US2445006A - Steroid keto hydroxy acids and their polybasic acid esters and method of preparing same - Google Patents
Steroid keto hydroxy acids and their polybasic acid esters and method of preparing same Download PDFInfo
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- US2445006A US2445006A US459828A US45982842A US2445006A US 2445006 A US2445006 A US 2445006A US 459828 A US459828 A US 459828A US 45982842 A US45982842 A US 45982842A US 2445006 A US2445006 A US 2445006A
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- acid
- keto
- hydroxy
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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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J3/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by one carbon atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J75/00—Processes for the preparation of steroids in general
Definitions
- the present invention relates to the manufacture of keto hydroxy acids .of the steroid series, and of their partial polybasic organic acid esters, and more particularly to the production of 3- hydroxy-l2-keto-etio cholanic acid and its.
- partial or half esters may be used as such, or may be dissolved in an alkali, preferably in the presence of an alcohol such as methanol or ethanol and heated at about 80 C. for two hours to saponify the partial esters by splitting off the polycarboxylic acid residue.
- an alcohol such as methanol or ethanol
- the free 3-hydroxy-12-keto cholanic acid or its lower homologues can be isolated.
- These lower homologues as well as their esters are new compounds and represent valuable intermediates for the manufacture of valuable therapeutic products.
- These acids may, by treatment with acylating agents, be acylated in the S-hydroxy group.
- acylating agents By boiling for example with acetic anhydride, or by treatment of the pyridine solution with acetyl chloride or acetic anhydride, the 3-acetoxy 12- keto cholanic acid may be obtained in the usual way.
- the propionate, butyrate, benzoate and other 3-esters can be prepared.
- oxidation with chromic acid with or without the addition of sulfuric acid, has proved tobe highly satisfactory
- other suitable oxidizing agents may be employed, for example, alkali permanganate in acetic acid solution or concentrated nitric acid.
- those polybasic acids may be used which form chlorides or simple anhydrides.
- acylating agents there may be employed malelc and fumaric anhydrides.
- Process for the manufacture of 12-xeto steroid compounds which comprises reacting a 3,12-dihydroxy steroid compound having in the I'Z-position a non-oxidizable group. with a mem- 5 her of the group consisting oi the anhydrides and chlorides of a polybasic organic acid to form the 3-partial ester, and thereafter oxidizing the secondary alcohol group in the iii-position to a hate group.
- Z is a radical of the group consisting of -COO ber of the group consisting of the anhydrides and chlorides of a polybasic organic acid to form the 3-partial ester, and thereafter oxidizing the secondary alcohol group in the 12-position to a keto group.
- R is a succinyl radical
- Process for the manufacture of steroid keto acids which comprises reacting a 3,12-dihydroxy cholanic acid and a suillcient amount of a member of the group consisting of the anhydrides and u chlorides of a polyhaslc organic acid to form the 3-partial ester, thereafter oxidizing the secondary alcohol group in the 12-position to a keto group, and saponifying the product to restore the 3- hydroxyl group.
Description
Patented July 13, 1948 s PATENT OFFICE STEROID KETO HYDROXY ACIDS AND THEIR POLYBASIC ACID ESTERS AND METHOD OF PREPARING SAME Erwin Schwenk, Montelair, N. 1., asslgnor to sobering Corporation, Bloomfield, N. J., a corporatlon of New Jersey A No Drawing. Application September 26, 1942, Serial N0. 459,828
15 Claims.
The present invention relates to the manufacture of keto hydroxy acids .of the steroid series, and of their partial polybasic organic acid esters, and more particularly to the production of 3- hydroxy-l2-keto-etio cholanic acid and its.
homologues, and the said esters of such acids.
It is known to prepare 3-hydroxy 12-keto cholanic acid by the oxidation of desoxycholic acid. The method consists in dissolving desoxycholic acid in glacial acetic acid whereby the 3- hydroxy group is acetylated, after which the addition of a chromic acid solution at low temperature will oxidize the remaining free hydroxy group in 12-positlon. However, the yields in this procedure are variable and not more than about 50% of the theory. This is apparently due to the fact that the acetylation of the acid is only partial, which causes the formation of a mixture of products from which the isolation of the desired 3-hydroxy 12-keto acid is diflicult and only possible with low yields, especially if carried out with larger amounts of material. This method gives even less favorable results when used for the preparation of the lower homologues of desoxycholic acid, with a shorter side chain, corresponding to the general formula:
CHI
CH: [a 10001?! cm H-(CHa), a
It is the general object of the present invention to provide an improved process for the manufacture of acids of the type represented by the above formula and also of the corresponding 3- hydroxy-12-keto cholanic acid.
I have found that improved yields of the above acids can be obtained if, prior to the oxidation, desoxycholic acid or its lower homologues or degradation products are first converted into the partial ester of a polybasic organic acid and especially of a dicarboxylic acid like phthalic or succinic acid as by reaction with the anhydride of such acid. This reaction is practically quantitative and involves only a relatively simple procedure. The so obtained partial or half esters of the polycarboxylic acids are then oxidized in any suitable manner as by means '0! chromic acid, and the reaction products, the partial or half esters of the 3-hydroxy-12-keto-acids, may then be isolated by precipitation on ice, sodium bisulfite being suitably employed to decompose excess oxidizing agents. These partial or half esters may be used as such, or may be dissolved in an alkali, preferably in the presence of an alcohol such as methanol or ethanol and heated at about 80 C. for two hours to saponify the partial esters by splitting off the polycarboxylic acid residue. By precipitation with mineral acids, the free 3-hydroxy-12-keto cholanic acid or its lower homologues can be isolated. These lower homologues as well as their esters are new compounds and represent valuable intermediates for the manufacture of valuable therapeutic products. Thus the 3 -hydroxy-12-keto-etio cholanic acid (:t=0 in the above formula) can be employed in the synthesis of certain naturally occurring hormones of the adrenal cortex.
These acids may, by treatment with acylating agents, be acylated in the S-hydroxy group. By boiling for example with acetic anhydride, or by treatment of the pyridine solution with acetyl chloride or acetic anhydride, the 3-acetoxy 12- keto cholanic acid may be obtained in the usual way. In similar fashion the propionate, butyrate, benzoate and other 3-esters can be prepared.
The following examples set forth the invention 5 in greater detail and by way of illustration:
ExAMPLr: 1.PREPARATION or 3-HYDROXY 12-Karo CHOLANIO A010 0 A. 3 (acid) succinate of desoxycholic acid 13 grams of succinic anhydride were dissolved in 50 cc. of anhydrous pyridine by warming. The solution was cooled to room temperature and 5 grams of desoxycholic acid were added. The reaction mixture was allowed to stand overnight and then poured into a mixture of 25 cc. H280. and ice water. 5.7 grams of'the succinate were obtained. A small amount was recrystallized from dilute CHaOI-I after treatment with charcoal for analysis.
CaHuOc, M. Wt. 492. M. P. 231-232 C.: Calc., C 68225; H 8.94%. Found C 67.98; H 8.79%.
Saponification equivalent-- Rotation-a=+51.5
B. Oxidation and saponification 5.7 grams of the succinate were dissolved in 125 cc. of acetic acid and an aqueous solution of 1.13 grams CrOa (1V O) in 5 cc. water was added to the cold solution. The mixture was allowed to stand at room temperature for 5 hours and then poured into 1250 cc. of ice water and a little bisulfite. The mixture was chilled overnight and then filtered. The 3-acid succinyl l2- ,keto cholanic acid was saponified by heating on C. Oxidation using nitric acid 6.8 grams of the succinate were added slowly with stirring to a mixture of 55.5 cc. nitric acid (specific gravity'1.5) and 42 cc. acetic acid at a temperature of 5 C. The stirring and cooling were continued for 1 hours and then the mixture was poured into ice water. The mixture was filtered and the 3-acid succinyl 12-keto cholanic acid was saponified by heating on steam bath in aqueous alkali for 2-3 hours. The alkaline solution was acidified with HCl. The 3-hydroxy 12- keto cholanic acid was recrystallized from dilute acetone.
5 grams M. P. 164-165". .Acetyl derivative M, P. 197-198 C. (Wintersteiner 197/8 C.)
Rotation a=112.3.
EXAMPLE 2.-PREPARATION P 3-HYDROXY 12-Knr0- NOR-CHOLANIC Acrn A. 3 (acid) succinate of nor-desoxycholic acid grams of nor-desoxycholic acid, 13.0 grams of succinic anhydride and 50 cc -of anhydrous pyridine were allowed to stand overnight. The reaction mixture was then poured into 25 cc. H2804 and ice water and the succinate filtered and dried. The substance was recrystallized from ether plus petrolether.
Yield-5.8 grams (90%). M. P. IMP-242 C.
Rotation a=+54.8.
Analysis: Ca'zH4207, 03.10., 67.74 C.; 8.84: H. Found, 67.54 C.; 9.06 H.
B. Oxidation and sapom'flcatz'on 4 Rotation =+69.7. Analysis: Cal-1x04. M. Wt. 376: Calc. C 73.35%: H 9.65%. Found C 73.47%: H 9.70%. Acetyl derivative M. P. 20'1.8-209.5 0."
Exam 3.Purl\aArIon or 3-HYDROXY 12-Klro- B -N -ca umc i A. 3 (acid) succinate o] bis-nor-des oz ilchlolic acid The succinate was made in the same way as for desoxycholic acid. The charge was 5 grams of bis-nor-desoxycholic acid, 12.5 grams of succinic anhydride and 50 cc. of anhydrous pyridine. The yield was 5.9 grams, M. P. 234-235 C. after recrystallization from ether plus petrolether.
Rotation a=+33.9.
Analysis: Casi-14001, Calc. C 67.19; H 8.68. Found C 67.00; H 9.00.
B. Oxidation and saponiflcat'ion EXAMPLE Ir-PREPARATION or 3-HYDROXY 12-Knro Errocnouuuc Am A. Succination 200 mg. of etio-desoxycholic acid were added to a cold solution of 525 mg. of succinic anhydride in 2.5 cc. of pyridine (anhydrous). The reaction was allowed to stand overnight at room temperature. heated for 1 hour on the steam bath and then poured into ice and H2804. The mixture was extracted with ether and theether extract dried and evaporated. M. P, 161-169 C.
B. Oxidation and saponification The 3 (acid) succinate of etio-desoxycholic acid was dissolved in 5 cc. acetic acid, cooled, and an aqueous solution of 57.5 mg. CrOa (1 /2 0) was added. After 5 hours at room temperature, the reaction was poured into ice water and bisulfite and chilled. The mixture was extracted with ether and the ether residue was saponified in aqueous alkali. mg. of 3-hydroxy 12-keto etiocholanic acid were obtained. M. P. 210-212 C. This material was dissolved in acetone and water added until turbid. The acetone was evaporated on under a funnel and the material crystallized in long needles. It was then recrystallized from acetone and ligroin. M. P. 213-215 C,
Analysis: Gaol-b004, Calc. 071.80%; H 9.04%. Found C 71.60%; H 9.23%. a(dioxam)=+127.2.
Acetyl derivative M. P. 205-206".
While oxidation with chromic acid, with or without the addition of sulfuric acid, has proved tobe highly satisfactory, other suitable oxidizing agents may be employed, for example, alkali permanganate in acetic acid solution or concentrated nitric acid.
Instead of the anhydrides oi the acids employed to protect the 3-hydroxyl group there may, in
certain instances, be employed the chlorides. In
general. those polybasic acids may be used which form chlorides or simple anhydrides. In addition to the acylating agents disclosed hereinabove, there may be employed malelc and fumaric anhydrides.
I claim! 1 1. succinic acid half-esters of a hydroxy ketoacid of the general formula on- 0 on,
11. Process for the manufacture of 12-xeto steroid compounds. which comprises reacting a 3,12-dihydroxy steroid compound having in the I'Z-position a non-oxidizable group. with a mem- 5 her of the group consisting oi the anhydrides and chlorides of a polybasic organic acid to form the 3-partial ester, and thereafter oxidizing the secondary alcohol group in the iii-position to a hate group. 10 12. A steroid compound of the formula on. on.
wherein Z is a radical of the group consisting of -COO ber of the group consisting of the anhydrides and chlorides of a polybasic organic acid to form the 3-partial ester, and thereafter oxidizing the secondary alcohol group in the 12-position to a keto group.
'1. Process according to claim 6 wherein the acylating agent is succinic anhydride.
8. Process according to claim 6 wherein the starting steroid acid is etio desoxycholic acid.
9. Process according to claim 6 wherein the starting steroid acid is bis-nor-desoxycholic acid.
10. Process according toclaim 6 wherein the starting steroid acid is desoxycholic acid.
50 wherein R is a succinyl radical.
13. Process for the manufacture of steroid keto acids which comprises reacting a 3,12-dihydroxy cholanic acid and a suillcient amount of a member of the group consisting of the anhydrides and u chlorides of a polyhaslc organic acid to form the 3-partial ester, thereafter oxidizing the secondary alcohol group in the 12-position to a keto group, and saponifying the product to restore the 3- hydroxyl group.
14. Process according to claim 13, wherein the acylating agent is succinic anhydride.
15. Process according to claim 13, wherein the starting steroid acid is etio-desoxycholic acid.
ERWIN SCHWENK.
REFERENCES CITED The following references are of record in the flle of this patent:
Hoehn. "Jour. Am. Chem. 300.," vol. 62, pages 569-570 (1940).
Marker, Jour. Am. Chem. Soc, vol. 60, pages 1334-1337 (1938).
4 1 Certificate of Correction Patent No. 2,445,006.
' ERWIN SCHWENK It is hereby certified thaterror appears in the printed specification of the-above numbered patent requiring correction as follows: Column 5, claim 1, for that portion of the formula reading read and that the said Letters Patent should beread vrith this correction therein that the same may conform to the record of the case in the Patent Oflice.
- Signed and sealed this 14th of September, A. D.-1948.
THOMAS F. MURPHY,
Assistant Commissioner of Patcntc;
July 1a, 1948.
Priority Applications (1)
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US459828A US2445006A (en) | 1942-09-26 | 1942-09-26 | Steroid keto hydroxy acids and their polybasic acid esters and method of preparing same |
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US459828A US2445006A (en) | 1942-09-26 | 1942-09-26 | Steroid keto hydroxy acids and their polybasic acid esters and method of preparing same |
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2607815A1 (en) * | 1986-12-05 | 1988-06-10 | Roussel Uclaf | NOVEL STEROID PRODUCTS COMPRISING, IN POSITION 23, A CETONIC RADICAL, THE PROCESS FOR PREPARING THEM, THEIR APPLICATION TO THE PREPARATION OF PRODUCTS OF THE 20-CETOPREGNANES SERIES AND THE INTERMEDIATES OF THIS ASSOCIATION |
-
1942
- 1942-09-26 US US459828A patent/US2445006A/en not_active Expired - Lifetime
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None * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2607815A1 (en) * | 1986-12-05 | 1988-06-10 | Roussel Uclaf | NOVEL STEROID PRODUCTS COMPRISING, IN POSITION 23, A CETONIC RADICAL, THE PROCESS FOR PREPARING THEM, THEIR APPLICATION TO THE PREPARATION OF PRODUCTS OF THE 20-CETOPREGNANES SERIES AND THE INTERMEDIATES OF THIS ASSOCIATION |
EP0275729B1 (en) * | 1986-12-05 | 1991-05-08 | Roussel-Uclaf | Steroids containing a keto group at position 23, their preparation, their use in the preparation of compounds of the 20-keto-pregnane series, and intermediates of this use |
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