GB2096614A - Synthesis of corticoid 17-esters - Google Patents
Synthesis of corticoid 17-esters Download PDFInfo
- Publication number
- GB2096614A GB2096614A GB8124654A GB8124654A GB2096614A GB 2096614 A GB2096614 A GB 2096614A GB 8124654 A GB8124654 A GB 8124654A GB 8124654 A GB8124654 A GB 8124654A GB 2096614 A GB2096614 A GB 2096614A
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- United Kingdom
- Prior art keywords
- group
- compound
- hydrolyzing
- formula
- hydroxy
- Prior art date
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J51/00—Normal steroids with unmodified cyclopenta(a)hydrophenanthrene skeleton not provided for in groups C07J1/00 - C07J43/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
- C07J5/0046—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa
- C07J5/0061—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa substituted in position 16
- C07J5/0069—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa substituted in position 16 by a saturated or unsaturated hydrocarbon group
- C07J5/0076—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa substituted in position 16 by a saturated or unsaturated hydrocarbon group by an alkyl group
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
- C07J7/008—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms substituted in position 21
- C07J7/0085—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms substituted in position 21 by an halogen atom
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Rheumatology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Pain & Pain Management (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Steroid Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A new route from compounds (I) to compounds (II> <IMAGE> (R = acyl; R<1> and R<2> are each halo, OH or acyloxy; X = H, Cl, F) comprises successively introducing the 17-ester and DELTA <1,4> functions while the 11-hydroxyl group is protected by trimethylsilylation. A typical product (II) is beclomethasone dipropionate.
Description
GB2096614A 1
SPECIFICATION
Process for the preparation of corticoids
5 This invention relates to a process for producing anti-inflammatory steroids characterised by the presence of an 11 /?-hydroxy substituent.
According to the processes of the present invention, the anti-inflammatory steroids can be obtained efficiently.
Examples of the anti-inflammatory steroids which can be produced by the process of the 10 invention are beclomethasone dipropionate, bethamethasone dipropionate, betamethasone 1 7-valerate and clobetasol propionate.
According to the process of the present invention, certain of the reaction sequences can be carried out on a 9a-CI compound.
At appropriate stages in the synthesis the opportunity exists for direct introduction of valuable 15 17-acylate groups; when the 17 and 21-ester groups are identical, both may be introduced simultaneously. This direct esterification is carried out using inexpensive reagents and yields are virtually quantitative. On the contrary, for example, according to conventional processes for converting beclomethasone to the 17, 21-dipropionate, beclomethasone is firstly converted to the corresponding 17, 21-cyclic orthoester by using triethyl orthopropionate which is very 20 expensive, and then the 17, 21-cyclic orthoester is hydrolyzed to form a 1 7-monoester of the 17a, 21-dihydroxy-20-keto steroid, and the resulting 17-monoester is acylated with an acylating agent and only after these tedious steps the 17, 21-dipropionate can be obtained.
In addition, during the DDQ dehydrogenation of certain of the 16/?-methyl-1 7a-hydroxy compounds mentioned in U.S. Patent No. 4,036,831, variable amounts of D-homoannulation 25 were observed to occur. This undesired side reaction was completely absent when the DDQ dehydrogenation was carried out on the 17a-acylates.
According to the present invention, there is provided a process for producing corticoids characterized by the following substituents:
(a) 16/?-methyl 30 (b) 17a-acyloxy
(c) A1-4
(d) 21-hydroxy or 21-acyloxyl or 21-halo from an 11/3-OH precursor steroid, of the 5a-pregnane series which comprises:
1) reacting the 11/J-QH precursor steroid with trimethyl-chlorosilane forming thereby the 35 corresponding 11 yS-trimethyl-siloxy steroid:
2) Hydrolyzing the 21 -acylate function (if desired),
3) Esterification of the 17a-hydroxy group which causes simultaneous esterification of any free 21-hydroxy group,
4) introduction of the A1 4 function with 2,3-dichloro-4,5-dicyano-benzoquinone (DDQ), 40 5) selectively hydrolyzing off a 21-acylate group, if desired,
6) hydrolyzing off the trimethyl-siloxy group to create the 11/J-OH group.
A preferred embodiment of the process comprises:
1) reacting a compound of the formula
10
15
20
25
30
45
45
xOH
50
H
55 with trimethylchlorosilane to produce a compound of the formula
55
2
GB2096614A
2
rOAr
5 (CH3I35''°
10
10
15
20
2) hydrolyzing the 21-acetate to produce a compound of the formula
(CHgJgSIO
15
20
3) esterifying the resulting compound with a propionic acid derivative to produce a compound 25 of the formula
25
30 (CH3)3Sio
35
4) treating the resulting compound with 2, 3-dichloro-4,5-dicyanobenzoquinone (DDQ) to produce a compound of the formula
40
45
(CH 3)3510
30
35
40
45
5) hydrolyzing the resulting compound to remove the trimethylsiloxy group to produce a 50 compound of the formula
50
55
60
55
60
(In the formulas above, AC is acetyl and Pr is propionyl.)
Compounds of formulae II to V are among those described and claimed in our co-pending application No. 7905372, published as 2,018,257.
According to the present invention, blocking the 11/?-OH and removing of the blocking group 65 may be carried out as shown below. 11/2-OH steroids are reacted with tromethylchlorosilane in 65
3
GB2 096 614A 3
pyridine to produce the corresponding 11/?-trimethylsiloxanes. Selective hydrolysis of the trimethylsiloxanes may be effected by treating with 40-60%, aqueous hydrofluoric acid, at room temperature, and preferably about 47-50%. This hydrolysis does not affect the esters at 21-and 17a-positions.
5 According to the present invention A1-4 is introduced into the steroids by dehydrogenation reaction with 2,3-dichloro-4,5-dicyanobenzoquinone (DDQ). The reaction can be conducted under the usual conditions (dioxane, sometimes with added acids) employed to favor production of the 1,4-dienoic-3-keto structure. In such case some coreaction about the 11/?-hydroxy occurs, for example, a dehydration at C-11 and C-12 leading to an enol which is rearranged to an 11-10 keto artifact. In particular, inferior performance occurs if a negative group such as F is attached to C-9. However, when the 11-hydroxy group has been converted to the trimethylsilyl ether group, the side reaction of DDQ dehydration (leading to formation of an 11-keto artifact) is completely inhibited.
Esterification of hydroxy groups at 21-position and 17a-position can be effected by various 15 known methods. For example, a derivative of the corresponding acid, for example, the anhydride in the presence of a catalytic strong acid.
Selective hydrolysis of ester at 21-position (e.g. methanolysis) may be carried out by a known procedure and this does not affect 17a-ester and 11/?-blocking group.
For further understanding of the present invention, the following specific examples thereof are 20 presented. Complete processes in accordance with the invention are illustrated in Examples 1 to 5 and 6 to 10, while the remaining Examples illustrate various optional and alternative steps.
10
15
20
EXAMPLE 1
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25
30
When 7.0 g of: 21-chloro-9a-fluoro-11yS, 1 7a-dihydroxy-16/?-methyl-5a-pregnane-3,20-dione [obtained from the corresponding 21-acetoxy compound (Carrington et al., J. Chem. Soc., 35 1961, 4560) by conventional procedures, viz., alkaline hydrolysis, reaction with methanesulfo-nyl chloride to give the 21-mesylate, followed by treatment with lithium chloride in dimethylfor-mamide] was treated with trimethylchlorosilane (3ml) in pyridine (16ml) at room temperature. After 2 hr. the solution was diluted with methyl isobuthyl ketone and 32ml of 6N sulphuric acid was added with agitation and cooling. The mixture was allowed to stratify, the organic layer was 40 separated and washed successively with dilute sulphuric acid, 10% aqueous sodium bicarbonate and finally with water. Concertration to a small volume gave a crystalline slurry from which there was obtained 7.5 g of 11 /?-trimethylsiloxy-21-chloro-9a-fluoro-1 7a-hydroxy-1 6-methyl-5a-preg-nane-3,20-dione. (m.p. 100-106°C).
rCl r- ci
45 EXAMPLE 2
(CH3)3SiO
60
5.0 g of: 11/?-trimethylsiloxy-21-chloro-9a-fluoro-1 7a-hydroxy-16/?-methyl-5a:-pregnane-3,20-di-one, 10 ml of propionic anhydride and 100 mg of para-toluenesulphonic acid were stirred and heated at 65° for 60 min, cooled to room temperature and diluted with 10 ml of dimethylfor-mamide, 3 ml of 10% aqueous sodium acetate was added at 45-50° and the reaction mixture kept at 45° for a further 30 min, then poured into 200 ml of iced water. After filtration an almost quantitative hield (5.4 g) of 11/3-trimethylsiloxy-21-chloro-9a-fluoro-1 7a-hydroxy-16/3-methyl-5a-pregnane-3,20-dione propionate, (m.p. Ca. 60°C)
35
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60
4
GB2096 614A 4
EXAMPLE 3
5 (oVa510
10
10
When 3.5 g of: 11^-trimethylsiloxy-21-chloro-9a-fluoro-17a-hydroxy-16/?-methyl-5a-pregnane-3,20-dione propionate was treated with 2,65 g of 2,3-dichloro-4,5-dicyanobenzoquinone (DDQ) 15 and 30 ml of dioxan was heated under reflux for 2 hours. The resulting dark colored suspension 15 was cooled, filtered from dichloro-dicyanohydroquinone, and evaporated to dryness. The residue was dissolved in chloroform and passed through a short column of neutral alumina (50 g). The solvent was evaporated under reduced pressure. The residue was crystalized from methanol to give 2.1 g of: 11/?-trimethylsiloxy-21-chloro-9a-fluoro-17a- hydroxy-16)6-methylpregna 1,4-20 diene-3,20-dione propionate, (m.p. 140-144°C). 20
EXAMPLE 4
25
30
35 35
1.0 g of: 11/3-trimethylsiloxy-21-chloro-9a-fluoro-17a-hydroxy-16jS-methylpregna-1,4-diene-3,20-dione propionate was powdered finely and suspended in 10 ml 49% aqueous hydrofluoric acid by stirring at 0°. After 7 minutes contact period about 5% of the starting material in a model experiment remained (by TLC(BPA)). The reaction product, was neutralized by pouring 40 into 12% sodium carbonate solution (200 ml), the solids were filtered, washed with water, 40
collected and dried. There was obtained 0.75 g of 21-chloro-9a-fluoro-11/3, 17a- dihydroxy-16/?-methylpregna-1,4-diene-3,20-dione 17-propionate (Clobetasol propionate, a known antiinflammatory agent).
45
50
55
60 To a solution of 5 g of 17a, 21-dihydroxy-16/?-methyl-5a-pregn-9(11)-en-3,20-dione 21-acetate 60 (Attenburrow et al., J. Chem. Soc., 1961, 4547) in tetrahydrofuran (100 ml) containing 0.46 m perchloric acid (20 ml) was added 1.35g of N-chlorosuccinimide at room temperature. The mixture was stirred for 30 minutes and then poured into dilute sodium metabisulphite. The product (5.2 g) which is 9a-chloro-11)8, 17a,21-trihydroxy-16/?-methyl-5a-pregnane-3,20-dione 65 21-acetate was obtained by filtration and a small sample was purified by recrystallization from 65
5
GB2096614A 5
ethyl acetate, (m.p. 166-169°C)
5 EXAMPLE 6
10
15
When 5 g of 9a-chloro-1 1/3,17a,21-trihydroxy-16/?-methyl-5a-pregnane-3,20-dione 21-acetate was treated exactly as in Example 1 with trimethylchlorosilane in pyridine solution there was 20 obtained 5.5 g of 11/?-trimethylsiloxy-9a-chloro-1 la, 21-dihydroxy-16/?-methyl-5a-pregnane-3,20-dione 21-acetate. (m.p. 120-123°C).
20
EXAMPLE 7
(CH3)3SiO
(CH3)3sio
25
30
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40
45
50
55
To a suspension of 5.5 g of 11/?-trimethylsiloxy-9a-chIoro-1 7a,21-dihydroxy-16/?-methyl-5a-pregnane-3,20-dione 21-acetate in 55 ml of methanol was slowly added a solution of 550 mg of potassium hydroxide in 15 ml of methanol. The mixture was stirred at 10° under nitrogen for 1 hr, neutralized with glacial acetic acid, and poured into 700 ml of iced water. After 1 hr the precipitate was collected, washed to neutrality with water and dried under vacuum. Yield: 4,8 g of 11/?-trimethylsiloxy-9a-chloro-1 7a,21-dihydroxy-16/?-methy!-5a pregnane-3,20-dione. (m.p. 160-164°C).
EXAMPLE 8
(CH3)3Sio
40
45
50
55
60 10 g of 11/?-trimethylsiloxy-9a-chloro-1 7a,21-dihydroxy-16/?-methyl-5a-pregnane-3,20-dione, 20 ml of propionic anhydride and 200 mg of para-toluenesuiphonic acid were heated together at 65° for 1 hr, then worked up as in Example 2 to afford 12.2 g of 11 /?-trimethylsiloxy-9a-chloro-1 7a,21-dihydroxy-16/8-methyl-5a-pregnane-3,20-dione 17, 21-dipropionate. (m.p. 99-103°C).
60
6
GB2096614A 6
EXAMPLE 9
(CH3)3sii
15
10
15
When 3.5 g of: 11/?-trimethylsiloxy-9a-chloro-1 la, 21-dihydroxy-16/3-methyl-5a:-pregnane-3,20-dione 17, 21-dipropionate was treated in all details as in Example 3 with 2,65 g of 2,3-dichloro-5,6-dicyanobenzoquinone in dioxane solution there was obtained 1.8 g of: 11/3-20 trimethylsiloxy-9a-chloro-1 la, 21-dihydroxy-16/3-methylpregna-1,4-diene-3,20-dione 17, 21-di- 20 propionate, (m.p. 175-180°C).
25 EXAMPLE 10
30
35
(CH3)3sio
25
30
35
When 1.0 g of: 11/3-trimethylsiloxy-9a-chloro-17a,21-dihydroxy-16/?-methylpregna-1,4-diene-3,20-dione 17, 21-dipropionate was treated exactly as described in Example 4 with 49% 40 queous hydrofluoric acid there was obtained 0.7 g of: 9a-chloro-11/3,17a,21-trihydraxy-16/3-methylpregna-1,4-diene-3,20-dione 17, 21-dipropionate (Beclomethasone dipropionate, a known anti-inflammatory agent).
40
To a suspension of 4.7 g of 11/3-trimethylsiloxy-9a-fluoro-17a,21-dihydroxy-16/?-methyl-5a-pregnane-3,20-dione 21-acetate (derived from compound 22 in the flow sheet of and by the 60 procedure converting to conpound 23 disclosed in U.S.P. 4,036,831) in 55 ml of methanol 60 was slowly added a solution of 550 mg of potassium hydroxide in 15 ml of methanol. The mixture was stirred at 10° under nitrogen for 1 hr, neutralized with glacial acetic acid, and poured into 700 ml of iced water. After 1 hr the precipitate was collected, washed to neutrality with water and dried under vacuum. Yield: 4.8 g of 11/3-trimethylsiloxy-9a-fluoro-17a,21-65 dihydroxy-16/?-methyl-5a-pregnane-3,20-dione. (m.p. 120-126°C). 65
7
GB2 096 614A 7
EXAMPLE 12
(CH3)3sii
(CH3) jSiO
15
12 g of 11/?-trimethylsiloxy-9a-fluoro-17a:,21-dihydroxy-16/?-methyl-5a-pregnane-3,20-dione, 20 ml of propionic anhydride and 200 mg of para-toluenesulphonic acid were heated together at 65° for 1 hr. then worked up as in Example 2 to afford 12.2 g of 11/?-trimethylsiloxy-9a-20 fluoro-17a,21-dihydroxy-16j6-methyl-5a-pregnane-3,20-dione, 17,21-dipropionate. (m.p. 80-84°C).
10
15
20
25 EXAMPLE 13
(CH3)3Sii
30
35
25
30
35
3.5 g of the product of previous example is treated as described in example 3 with 2.65 g of DDQ in dioxane solution there is obtained 2.3 g of 11/?-trimethylsiloxy-17a,21-dipropionyloxy-40 9a-fluoro-16/?-methylpregna-1,4-diene-3,20-dione. (m.p. 150-158°C).
40
EXAMPLE 14 (CH3)3SiO
55
4.3 g of the finely divided product of the previous example is treated with 45 ml of 49% aqueous hydrofluoric acid exactly as described in example 4 to yield except that the reaction time used was 7 minutes after recrystallization from ethyl acetate, 3.4 g of betamethasone 60 dipropionate.
45
50
55
60
8
GB2 096 614A
8
EXAMPLE 1 5
• OAc O
'OH
(CH3)3SiC
,CH,
10
15
Step 1
H
(CH3)3SiO
10
15
20
25
A mixture of 11/?-trimethylsiloxy-17a-hydroxy-21-acetoxy-9a-fluoro-16/?-methyl-5a:-pregnane-3,20-dione (e.g. product of Example 12 of U.S. Patent No. 4,036,831) 4 g), valeric anhydride (6 ml), valeric acid (20 ml) and para-toluene-sulphonic acid (0.5 g) is stirred at room temperature for 16 hours. The excess of anhydride is destroyed by careful addition of ice (2 g) and the reaction mixture (a solution) then poured into iced-water (1 50 ml). The steroid which precipitates is filtred off, washed with water and dried under vacuum. Recrystallization from diisopropyl ether gives 3.2 g of 11/?-trimethylsiloxy-17a-valeroxy-21-acetoxy-9a-fluoro-16/? methyl-5a-pregnane-3,20-dione. (m.p. 80-85°C).
20
25
30
35
EXAMPLE 16
{CH3)3sio
(CH3)3gio
30
35
40
When 3.5 g of the product of previous Example is treated as described in example 3 with 2.65 g of 2,3-dichloro-4,5-dicyanobenzoquinone in dioxane solution there is obtained 2.0 g of 11/?-trimethylsiloxy-1 7a-valerox-21-acetoxy-9a-fluoro-16/?-methylpregna-1,4-diene-3,20-dione. (m.p. 124°C).
45
40
45
50
55
60
EXAMPLE 17
(cH3>3sil
(CH3)3SiO
50
55
60
65
To a solution of 1 g of the product of previous Example in 20 ml of methanol is added 2 drops of 70% perchloric acid and the mixture kept at 20-25° for 18 hr. and then poured into 200 ml of water. Extraction with dichloromethane, followed by crystallization from acetone/hexane affords 0.3 g of 11/?-trimethylsiloxy-1 la- valeroxy-21 -hydroxy-9a-fluoro-16/3 methylpregna-1,4-diene-3,20-dione. (m.p. 186-188°C). 65
9
GB2 096 614A 9
EXAMPLE 18
15
The 0.8 g of finely divided product of previous Example is treated with 8 ml 49% aqueous hydrofluoric acid exactly as described in example 4 to yield 0.6 g of betamethasone valerate.
20
EXAMPLE 19 (CH3)3qio-
. KNOWN | Step 6
BETA"VALERATE
10
15
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25
30
35 35
5 g of the product of Example 16 is hydrolyzed as in Example 4 except that a reaction time of 10 minutes is employed to yield betamethasone 17a-valerate 21-acetate (2.2 g) convertible by known procedure (e.g. Great Britain 1,097,164) into betamethasone valerate. (The aqueous HP hydrolysis step goes better on the 21-alcohol, probably because of increased hydrophilicity).
40 40
Claims (3)
1) reacting a compound of the formula
10
GB2096614A
10
r OAr
10
10
with trimethylchlorosilane to produce a compound of the formula
15
20
rOAr
(CH^JgSio
15
20
25
2) hydrolyzing the 21-acetate to produce a compound of the formula
(CHglgSio rOH = 0 OH
30
rrv
35
± 1 cu
3) esterifying the resulting compound with a propionic acid derivative to produce a compound of the formula
25
30
35
40
45
(CH3)3sio
40
45
4) treating the resulting compound with 2,3-dichloro-4,5-dicyanobenzoquinone (DDQ) to 50 produce a compound of the formula
55
(CH 3)3510
XM
60
5) hydrolyzing the resulting compound to remove the trimethylsiloxy group to produce a compound of the formula
50
55
60
11
GB2 096 614A 11
10
15
20
25
(In the formulas above, AC is acetyl and Pr is propionyl.)
3. A process according to claim 1 substantially as herein described with reference to Examples 1 to 4, 5 to 10, 11 to 14, 15 to 18 or 19.
4. A corticoid compound made by a process according to any preceding claim.
CLAIMS (23 Feb 1982)
1. A process for producing a corticoid characterised by the following formula:
C_V\,
10
15
20
25
30 wherein R represents an acyl group, R1 represents an acyloxy or hydroxy group or a halogen atom and X represents H, or CI, from an 11/?-hydroxy precursor steroid of the 5a-pregnane series having the formula:
30
35
40
45
wherein R2 represents an acyloxy or hydroxy group or a halogen atom and X is as defined above, which process comprises:
1) reacting the 11/J-0H precursor steroid with trimethylchlorosilane forming thereby the corresponding 11 /?-trimethylsiloxy steroid:
50 2) Hydrolyzing any 21-acylate function (if desired),
3. A process according to claim 1 substantially as herein described with reference to the Examples.
35
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45
50
55
Printed for Her Majesty's Stationery Office by Burgess & Son (Abingdon) Ltd.—1982.
Published at The Patent Office, 25 Southampton Buildings, London, WC2A 1AY, from which copies may be obtained.
3) Esterification of the 17a-hydroxy group which causes simultaneous esterification of any free 21-hydroxy group,
4) introduction of the A14 function with 2,3-dichloro-4, 5-dicyano-benzoquinone (DDQ),
5) selectively hydrolyzing off any 21-acylate group, if desired and
55 6) hydrolyzing off the trimethyl-siloxy group to leave an 11/8-OH group.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1589478A JPS54109958A (en) | 1978-02-16 | 1978-02-16 | Steroid compound and its manufacture |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB2096614A true GB2096614A (en) | 1982-10-20 |
| GB2096614B GB2096614B (en) | 1983-02-16 |
Family
ID=11901485
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB8124654A Expired GB2096614B (en) | 1978-02-16 | 1979-02-15 | Synthesis of corticoid 17-esters |
| GB7905372A Expired GB2018257B (en) | 1978-02-16 | 1979-02-15 | 11 silylation in corticoid synthesis |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB7905372A Expired GB2018257B (en) | 1978-02-16 | 1979-02-15 | 11 silylation in corticoid synthesis |
Country Status (6)
| Country | Link |
|---|---|
| JP (1) | JPS54109958A (en) |
| AT (1) | AT369020B (en) |
| DE (1) | DE2905674A1 (en) |
| GB (2) | GB2096614B (en) |
| NL (1) | NL7901259A (en) |
| PH (1) | PH14881A (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NZ225100A (en) * | 1987-06-29 | 1991-09-25 | Merck & Co Inc | Reaction of steroids (including 4-azasteroids) with a silylating agent in the presence of a quinone to introduce a delta' double bond and silylated intermediates |
| US5084574A (en) * | 1988-04-18 | 1992-01-28 | Merck & Co., Inc. | Dehydrogenation process |
| US5120847A (en) * | 1990-08-27 | 1992-06-09 | Merck & Co., Inc. | Process for iodinating or brominating the α-methylenic carbon of a secondary amide |
| US5091534A (en) * | 1990-08-27 | 1992-02-25 | Merck & Co., Inc. | Trialkylsilyl trifluoromethanesulfonate mediated α-methylenic carbon functionalization of 4-AZA-5α-androstan-3-one steroids |
-
1978
- 1978-02-16 JP JP1589478A patent/JPS54109958A/en active Granted
-
1979
- 1979-02-14 DE DE19792905674 patent/DE2905674A1/en not_active Ceased
- 1979-02-15 GB GB8124654A patent/GB2096614B/en not_active Expired
- 1979-02-15 PH PH22198A patent/PH14881A/en unknown
- 1979-02-15 GB GB7905372A patent/GB2018257B/en not_active Expired
- 1979-02-16 NL NL7901259A patent/NL7901259A/en not_active Application Discontinuation
- 1979-02-16 AT AT0123679A patent/AT369020B/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| JPS54109958A (en) | 1979-08-29 |
| GB2018257A (en) | 1979-10-17 |
| NL7901259A (en) | 1979-08-20 |
| GB2018257B (en) | 1982-12-08 |
| AT369020B (en) | 1982-11-25 |
| PH14881A (en) | 1982-01-08 |
| DE2905674A1 (en) | 1979-08-30 |
| ATA123679A (en) | 1982-04-15 |
| GB2096614B (en) | 1983-02-16 |
| JPS569520B2 (en) | 1981-03-02 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PCNP | Patent ceased through non-payment of renewal fee |