US2894962A - Oxidation of pseudosapogenins - Google Patents
Oxidation of pseudosapogenins Download PDFInfo
- Publication number
- US2894962A US2894962A US693784A US69378457A US2894962A US 2894962 A US2894962 A US 2894962A US 693784 A US693784 A US 693784A US 69378457 A US69378457 A US 69378457A US 2894962 A US2894962 A US 2894962A
- Authority
- US
- United States
- Prior art keywords
- pseudosapogenin
- hydroxy
- pseudodiosgenin
- oxidation
- oxo
- 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 - Lifetime
Links
- 238000007254 oxidation reaction Methods 0.000 title description 20
- 230000003647 oxidation Effects 0.000 title description 19
- 238000000034 method Methods 0.000 claims description 34
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 19
- 230000001590 oxidative effect Effects 0.000 claims description 18
- 229910052783 alkali metal Inorganic materials 0.000 claims description 10
- 239000003960 organic solvent Substances 0.000 claims description 7
- IQDKIMJGXXRZGR-WZEVQZNYSA-N pseudosarsasapogenin Chemical compound C([C@H]1CC2)[C@@H](O)CC[C@]1(C)[C@@H](CC[C@]13C)C2[C@@H]3C[C@H]2[C@@H]1C(C)=C(CC[C@@H](CO)C)O2 IQDKIMJGXXRZGR-WZEVQZNYSA-N 0.000 claims description 7
- -1 ALKALI METAL METAPERIODATE SALT Chemical class 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 6
- IQDKIMJGXXRZGR-HUEIYZRMSA-N pseudosmilagenin Chemical compound C([C@H]1CC2)[C@@H](O)CC[C@]1(C)[C@@H](CC[C@]13C)[C@@H]2[C@@H]3C[C@H]2[C@@H]1C(C)=C(CC[C@H](CO)C)O2 IQDKIMJGXXRZGR-HUEIYZRMSA-N 0.000 claims description 6
- YHGXHXTZNBXLKF-UHFFFAOYSA-N Pseudohecogenin Natural products C1CC2CC(O)CCC2(C)C(CC(=O)C23C)C1C3CC1C2C(C)=C(CCC(CO)C)O1 YHGXHXTZNBXLKF-UHFFFAOYSA-N 0.000 claims description 5
- IQDKIMJGXXRZGR-UHFFFAOYSA-N Pseudotigogenin Natural products C1CC2CC(O)CCC2(C)C(CCC23C)C1C3CC1C2C(C)=C(CCC(CO)C)O1 IQDKIMJGXXRZGR-UHFFFAOYSA-N 0.000 claims description 5
- 150000001340 alkali metals Chemical class 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- IQDKIMJGXXRZGR-MEBFULDVSA-N pseudotigogenin Chemical compound C([C@@H]1CC2)[C@@H](O)CC[C@]1(C)[C@@H](CC[C@]13C)[C@@H]2[C@@H]3C[C@H]2[C@@H]1C(C)=C(CC[C@H](CO)C)O2 IQDKIMJGXXRZGR-MEBFULDVSA-N 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- YHGXHXTZNBXLKF-RVKDJADKSA-N tribufuroside C Chemical compound C([C@@H]1CC2)[C@@H](O)CC[C@]1(C)[C@@H](CC(=O)[C@]13C)[C@@H]2[C@@H]3C[C@H]2[C@@H]1C(C)=C(CC[C@H](CO)C)O2 YHGXHXTZNBXLKF-RVKDJADKSA-N 0.000 claims description 5
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 21
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 16
- 150000001875 compounds Chemical class 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 7
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 6
- 239000012286 potassium permanganate Substances 0.000 description 6
- 230000002378 acidificating effect Effects 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- 229930183217 Genin Natural products 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 239000003550 marker Substances 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 150000003431 steroids Chemical class 0.000 description 3
- INLFWQCRAJUDCR-IQVMEADQSA-N (1R,2S,4S,5'S,6R,7S,8R,9S,12S,13S)-5',7,9,13-tetramethylspiro[5-oxapentacyclo[10.8.0.02,9.04,8.013,18]icosane-6,2'-oxane] Chemical compound O([C@@H]1[C@@H]([C@]2(CC[C@@H]3[C@@]4(C)CCCCC4CC[C@H]3[C@@H]2C1)C)[C@@H]1C)[C@]11CC[C@H](C)CO1 INLFWQCRAJUDCR-IQVMEADQSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- HCLZRHPLJTXDNX-UHFFFAOYSA-N [O-2].[O-2].[O-2].[Cr+6].CC(O)=O Chemical compound [O-2].[O-2].[O-2].[Cr+6].CC(O)=O HCLZRHPLJTXDNX-UHFFFAOYSA-N 0.000 description 2
- 230000021736 acetylation Effects 0.000 description 2
- 238000006640 acetylation reaction Methods 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 229940117975 chromium trioxide Drugs 0.000 description 2
- WGLPBDUCMAPZCE-UHFFFAOYSA-N chromium trioxide Inorganic materials O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 description 2
- GAMDZJFZMJECOS-UHFFFAOYSA-N chromium(6+);oxygen(2-) Chemical compound [O-2].[O-2].[O-2].[Cr+6] GAMDZJFZMJECOS-UHFFFAOYSA-N 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 238000002329 infrared spectrum Methods 0.000 description 2
- KHIWWQKSHDUIBK-UHFFFAOYSA-M periodate Chemical class [O-]I(=O)(=O)=O KHIWWQKSHDUIBK-UHFFFAOYSA-M 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- 239000003021 water soluble solvent Substances 0.000 description 2
- FCYQTGCEDUOHLT-LEKSSAKUSA-N 1-[(8s,9s,10r,13s,14s,17s)-10,13-dimethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1h-cyclopenta[a]phenanthren-17-yl]ethanone Chemical compound C1C=C2CCCC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 FCYQTGCEDUOHLT-LEKSSAKUSA-N 0.000 description 1
- FUFLCEKSBBHCMO-UHFFFAOYSA-N 11-dehydrocorticosterone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)C(=O)CO)C4C3CCC2=C1 FUFLCEKSBBHCMO-UHFFFAOYSA-N 0.000 description 1
- FJNCXZZQNBKEJT-UHFFFAOYSA-N 8beta-hydroxymarrubiin Natural products O1C(=O)C2(C)CCCC3(C)C2C1CC(C)(O)C3(O)CCC=1C=COC=1 FJNCXZZQNBKEJT-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- MFYSYFVPBJMHGN-ZPOLXVRWSA-N Cortisone Chemical compound O=C1CC[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 MFYSYFVPBJMHGN-ZPOLXVRWSA-N 0.000 description 1
- MFYSYFVPBJMHGN-UHFFFAOYSA-N Cortisone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)(O)C(=O)CO)C4C3CCC2=C1 MFYSYFVPBJMHGN-UHFFFAOYSA-N 0.000 description 1
- DWCSNWXARWMZTG-UHFFFAOYSA-N Trigonegenin A Natural products CC1C(C2(CCC3C4(C)CCC(O)C=C4CCC3C2C2)C)C2OC11CCC(C)CO1 DWCSNWXARWMZTG-UHFFFAOYSA-N 0.000 description 1
- MUCRYNWJQNHDJH-OADIDDRXSA-N Ursonic acid Chemical compound C1CC(=O)C(C)(C)[C@@H]2CC[C@@]3(C)[C@]4(C)CC[C@@]5(C(O)=O)CC[C@@H](C)[C@H](C)[C@H]5C4=CC[C@@H]3[C@]21C MUCRYNWJQNHDJH-OADIDDRXSA-N 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 238000005904 alkaline hydrolysis reaction Methods 0.000 description 1
- LZLOFGMGFADIKQ-UHFFFAOYSA-N benzene;1,4-dioxane Chemical compound C1COCCO1.C1=CC=CC=C1 LZLOFGMGFADIKQ-UHFFFAOYSA-N 0.000 description 1
- 229960004544 cortisone Drugs 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- WQLVFSAGQJTQCK-VKROHFNGSA-N diosgenin Chemical compound O([C@@H]1[C@@H]([C@]2(CC[C@@H]3[C@@]4(C)CC[C@H](O)CC4=CC[C@H]3[C@@H]2C1)C)[C@@H]1C)[C@]11CC[C@@H](C)CO1 WQLVFSAGQJTQCK-VKROHFNGSA-N 0.000 description 1
- WQLVFSAGQJTQCK-UHFFFAOYSA-N diosgenin Natural products CC1C(C2(CCC3C4(C)CCC(O)CC4=CCC3C2C2)C)C2OC11CCC(C)CO1 WQLVFSAGQJTQCK-UHFFFAOYSA-N 0.000 description 1
- 125000000532 dioxanyl group Chemical group 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000003163 gonadal steroid hormone Substances 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 150000003130 pregnenes Chemical class 0.000 description 1
- 244000057424 walen Species 0.000 description 1
- 239000003799 water insoluble solvent Substances 0.000 description 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
- C07J75/00—Processes for the preparation of steroids in general
Definitions
- the conversion of sapogenins to 16-dehyd1'opregnenes is achieved by a three-step process comprising converting the sapogenins to pseudosapogenins, oxidizing the pseudosapogenins to 16B-acyloxypregnanes, and hydrolytically cleaving the l6fl-acyloxy esters to obtain the 16-dehydropregnenes.
- the latter are useful intermediates for production of physiologically active steroids such as male and female sex hormones and cortisone.
- the present invention relates to an improved process for oxidizing pseudosapogenins to 16,8-acyloxypregnanes.
- 16 8- acyloxypregnanes will in some instances include compounds, such as those with the steroid nucleus of diosgenin having a C-(6) double bond, which should technically be called 16,8-acyloxypregnenes.
- 168-acyloxypregnenes one name will be used to refer to groups of compounds obtained by the process of this invention.
- a further disadvantage of the commonly used chromium trioxide-acetic acid system is that the 3-hydroxyl groups must be protected, as by acetylation, or they would otherwise be oxidized to 3-ketones. It has also been reported that chromium trioxide-acetic acid oxidation of unacetylated pseudosapogenins at times produces 20-hydroxy compounds.
- the process of the present invention may be used to oxidize unacetylated pseudosapogenins without causing these undesirable effects. At times it is desirable to oxidize unacetylated pseudosapogenins which are crystalline, easily purified compounds Whereas pseudosapogenin acetates are oily and are difficulty to purity.
- the object of the present invention is to avoid the difiiculties encountered by the oxidation of pseudosapogenins in acid media.
- Another object of the present invention is to make new compounds, 16fl-valeroxypregnanes, unobtainable by previously reported oxidation processes.
- a pseudosapogenin such as pseudosarsasapogenin, pseudosmilagenin, ll-oxopseudodiosand pseudodiosgenin, 12-oxo-pseudodiosgenin, genin, pseudotigogenin, ll-oxo-pseudotigogenin, pseudohecogenin, is converted to the corresponding 16;?- acyloxypregnane by a process comprising dissolving the pseudosapogenin in an inert, water soluble organic solvent not attacked by an alkaline oxidizing system, for example, dioxane, tetrahydrofuran, or tertiary butyl alcohol, and oxidizing the pseudosapogenin therein by mixing therewith an aqueous solution containing, based upon "the Weight of pseudosapogenin, about a 2 to 8 molar ratio of a water soluble alkali metal metaperiodate salt, such as sodium
- an alkaline agent to maintain a pH above 7.0, preferably in the range of pH 7.0 to 10.0, as that obtained with potassium carbonate.
- the molar ratios of permanganate salt, metaperiodate salt and pseudosapogenin are of great importance. Best results were obtained when ratios of 1 mole pseudosapogenin, 8 moles of sodium metaperiodate and 0.13 mole potassium permanganate were used. Increasing the molar ratio of the permanganate salt gave poorer results. However, the reaction is operative at molar ratios other than those which give the best results, especially as rewards to the sodium metaperiodate where molar ratios of 2 to 4 times that of the pseudosapogenin were used successfully.
- an inert, water solublejsolvent' is critical to the operativeness of the invention.
- the disclosed solvents of this category are dioxane, tetrahydrofuran and tertiary butyl alcohol, other water soluble ethers and alcohols which are not attacked by the oxidizing system may be used- Mixtures of these inert, water soluble solvents with water insoluble solvents such as benzene, hexane, heptaue and ethyl ether may also be used as vehicles for the pseudosapogenins.
- the present invention isapplicable to all types of pseu dosapogenins. Surprisingly, although thepseudosapo genin 20(22) double bond is readily attacked, as illustrated by the following diagram, double bondsin the j 3 steroid nucleus, such as the important 5(6) double bond, are not attacked.
- EXAMPLE 1 Oxidation of pseudosarsasapogenin
- Ten grams of pseudosarsasapogenin were dissolved in 1440 ml. of purified dioxane. This solution was mixed with 2400 ml. of benzene.
- An aqueous solution was prepared containing 41.0 g. of sodium metaperiodate, 10.0 g. of anhydrous potassium carbonate and 1.2 g. of potassium permanganate in 2650 ml. of water.
- To this solution was added the benzene-dioxane solution of pseudosarsasapogenin and the mixture vigorously stirred for one hour. The upper solvent layer was drawn 01f and the residual aqueous layer extracted twice with one liter of benzene each time.
- pseudotigogenin Was converted to 3,8-hydroxy-16p-( methyl-a-hydroxy) valeroxy-allopregnan-20-one which on alkaline hydrolysis gave 3fi-hydroxy-16-aJlopregnen-20- one.
- EXAMILE 5 In the manner described in Example 3 pseudohecogenin was converted to 3fl-hydroxy-16/8-(y-methyl-6-hydroxy) valeroxy-allopregnan-12,20-dione; ll-oxo-pseudotigogenin gave SB-hydroxy-16fi-( -rnethyl-6-hydroxy) -valeroxy-allopregnan-11,20-dione; 12-oxo-pseudodiosgenin gave 3,8-
- the ll-oxo-pseudodiosgenin may be prepared according to the process described in the copending application of Rothman et 211., Serial No. 644,- 184, filed March 5, 1957, on page 5, lines 20-26.
- Each of the above 16,8-valeroxy compounds had infrared spectra in accordance with the above structures and on a1kaline hydrolysis was converted to the corresponding 16-dehydropregnene.
- the 16,8-valeroxypregnanes (pregnenes) which result from the described alkaline oxidation procedure are new compounds unobtainable by the previously reported acidic oxidation processes.
- Acidic oxidation of acetylated pseudosapogenins yields acetylated 16/3-acyloxy compounds. Any hydrolysis to remove the acetate groups also cleaves the l6-acyloxy ester linkage to produce 16- dehydropregnenes (pregnedienes).
- Acidic oxidation of unacetylated pseudosapogenins results in oxidation of the 3-hydroxy group to give the 3-ketone and also oxidizes the terminal hydroxy group of the 16-acyloxy side chain.
- the new compounds can only be obtained by alkaline oxidation procedures.
- a process for oxidizing a pseudosapogenin to its corresponding 16B-acyloxypregnane comprising dissolving said pseudosapogenin in an inert water soluble organic solvent not attacked by an alkaline oxidizing system, and oxidizing said pseudosapogenin by mixing therewith an aqueous solution containing, based upon weight of pseudosapogenin, about a 2 to 8 molar ratio of a water soluble alkali metal metaperiodate salt, about 0.10 to 0.15 molar ratio of a water soluble alkali metal permanganate salt, and an alkaline agent to maintain a pH above 7.0.
- pseudosapogenin is selected from the group consisting of pseudosarsasapogenin, pseudosmilagenin, pseudodiosgenin, ll-oxopseudodiosgenin, 12-oxo-pseudodiosgenin, pseudotigogenin, ll-oxo-pseudotigogenin, and pseudohecogenin.
- alkali metal metaperiodate is sodium metaperiodate
- the alkali metal permanganate is potassium permanganate
- the alkaline agent is potassium carbonate
- the water solubl organic solvent not attacked by an oxidizing system is tertiary butyl alcohol.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
Description
2,894,962 OXIDATION F PSEUDOSAPOGENINS Monroe E. Wall, Oreland, and Samuel Serota, Philadel- Patented July 14, 1959 ice dosapogenins are quite stable to alkaline oxidation conditions. We have found a novel oxidizing system conphia, Pa., assignors to the United States of America as represented by the Secretary of Agriculture No Drawing. Application October 31, 1957 Serial No. 693,784
19 Claims. (Cl. 260-39745) (Granted under Title 35, US. Code (1952), see. 266) A non-exclusive, irrevocable, royalty-free license in the invention herein described, throughout the world for all purposes of the United States Government, with the power to grant sublicenses for such purposes, is hereby granted to the Government of the United States of America. v
The conversion of sapogenins to 16-dehyd1'opregnenes is achieved by a three-step process comprising converting the sapogenins to pseudosapogenins, oxidizing the pseudosapogenins to 16B-acyloxypregnanes, and hydrolytically cleaving the l6fl-acyloxy esters to obtain the 16-dehydropregnenes. By methods well known to those versed in the art the latter are useful intermediates for production of physiologically active steroids such as male and female sex hormones and cortisone.
The present invention relates to an improved process for oxidizing pseudosapogenins to 16,8-acyloxypregnanes.
The oxidation products referred to collectively as 16 8- acyloxypregnanes will in some instances include compounds, such as those with the steroid nucleus of diosgenin having a C-(6) double bond, which should technically be called 16,8-acyloxypregnenes. For purposes of simplicity, one name will be used to refer to groups of compounds obtained by the process of this invention.
Previously the only known methods for converting pseudosapogenins to the corresponding 16/3-acyloxypregnanes involved oxidation in acid media. For example, the most commonly used system was chromium trioxide in acetic acid. Occasionally hydrogen peroxide in acetic acid has been used. Certain disadvantages are inherent in the use of acidic oxidation conditions. Acid sensitive groupings such as oxides are easily cleaved. Furthermore, when 16,8-acyloxypregnanes are produced under these acidic conditions, invariably some of the product is hydrolyzed to the 16-dehydropregnene. The latter in the presence of excess oxidant undergo undesirable reactions, thus lowering the yields.
A further disadvantage of the commonly used chromium trioxide-acetic acid system is that the 3-hydroxyl groups must be protected, as by acetylation, or they would otherwise be oxidized to 3-ketones. It has also been reported that chromium trioxide-acetic acid oxidation of unacetylated pseudosapogenins at times produces 20-hydroxy compounds. The process of the present invention may be used to oxidize unacetylated pseudosapogenins without causing these undesirable effects. At times it is desirable to oxidize unacetylated pseudosapogenins which are crystalline, easily purified compounds Whereas pseudosapogenin acetates are oily and are difficulty to purity.
The object of the present invention is to avoid the difiiculties encountered by the oxidation of pseudosapogenins in acid media.
Another object of the present invention is to make new compounds, 16fl-valeroxypregnanes, unobtainable by previously reported oxidation processes.
It is Well known to those versed in the art that pseusolution of permanganate and metasisting of an aqueous under alkaperiodate ions which functions successfully line conditions. v
According to the present invention a pseudosapogenin such as pseudosarsasapogenin, pseudosmilagenin, ll-oxopseudodiosand pseudodiosgenin, 12-oxo-pseudodiosgenin, genin, pseudotigogenin, ll-oxo-pseudotigogenin, pseudohecogenin, is converted to the corresponding 16;?- acyloxypregnane by a process comprising dissolving the pseudosapogenin in an inert, water soluble organic solvent not attacked by an alkaline oxidizing system, for example, dioxane, tetrahydrofuran, or tertiary butyl alcohol, and oxidizing the pseudosapogenin therein by mixing therewith an aqueous solution containing, based upon "the Weight of pseudosapogenin, about a 2 to 8 molar ratio of a water soluble alkali metal metaperiodate salt, such as sodium metaperiodate, about a 0.10 to 0.15, preferably 0.13 molar ratio of a water soluble alkali metal permanganate salt, such as potassium permanganate, and
an alkaline agent to maintain a pH above 7.0, preferably in the range of pH 7.0 to 10.0, as that obtained with potassium carbonate.
The molar ratios of permanganate salt, metaperiodate salt and pseudosapogenin are of great importance. Best results were obtained when ratios of 1 mole pseudosapogenin, 8 moles of sodium metaperiodate and 0.13 mole potassium permanganate were used. Increasing the molar ratio of the permanganate salt gave poorer results. However, the reaction is operative at molar ratios other than those which give the best results, especially as rewards to the sodium metaperiodate where molar ratios of 2 to 4 times that of the pseudosapogenin were used successfully.
The presence of an inert, water solublejsolvent'is critical to the operativeness of the invention. Although the disclosed solvents of this category are dioxane, tetrahydrofuran and tertiary butyl alcohol, other water soluble ethers and alcohols which are not attacked by the oxidizing system may be used- Mixtures of these inert, water soluble solvents with water insoluble solvents such as benzene, hexane, heptaue and ethyl ether may also be used as vehicles for the pseudosapogenins. When the solutionof a pseudosapogenin in inert, water soluble solvent is shaken with an aqueous solution of carbonate, permanganate and metaperiodate salts the desired oxidation reaction commences immediately and rapidly proceeds to completion. Surprisingly, no reaction occurs if the water soluble organiclsolvent' is-omitted. Thus shaking a fine dispersion of the. pseudosapogenin in the aqueous alkaline oxidizing media gave no reaction. Similarly, attempts to oxidize a benzene solution to pseudodropregnene. The aqueous'layer may be evaporated to a small volume whereupon much of the unreacted sodium metaperiodate crystallizes out and may be recovered by. filtration.
The present invention isapplicable to all types of pseu dosapogenins. Surprisingly, although thepseudosapo genin 20(22) double bond is readily attacked, as illustrated by the following diagram, double bondsin the j 3 steroid nucleus, such as the important 5(6) double bond, are not attacked.
CHaOH CH CH'CH3 uide... t
Neither are isolated carbonyl groups attacked. The method is applicable to pseudosapogenin diacetates, but in general works more smoothly with the unacetylated forms.
The practice of the present invention is illustrated by the following examples:
EXAMPLE 1 Oxidation of pseudosarsasapogenin Ten grams of pseudosarsasapogenin were dissolved in 1440 ml. of purified dioxane. This solution was mixed with 2400 ml. of benzene. An aqueous solution was prepared containing 41.0 g. of sodium metaperiodate, 10.0 g. of anhydrous potassium carbonate and 1.2 g. of potassium permanganate in 2650 ml. of water. To this solution was added the benzene-dioxane solution of pseudosarsasapogenin and the mixture vigorously stirred for one hour. The upper solvent layer was drawn 01f and the residual aqueous layer extracted twice with one liter of benzene each time. The benzene extracts were combined, washed with water and then all the solvent removed in vacuo. The product, 3;? hydroxy-16fi('y-methyl-d-hydroxy) valeroxy-pregnan-ZO-one, weighed 11.0 grams and was a yellow viscous oil. The infrared spectrum showed two carbonyl groups consistent with the assigned structure, 1735 GEL-1 (ester) and 1700 cmr (20-ketone). Alkaline cleavage with potassium hydroxide in teritary butanol gave 7.0 g. of 3,8-hydroxy-16-pregnen-20-one.
EXAMPLE 2 Oxidation of pseudosmilagenin In a manner similar to Example 1, 10.0 grams of pseudosmilagenin give 10.5 g. of 3/3-hydroxy-16fl('y-methyla-hydroxy) valeroxy-pregnan-ZO-one which on alkaline hydolysis gave 3p3-hydroxy-16-pregnen-20-one.
EXAMPLE 3 Oxidation of pseudodiosgenin Pseudodiosgenin (0.42 g.) was dissolved in 60 ml. of tertiary butanol. The solution was added with vigorous agitation to an aqueous solution containing 1.7 g. of sodium metaperiodate, 0.42 g. of potassium carbonate, and 0.05 g. of potassium permanganate in 110 ml. of water. After shaking five minutes, the mixture was extracted with benzene. On evaporation of the benzene, 0.5 g. of the desired product 3 3-hydroxy-16,6(y-methyl-6-hydroxy) valeroxy 5-pregnen-20-one was obtained. Acetylation of this compound gave a diacetate identical to the prodnot obtained by the chromium trioxide oxidation of pseudodiosgenin diacetate. Alkaline cleavage of the un- In the same manner as described in Example 3, except that tetrahydrofuran was substituted for tertiary butanol,
pseudotigogenin Was converted to 3,8-hydroxy-16p-( methyl-a-hydroxy) valeroxy-allopregnan-20-one which on alkaline hydrolysis gave 3fi-hydroxy-16-aJlopregnen-20- one.
EXAMILE 5 In the manner described in Example 3 pseudohecogenin was converted to 3fl-hydroxy-16/8-(y-methyl-6-hydroxy) valeroxy-allopregnan-12,20-dione; ll-oxo-pseudotigogenin gave SB-hydroxy-16fi-( -rnethyl-6-hydroxy) -valeroxy-allopregnan-11,20-dione; 12-oxo-pseudodiosgenin gave 3,8-
' hydroxy 16/3-('y-methyl-6-hydroxy) valeroxy-S-pregnen- 12,20-dione; 11-oxo-pseudodiosgenin gave 3B-hydroxy- ('y methyl-e-hydroxy)-valeroxy-5-pregnen-l1,20- dione. The 12-oxo-pseudodiosgenin may be prepared according to the process described in an article in J. Org. Chem. 22, 182 (1957) on page 185, column 1, lines 1-4 of the last paragraph, this compound being identical to the compound pseudogentrogenin diacetate recited on line 5 of said article. The ll-oxo-pseudodiosgenin may be prepared according to the process described in the copending application of Rothman et 211., Serial No. 644,- 184, filed March 5, 1957, on page 5, lines 20-26. Each of the above 16,8-valeroxy compounds had infrared spectra in accordance with the above structures and on a1kaline hydrolysis was converted to the corresponding 16-dehydropregnene.
The 16,8-valeroxypregnanes (pregnenes) which result from the described alkaline oxidation procedure are new compounds unobtainable by the previously reported acidic oxidation processes. Acidic oxidation of acetylated pseudosapogenins yields acetylated 16/3-acyloxy compounds. Any hydrolysis to remove the acetate groups also cleaves the l6-acyloxy ester linkage to produce 16- dehydropregnenes (pregnedienes). Acidic oxidation of unacetylated pseudosapogenins, as mentioned heretofore, results in oxidation of the 3-hydroxy group to give the 3-ketone and also oxidizes the terminal hydroxy group of the 16-acyloxy side chain. Hence, the new compounds can only be obtained by alkaline oxidation procedures.
We claim:
1. A process for oxidizing a pseudosapogenin to its corresponding 16B-acyloxypregnane comprising dissolving said pseudosapogenin in an inert water soluble organic solvent not attacked by an alkaline oxidizing system, and oxidizing said pseudosapogenin by mixing therewith an aqueous solution containing, based upon weight of pseudosapogenin, about a 2 to 8 molar ratio of a water soluble alkali metal metaperiodate salt, about 0.10 to 0.15 molar ratio of a water soluble alkali metal permanganate salt, and an alkaline agent to maintain a pH above 7.0.
2. The process of claim'l in which the pseudosapogenin is selected from the group consisting of pseudosarsasapogenin, pseudosmilagenin, pseudodiosgenin, ll-oxopseudodiosgenin, 12-oxo-pseudodiosgenin, pseudotigogenin, ll-oxo-pseudotigogenin, and pseudohecogenin.
3. The process of claim 1 in which the pseudosapogenin is pseudosarsasapogenin.
4. The process of claim 1 in which the pseudosapogenin is pseudosmilagenin.
5. The process of claim 1 in which the pseudosapogenin is pseudodiosgenin.
6. The process of claim 1 in which the pseudosapogenin is ll-oxo-pscudodiosgenin.
7. The process of claim 1 in which the pseudosapogenin is 12-oxo-pseudocliosgenin.
8. The process of claim 1 in which the pseudosapogenin is pseudotigogenin.
9. The process of claim 1 in which the pseudosapogenin is ll-oxo-pseudotigogenin.
10. The process of claim genin is pseudohecogenin.
11. 3,8 hydroxy 1618 (v methyl 5 hydroxy)- valeroxy-S -pregnen-1 1,20-dione.
12. 35 hydroxy 16B ('y methyl 6 hydroxy)- valeroxy-S-pregnen-12,20-dione.
13. The process of claim 1 wherein the alkali metal periodate is sodium metaperiodate.
14. The process of claim 1 wherein the alkali metal permanganate is potassium permanganate.
15. The process of claim 1 wherein the alkaline agent is potassium carbonate.
16. The process of claim 1 wherein the inert water soluble organic solvent not attacked by an oxidizing system is dioxane.
17. The process of claim 1 wherein the inert water soluble organic solvent not attacked by an oxidizing system is tetrahydrofuran.
1 in which the pseudosapo- 18. The process of claim 1 wherein the inert Water soluble organic solvent not attacked by an oxidizing system is tertiary butyl alcohol.
19. The process of claim 1 wherein the alkali metal metaperiodate is sodium metaperiodate, the alkali metal permanganate is potassium permanganate, the alkaline agent is potassium carbonate, and the water solubl; organic solvent not attacked by an oxidizing system is tertiary butyl alcohol.
References Cited in the file of this patent UNITED STATES PATENTS 2,352,851 Marker et a1. July 4, 1944 2,409,293 Marker Oct. 15, 1946 2,420,490 Marker May 13, 1947 2,716,125 Hirschmann Aug. 23, 1955 2,830,986 Walens et a1 Apr. 15, 1958
Claims (3)
1. A PROCESS FOR OXIDIZING A PSEUDOSAPOGENIN TO ITS CORRESPONDING 16B-ACYLOXYPREGNANE COMPRISING DISSOLVING SAID PSEUDOSAPOGENIN IN AN INERT WATER SOLUBLE ORGANIC SOLVENT NOT ATTACKED BY AN ALKALINE OXIDIZING SYSTEM, AND OXIDIZING SAID PSEUDOSAPOGENIN BY MIXING THEREWITH AN AQUEOUS SOLUTION CONTAINING, BASED UPON WEIGHT OF PSEUDOSAPOGENIN, ABOUT A 2 TO 8 MOLAR RATIO OF A WATER SOLUBLE ALKALI METAL METAPERIODATE SALT, ABOUT 0.10 TO 0.15 MOLAR RATIO OF A WATER SOLUBLE ALKALI METAL PERMANGANATE SALT, AND AN ALKALINE AGENT TO MAINTAIN A PH ABOVE 7.0.
2. THE PROCESS OF CLAIM 1 IN WHICH THE PSEUDOSAPOGENIN IS SELECTED FROM THE GROUP CONSISTING OF PSEUDOSARSASAPOGENIN, PSEUDOSMILAGENIN, PSEUDODIOSGENIN, 11-OXOPSEUDODIOSGENIN, 12-OXO-PSEUDODIOSGENIN, PSEUDOTIGOGENIN, 11-OXO-PSEUDOTIGOGENIN, AND PSEUDOHECOGENIN.
6. THE PROCESS OF CLAIM 1 IN WHICH THE PSEUDOSAPOGENIN IS 11-OXO-PSEUDODIOSGENIN.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US693784A US2894962A (en) | 1957-10-31 | 1957-10-31 | Oxidation of pseudosapogenins |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US693784A US2894962A (en) | 1957-10-31 | 1957-10-31 | Oxidation of pseudosapogenins |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US2894962A true US2894962A (en) | 1959-07-14 |
Family
ID=24786104
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US693784A Expired - Lifetime US2894962A (en) | 1957-10-31 | 1957-10-31 | Oxidation of pseudosapogenins |
Country Status (1)
| Country | Link |
|---|---|
| US (1) | US2894962A (en) |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2352851A (en) * | 1941-05-15 | 1944-07-04 | Parke Davis & Co | Sapogenin derivatives and preparation of same |
| US2409293A (en) * | 1941-06-30 | 1946-10-15 | Parke Davis & Co | Hormone intermediates and preparation of same |
| US2420490A (en) * | 1941-06-30 | 1947-05-13 | Parke Davis & Co | delta-pregnenediols and process for producing the same |
| US2716125A (en) * | 1953-10-14 | 1955-08-23 | Merck & Co Inc | 3(beta)-acetoxy-16(delta-acetoxyisocaprooxy)-allopregnanedione-11, 20 |
| US2830986A (en) * | 1956-02-20 | 1958-04-15 | Henry A Walens | Gentrogenin and correllogenin |
-
1957
- 1957-10-31 US US693784A patent/US2894962A/en not_active Expired - Lifetime
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2352851A (en) * | 1941-05-15 | 1944-07-04 | Parke Davis & Co | Sapogenin derivatives and preparation of same |
| US2409293A (en) * | 1941-06-30 | 1946-10-15 | Parke Davis & Co | Hormone intermediates and preparation of same |
| US2420490A (en) * | 1941-06-30 | 1947-05-13 | Parke Davis & Co | delta-pregnenediols and process for producing the same |
| US2716125A (en) * | 1953-10-14 | 1955-08-23 | Merck & Co Inc | 3(beta)-acetoxy-16(delta-acetoxyisocaprooxy)-allopregnanedione-11, 20 |
| US2830986A (en) * | 1956-02-20 | 1958-04-15 | Henry A Walens | Gentrogenin and correllogenin |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US2894962A (en) | Oxidation of pseudosapogenins | |
| US3077482A (en) | 19-oxygenated steroids and process for their manufacture | |
| GB1472922A (en) | Pregnanoic acid derivatives | |
| US2366204A (en) | Keto-steroids and method of obtaining same | |
| US2716125A (en) | 3(beta)-acetoxy-16(delta-acetoxyisocaprooxy)-allopregnanedione-11, 20 | |
| CH624684A5 (en) | ||
| DE2243480A1 (en) | PROCESS FOR THE MANUFACTURING OF STEROIDS OF THE PREDNISOLON SERIES | |
| US2677695A (en) | Process for preparing 17alpha-hydroxy 20-keto steroids | |
| US2759928A (en) | Compounds for synthesizing steroids | |
| CH620451A5 (en) | ||
| US3176032A (en) | 17alpha, 21-diacyloxy derivatives of 6alpha-methyl-delta1, 4-pregnadien-3, 20-dione and of 6alpha-methyl-delta4-pregnen-3, 20-dione | |
| US2715621A (en) | Steroids | |
| US2779774A (en) | 3beta-oxy-delta16-allopregnenedione-11, 20 and process | |
| US2304837A (en) | Hydroxy pregnane derivatives and preparation of same | |
| DE2237202A1 (en) | PROCESS FOR THE PRODUCTION OF 17 (2-HALOAETHYLIDEN) STEROIDS | |
| US2339281A (en) | Derivatives of sapogenins and their preparation | |
| US2912444A (en) | Process of preparing 17-hydroxy-20-ketosteroids | |
| US2309867A (en) | Substituted derivatives of saturated or unsaturated pregnanediones | |
| DE1618875C3 (en) | Process for the preparation of Salpha-halogen-öbeta-acyl-oxysteroids | |
| US2320847A (en) | delta 5-cholestenone-3 and a method for producing the same | |
| US3128291A (en) | New hemiacetals and hemicaetal esters of the androstane series and a method for their production | |
| US2914544A (en) | Production of cyclopentanophenan-threne compounds | |
| US2931806A (en) | dl-delta5-3-ethylenedioxy-11-keto-20-cyano pregnenes | |
| US2786836A (en) | Compounds for synthesizing steroids | |
| DE930030C (en) | Process for the preparation of 16, 17-Oxydo -? - pregnen-3, 20-dione |