US2108646A

US2108646A - Sterine derivatives and process of preparing them

Info

Publication number: US2108646A
Application number: US49644A
Authority: US
Inventors: Bockmuhl Max; Ehrhart Gustav; Ruschig Heinrich
Original assignee: Winthrop Chemical Co Inc
Current assignee: Winthrop Chemical Co Inc
Priority date: 1934-11-17
Filing date: 1935-11-13
Publication date: 1938-02-15
Anticipated expiration: 1955-02-15

Description

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Patented Feb 15 1938 STERE DERHWA'EHWES @F PREPARING 'illiti Max Eocilhi, Gustav Ehrhart, and iillech Ruschig, Franlizidrt on-the-Main-Heehst, i as a y, assianors to Winthrop @hemicail @dlllllilparry, Tina, New York, N. iii, a corporation oi? New York No Drawing,

riali No. taste. in

M matures.

The present invention relates toa process of preparing derivatives of the acids of the general formula: n

' CH2 R-C-COOH Grignards reagent into tertiary alcohols which,

after dehydration, were subjected to an oxidation process.

Now We have found that the lretones may advantageously be produced by decomposing the above named acids according to Curtius' method and transforming the amines thus obtained by oxidation methods into the corresponding ketones.

The process may be carried out by transforming one of these acidsinto the acid halide, par ticularly into the acid chloride, then causing the halide to react with an alkali azidaespecially sodium azide, preferably in an aqueous acetone solution so as to form the corresponding organic azide and transforming the last named product into the isocyanate by heating it. The isocyanate is converted into the amine by one of the usual methods, such as by addition of mineral acid, especially sulfuric acid of, for instance, 60% strength. The amine thus obtained may be treated with oxidizing agents. It the amine is treated with sodium nitrite the corresponding amine nitrite is formed and by heating. the cor responding alcohol is obtained therefrom. By treating the alcohol with oxidizing agents, for instance, with chromic acid or potassium permanganate the alcohol may be transformed into the corresponding ketone.

The new process has proved to be of particular advantage in the treatment of such acids of the above named general formula, in which R stands Application Ncvember it, 1935, Se-

Qermany November i7,

for the tetracyclic ring structure of the sterol series, for instance, of acids of the following formulae Thus, for instance, in fii-hydroxybis-norcholenic acid or 3-acylhydroxy-bis-nor-chclenic acid the side chain may be converted by our new process into the corresponding lretone. In this case the double bond standing in 5.6-position may, if desired, be saturated with bromine and the ketone obtained may be debrominated. If the double bond is saturated with hydrogen in the 3-hydroxy-bis-norcholenic acid or in the 3- acylhydroxy-bis-norcholenic acid, there is obtained according to the new process the corresponding ketone of the cholane series. Accord ing to this process products of the following general formula are obtained.

CH: R -CX in which R stands for the tetracyclic ring structure of the sterine series and X stands for the group -NHs, N=C=O or -H The amines which correspond with the following formulae:

in which Y stands for hydroxyl or acylated hydroxyl in which Y stands for hydroxyl or acylated hydroxyl.

in which Y stands for hydroxyl or acylated hydroxyl are readily soluble in organic solvents, even in petroleum ether, crystallizable in the form of weakly yellowish needles.

The alcohol of the formula:

on. In, /C\CH; H cn= mo B--ccon H3 I c H o n Ah forms white colorless crystals of the melting point of between 179 C. to 0., is difficulty soluble in petroleum ether, readily soluble in alcohol and crystallizable from acetic ester.

The products mentioned are to be used as therapeutics or for the preparation of medicaments.

The following example serves to illustrate our invention, but it is not intended to limit it thereto:

(a) 5 grams of acetoxy-bis-norcholenic M dv are heated in a reflux apparatus for 2 hours in 50 cc. of dry benzene with 15 grams of thionyl chloride. The reaction solution is evaporated to dryness under reduced pressure; the residue is dissolved in 50 cc. of acetone, the solution is cooled to 0 0., and an ice-cooled solution of 1.6 grams of pure sodium azide in 5 cc. of water is then entered gradually drop by drop, while shaking. The acet-bis-norcholenic acid azide-separates in the form of a white-reddish precipitate. In order to complete the precipitation the reaction solution is cooled in a mixture of ice and sodium chloride, the azide is immediately filtered by suction and subsequently washed with cold acetone. The almost dry product is at once taken up in 50 cc. of dry toluene since it easily assumes an oily state when exposed to the air; any entrained sodium chloride and a small quantity of smeary substances remain. The toluene solution is dried over sodium sulfate in an ice-chest for 30 minutes.

(b) The dry toluene. solution is filtered and then gradually heated to boiling. The elimination of nitrogen sets in at 40 C.; the course of the reaction may be observed by collecting the nitrogen in a cylinder. The amount of gas evolved on an average amounts to about 250cc. to 275 cc. After 1 hour the reaction is complete. The reaction solution is evaporated under reduced pressure and the crystalline isocyanate is heated for 3 hours in a reflux apparatus with a mixture of acetic anhydride and glacial acetic acid (60 cc. of anhydride and 15 cc. of glacial acetic acid). The isocyanate may be obtained in a pure form by recrystallizing it twice from petroleum ether. It crystallizes in the form of clustered needles. It is readily soluble in all organic solvents. The yield amounts to 1.75 grams to 2.2 grams. The melting point of the .iso'cyanate is at 103 C., after sintering at 98 C.

Calculated C 74. 8 H 9. 1 N 3. 64 Found C 74.87 H8.8l N3.98

The saponiflcation of the isocyanate can be contains the desired acetylamine which is recrystallized from ethyl acetate. Yields 2.4 grams; point of decomposition 243 C.

Instead of heating the isocyanate in a mixture of acetic anhydride and glacial acetic acid the process may also be carried out as follows: 1.2 gramsof 3-acetoxy-ternorcholenylisocyanate are dissolved in 30 cc. of ether and 30 cc. of benzene and 40 grams of ice-cold sulfuric acid of 60% strength are added which, however, do not mix with the solution, but form the lower layer. The whole is thoroughly stirred at room temperature for 15 minutes, the mixture becoming more and more viscous in consequence of the precipitation of the amine sulfate and finally solidifying to a thick magma. Water is'then added to the mixture and the amine sulfate'is obtained by centrifuging. .The amine sulfate is then dissolved in an alcoholic caustic potash solution of 5% strength, the mixture is diluted with water and shaken with ether. On introduction of hydrogen chloride into the washed and dried ethereal solution the amine hydrochloride precipitates. It readily dissolves in alcohol, is precipitated sparingly on addition of water, but is readily u Iv all

till

precipitated on addition of dilute hydrochloric acid in well formed crystals (prisms). Point of decomposition at about 348 C. Yield 0.88 gram=about 80% of the theoretical.

(c) The 3-acetoxy-bis-norcholenyl acetylamine is deacetylated by boiling it with an alcoholic caustic potash solution of strength. The solution is poured into water, the amine being obtained as a solid precipitate. It is recrystallized from aqueous dioxane. Alternatively, the aqueous alkaline mixture may be shaken with chloroform, the chloroform solution dried with sodium sulfate and the amine precipitated by introduction of hydrogen chloride. It is likewise obtained by taking up the amine hydrochloride in alcoholic caustic potash solution, precipitating the amine with water and recrystalli zing it from aqueous dioxane. Point of decomposition 243.5 C., after previous sintering at 239 C.

CnHuONJ mo] of H10 With the aid of suitable oxidizing agents, such as chromic acid in glacial acetic acid or nitrous acid, the amine is transformed, after protection of its double bond with bromine, in known manner into the corresponding ketone or pregnene diol respectively.

(d) An ethereal solution of 0.8 gram of acetoxy-ternorcholenylamine is shaken with 30 cc. of an ice-cold solution of HNO2 made from 1 gram of NaNO: and 0.5 gram of concentrated sulfuric acid. The amine nitrite is immediately precipitated in the form of flakes and is obtained by centrifuging. The amine nitrite is of good stability, even to air. In order to oxidize the amino group the amine nitrite is suspended in a solution of HNO; which has been prepared from 70 cc. of alcohol, 8 cc. of 2N acetic acid, 20 cc. of water and 1.6 grams of NENOz and cooled to 0 C. The mixture is then gradually heated on a steam bath; at 50 C. the amine nitrite is dissolved; at 55 C. to 60 C. the evolution of nitrogen 'sets in and after 1 hour it is finished (final tem- Derature 75 0.). The solution-is then mixed with water and the colloidal mixture is shaken with ether. On evaporation of the ether the residue amounts to 0.56 gram. It is crystalline and free from nitrogen stances.

For the purpose of separation the residue is heated in a reflux apparatus for 30 minutes in cc. of an alcoholic caustic potash solution of 10% strength and the solution is then poured into ice-.

cold water acidified with dilute sulfuric acid. lf'he colloidal mixture is shaken with ether and the ethereal solution is dried. The residue obtained by evaporating the ether contains the alcohol expected to be produced by the reaction with nitrite and the hydrocarbon obtained by simultaneous elimination of water.

The whole is then dissolved in a small quantity of ethyl acetate and"the solution is mixed with much petroleum ether. The alcohol above mentioned is thus obtained in a well crystalline state. Yield 250 mg. In order to better purify it the alcohol is distilled preferably in a high vacuurn. lit distills at a temperature between 170 C. and 220 C. under a pressure of il.02 mm. The

and consists of two subj formula C21H32O. It is obtained by recrystallization from aqueous alcohol in the form of well crystallized needles. Melting point 120 C.

We claim:

1. The process which comprises transforming into the acid halide a compound of the following general formula:

'RCCOOH in which R stands for a polycyclic hydroaromatic radical of-the sterine series, transforming the acid halide into the azide by causing it to act upon an alkali azide, transforming the azide by heating-it into the isocyanate and saponifying the latter to form the amine and converting said amine into the alcohol.

' 2. The process which comprises transforming.

into the acid halide a compound of the following general formula:

in which R stands for the tetracyclic ring structure of the sterine series, transforming the acid halide into the azide by causing it to act upon an alkali azide, transforming the azide by heating it into the isocyanate and saponifying the latter to form the amine.

8. The process which comprises transforming into the acid halide a compound of the following formula:

transforming the acid halide into the azide by causing it to act upon an alkali azide, transforming the azide by heating it into the isocyahate and saponiiying the latter to form the amine.

5. The process which comprises transforming into the acid halide a compound of the following transforming the acid halide into the azide by causing it to act upon an alkali azide, transforming the azide by heating it into the isocyanate and saponifying the latter to form the amine and transforming the amine into the lretone with the aid of an oxidizing agent.

6. The process which comprises transforming into the acid chloride a compound of the following forinuia:

transforming the acid chloride into the azide by causing it to act upon sodium azide, saponifying the latter with sulfuric acid and transforming the amine thus obtained into the corresponding alcohol by means of nitrous acid and causing chromic acid to act upon said alcohol.

'7. The process which comprises transforming into the acid chloride 2. compound of the follow- 40 ing formula: a

CH; K H;

/C\(|3Ha H /CH: H1O o--oo-oou H: i 45 /H\ /H H mo 0 o o t I a H no 0 o H: 50 transforming the acid chloride into the azide by causing it to act upon sodium azide in aqueous acetone, dissolving the azide in toluene and heating this solution, isolating the isocyanate, saponifying the latter with sulfuric acid of 60% strength and transforming the aminethus obtained into the corresponding alcohol by means of nitrous acid. and causing chromic acid to act upon said alcohol.

60 8. The process which comprises transforming into the acid halide a compound of the following formula:

65 mo o---o-ccoon transforming the acid halide into the azide by causing it to act upon an alkali azide, transforming the-azide byheating it-into thelsocyanate and saponifying the latter to form the amine and transforming the amine into the ketone with the aid of an oxidizing agent.

9. The process which comprises transforming in the acid chloride a compound of the following formula:

transforming the acid chloride into the azide by causing it to act with sodium azide, saponifying the latter with sulfuric acid and transforming the amine thus obtained into the corresponding alcohol by meansof nitrous acid and causing chromic acid to act upon said alcohol.

10. The process which comprises transforming into the acid chloride a compound of the following formula:

CH; H:

ture of the sterine series and X is a memberof the group consisting of -NH:, N=C=O and -OH.

12. As new products the compounds of the following general formula:

in which Y is a member of the group consisting of lnvdroxyl and acyloxy; said products being soluble in organic solvents, capable of being precipitated with nitrous acid while forming a, salt stable at the air, capable of being easily precipltated in the form of their hydrochlorides from an alcoholic solution with the aid of mineral acids to form'colorless crystals.

18. As new products the compounds of the following general formula:

v in which Y stands for hydroxyl or an ac yloxy 14. As a new product the compound of the following formula:

on m

said product forming white colorless crystals of the melting point 01 between 179 C. to 180 0., diflicultly soluble in petroleum ether, readily soluble in alcohol and crystalliz'abl from acetic ester.

MAX BOCKMUHL. aus'mv EHRHART. mammen 'RUSCHIG.