US2397656A - Derivatives of the cyclopentanoperhydrophenanthrene series and process of making same - Google Patents

Derivatives of the cyclopentanoperhydrophenanthrene series and process of making same Download PDF

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US2397656A
US2397656A US541096A US54109644A US2397656A US 2397656 A US2397656 A US 2397656A US 541096 A US541096 A US 541096A US 54109644 A US54109644 A US 54109644A US 2397656 A US2397656 A US 2397656A
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keto
acid
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cyclopentanoperhydrophenanthrene
derivatives
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Thomas F Gallagher
William P Long
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Government of the United States of America
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    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J75/00—Processes for the preparation of steroids in general

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  • l'his invention relates to hormone-like compounds of the cortical steroltype, particularly hormone-like derivatives of cyclopentanoperhydrophenanthrene having an oxygen function at carbon I I and to an improved method of synthesizing these compounds.
  • This invention has as its object a practical and economical process of preparing hormone-like cortical steroid type compounds. Another object of this invention is to provide a method of preparing a hormone-like derivative of cyclopentanoperhydrophenanthrene having an oxygen function at carbon I I.
  • The'compoundsof the present invention have an oxygen function, e. g. a hydroxyl or keto or substituted hydroxyl or keto group at the carbon ll position of the steroid nucleus.
  • the compounds are prepared from cyclopentanoperhydrophenanthrene derivatives, l. e. compounds with asteroid nucleus characterized by a ketonic group at the carbon 12 position of the nucleus.
  • Previous attempts to introduce an oxygen function at carbon 11 and still maintain a reactive keto group at carbon 12 have been unsuccessful.
  • the introduction of an oxygen function at the carbon 11 position of the sterol nucleus has resulted in the formation of rearrangement products lacking an active keto group at the carbon 12 positiongroup without destroying the oxygen function introduced at the carbon 11 position.
  • the desired product or epimers having a reactive keto group at carbon 12 may be separated from undesired products by fractional crystallization or by various other means known in the it art.
  • One preferred method of separation is based upon the discovery that substantially all of the desired product occurs as an epimer which forms an insoluble sodium salt while the undesired products for the most part form soluble sodium salts.
  • the insoluble sodium salt may be isolated and treated as follows:
  • step six Reduction of the hydrazone derivative ob tained by step six whereby the hydrazone group which replaced the keto group is converted to a methylene group at the carbon 12 position of the nucleus;
  • Methyl Desoxycholate Commercial desoxycholic acid [3(a) 1'2 dihydroxy'cholanic acid] is first esterified by suspending 450 grams of well dried desoxycholic acid in approximately one liter of dry methanol, adding 0.5 to 1.0 cc. of concentrated sulphuric acid in 25 cc. of methanol and, after stoppering the flask, allowing the mixture to stand at room temperature for twenty-four hours. Over this period the desoxycholic acid dissolves and the methyl ester crystallizes. The reaction mixture is then filtered with suction, the precipitate Washed well by suspension in very cold methanol and dried. The material obtained melts at 97-102 C. (corrected) and, although somewhat impure, is satisfactory for use in the further steps of the process.
  • step II 3(a) acetoxy 12 hydroxy' methyl cholanate: 400 gramsof methyl desoxycholate .obtained by step I are dissolved in 750 cc. of pyridine which has been distilled over barium oxide. To this solution, 165 cc. (1.6 mole) of freshly distilled acetic anhydride are added and the mixture alwith water andall aqueous 'fractionsjdiscarded.
  • thehydrolysis be conducted at low temperature, i. e. not above about 40 C. If the reaction mixture is heated, the resulting products do not contain (or retain)v the active keto group at carbon 12. After standing, a heavy' precipitate forms; the solution is next chilled overnight at -10 C. and filtered withvgentle suction while still cold. The precipitate is washed twice by suspension in a small volume of ice cold water and dried without heating.v
  • the precipitate thus obtained contains. a desired (reactive keto) epimer as an insoluble sodium salt while the filtrate retains for the most part the undesired products as soluble sodium salts.
  • a desired (reactive keto) epimer as an insoluble sodium salt while the filtrate retains for the most part the undesired products as soluble sodium salts.
  • One epimer with a reactive '12-keto group does form a soluble sodium salt. It maybe recovered from the filtrate by crystallization if desired, although as it is present only in small amounts its recovery has generally not been found worthwhile. This diiierence in solubilities of the sodium salts provides (an unusually satisfactory means for separation and recovery of substantially all of the desired product characterized by the reactive keto group.
  • Additional insoluble sodium salt maybe recovered from the filtrate or reaction mixture by acidifying; the filtrate under -ether, extracting with ether, washing the extract with water, drying the washed extract over sodium sulfate, :distilling on the ether, dissolving the oily residue in ethanol; neutralizing with caustic alkali, diluting with Water and allowing the product to stand at about '10 C. .
  • step VI Wolff-Kishner reduction of the 3. -dihydroxy-12- keto cholanic acid .hydrazone: About 5 grams of the hydrazone obtained by step VI are introduced into 'a glass or steel bomb tube and cc. of sodium ethylate prepared from 3 grams of sodium added along-with 0.5 .cc. of onehundred per cent hydrazine hydrate. The tube is then cooling, the tube is opened .and the contents rinsed outwith alcohol, water or other solvent.
  • step VII Isolation of 3,1l-dihydroxy cholanic acid as the methyl ester:
  • the reaction product obtained by step VII is preferably rinsed from the bomb tube with ninety-five per cent ethanol so that the final volume is one liter of ethanol for each 40 grams of the sodium salt hydrazone reduoed.
  • This solution is heated and neutralized to phenolphthalein with dilute aqueous hydrochloric acid and an additional amount of water sufiicient to bring the volume to two liters added.
  • One liter of 0.3 N barium hydroxide is next added, to the hot aqueous alcohol solution and finally one liter of hot water added slowly with constant stirring.
  • the flask is then stoppcred and allowed to cool overnight.
  • the insoluble barium salt is removed by filtration and the filtrate containing soluble barium salts acidified under ether and extracted twice with fresh portions of ether.
  • the ether solution is washed thoroughly with water,

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Steroid Compounds (AREA)

Description

Patented Apr. 2, 1946 DERIVATIVES OF THE CYCLOPENTANO- PERHYDROPHENANTHRENE SERIES AND PROCESS OF MAKING SAME 'Thomas F. Gallagher and William P. Long, Chicago, Ill., assignors to the Government of the United States of America, as represented by the Secretary of War and his successors in ofiice No Drawing. Application J une 19, 1944, Serial No. 541,096
4 Claims.
l'his invention relates to hormone-like compounds of the cortical steroltype, particularly hormone-like derivatives of cyclopentanoperhydrophenanthrene having an oxygen function at carbon I I and to an improved method of synthesizing these compounds.
It has been known for some time that the adrenal steroids were important medical compounds having particular utility in hormone therapy. These compounds are characterized by their complex molecular structure and have the following ring system: I I
The various processes of preparing these compounds suggested heretofore have been relatively unsatisfactory; Thus, the prior processes have been found tedious, complicated and difiicult to control and the resulting yields therefrom of desired sterols too low for practical operation.
This invention has as its object a practical and economical process of preparing hormone-like cortical steroid type compounds. Another object of this invention is to provide a method of preparing a hormone-like derivative of cyclopentanoperhydrophenanthrene having an oxygen function at carbon I I.
'Other objects will be apparent from the following description of theinvention.
The'compoundsof the present invention have an oxygen function, e. g. a hydroxyl or keto or substituted hydroxyl or keto group at the carbon ll position of the steroid nucleus. In carryin out the invention, the compounds are prepared from cyclopentanoperhydrophenanthrene derivatives, l. e. compounds with asteroid nucleus characterized by a ketonic group at the carbon 12 position of the nucleus. Previous attempts to introduce an oxygen function at carbon 11 and still maintain a reactive keto group at carbon 12 have been unsuccessful. In prior processes, the introduction of an oxygen function at the carbon 11 position of the sterol nucleus has resulted in the formation of rearrangement products lacking an active keto group at the carbon 12 positiongroup without destroying the oxygen function introduced at the carbon 11 position.
above about 40 C., and preferably at roomtempera-ture (20 C.), of asteroid nucleus characterized by a halogen group at the carbon 11 position and a ketonic group at the carbon 12 position. The temperature at which the hydrolysis is carried out is of utmost importance since it has been found that substantially no-sterol compound having an oxygen function at the carbon 11 position and a reactive keto group at the carbon 12 position is formed by hydrolysis at temperatures above 40 C. A preferred illustrative method of practicing the present invention is as follows:
1. Preparing an alkyl desoxycholate by esterifying commercial desoxycholic acid;
2. Preparing a 3-acyl derivative of the alkyl desoxycholate V by partial acylation of the ester product obtained by step one; u
3. Preparing a. 12-keto derivative of the 3-acylalkyl desoxycholate by oxidizing the product ob tained by step two;
4. Preparing an ll-brom derivative of the 3- acyl-12-keto alkyl desoxycholate by brominating the product obtained by step three;
5. Preparing 3-11-dihydroxy-12-keto cholanic acid by hydrolysis at a temperature not above about 40 C. of the ll-bromproduct obtained by step four.
The desired product or epimers having a reactive keto group at carbon 12 may be separated from undesired products by fractional crystallization or by various other means known in the it art. One preferred method of separation is based upon the discovery that substantially all of the desired product occurs as an epimer which forms an insoluble sodium salt while the undesired products for the most part form soluble sodium salts. The insoluble sodium salt may be isolated and treated as follows:
6. Preparing the hydrazone of the insoluble sodiumsalt of 3,11-dihydroxy-12 keto-cholanic acid obtained by step five;
7. Reduction of the hydrazone derivative ob tained by step six whereby the hydrazone group which replaced the keto group is converted to a methylene group at the carbon 12 position of the nucleus;
8. Isolation of the 3,11-dihydroxy cholanic acid obtained by step seven as an alkyl ester.
The following example serves to illustrate the present invention but is not intended to limit it thereto:
I. Methyl Desoxycholate: Commercial desoxycholic acid [3(a) 1'2 dihydroxy'cholanic acid] is first esterified by suspending 450 grams of well dried desoxycholic acid in approximately one liter of dry methanol, adding 0.5 to 1.0 cc. of concentrated sulphuric acid in 25 cc. of methanol and, after stoppering the flask, allowing the mixture to stand at room temperature for twenty-four hours. Over this period the desoxycholic acid dissolves and the methyl ester crystallizes. The reaction mixture is then filtered with suction, the precipitate Washed well by suspension in very cold methanol and dried. The material obtained melts at 97-102 C. (corrected) and, although somewhat impure, is satisfactory for use in the further steps of the process.
II. 3(a) acetoxy 12 hydroxy' methyl cholanate: 400 gramsof methyl desoxycholate .obtained by step I are dissolved in 750 cc. of pyridine which has been distilled over barium oxide. To this solution, 165 cc. (1.6 mole) of freshly distilled acetic anhydride are added and the mixture alwith water andall aqueous 'fractionsjdiscarded.
The semi-crystalline residue obtained during the reaction is then dissolved in the ether and the resulting solution extracted with small portions I dition to the water is too fast the product is oily and washing thereof difficult. The product obtained is filtered with gentle suction and washed five times by suspension in water and vigorous mechanical stirring. The filtrates are yellow and are discarded. After the last washing, the product which is a pale yellow to white powdery solid is filtered as dry as possible and dissolved in six liters of ninety-five per cent ethanol. a
V. 3,11-dihydroxy-12-keto-cholanic acid: To the alcohol solution of the brom-ketones obtained by step-IV, four liters of 2.6 N sodium hyof five percent sulphuric acid-five per cent sodium carbonate and finally thoroughly with water. After drying over sodium sulfate, the ether is distilled off in the usual manner. The crystalline residue obtained may be recrystallized from methanol and melts at about -124-126 C.
III. 3(a) acetoxy '12-keto methyl cholanatez 'ture is allowed to stand with continued stirring for another hour and then about 15'00 cc.'-of water are added slowly whilexstirring is com tinued. The crystalline mass is filtered, washed twice by suspension in water, filtered as dry as, possible and dissolved in ethanol. This requires a large volume of alcohol to effect solution and since the product crystallizes with great ease, the solution must be filtered while very hot. The crystalline product obtained, 3(a) .acetoxy l2- keto methyl cholanate, melts at about 147% 14.9" C. and is sufficiently pure for bromination purposes. I
IV. 3(a) acetoxy 11 brom-l'2-keto methyl cholanate: About 410 grams of the keto ester obtained by step III are dissolved in one liter of stable acetic acid and 295 cc. of 6.8 'N Brz in glacial acetic acid added (1.1 'molesBrz). The mixture is stoppered and set aside at room temperature for "about five days. The reaction solution is next poured slowly from a droppingv funnel into a large quantity of ice cold water'with continued vigorous stirring. If the addition is made slowly and the stirring "is continuous the product'is sandy and easily filtrable. If the addroxide are added with stirring, the bottle stopperedand set aside at room temperature for about twenty-four to thirty hours. It is important that thehydrolysis be conducted at low temperature, i. e. not above about 40 C. If the reaction mixture is heated, the resulting products do not contain (or retain)v the active keto group at carbon 12. After standing, a heavy' precipitate forms; the solution is next chilled overnight at -10 C. and filtered withvgentle suction while still cold. The precipitate is washed twice by suspension in a small volume of ice cold water and dried without heating.v
The precipitate thus obtained, contains. a desired (reactive keto) epimer as an insoluble sodium salt while the filtrate retains for the most part the undesired products as soluble sodium salts. One epimer with a reactive '12-keto group does form a soluble sodium salt. It maybe recovered from the filtrate by crystallization if desired, although as it is present only in small amounts its recovery has generally not been found worthwhile. This diiierence in solubilities of the sodium salts provides (an unusually satisfactory means for separation and recovery of substantially all of the desired product characterized by the reactive keto group.
Additional insoluble sodium salt maybe recovered from the filtrate or reaction mixture by acidifying; the filtrate under -ether, extracting with ether, washing the extract with water, drying the washed extract over sodium sulfate, :distilling on the ether, dissolving the oily residue in ethanol; neutralizing with caustic alkali, diluting with Water and allowing the product to stand at about '10 C. .The insoluble sodium salt obtained as a precipitate'is then washed by suspension in cold water and dried without heating.
VI. Hydrazone of the insoluble sodium salt of 3,11-dihydroxy-12-keto cholanic'acidi About 100 grams of the dried insoluble sodium salt obtained by step V are dissolved in 1400 cc. of absolute ethanol under reflux. To the resulting solution 25, cc. of e 100 per cent hydrazine hydrate are added and refluxing continued for one hour. Approximately two-thirds of the alcohol is then distilled off and the residual solution allowed to crystallize. The mother'liquors from this crop of crystals upon further concentration yield several additional crops ofhydra zone. The hydrazone obtained is quite hygroscopic and should be storedina dessicator. p
VII. Wolff-Kishner reduction of the 3. -dihydroxy-12- keto cholanic acid .hydrazone: About 5 grams of the hydrazone obtained by step VI are introduced into 'a glass or steel bomb tube and cc. of sodium ethylate prepared from 3 grams of sodium added along-with 0.5 .cc. of onehundred per cent hydrazine hydrate. The tube is then cooling, the tube is opened .and the contents rinsed outwith alcohol, water or other solvent.
VIII. Isolation of 3,1l-dihydroxy cholanic acid as the methyl ester: The reaction product obtained by step VII is preferably rinsed from the bomb tube with ninety-five per cent ethanol so that the final volume is one liter of ethanol for each 40 grams of the sodium salt hydrazone reduoed. This solution is heated and neutralized to phenolphthalein with dilute aqueous hydrochloric acid and an additional amount of water sufiicient to bring the volume to two liters added. One liter of 0.3 N barium hydroxide is next added, to the hot aqueous alcohol solution and finally one liter of hot water added slowly with constant stirring. The flask is then stoppcred and allowed to cool overnight. The insoluble barium salt is removed by filtration and the filtrate containing soluble barium salts acidified under ether and extracted twice with fresh portions of ether. The ether solution is washed thoroughly with water,
HO 041150 OOH 1 Esterlfication (MeOH) 1 HO CAHaCOOMe i Acetic aiihydrlde (Pyridine) HO 014E800 OMe AcO OrOa
III 0 1 Br: 3i:
C HgCOOMe AcO Alkali Hydrolysis (NaOH) AcO evaporated to dryness, and traces of water removed from the residue by distilling benzene two or three times from the residue. (The free acid may be isolated from this fraction by acidification with excess hydrochloric acid and filtration.) The oily material is preferably dissolved in dry methanol, a small amount of concentrated sulphuric acid added, and the solution allowed to stand at room temperature for from four to five 0 cimoopiva l ydrazine HzNz C HaO 0 ONa reduction CAHSCO ONa VII Reacidificetion ZCitCOOH v U Esterlflcation (MeOH) VIII CAHlCOOMB 7 Having thus described our invention, what we about 40 C. to form an alkali salt of 3,11-dihydroxy-l2-keto cholanic acid reacting said salt with hydrazine to form the 3,11-dihydrxy-12- hydrazone derivative thereoi and thereafter reducing said l2-hydrazone derivative to form 3,11- clihydroxycho lanic acid.
2. The compound"3,l'l-dihydroxy cholariicacid. 3. A process for the production of 3,11-dih drox 'ch olanic acid which comprises subjecting alkali hydrolysis at a'tempera'ture not above about 40 G. to form an alkali salt of 3,ll'-'dihy'dioily+ 12-k'et6 choianic aciti, reacting-saw salt with hydrazine to form the 3,11-dihylroiZy-l'2-liydrazone derivative thereof and thereafter reducing said 7 12-hydrazone derivative to form 3,=1 '1 olihydroi y cholanic aci'gi.
4. A process for the production of 3,l-l-dihydroxy chol'anio acid whiohoomprises hydroiyzing 3(u)-' acetoxy-l1-brom-12-keto 'me't'h'yl cholonate with sodium hydroxide at'a temperature of about C. to form an insoluble sodium s'alt of 3,11'-dihyciroxy-lZ-keto cholar'ilc acid, reacting said salt with hydrazine to term the 3,1'1-dih'ydroxy-12- hydra'zo'ne derivative thereof, and thereafter re-' ducing said 12hydrazoiie'derivative to form 3,11- uiiiydroxy cholan'ic acid. 7 I
THOMAS E. GALLAGHER. WILLIAM P. LONG.
US541096A 1944-06-19 1944-06-19 Derivatives of the cyclopentanoperhydrophenanthrene series and process of making same Expired - Lifetime US2397656A (en)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2447325A (en) * 1946-06-24 1948-08-17 Research Corp Production of 3,11-oxygenated steroids
US2656363A (en) * 1950-10-30 1953-10-20 Syntex Sa Process for preparing cyclopentanoperhydrophenanthrene derivatives
US2734899A (en) * 1956-02-14 Manufacture of bromevated steroid
US2806849A (en) * 1953-11-25 1957-09-17 Gnrd Patent Holdings Ltd Process for the preparation of steroid substances

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2734899A (en) * 1956-02-14 Manufacture of bromevated steroid
US2447325A (en) * 1946-06-24 1948-08-17 Research Corp Production of 3,11-oxygenated steroids
US2656363A (en) * 1950-10-30 1953-10-20 Syntex Sa Process for preparing cyclopentanoperhydrophenanthrene derivatives
US2806849A (en) * 1953-11-25 1957-09-17 Gnrd Patent Holdings Ltd Process for the preparation of steroid substances

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