy compound.
- the reaction mixture is prepared and reacted in the same way as the reaction solution described in route A during the preparation.
- the mixture is then cooled to -3 ° C. and 30 ml of triethylamine are added.
- the still moist product is dissolved in a mixture of 560 ml of tetrahydrofuran and 240 ml of methanol, 150 ml of 6N aqueous sulfuric acid are added at 25 ° C. and the mixture is stirred at 55 ° C. for 4 hours.
- Example 2 a) 25.0 g of 3, 17-diacetoxy-estra-1,3,5 (10), 16-tetraene (prepared according to Example 1) are dissolved in 175 ml of isopropanol and spatially at 20 ° C. with 12.5 G
- Dibromodimethylhydantoin added. The mixture is stirred for a further 2 hours, 0.75 g of p-toluenesulfonic acid is added and the mixture is stirred for a further 30 minutes.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
Abstract
L'invention concerne un procédé de préparation de dérivés de 16α-hydroxy-estra-1,3,5(10)-triène qui répondent à la formule générale (I), dans laquelle R1 désigne un atome d'hydrogène, un groupe alkyle avec au maximum 4 atomes de carbone, un groupe benzyle ou un groupe acyle avec au maximum 8 atomes de carbone; et X et Y symbolisent ensemble un groupe oxo ou X désigne un groupe hydroxyle et Y un atome d'hydrogène. Ce procédé se caractérise en ce que l'on convertit un dérivé d'estra-1,3,5(10),16-tétraène en 16α,17α-époxyde au moyen de peracides, on clive celui-ci au moyen d'acides minéraux ou on le convertit dans le dérivé correspondant de 16α-brome au moyen d'un réactif qui libère des cations de brome, puis on convertit celui-ci en un dérivé de 16β-brome, on remplace le brome par un groupe hydroxyle et on réduit le cas échéant le dérivé de 16α-hydroxy-1,3,5(10)triène-17-one ainsi obtenu au moyen d'hydrure de bore de sodium en présence d'une forte solution tampon aqueuse d'une valeur de pH comprise entre 5 et 6,5, jusqu'à obtenir le dérivé correspondant de 16α,17β-trihydroxy-estra-1,3,5(10)-triène.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19631541 | 1996-07-25 | ||
| DE1996131541 DE19631541C1 (de) | 1996-07-25 | 1996-07-25 | Verfahren zur Herstellung von 16alpha-Hydroxy-estra-1,3,5(10)-trien-Derivaten |
| PCT/EP1997/003708 WO1998004577A1 (fr) | 1996-07-25 | 1997-07-11 | PROCEDE DE PREPARATION DE DERIVES DE 16α-HYDROXY-ESTRA-1,3,5(10)-TRIENE |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP0915905A1 true EP0915905A1 (fr) | 1999-05-19 |
Family
ID=7801803
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP97935517A Withdrawn EP0915905A1 (fr) | 1996-07-25 | 1997-07-11 | PROCEDE DE PREPARATION DE DERIVES DE 16$g(a)-HYDROXY-ESTRA-1,3,5(10)-TRIENE |
Country Status (6)
| Country | Link |
|---|---|
| EP (1) | EP0915905A1 (fr) |
| JP (1) | JP2000515163A (fr) |
| AU (1) | AU3848297A (fr) |
| CA (1) | CA2260121A1 (fr) |
| DE (1) | DE19631541C1 (fr) |
| WO (1) | WO1998004577A1 (fr) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1149838A1 (fr) * | 2000-04-28 | 2001-10-31 | AZIENDE CHIMICHE RIUNITE ANGELINI FRANCESCO A.C.R.A.F. S.p.A. | Estriol substantiellement exempt de 16alpha, 17alpha-estra-1,3,5(10)-triène-3,16,17-triol |
| WO2012032529A1 (fr) | 2010-09-08 | 2012-03-15 | Reliance Life Sciences Pvt. Ltd | Réduction stéréosélective de l'alpha-hydroxycétone |
| CN108047295A (zh) * | 2017-12-29 | 2018-05-18 | 广西万德药业有限公司 | 雌三醇的高效合成方法 |
-
1996
- 1996-07-25 DE DE1996131541 patent/DE19631541C1/de not_active Expired - Lifetime
-
1997
- 1997-07-11 JP JP10508425A patent/JP2000515163A/ja active Pending
- 1997-07-11 WO PCT/EP1997/003708 patent/WO1998004577A1/fr not_active Ceased
- 1997-07-11 CA CA 2260121 patent/CA2260121A1/fr not_active Abandoned
- 1997-07-11 EP EP97935517A patent/EP0915905A1/fr not_active Withdrawn
- 1997-07-11 AU AU38482/97A patent/AU3848297A/en not_active Abandoned
Non-Patent Citations (1)
| Title |
|---|
| See references of WO9804577A1 * |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2000515163A (ja) | 2000-11-14 |
| AU3848297A (en) | 1998-02-20 |
| DE19631541C1 (de) | 1997-09-18 |
| CA2260121A1 (fr) | 1998-02-05 |
| WO1998004577A1 (fr) | 1998-02-05 |
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