GB1564808A - 23,24-epoxy-25-hydroxycholestane derivatives - Google Patents
23,24-epoxy-25-hydroxycholestane derivatives Download PDFInfo
- Publication number
- GB1564808A GB1564808A GB2314077A GB2314077A GB1564808A GB 1564808 A GB1564808 A GB 1564808A GB 2314077 A GB2314077 A GB 2314077A GB 2314077 A GB2314077 A GB 2314077A GB 1564808 A GB1564808 A GB 1564808A
- Authority
- GB
- United Kingdom
- Prior art keywords
- epoxy
- hydroxy
- group
- cholestane
- lower alkoxy
- 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.)
- Expired
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J53/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by condensation with a carbocyclic rings or by formation of an additional ring by means of a direct link between two ring carbon atoms, including carboxyclic rings fused to the cyclopenta(a)hydrophenanthrene skeleton are included in this class
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
PATENT SPECIFICATION
( 11) 1 564 808 o e ( 21) Application No 23140/77 ( 22) Filed 8 Oct 1976 ( 62) Divided out of No 1 564 806 ( 31) Convention Application No 621 319 ( 32) Filed 10 Oct 1975 ( 31) Convention Application No 623 859 ( 32) Filed 20 Oct 1975 in ( 33) United States of America (US) ( 44) Complete Specification published 16 April 1980 ( 51) INT CL 3 C 07 J 53/00 ( 52) Index at acceptance C 2 U 4 A 3 4 C 4 X 4 C 9 A 4 DX 4 N 6 X 4 N 6 Y ( 54) 23,24-EPOXY-25-HYDROXY-CHOLESTANE DERIVATIVES ( 71 We, F HOFFMAN-LA ROCHE & CO, AKTIENGESELLSCHA FT, a Swiss Company of 124-184 Grenzacherstrasse, Basle, Switzerland, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and
by the following statement:-
The present invention is concerned with 23,24-epoxy-25-hydroxy-cholestane derivatives.
The 23,24-epoxy-25-hydroxy-cholestane derivatives provided by the present invention have the following general formula wherein R 1 represents a hydroxy, lower alkoxy, phenyl-(lower alkoxy), lower alkanoyloxy or benzoyloxy group.
The 23-24-epoxy-25-hydroxy-cholestane derivatives of formula I are useful in the manufacture of the cholesterol derivatives which are claimed per se in the specification of our copending Application for Letters Patent No 41938/76 (now
Serial No 1,564,806).
As used in this description and in the claims appended hereto, the term "lower alkyl" refers to a straight-chain or branched-chain saturated monovalent substituent consisting solely of carbon and hydrogen and containing from I to 8 carbon atoms Examples of lower alkyl groups are methyl, ethyl, n-propyl, isopropyl, tert butyl, hexyl and octyl The term "lower alkoxy" refers to a monovalent substituent which consists of a lower alkyl group linked through an ether oxygen atom having its free valence bond from the ether oxygen atom.
Examples of lower alkoxy groups are methoxy, ethoxy, isopropoxy and tert butoxy.
The term "phenyl-(lower alkoxy") refers to a lower alkoxy group which is substituted by a phenyl group Examples of phenyl-(lower alkoxy) groups are benzyloxy, 2-phenyl-ethoxy and 4-phenylbutoxy The term "lower alkanoyloxy" refers to the residue of a C,-C 8 alkanoic acid formed by removal of the hydrogen from the hydroxyl moiety of the carboxyl group Examples of lower alkanoyloxy groups are formyloxy, acetoxy, butyryloxy and hexanoyloxy.
In the formulae given in this description and in the accompanying claims, the various substituents and hydrogen atoms are shown as being joined to the steroid nucleus by one of these notations; namely, a solid line () indicating a substituent or hydrogen atom which has the p configuration (i e above the plane of the molecule), a broken line ( 111111) indicating a substituent or hydrogen atom which has the a-configuration (i e below the plane of the molecule) or (except in the case of the formula II compounds) a wavy line () indicating a substituent or (I) ( 19) hydrogen atom which may have the a or p-configuration The formulae all show the compounds in their absolute stereochemical configurations Since the starting materials are derived from naturally occurring stigmasterol, the products exist in the single absolute configuration shown herein.
The nomenclature adopted to define the stereochemistry about the 23,24 5 double bond and the absolute configuration of substituents bound to carbon atoms 23 and 24 of the steroid nucleus is described in The Journal of Organic Chemistry, 35, 2849 ( 1970) under the title "IUPAC Tentative Rules for the Nomenclature of Organic Chemistry Section E Fundamental Stereochemistry " In a preferred embodiment of the present invention, R, in formula I represents 10 a lower alkoxy group, especially the methoxy group, and the absolute configuration of the epoxy group is 23 R,24 S or 23 R,24 R.
The 23,24-epoxy-25-hydroxy-cholestane derivatives of formula I hereinbefore can be prepared by contacting a cholestene derivative of the general formula H CH 3 % 24 CH 3 CHCI H 3 II 1 I H H (Y i 1 3 R 1 wherein R, has the significance given earlier, with a lower alkyl or aryl(lower alkyl) hydroperoxide in the presence of a compound of the general formula 17 CH 2 I /oó -.
HC ' V (ii I) CH 2 -2 R 8 wherein R 7 and R 8 each represent a hydrogen atom or a lower alkyl group, in an inert solvent at a reduced temperature 20 The cholestene derivatives of formula II are claimed per se in the specification of our copending Application for Letters Patent No 23139/77 (now Serial No.
1564807) and can be prepared as described therein.
In the aforementioned process for the preparation of the 23,24-epoxy-25hydroxy-cholestane derivatives of formula I, the 23,24-double bond in a cholestene 25 derivative of formula II is stereospecifically epoxidised in the presence of a catalytic amount of a vanadyl acetylacetonate of formula III in a suitable inert organic solvent at a reduced temperature.
Suitable lower alkyl hydroperoxides include methyl, ethyl, propyl, isopropyl, sec butyl and tert butyl hydroperoxides Suitable aryl-(lower alkyl) hydroperoxides 30 include cumyl hydroperoxide Branched-chain hydroperoxides are preferred.
Tert butyl hydroperoxide is most preferred Suitable inert organic solvents include aromatic solvents such as benzene and toluene and halogenated hydrocarbons such as methylene chloride, chloroform and carbon tetrachloride Aromatic hydrocarbons are preferred with toluene being most preferred 35 Among the vanadyl acetylacetonates of formula III which are suitable for the stereospecific epoxidation there may be mentioned those in which R 7 and R 8 each independently and simultaneously represent a hydrogen atom and a lower alkyl group containing from I to 6 carbon atoms Vanadyl acetylacetonates of formula III in which R 7 and R 8 simultaneously represent a hydrogen atom or a lower alkyl 40 group are preferred Vanadyl acetylacetonate is most preferred.
The amounts of lower alkyl hydroperoxide and vanadyl acetylacetonate of formula III, both relative to the amount of cholestene derivative of formula II, which may be used in the stereospecific epoxidation are not narrowly critical and 1,564,808 can vary from I to 5 moles of lower alkyl hydroperoxide and from 0 01 to 10 weight per cent of the vanadyl acetylacetonate The stereospecific epoxidation is preferably carried out using about a 2 5 molar excess of the hydroperoxide and about 1 weight per cent of the vanadyl acetylacetonate.
Vanadyl acetylacetonates of formula II can be prepared by the method 5 described by R A Rowe, et al, Inorganic Synthesis, 5, 113 ( 1957) and references cited therein.
The stereospecific epoxidation of 23,24-double bond of a cholestene derivative of formula II is conveniently carried out by mixing the reagents and substrate at an initial reaction temperature between -100 C and -50 C and then allowing the 10 temperature to rise slowly to between -40 C and + 20 C An initial temperature of about -80 C and a final temperature of about -20 C is most preferred.
The following Examples illustrate the manner in which the 23,24-epoxy-25hydroxy-cholestane derivatives provided by this invention can be prepared.
Example 1 15
23 R,24 S-Epoxy-2 S-hydroxy-6/-methoxy-3 a,5-cyclo-5 a-cholestane A mixture of 0 103 g ( 0 00025 mole) of 25-hydroxy-6 p-methoxy-3 a,5cyclo-5 acholest-23 (E)-ene, 0 001 g of vanadyl acetylacetonate and 3 ml of toluene was cooled to -78 C and 0 060 g ( 0 00060 mol) of 90 % tert butyl hydroperoxide/10 % tert butyl alcohol in 3 ml of toluene were added dropwise After completion of the 20 addition, the solution was stirred at -78 C for 2 hours and then allowed to warm slowly to -20 C The solution was stirred at -20 C for 6 hours 50 ml of methylene chloride were added to the mixture and the solution was washed successively with ml of saturated aqueous sodium bisulphite solution and 25 ml of water The organic phase was dried over anhydrous magnesium sulphate, filtered and the 25 filtrate was concentrated under reduced pressure Chromatography of the residue on silica gel gave 0 088 g ( 81 %) of 23 R,24 S-epoxy-25-hydroxy-6 pmethoxy-3 a,5cyclo-5 a-cholestane (melting point 112 -113 C) by evaporation in the' 2 % acetone/methylene chloride fractions; lal 5 "= + 52 9 (c= 1 06 in chloroform).
Example 2 30
23 R,24 R-Epoxy-25-hydroxy-6 13-methoxy-3 a,5-cyclo-5 a-cholestane A mixture of 0 103 g ( 0 00025 mol) of 25-hydroxy-6/-methoxy-3 a 5,-cyclo5 acholest-23 (Z)-ene, 0 001 g of vanadyl acetylacetonate and 3 ml of toluene was cooled to -78 C and 0 060 g ( 0 00060 mol) of 90 % tert butyl hydroperoxide/10 % tert butyl alcohol in 3 ml of toluene was added dropwise After completion of the 35 addition, the solution was stirred at -78 C for 2 hours and then allowed to warm slowly to -20 C The solution was stirred at -20 C for 6 hours 50 ml of methylene chloride were added to the mixture and the solution was washed successively with ml of saturated aqueous sodium bisulphite solution and 25 ml of water The organic phase was dried over anhydrous magnesium sulphate, filtered and the 40 filtrate was concentrated under reduced pressure Chromatography of the residue on silica gel gave 0 083 g ( 77 %) of 23 R,24 R-epoxy-25-hydroxy-6/3methoxy-3 a,5cyclo-Scr 5-cholestane.
Claims (4)
1 A 23,24-epoxy-25-hydroxy-cholestane derivative of the general formula 45 CH 3 | H f CH CH 3 R 1 wherein R, represents a hydroxy, lower alkoxy, phenyl-(lower alkoxy), lower alkanoyloxy or benzoyloxy group.
2 A 23,24-epoxy-25-hydroxy-cholestane derivative of formula I given in claim 1, wherein R, represents a lower alkoxy group and the absolute configuration of the 50 epoxy group is 23 R,24 S or 23 R,24 R.
1,564,808 4 1,564,808 4
3 The 23,24-epoxy-25-hydroxy-cholestane derivative as set forth in claim 2, wherein R, represents a methoxy group and the absolute configuration of the epoxy group is 23 R,245.
4 The 23,24-epoxy-25-hydroxy-cholestane derivative as set forth in claim 2, wherein R 1 represents a methoxy group and the absolute configuration of the 5 epoxy group is 23 R,24 R.
For the Applicants, CARPMAELS & RANSFORD, Chartered Patent Agents, 43, Bloomsbury Square, London, WC 1 A 2 RA.
Printed for Her Majesty's Stationery Office by the Courier Press, Leamington Spa, 1980.
Published by the Patent Office, 25 Southampton Buildings, London, WC 2 A l AY, from which copies may be obtained.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US05/621,319 US3994878A (en) | 1975-10-10 | 1975-10-10 | Syntheses of 24R,25- and 24S,25-dihydroxycholesterol and alkanoyl derivatives thereof |
| US05/623,859 US4038272A (en) | 1975-10-20 | 1975-10-20 | Stereospecific syntheses of 24r,25- and 24s,25-dihydroxycholesterol and alkanoyl derivatives thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| GB1564808A true GB1564808A (en) | 1980-04-16 |
Family
ID=27088923
Family Applications (5)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB2313977A Expired GB1564807A (en) | 1975-10-10 | 1976-10-08 | Cholestene derivatives |
| GB4193876A Expired GB1564806A (en) | 1975-10-10 | 1976-10-08 | Cholesterol derivatives |
| GB2314277A Expired GB1564810A (en) | 1975-10-10 | 1976-10-08 | Cholesterol derivatives |
| GB2314077A Expired GB1564808A (en) | 1975-10-10 | 1976-10-08 | 23,24-epoxy-25-hydroxycholestane derivatives |
| GB2314177A Expired GB1564809A (en) | 1975-10-10 | 1976-10-08 | 24,25-epoxy-cholestane derivatives |
Family Applications Before (3)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB2313977A Expired GB1564807A (en) | 1975-10-10 | 1976-10-08 | Cholestene derivatives |
| GB4193876A Expired GB1564806A (en) | 1975-10-10 | 1976-10-08 | Cholesterol derivatives |
| GB2314277A Expired GB1564810A (en) | 1975-10-10 | 1976-10-08 | Cholesterol derivatives |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB2314177A Expired GB1564809A (en) | 1975-10-10 | 1976-10-08 | 24,25-epoxy-cholestane derivatives |
Country Status (8)
| Country | Link |
|---|---|
| JP (1) | JPS5246061A (en) |
| AT (1) | AT355236B (en) |
| CH (1) | CH628907A5 (en) |
| DE (1) | DE2645527A1 (en) |
| FR (2) | FR2407941A1 (en) |
| GB (5) | GB1564807A (en) |
| IT (1) | IT1068692B (en) |
| NL (1) | NL7611155A (en) |
Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH644873A5 (en) * | 1980-02-12 | 1984-08-31 | Hoffmann La Roche | METHOD FOR PRODUCING CHOLESTEROL DERIVATIVES. |
| DK2753632T3 (en) | 2011-09-08 | 2023-07-10 | Sage Therapeutics Inc | NEUROACTIVE STEROIDS, COMPOSITIONS AND USE THEREOF |
| TR201817995T4 (en) | 2013-03-13 | 2019-02-21 | Sage Therapeutics Inc | NEUROACTIVE STEROIDS AND METHODS OF USE |
| IL282048B2 (en) | 2015-07-06 | 2024-09-01 | Sage Therapeutics Inc | Oxysterols and methods of use thereof |
| CA2991311A1 (en) * | 2015-07-06 | 2017-01-12 | Sage Therapeutics, Inc. | Oxysterols and methods of use thereof |
| CN109195604B (en) | 2016-04-01 | 2023-11-14 | 萨奇治疗股份有限公司 | Oxysterol and methods of use thereof |
| WO2017193046A1 (en) | 2016-05-06 | 2017-11-09 | Sage Therapeutics, Inc. | Oxysterols and methods of use thereof |
| MD3481846T2 (en) | 2016-07-07 | 2021-11-30 | Sage Therapeutics Inc | 11-substituted 24-hydroxysterols for use in the treatment of NMDA related conditions |
| CN110023323A (en) | 2016-09-30 | 2019-07-16 | 萨奇治疗股份有限公司 | The oxygen sterol that C7 replaces and its method as NMDA regulator |
| ES2952106T3 (en) | 2016-10-18 | 2023-10-27 | Sage Therapeutics Inc | Oxysterols and procedures for their use |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NL7402846A (en) * | 1973-03-02 | 1974-09-04 | ||
| US3822254A (en) * | 1973-05-21 | 1974-07-02 | Hoffmann La Roche | Synthesis of 25-hydroxycholesterol |
-
1976
- 1976-09-28 CH CH1224676A patent/CH628907A5/en not_active IP Right Cessation
- 1976-10-08 GB GB2313977A patent/GB1564807A/en not_active Expired
- 1976-10-08 GB GB4193876A patent/GB1564806A/en not_active Expired
- 1976-10-08 AT AT751376A patent/AT355236B/en not_active IP Right Cessation
- 1976-10-08 GB GB2314277A patent/GB1564810A/en not_active Expired
- 1976-10-08 IT IT2816476A patent/IT1068692B/en active
- 1976-10-08 GB GB2314077A patent/GB1564808A/en not_active Expired
- 1976-10-08 GB GB2314177A patent/GB1564809A/en not_active Expired
- 1976-10-08 JP JP12050076A patent/JPS5246061A/en active Pending
- 1976-10-08 NL NL7611155A patent/NL7611155A/en not_active Application Discontinuation
- 1976-10-08 DE DE19762645527 patent/DE2645527A1/en not_active Ceased
- 1976-10-11 FR FR7630450A patent/FR2407941A1/en active Granted
-
1977
- 1977-04-22 FR FR7712223A patent/FR2351998A1/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| AT355236B (en) | 1980-02-25 |
| GB1564806A (en) | 1980-04-16 |
| GB1564810A (en) | 1980-04-16 |
| FR2407941A1 (en) | 1979-06-01 |
| NL7611155A (en) | 1977-04-13 |
| FR2351998A1 (en) | 1977-12-16 |
| GB1564809A (en) | 1980-04-16 |
| DE2645527A1 (en) | 1977-04-21 |
| FR2351998B1 (en) | 1980-04-25 |
| CH628907A5 (en) | 1982-03-31 |
| JPS5246061A (en) | 1977-04-12 |
| FR2407941B1 (en) | 1980-05-16 |
| IT1068692B (en) | 1985-03-21 |
| ATA751376A (en) | 1979-07-15 |
| GB1564807A (en) | 1980-04-16 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PS | Patent sealed | ||
| PCNP | Patent ceased through non-payment of renewal fee |