WO1998004577A1 - VERFAHREN ZUR HERSTELLUNG VON 16α-HYDROXY-ESTRA-1,3,5(10)-TRIEN-DERIVATEN - Google Patents
VERFAHREN ZUR HERSTELLUNG VON 16α-HYDROXY-ESTRA-1,3,5(10)-TRIEN-DERIVATEN Download PDFInfo
- Publication number
- WO1998004577A1 WO1998004577A1 PCT/EP1997/003708 EP9703708W WO9804577A1 WO 1998004577 A1 WO1998004577 A1 WO 1998004577A1 EP 9703708 W EP9703708 W EP 9703708W WO 9804577 A1 WO9804577 A1 WO 9804577A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- estra
- derivative
- triene
- bromine
- hydroxy
- Prior art date
Links
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
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU38482/97A AU3848297A (en) | 1996-07-25 | 1997-07-11 | Process for preparing 16alpha-hydroxy-estra-1,3,5(10)-triene derivatives |
EP97935517A EP0915905A1 (de) | 1996-07-25 | 1997-07-11 | VERFAHREN ZUR HERSTELLUNG VON 16$g(a)-HYDROXY-ESTRA-1,3,5(10)-TRIEN-DERIVATEN |
JP10508425A JP2000515163A (ja) | 1996-07-25 | 1997-07-11 | 16α―ヒドロキシ―エストラ―1,3,5(10)―トリエン誘導体の製造方法 |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE1996131541 DE19631541C1 (de) | 1996-07-25 | 1996-07-25 | Verfahren zur Herstellung von 16alpha-Hydroxy-estra-1,3,5(10)-trien-Derivaten |
DE19631541.7 | 1996-07-25 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1998004577A1 true WO1998004577A1 (de) | 1998-02-05 |
Family
ID=7801803
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP1997/003708 WO1998004577A1 (de) | 1996-07-25 | 1997-07-11 | VERFAHREN ZUR HERSTELLUNG VON 16α-HYDROXY-ESTRA-1,3,5(10)-TRIEN-DERIVATEN |
Country Status (6)
Country | Link |
---|---|
EP (1) | EP0915905A1 (de) |
JP (1) | JP2000515163A (de) |
AU (1) | AU3848297A (de) |
CA (1) | CA2260121A1 (de) |
DE (1) | DE19631541C1 (de) |
WO (1) | WO1998004577A1 (de) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1149838A1 (de) * | 2000-04-28 | 2001-10-31 | AZIENDE CHIMICHE RIUNITE ANGELINI FRANCESCO A.C.R.A.F. S.p.A. | Estriol, die im wesentlichen kein 16alpha, 17alpha-estra-1,3,5(10)-triene-3,16,17-triol enthält |
WO2012032529A1 (en) | 2010-09-08 | 2012-03-15 | Reliance Life Sciences Pvt. Ltd | Stereoselective reduction of alpha-hydroxyketone |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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 EP EP97935517A patent/EP0915905A1/de not_active Withdrawn
- 1997-07-11 AU AU38482/97A patent/AU3848297A/en not_active Abandoned
- 1997-07-11 CA CA 2260121 patent/CA2260121A1/en not_active Abandoned
- 1997-07-11 JP JP10508425A patent/JP2000515163A/ja active Pending
- 1997-07-11 WO PCT/EP1997/003708 patent/WO1998004577A1/de not_active Application Discontinuation
Non-Patent Citations (9)
Title |
---|
CHEMICAL ABSTRACTS, vol. 102, no. 5, 4 February 1985, Columbus, Ohio, US; abstract no. 046179, TONG Z ET AL: "Syntheses of 16-substituted estradiol derivatives" page 600; column 1; XP002046765 * |
D. KIESEWETTER ET AL: "Synthesis of 16-Fluoroestrogens by Unusually Facile Fluoride Ion Displacement Reactions: Prospects for the Preparation of Fluorine-18 Labeled Estrogens", JOURNAL OF ORGANIC CHEMISTRY., vol. 49, no. 25, 14 December 1984 (1984-12-14), EASTON US, pages 4900 - 4905, XP002046762 * |
ELCE J S ET AL: "Synthesis of estrogen monoglucuronides", JOURNAL OF THE CHEMICAL SOCIETY, SECTION C: ORGANIC CHEMISTRY., no. 7, 1967, LETCHWORTH GB, pages 542 - 550, XP002046758 * |
G. MARRIAN ET AL: "16.alpha.-Hydroxyestrone in the Urine of Pregnant Women", BIOCHEMICAL JOURNAL, vol. 66, 1957, pages 60 - 65, XP002046760 * |
J. FISHMAN ET AL: "Synthesis of 1,3,5(10)-Estratriene-3,16.beta.,17.alpha-triol", JOURNAL OF ORGANIC CHEMISTRY., vol. 23, no. 8, 1958, EASTON US, pages 1190 - 1192, XP002046764 * |
M. NUMAZAWA ET AL: "Stereospecific Synthesis of 16.alpha.-Hydroxy-17-oxo Steroids by Controlled Alkaline Hydrolysis of Corresponding 16-Bromo 17-Ketones and Its Reaction Mechanism", JOURNAL OF ORGANIC CHEMISTRY., vol. 47, no. 21, 8 October 1982 (1982-10-08), EASTON US, pages 4024 - 4029, XP002046763 * |
N. S. LEEDS ET AL: "Studies of Steroid Ring D Epoxides of Enol Acetates: A New Synthesis of Estriol and of Androstan-3.beta.,16.alpha.,17.beta.-triol", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY., vol. 76, no. 11, June 1954 (1954-06-01), DC US, pages 2943 - 2948, XP002046761 * |
NAMBARA T ET AL: "Syntheses of estriol mono-D-glucuronides", CHEMICAL AND PHARMACEUTICAL BULLETIN, vol. 15, no. 8, 1967, TOKYO JP, pages 1232 - 1238, XP002046759 * |
YIYAO GONGYE, no. 8, 1984, pages 14 - 17 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1149838A1 (de) * | 2000-04-28 | 2001-10-31 | AZIENDE CHIMICHE RIUNITE ANGELINI FRANCESCO A.C.R.A.F. S.p.A. | Estriol, die im wesentlichen kein 16alpha, 17alpha-estra-1,3,5(10)-triene-3,16,17-triol enthält |
WO2012032529A1 (en) | 2010-09-08 | 2012-03-15 | Reliance Life Sciences Pvt. Ltd | Stereoselective reduction of alpha-hydroxyketone |
Also Published As
Publication number | Publication date |
---|---|
AU3848297A (en) | 1998-02-20 |
CA2260121A1 (en) | 1998-02-05 |
EP0915905A1 (de) | 1999-05-19 |
JP2000515163A (ja) | 2000-11-14 |
DE19631541C1 (de) | 1997-09-18 |
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