US2369065A - Halosteroids and preparation of the same - Google Patents

Description

Patented Feb. 6, 1945 UNITED STATES PATENT- o escapes" THE SAME I v Russell: Earl Marker, State College, Pa, and Harry M Crooks, In, Detroit, Mich., assignors to Parke, Davis &' Com corporation of; Michigan Application September 4, 1941, Serial No. 409,590

N" Drawing,

pany, Detroit, Mich*., a

18 Claims. (Cl. 260-397.3)

This invention relates to halosteroids and preparation of the same.

More particularly this invention relates to halosteroids which are useful as intermediates for the preparation of androst'ane derivatives.

The terms androstane and pregnane as used in this specification and in the appended claims are to be understood as comprehending steroids of 19 and 21 carbon atoms respectively, regardless of the particular stereo-chemical configuration in the nucleus. For example, the term androstane compound isto be understood to include compounds having the allo-" configuration at C suchv as androsterone, or steroids having the regular configuration at C: such as etio-cholanol-3 (,3) -one-17, as well as ring-unsaturated steroids such as testosterone.

It has now been found that ZO-ketO-pregnane compounds having in ring. D the structure are surprisingly readily halogenated, that is to say, chlorinated or brominat'ed'. It has been found that this halogenati'on proceeds readily at moderate temperatures and indeed the first'ha'l'ogen atom, which becomes attached to (3-17 can be introduced at room temperature. A second, halogen atom, which becomes attachedto 0-21, can also be introduced at moderate temperatures, best above 30 0'. Much higher temperatures than approximately 100 0. should be avoided because the new halosteroids are somewhat prone to thermal decomposition. it has also been found that the halogenation may be controlled to proceed stepwise, with intermediate formation of the 17-halo-20-keto-pregnane compounrL'or the two steps may be effected simultaneously, with direct production of the 17,2i-dihalo keto-pregnanecompoundl v The halogenation is best conducted in the presence of a' solvent inert to elementary chlorineor bromine. Such solvents include the liquid lower organic acids, such as acetic acid, propionic acid, etc., halohydrocarbons, such as carbon less of the nature of'the' 'suiistitcents or groupings in rings A, B and C.

This does nct imply, however, that rings A, B

' have added halogen at the double bond as well as is have u substituted halogen in the grouping attached to ring D. may be iuustrateu as follows in the case of s pregnen'oi-s-(pw 2(i'acetatez'. ,1 v j orne -o 1 5,. 6, 17, 2l-tetrabronio-pregnanol-3(pique-20 acetate. A variant oi the above illustration consists first in saturating the ring double bond of the nuclearly unsaturated '20-keto-pregnane compound with halogen, or evenwith hydrogen halide, and

then reacting with halogen, for example, as

follows:

. A'x esnee lsww i? e e e.

iii-ma ma;

5-chlorppregnanol-3(B)-one-20 benzoate to-carbon double bonds in rings A, B and C at the same time that halogenation occurs at ring D,

compounds which are halogenated at ring Dian'd'.

which also have a ring A, B or C double bond cannot be directly obtained by halogenation, but 5 must be. obtained by a, combination of reactions. As an illustration, A -pregneno1-3(,B)-0ne-20 can be brominated in an inert solvent such as car bon tetrachloride, the; 5,6,17,21 tetrabromopregnano1-3(,8)on--20" thus obtained oxidized with chromic acid in acetic acid at room temperature to give 5,6,17,2-1-tetrabromo pregnandione-3-2O and the lattertreated with 2 moles of potassium iodide in boiling alcohol to obtain 17,21 dibromo ,A -pre 'gnenedione 3,20 of formula: i.

17,21-dibromc A pregfienedione-iiflfl As nth pfseae'e of nuclear lretone groups in the zo-ketd-pregnanecompound being halo= genated may result'in nuclear halogenation at methylene groups adjacent to the nuclear ketone grouping. Thus, pregnanedione-3,20 on chlo- ,rination yields a mixture of chloro-pregnane- 5 diones containing from one to four chlorine 1 atom at positions 2, ,4, l7 and 21; the order of substitution being in the main 4, 17, 21 and 2 in I the regular and 2, 1'7, 21 and. 4 in the allo series. The same order of halogenation occurs in both series when trihalogenating or dihalogenating. When dihalogenating, for example, the main reaction inlthe-regular series appears to go as illustrated by the following:

I CH3 CI Ia CH3 (|J 0 Pregnanedione-mo lClr-HdAO I t 6 CH3 CH3 -(|J=0 0" yv C1 bon-to-carbon double bond or a ketonegrouping may result in the halogen attacking at these groupings, practically all other groupings remain unaffected by thehalogen; Halogen atom'or ester groupings in rings A; B'or Q remain unaffected, duringthe halogenation. It the halogenation is conducted in a liquid lower organic acid, such as O acetic acid, hydroxyligroups in the nucleus may. be esterified by the catalytic action of the hydro-, halic acid formed as a'by-product during the halogenation. This is illustrated in Example 7A. ,The reactions of the l7-bromo-20-keto-pregnane compounds are summarized in the diagram below. 7

l CH3 CH; (l1 0 (EH: o o w D Reducing agent I-- 4 CH3 CHI" =O CO OHj D i D I OH:

As the above diagram indicates the I'I-bromor ZO- keto pregnane' compounds are' readily reduced to 20-keto-pre'gnane compounds'bynumer need-oat ing diagram.

on, cm i on: CH; lv o=o err-.011 D Br Nit-Eton Amalgamated Zn \Ij Br and H01 The action or dehydrohalogenating agents on 17-bromo-20-keto-pregnane compounds leads to A -unsaturated 20-ke'to-pregnane compounds. Dehydrohalogenating agents suitable for this punpo'se include the com'bination of an Organic-acid and an inorganic salt or an organic acid, also a tertiary base. It has-been found that potassium acetate and acetic acid, sodium acetateacetic acid and also pyridine are 'particularlysatisfac- 'tory dehydrohalogenating agents, but of course other substances may be used such as sodium benzoate in valeric acid, dimethylanili-ne, 'quinoline, triethanolamine.,:etc.

I The action of alkaline agents on a 17- bromo- 'Z'O ketO-pregnane compound leads to molecular rearrangement with the formation of a 17- methyl-etimcholanie acid or a derivative of the carb'oixyl group thereof. For example, if 17- -bromo-allo-pregnanone-20 is refluxed with methanolic potassium bicarbonate, there is obtained the methyl ester of l'7-methyl-etio-allochola-nic acid, as illustrated below.

CH CH3 Methyl 17-methyl-etio-allo-cholanate The new esters of the type of methyl 1'?- methyl-etio-allo-cholanate are very resistant to l;

hydrolysis which mayaccountin tor-the surprising result-that an ester iszobtained iroma reaction-which would ordinarily vhe expected to yield a hydrolyzed product. The reaction mechanism :is :obscure', but it appears that the (nature of the product is "determined ,by the nature of thesolv'en't employed. For example, if 'ethanolic sodium bicarbonate, instead of methanolic bicarbonate, is reacted with i l-promo-alloepregnanol 20, :the nrpro-duct is cholanate. l a 1 As has already been indicated, the 17,-bromo- ZO-keto-pregnane compounds maybe further halogenated, thereby forming ;17,21-:dihalo-20- .keto-epregnane compounds; By using, for the sec.- ond step of halogenation, a halogendifierent from that alreadypresent at 0-17 a mixed '1 ,;21-

dihalo-20-keto-pregnane compound. can be obtained. Thus 17--chlor o-al1o-pregnanone-20may be brominatedat 35 C. with formationofl'lchloro-Z'l-bromo-a1lo-pregnanone-20.

The reactions of the 17,21-dihalo20-ketopregnane compounds are summarized in the following diagram:

OHZX CH; CHaX C=() CH3 o Dehydrohalogenating D I X agent N D l Reducing i agent Strong alkali on; coon CH3 (3 0 8 (I) H D D As the above diagram shows, the reactions of the 17,21-dihalo-20-keto-pregnane compounds are somewhat analogous to the reactions of the 17 halo'-20-keto-pregnane compounds. Thus both classes of compounds are reduced with formation of 20-keto-pregnane compounds, both classes of compounds can be dehydrohalogenated with formation of unsaturated "steroids and-both classes of compounds undergo molecular rearrangement when treated with alkaline agents.

The remarks that have been made as to the type of reagents useful in "reactions with 17-ha1opregnane compounds apply also in the case of 7 can be effected 'by reagents such as zinc and acetic acid, iron and acetic acid, or catalytic hydrogenation in the presence of palladium and pyridine, or more generally by, (a) the combination of a metal and a substance reactive therewith to form nascent hydrogen and (b) catalytic hydrogenation in the presence of palladium and a tertiary amine. It ,hasalso beenfound that the combination of formic acid and a salt thereof is a satisfactory reducing agent for this reaction.

' The:dehydrohalogenation of 17,2l-dihalo 2dketo-pregnane compounds to, 21 -,halo-A -unsaturated ZO-keto-pregnane compounds can be affected by reagents such-as potassium acetate and acetic acid;

The treatment of a 17,21-dihalo-20 keto-preg fnane compound with strong alkali' leads to the formation o-ia zi zl-pregnenoic acid-era derive:-

tive at the'carboxyl' group thereof. The reaction is best conducted in 'an alcoholic solution using a large excess of strong alkali. Under these conditions there is formed, along with free A -21- pregnenoic acid; a quantity of the ester thereof withthe alcohol used as'a solvent. For example, methanolie potassium hydroxide and 17,21-dibromo-allo-pregnanone-20 yield A -2l-allo-pregnenoic acid together with some methyl A -21- allo-pregnenoate. If the reaction is conducted in ethanol or propanol there is obtained, instead of the methyl ester, the ethyl ester or the propyl ester, respectively. Other strong bases may be used instead of potassium hydroxide, such as bases including sodium hydroxide, sodium ethylate,

potassium methylate, etc.

It will be appreciated that this invention comprehends several new classes of steroids, of which an important group consists of compounds of the formula CHa . l X WY Y VXX v and compounds of the formula CH: CH;

and A represents a carbon-to-carbon double bond included between C5 and one of C4 and Ca.

ingi'pointi of1iallo-preghanone-20, M; P. ..132f, by twenty degrees.

" Anal. 03.1011. for CzrHaaOBr: C, 66.2;."I-I,,8.7. Found: C, 65.8; H; 8.8.

B. 17,21.-dibromo-allo-pregna.none-20. To 500 mg. of17-bromo-allo-pregnanone-20 in 35 cc. of glacial acetic acid is added at '35" .C.- 2 drops of 45% aqueous hydrobromic acid and 1.3. cc. of 1.0 M. bromine in acetic acid. After standing for one hour the solution is diluted with water,

filtered, and the solid washed with water. Crystallization from acetone yields a product melt ing at 128-130 C. This is 17,21-dibromo-allopregnanone-20. I 1

Anal. calcd. for C21H32OBr2-3 Found: C, 54.8; H, 7.0.

Example 2 c, 55.0 I-I, 6.6.

, mine. The solution is allowed to stand for thirty Thisinvention may be further illustrated by the following examples.

Example 1 A.17-bromo-allo pregnanone-20.To a. solution of 10 g. of a11o-pregnanone-20 in 200 .cc. of

glacial acetic acid is added 10' drops of concentrated hydrobromic acid and 33.2 cc. of a 1 M. (-1 molar) solution of bro-mine in acetic acid. After standing fifteen minutes thesolution is minutes, then poured into 500 cc. ofv ice-water and filtered. The .rathergummy precipitate is taken up in ether, washed with water and saturated sodium bicarbonate solution and the ether-evaporated. The residue is crystallized from acetone to give 17,21-dibromo-allo-pregnanone-20, M. P. 128-30 C. This gives a depression when mixed with a sample of either 17-bromo-allo-pregnanone-20, M. P. 12 7 C. or allo-pregnanone-ZO, M, P. 132C.

Example 3 A. 17-bromo-alZo-pregnandZ-3(o) -one-20.To a solution of 17 g. of allo-pregnanol-3(,3) -onee20 in 1 liter of acetic acid is addedat room temperature, dropwise, 54 cc. of a 1 M. solution of bromine in acetic acid. The solution is allowed to stand ten minutes, and then 1 liter of Water is added. The gummy precipitate is collected, taken up in-ether, the ethereal layer washed well with water, and then evaporated. The residue is crystallized from aqueous methanol and from ether-pentane. The product, 17-bromo-allopregnanol-3(,3) -one-20, has M. P. 93-96 C.

Anal. calcd. for Gail-11330231: C, 63.5; H, 8.4. Found: C, 63.6; H, 8.1. B. 17,21 dibromo-aZlmpregnanoZ-B(p)-one-20 acetate.To a solution'of 18 g. of 1'7-bromoallo-pregnanol-3(;3)-one-20 in 1 liter of acetic acid is added, at 40 C. one equivalent of a 1 M. solution of bromine in acetic acid. After the bromine has reacted, the solution is diluted with water and the precipitate is taken up in ether.

} The ethereal layer is Washed with water, dilute poured into water, extracted with ether and the ethereal extract washed free of acetic acid with water and dilute sodium carbonate 'soluti'on. Evaporation of the ether gives a residue which is crystallized from ether-methanol and acetone to give crystals, M. P, 127-9 C., of l'l-bromo-allo- 'pregnanone-20. This product depresses the meltsodium carbonate solution, and finally with water. The ether is removed and the residue is crystallized from methanol. The purified 17,21- dibromo-allo-pregnanol-3( 3) -one-20 acetate has M. P. 174 C.

The esterification of the 3-OI-I during the reaction is probably due to the catalytic effect of the hydrogen bromide present."

7 Example 4 I A. 17-bromo-2Jreghanol-3Q3) -one-20 acetate-- A solution of 5 g. of pregnanol-3(o)-one-20 acetate and twodrops of 48% hydrobromic acid in aacaocs tallized from methanol to give compact White crystals of 17 bromo pregnanol e 3(5) -one-20 acetate of M. P. 1524 54 C.

Anal. calcd. for C23H3503BI'Z C, 62.9; H, 8.0.

Found: C, 63.0; H, 7.8.

Example 5 A. 17 bromo pregnanoZ-Mo) -one-20.To a solution of 1.0 g. of pregnanol-3(p).'-one-20 in 50 cc. of glacial acetic acid at=25 C. is added 2 drops at 48% hydrobromic acid. Then 3.13 cc. of a 1 M. solution of bromine in acetic acid is added slowly. After the bromine is all absorbed, the mixture is poured into water and the precipitated solid collected and washed with water. The product is crystallized from ether to give compact white crystals of 17-bromo-pregnanol- 3(3) -ne-20 of M. P. 169171 C.

Anal. calcd. for C21H33O2Br: C, 63.5; H, 8.4. Found: C, 63.1; H, 8.3.

Example 6 A. 17,21-dibromo-pregnanoi-3(;3) -one-20 acetate.-A solution of g. or pregnanol-MB) -one'- acetate in 150 cc. of glacial acetic acid contalning 2' drops of 48% hydrobromic acid is warmed to 40 C. and then 29 cc. of 1 M. bromine in acetic acid is added dropwise. After the solution has stood for fifteen minutes it is .poured into water and the precipitated solid collected and washed with water. The solid is recrystallized from acetone to-give. white crystals of 17,21- dibromo-pregnanol-Mpi-one-20 acetate of M. P. 190-191 c. p

Anal. calcd. for C23H 4O:Br2: G, 53.3; H, 6.6. Found: C, 52.9; Bi, 6.7.

Example 7 A. 17,21 -dibromo-pregnanol-3 e) -0ne-20.-T0

a solution of 10 g. of pregnanol-3(e)-one20 in '300 cc. of glacial acetic acid at 40 C. is added several drops of 48% hydrobromic acid. Then 626 cc. of 1 M. bromine in acetic acid: is added dropwise. After the addition of bromine is completed, the solution is poured into water and the precipitated solid collected and washed with water. The solid is crystallized from ether to give thick white needles of 17,21-dibromo-pregnanol-3(5)-one-20 of M. P. 190-192 C.

Example 8 17-chloro 1 allo pregflanol-Mfi) -one'-20 ace- 5,6,17,21-tetrabromo-pregnanol-3to) cne-20' ace:

tate.- A 1% solution of chlorine iii-chloroform standardized by titration of the available chlorine, for example with potassium iodide and StfilGFl.

To a solution of 1 g. or alio-pregiiasol-smh one-20 acetate in 30cc. of acetic acid at 30 C. is added 10 cc. of an accurately standardized 1% solution of chlorine in chloroform. After the mixture has stood for an hour it is diluted with water and extracted with ether. The ethereal extract is washed with sodium bicarbonate solution and with water and then the extract is evaporated on a steam bath. The residue is 1'7 chlordane-pregnan ies(c) r ced acetate. it may be purified by crystallization from dilute acetone.

Example 10 A. 5,6,17,21-tetrabromo pregnanol-Mm-one- 20 acetata-To a solution of 10 g. of A -pregnenol-3(e) -one'20 acetate in 200 cc. of acetic acid is added 28.5 do. of a 1 M. solution ofbromine in acetic acid. Thil a few drops of 43% hydro bromic acid are added, followed by an additional 57' cc. of 1 M. bromine in acetic acid. The Solution is warmed to C. to insure complete" reaction and then the mixture is allowed to stand at room temperature. which has deposited is collected and washed with ether. This is 5,6,17,2l -tetrabromo-pregnanol- 303) -one-20 acetate of M. P. 172 C. dec.

Anal. calcd. for C23H32O3Br: C, 4028; H, 4.8. Found: C, 40.6; H, 4.8. v u

Bromi-nation or A -pregnenol-3;(fl )=one-20 by the same procedurev gives the same product.

tate.

B. 17,21 -dibromo d pregnenol-Mpl-one-ZO acetate-A solution of'4.36 g. of sodium iodid in 40 100 cc. of alcohol is added to a boiling solution of 10 g. of 5,6,17,21-tetrabromo-pregnanol-3(p)- one-20 acetate in 1500 cc. of ethanol and the mixture boiled for an hour. Then water is added and the mixture is extracted withetner. ethereal extract is washed with dilute sodium bicarbonate solutioriaiid with water and theii'tl'ie ether is removed on the steam bath. The residue is 17,21-dibromo-A pregnenol-3( 3)-one-20 acetate. It may be purified by crystallization from dilute acetone. However, this is unnecessary if the substance is to be used in the next step.

Example 11 A. aainzi-tet biomo Mahatma-i 20 pmpionata-To a solution of 0.60 g. of- A pregnenol ile) -one-20 in 1 0-oc of propionic acid is added 5137 cc.-oi' a 1 solutionof bromine in neno1=-3(e --one--20- propionate is treated with Bromine in the manner described' abdve. A

While this invention has been destined and illustrated with especial reference to certain forms of the invention, and these forms have been explained in terms of a particular theory, it is to be understood that this invention is not limited to these specific forms, nor is its operability in any way affected by the ultimate cor- After several hours the solid rectness of the particular theories herein employed.

What we claim as our invention is: 1. Process for the preparation of a halosteroidn having at ring D the structure CHzX where X is a member of the class consisting of chlorine and bromine which comprises reacting a steroid having at ring D the structure D 1 I with a member of the class consisting of chlorine and bromine.

2. Process for the preparation of a halosteroid.

having at ring D the structure 'cmx' CH3 O where X and X are members of the class consisting of chlorine and bromine which comprises reacting, under relatively mild conditions, a steroid having at ring D the structure CH2 CH4 l with a member of the class consisting of chlorine and bromine, and further halogenating the steroid having at ring D the structure v thus produced by reacting it above 30 0. with a member of the class consisting of chlorine and bromine; 1 3. In a process according to claim 2, the step which comprises reacting, under relatively mild conditions, a steroid having at ring D the structure with amember of the class consisting of chlorine and bromine thereby producing a steroid having atring D the structure t. CH3

c= be 4. Process for the preparation of a'halosteroi'd having at ring D the structure c v where X and X are members of the class con-' sisting of chlorine and bromine which comprises halogenating a steroid having at ring D the structure CH3 2: be

Where X is a member of the classconsisting of chlorine and bromine by reacting said steroid above 30 C. with a member of the class con: sisting of chlorine and bromine.

5. A ,halosteroid having in ring D the formula where X and X are members of the class consisting of chlorine and bromine.

6. A halosteroid of the formula 7. Process for the preparation of a halosteroid of the formula OHzX where the X groups are members of the class con;

sisting of chlorine and bromine and Y" is a mem ber of the class consisting of and groups hydrolyzable to t.

which comprises reacting a steroid of the. formula with a member of the class consisting of chlorine and bromine the quantity of said halogenating agent being at least six gram-atoms per grammole of said steroid. i

8. Process for the preparation of a halosteroid of the formula with a member of the class consisting of chlorine and bromine the quantity of said halogenating agent being at least four gram-atoms per grammole of said steroid.

9. A halosteroid of the formula arms: 7

CH: CH:

where Y represents 10. A lower fatty acid ester of a 17,21-dibromopregnanol-3-one-20.

-11. 17,21-dibromo-pregnanol-3(p)-one-20 acetate melting at approximately ISO-191 C.

12. 17,21 -dibromo pregnanol 3(p) -one 20 melting at approximately 190-192 C.

13. Process for the preparation of ahalosteroid of the formula where X is a member of the class consisting of chlorine and bromine and Y" is a member of the class consisting of H and groups hydrolyzable to I OH which comprises reacting a steroid of the formula CH3 CH3 with at least six gram-atoms per gram-mole of 1 said steroid, of a member of the class consisting of chlorine and bromine, and subjecting the tetra-halosteroid of formula JHiX c=o X thus formed to partial dehalogenation by treating it with a soluble iodide.

- 14. Process for preparing a lower fatty acid R ester of a 17,21-dibromo-pregnanol-3-one-20 which comprises reacting a lower fatty acid ester of pregnanol-3-one-20 with at least four'gramatoms of bromine per gram-mole of ketone.

15. Process for preparing 17,21-dibromo-pregnano1-(,6) -one-20 acetate which comprises reacting pregnanol-3(;8)-one-20 acetate in acetic acid at 30-100 C. with at least four gram-atoms of bromine per gram-mole of ketone.

16. Process for preparing 17,21-dibromo-pregnanol-3(;3 -one-20 which comprises reacting pregnanol'-3(,3)-one-20 with at least four gramatoms of bromine per gram-mole of ketone.

17. A halosteroid having in ring D the formula D I Br 18. 17,21-dibrorno-A -pregnenedione 3,20.

RUSSELL EARL MARKER. HARRY M. CROOKS, JR.