US2920085A - Process for the hydrolysis of the 3-enamine of 6alpha-methyl-11beta, 21-dihydroxy-4,17(20)-pregnadien-3-one - Google Patents
Process for the hydrolysis of the 3-enamine of 6alpha-methyl-11beta, 21-dihydroxy-4,17(20)-pregnadien-3-one Download PDFInfo
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- US2920085A US2920085A US788051A US78805159A US2920085A US 2920085 A US2920085 A US 2920085A US 788051 A US788051 A US 788051A US 78805159 A US78805159 A US 78805159A US 2920085 A US2920085 A US 2920085A
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- United States
- Prior art keywords
- pregnadien
- dihydroxy
- methyl
- enamine
- hydrolysis
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- 230000007062 hydrolysis Effects 0.000 title claims 2
- 238000006460 hydrolysis reaction Methods 0.000 title claims 2
- 238000000034 method Methods 0.000 title claims 2
- URZZKSAZQICNQI-BNWDEUASSA-N (6s,8s,9s,10r,11s,13s,14s)-11-hydroxy-17-(2-hydroxyethylidene)-6,10,13-trimethyl-2,6,7,8,9,11,12,14,15,16-decahydro-1h-cyclopenta[a]phenanthren-3-one Chemical compound C([C@@]12C)CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)C(=CCO)CC[C@H]21 URZZKSAZQICNQI-BNWDEUASSA-N 0.000 title 1
- -1 3-PYRROLIDYL ENAMINE Chemical class 0.000 claims 1
- 239000002253 acid Substances 0.000 claims 1
- 238000005904 alkaline hydrolysis reaction Methods 0.000 claims 1
- 150000003839 salts Chemical class 0.000 claims 1
Classifications
-
- 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
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J75/00—Processes for the preparation of steroids in general
Definitions
- This invention relates to an improved process for the hydrolysis of certain steroid 3-enamines, to the corresponding 3'-keto steroids, more particularly to' an improvement in the alkaline hydrolysis of the 3-pyrrolidyl enamine of 6a-rnethyl-11,8,21-dihydroxy-4,17(20) pregnadien-3-one which comprises converting theS-enamine to-an acid addition salt thereof prior to the alkaline hydrolysis.
- the starting compound in the process of this invention is the 3-pyrrolidyl enamine of 6a-methyl-11p,21-dihydroxy-4,17(20)-pregnadien-3-one, especially the 3-pyrrolidyl enamine of 6a-methyl-11p,21-dihydroxy-4,17(20)- [cisJ-pregnadien-B-one, which is prepared from 3,11-diketo-4,l7(20)-pregnadien-21-oic acid methyl ester (Spero et al., supra).
- additiofisalt is madealkaline immediately as the yield-of: desired product is reduced when the 3-enamine ismaimtainedunder aqueous acidic conditions for prolongedperiods; Moreovenbecause of the presence of the labile 1*1 flehydroxy group, heating under aqueous acidic condi-- tions should be avoided.
- Acid addition salts which may be employed include both inorganic and organic acid addition salts, preferably the latter, especially lower-hydrocarbon carboxylic acid addition salts, i.e., containing from 1 to 8 carbon atoms.
- Representative acidadditionsalts e.g.,.prepared from thecorresponding 3-enamine and acid, include the hydro-' chloride, hydrobromide, sulfate, phosphate, nitrate, acetate, formate, propionate, butyrate, chloroacetate ben zoate, .trichlorobenzoate, trifiuoroacetate, etc.
- the corresponding trans isomer is prepared by starting with methyl 3,11-diketo-4,17(20)-[trans]-pregnadien-21- oic acid methyl ester which, in turn, is prepared by refluxing a methanolic solution of the corresponding cis isomer in the presence of sodium methoxide.
- the ether layer obtained as described in the prepara tion and containing the 3-pyn'olidyl-6-methyl-l15,21-dihydroxy-3,5,l7(20)-[cisJ-pregnatriene was decanted from the precipitated inorganic salts and the salts then extracted with two 25-ml. portions of ether.
- the ether phase and ether extracts were combined and then mixed with a solution of 3 ml. of acetic acid in 15 ml. of methanol, thereby producing the minimum acid addition salt.
- 37 ml. of 10% aqueous sodium hydroxide was immediately added to the acidic mixture which was then stirred for minutes. 40 ml. of water was added and the ether layer separated.
- aqueous layer was extracted with 40 ml. of ether and the ether extract and ether layer combined and then washed successively with dilute hydrochloric acid, water, aqueous sodium bicarbonate and then saturated aqueous sodium chloride solution.
- the ether was dried over sodium sulfate and then distilled leaving a 3.2 g. residue of 11fl,21-dihydroxy-4,17(20)- [cisl-pregnadien-B-one.
- salt is a lower-hydrocarbon carboxylic acid addition salt.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Steroid Compounds (AREA)
Description
States r Mich., assignors to. The Upjohn Micl1., a corporationof Dela- Barney J. Magerlein,
Spero, Kalamazoo, Company, Kalamazoo, ware.
No Drawing. Application January 21', 1959 Serial No..788,051
'5 Claims.v (Cl. 260-39145) This invention relates to an improved process for the hydrolysis of certain steroid 3-enamines, to the corresponding 3'-keto steroids, more particularly to' an improvement in the alkaline hydrolysis of the 3-pyrrolidyl enamine of 6a-rnethyl-11,8,21-dihydroxy-4,17(20) pregnadien-3-one which comprises converting theS-enamine to-an acid addition salt thereof prior to the alkaline hydrolysis.
The alkaline hydrolysis of 3-enamines is a known reaction [Hogg et al., J. Am. Chem. Soc., 77: 4436 (1955)]. However, when this reaction was applied to the 3-pyrrolidyl enamine of 6a-methyl-11,8,21-dihydroxy-4, 17(-20)*pregnadien-3-one [Spero et al., J. Am. Chem. Soc., 78: 6213 (1956)],the yield ofdesired 6u-methyl- 1 1/3,21-dihydroxy-4,17 (20)-pregnadien-3-one was considerablydessthan was obtained-when the corresponding hydrolysis was conducted on the 3-pyrrolidyl enamine of 115,21 dihydroxy 4,17(20) pregnadien 3 one. Whereas the hydrolysis of the latter compound at room temperature produced satisfactory yields, the hydrolysis of the former compound under the same conditions gave only a 20% yield of desired product, calculated on the starting 3,11-diketo-6a-methyl-4,17(20)-[cis]-pregnadien- 21-oic acid methyl ester. Even prolonged heating raised the yield only slightly.
We have now found that when the 3-pyrrolidyl enamine of 6a methyl 115,21 dihydroxy 4,17(20) [cis]- pregnadien 3 one, i.e., 3 pyrrolidyl 6 methyl- 11fl,21 dihydroxy 3,5,17(20) [cis] pregnatriene, is converted'to an acid addition salt thereof prior to the hydrolysis, an over-all yield of about 40-50%, calculated from the starting 3,11-diketo-6u-methyl-4,17(20)-[cis]- pregnadien-Zl-oic acid methyl ester, can be achieved even without heating. Whereas the hydrolysis reaction without the acid addition salt step required chromatographic separation in order to isolate the desired product, the process of this invention gave more than twice the amount of product by direct crystallization, an advantage of particular significance in commercial production. This increase in yield of an intermediate useful in the production of the highly active anti-inflammatory agent 6amethyl 11fi,17a,21 trihydroxy 4 pregnene 3,20- dione 21-acetate, is particularly significant in view of the number of steps necessary for its production (Spero et al., supra).
The starting compound in the process of this invention is the 3-pyrrolidyl enamine of 6a-methyl-11p,21-dihydroxy-4,17(20)-pregnadien-3-one, especially the 3-pyrrolidyl enamine of 6a-methyl-11p,21-dihydroxy-4,17(20)- [cisJ-pregnadien-B-one, which is prepared from 3,11-diketo-4,l7(20)-pregnadien-21-oic acid methyl ester (Spero et al., supra).
These enamines are converted to an acid addition salt by reaction with an inorganic or organic acid in the usual manner for the production of amine acid addition salts. However, if aqueous conditions are employed, it is pre ferred that the solution or suspension containing the acid 2,920,085 Patented J an. 5,1 19.60
additiofisalt is madealkaline immediately as the yield-of: desired product is reduced when the 3-enamine ismaimtainedunder aqueous acidic conditions for prolongedperiods; Moreovenbecause of the presence of the labile 1*1 flehydroxy group, heating under aqueous acidic condi-- tions should be avoided.
Acid addition salts which may be employed include both inorganic and organic acid addition salts, preferably the latter, especially lower-hydrocarbon carboxylic acid addition salts, i.e., containing from 1 to 8 carbon atoms. Representative acidadditionsalts, e.g.,.prepared from thecorresponding 3-enamine and acid, include the hydro-' chloride, hydrobromide, sulfate, phosphate, nitrate, acetate, formate, propionate, butyrate, chloroacetate ben zoate, .trichlorobenzoate, trifiuoroacetate, etc.
The following preparation and example are illustrative offtheprocess of this invention, but are not to be construed as limiting.
' PREPARATION 3-pyrrolidyl-6-methyl-11fl21-dihydr0xy-3,5,17(20) [cis]-pregnatriene p A solution of 3.7 g. of 6a-rneth'yl-3,11,diketo-4,17(20)-- [cisLpregnadien-Zl-oic acid methyl ester [Spero et al.,.
I. Am. Chem. Soc., 78: 6213 (1956)], 70 mg. of ptoluene-sulfonic acid and 1.65 ml. of pyrrolidine in 'ml..
of," benzene was refluxed for one hour with the water formed during the reaction being continuously separated? from the refluxing benzene in a Dean-Stark trap. The solventwas then removed under vacuum. The residue, consisting essentially of 3-pyrrolidyl-6-methyl-ll-keto- 3,5,17(20)-[cis]-pregnatrien-Zl-oic acid methyl ester, was dissolved in 50 ml. of anhydrous ether and then added to a suspension of 1.2 g. of lithium aluminum hydride in ml. of ether. After heating under reflux for one hour, the reaction mixture was cooled and then 7.5 ml. of ethyl acetate was cautiously added followed by 18 ml. of water to precipitate the inorganic salts as a thick paste. The ether phase contained the dissolved 3-pyrrolidyl 6 methyl 115,21 dihydroxy 3,5,17(20)-[cis]- pregnatriene.
The corresponding trans isomer is prepared by starting with methyl 3,11-diketo-4,17(20)-[trans]-pregnadien-21- oic acid methyl ester which, in turn, is prepared by refluxing a methanolic solution of the corresponding cis isomer in the presence of sodium methoxide.
EXAMPLE 6ot-methyl-11fi,21-dihydroxy-4,17(20)-[cis]- pregnadien-3-one A. OLD METHOD The total reaction mixture obtained as described in the preparation and containing the 3-pyrrolidyl-6-methyl- 115,21 dihydroxy 3,5,17(20) [cis] pregnatriene was distilled to dryness under vacuum and the residue covered with nitrogen and to it was then added ml. of methanol. After stirring at 25 C. for 5 minutes, 10 ml. of 5% sodium hydroxide was added. The reaction mixture was stirred at 25 C. for 1.5 hours. The pH of the mixture was adjusted to 7 with 3 ml. of acetic acid and the solvent distilled under vacuum. A solution of 12.5 ml. of concentrated hydrochloric acid in 200 ml. of water was added. The product was extracted from the resulting mixture with methylene chloride. The solution was dried and the methylene chloride distilled. The 3 g. residue was dissolved in ethyl acetate and seeded, but crystals failed to form so the solution was evaporated to dryness, redissolved in 400 ml. of methylene chloride and chromatographed over 240 g. of magnesium silicate (Florisil). The column was developed with hexanes (Skellysolve B) containing increasing proportions of ace tone. 1.03 g. of 11p,2l-dihydroxy-4,17(20)-[cisl-pregnadien-3-one was eluted with hexanes plus 20% acetone and hexanes plus 30% acetone. No significant amount of this compound was present in any of the other eluate fractions. Purification of this compound by crystallization from ethyl acetate gave 0.7 g., a yield of 20% of the theoretical, calculated from the starting 3,11-diketo-6amethyl-4,17(20)-[cis]-pregnadien-21-oic acid methyl ester, of crystals melting at 172-174" C., having an [411 of +125 (CI-ICI anda Mir. of aM 15,200 13,. NEW METHOD The ether layer obtained as described in the prepara tion and containing the 3-pyn'olidyl-6-methyl-l15,21-dihydroxy-3,5,l7(20)-[cisJ-pregnatriene was decanted from the precipitated inorganic salts and the salts then extracted with two 25-ml. portions of ether. The ether phase and ether extracts were combined and then mixed with a solution of 3 ml. of acetic acid in 15 ml. of methanol, thereby producing the minimum acid addition salt. 37 ml. of 10% aqueous sodium hydroxide was immediately added to the acidic mixture which was then stirred for minutes. 40 ml. of water was added and the ether layer separated. The aqueous layer was extracted with 40 ml. of ether and the ether extract and ether layer combined and then washed successively with dilute hydrochloric acid, water, aqueous sodium bicarbonate and then saturated aqueous sodium chloride solution. The ether was dried over sodium sulfate and then distilled leaving a 3.2 g. residue of 11fl,21-dihydroxy-4,17(20)- [cisl-pregnadien-B-one. Purification of this compound by crystallization from ethyl acetate gave 1.5 g., a yield of 44% of the theoretical calculated from the starting v 4 3,11 diketo methyl 4,17 (20) [cis] pregnadien- 21-oic acid methyl ester, of crystals melting at 172-174 C., having an [oil of (CHCI and 2.
Min. f 242, aM 14,850
Following the above procedure, comparable results are obtained by substituting an equivalent amount of methanolic hydrogen chloride for the acetic acid or the correspondingtrans isomer as starting compound.
We claim:
1. In a process for the hydrolysis of the 3-pyrrolidyl enamine of 6a-rnethyl-1 1 18,2 1-dihydroxy-4, l 7 20) -pregnadien-S-one under alkaline conditions to produce 6amethyl-11,3,21-dihydroxy-4,17(20)-pregnadien-3-one, the improvement which comprises converting the 3-enamine to an acid addition salt thereof prior to the alkaline hydrolysis.
2. The process of claim 1, wherein the acid addition salt is an organic acid addition salt.
3. The process of claim 1, wherein the acid addition.
salt is a lower-hydrocarbon carboxylic acid addition salt.
4. The process of claim 1, wherein the acid addition salt is the acetate.
5. The process of claim 1, wherein the starting compound is 3-pyrrolidyl-6-methyl-11p,21-dihydroxy-3,5,17- (20)-[cis]-pregnatriene and the acid addition salt is the acetate.
UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No, 2,920,085
Barney J, Magerlein et a1,
It is hereby certified that error appears in the-printed specification of the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.
101cm 3, line for "minimum" read m iminium no Signed and sealed this 7th. day of June 1960.
(SEAL) Attest:
KARL H AXLINE ROBERT C. WATSON Commissioner of Patents Attesting Officer
Claims (1)
1. IN A PROCESS FOR THE HYDROLYSIS OF THE 3-PYRROLIDYL ENAMINE OF 6A-METHYL-11B,21-DIHYDROXY-4,17(20)-PREGNADIEN-3-ONE UNDER ALKALINE CONDITIONS TO PRODUCE 6AMETHYL-11B,21-DIHYDROXY-4,17(20)-PREGNADIEN-3-3-ONE, THE IMPROVEMENT WHICH COMPRISES CONVERTING THE 3-ENAMINE TO AN ACID ADDITION SALT THEREOF PRIOR TO THE ALKALINE HYDROLYSIS.
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US788051A US2920085A (en) | 1959-01-21 | 1959-01-21 | Process for the hydrolysis of the 3-enamine of 6alpha-methyl-11beta, 21-dihydroxy-4,17(20)-pregnadien-3-one |
| GB41303/59A GB869777A (en) | 1959-01-21 | 1959-12-04 | Improvements in or relating to the manufacture of steroids |
| DEU6769A DE1115247B (en) | 1959-01-21 | 1959-12-23 | Process for the preparation of 6ª ‡ -Methyl-11ª ‰, 21-dioxy-4, 17 (20) -pregnadien-3-one by alkaline hydrolysis of the 3-pyrrolidyleneamine of 6ª ‡ -Methyl-11ª ‰, 21-dioxy-4, 17 (20) -pregnadien-3-ons |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US788051A US2920085A (en) | 1959-01-21 | 1959-01-21 | Process for the hydrolysis of the 3-enamine of 6alpha-methyl-11beta, 21-dihydroxy-4,17(20)-pregnadien-3-one |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US2920085A true US2920085A (en) | 1960-01-05 |
Family
ID=25143293
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US788051A Expired - Lifetime US2920085A (en) | 1959-01-21 | 1959-01-21 | Process for the hydrolysis of the 3-enamine of 6alpha-methyl-11beta, 21-dihydroxy-4,17(20)-pregnadien-3-one |
Country Status (3)
| Country | Link |
|---|---|
| US (1) | US2920085A (en) |
| DE (1) | DE1115247B (en) |
| GB (1) | GB869777A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3444160A (en) * | 1967-04-03 | 1969-05-13 | Upjohn Co | Protection of delta**4-3-ketosteroids by the formation of protonated 3-enamines |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2849464A (en) * | 1957-05-27 | 1958-08-26 | Upjohn Co | 6-methyl, delta4, 3-keto androstene derivatives |
-
1959
- 1959-01-21 US US788051A patent/US2920085A/en not_active Expired - Lifetime
- 1959-12-04 GB GB41303/59A patent/GB869777A/en not_active Expired
- 1959-12-23 DE DEU6769A patent/DE1115247B/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2849464A (en) * | 1957-05-27 | 1958-08-26 | Upjohn Co | 6-methyl, delta4, 3-keto androstene derivatives |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3444160A (en) * | 1967-04-03 | 1969-05-13 | Upjohn Co | Protection of delta**4-3-ketosteroids by the formation of protonated 3-enamines |
Also Published As
| Publication number | Publication date |
|---|---|
| GB869777A (en) | 1961-06-07 |
| DE1115247B (en) | 1961-10-19 |
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