CA2187522A1 - Synthesis of 17.beta.-cyano-3-ethoxy-17.alpha.-hydroxy-6-methylandrosta-3,5,9(11)-triene - Google Patents
Synthesis of 17.beta.-cyano-3-ethoxy-17.alpha.-hydroxy-6-methylandrosta-3,5,9(11)-trieneInfo
- Publication number
- CA2187522A1 CA2187522A1 CA002187522A CA2187522A CA2187522A1 CA 2187522 A1 CA2187522 A1 CA 2187522A1 CA 002187522 A CA002187522 A CA 002187522A CA 2187522 A CA2187522 A CA 2187522A CA 2187522 A1 CA2187522 A1 CA 2187522A1
- Authority
- CA
- Canada
- Prior art keywords
- cyano
- triene
- ethyl ether
- methylandrosta
- beta
- 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.)
- Abandoned
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
- C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
- C07J41/0094—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 containing nitrile radicals, including thiocyanide radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
- C07J1/0003—Androstane derivatives
- C07J1/0011—Androstane derivatives substituted in position 17 by a keto group
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Toxicology (AREA)
- Steroid Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
17.beta.-Cyano-3,17.alpha.-dihydroxy-6-methylandrosta-3,5,9(11)-triene 3-ethyl ether (II) is prepared by reacting 3-hydroxy-6-methylandrosta-3,5,9(11)-trien-17-one 3- ethyl ether (I) with hydrogen cyanide at a pH of about 7 to about 11. The product is a useful intermediate in the production of pharmacologically active steroids including methylprednisolone.
Description
wo 9s/30684 ~ 1 ~ 7 S 2 2 r~l~LI~ -SYNTHESIS OF 17~CYANO-3-E'l~IOXY-17a-HYDROXY-6-r ~r~r.Ar~DRoSTA-3.Fj.s(ll)-TRENE
BACKGROUND OF THE INVENl'ION
1 Field of the Invention 6 The present invention is a chemical process for the ~ -.. , of a 17-keto steroid to the l,U..~ .,yunLllg 17~-cyano-17a-hydroxy steroid.
BACKGROUND OF THE INVENl'ION
1 Field of the Invention 6 The present invention is a chemical process for the ~ -.. , of a 17-keto steroid to the l,U..~ .,yunLllg 17~-cyano-17a-hydroxy steroid.
2. Descri"tion of the Related Art The i ~ " of 17-keto steroids to the l,ULl~,_,JULldill~' I,y~llullyul11.6 (17~-cyano-17a-hydroxy steroids) is known to those skilled in the art.
US Patents 4,500,461 and 4,548,748 discloses a process fûr l~ g ~4-
US Patents 4,500,461 and 4,548,748 discloses a process fûr l~ g ~4-
3,17-diketo steroids to the ~UlLC..~U~.l~g 17~-cyano-17a-hydroxy steroid by use of acetone L, ' .rLil~ and potassium cyanide. EXAMPLEs 1 and 25 discloses a process for the 1, ~... '...., ._ I: . of a ~4-3,17-diketo sterûid v~ithout 1.- I : l .. I: .. . at C6.
EXAMPLE 2 discloses a process for the l r~ :- . of a ~4~9(~ 3,17-diketo 16 steroid without a~ .. at C6. EXAMPLE 26 disclûses a prûcess for the ., r.. -1:.. of a~ 4-3,17-diketogteroidviithout a~ atC6. EXAMPLE
27 discloses a process for the 1~ r....... - 1 .. of a 6a-methyl-11~-hydroxy-~4-3,17-diketo steroid. EXAMPLE 28 discloses a process for the 1..~ -AF-- "~ of a 6a-methyl-~1~4-3,17-diketo steroid. These patents also disclose 17~-cyano-3,17a-20 dihydroxy-5-ene 3-ethylidine ketal ethers (EXAMPLE 3) and 17~-cyano-3,17a-dihydroxy-3,5-diene 3-rnethyl ethers (EXAMPLE 24). However, in both ca6es the 17-keto steroid was first 1..." r . -~1 to the cu~ ul.L~lG 17-~JGll~l.JLh~ and then the C3 filnrt;~nol;ty in the A-ring was I ,_.. ~I-... ~.l into the ether.
US Patent 4,921,638 discloses 17~-cyano-3,17a-dil.yLuA.~ al.dluD G-3,5,9(11)-25 triene 3-methyl ether (rl~GlGLiUll 1) and 17~-cyano-6-fluoro-3,17a-yLuAy~Lua~a-3,5,9(11)-triene 3-methyl ether (n~,G. ~iu~ 5). In addition, US
Patent 4,921,638 (EXAMPLE 89) discloses the production of 173-cyano-9a,17a-1;1IY~hUAYG~dI uOW-en-3-one from the corresponding 17-keto steroid using potassium cyanide, sulfilric acid, methanol and water.
J. Am. Chem. Soc., 75, 650 (1953) discloses the ~u.. . of the 17-~.~GIIullydli~ of androst^4-ene-3,17-dione and its conver6ion to the cul~ ,uL.L..~ 3-enol etbyl ether, the 3-enol benzyl ether and the 3-ethylene glycol ketal.
h'elu. Chem. Acta, 33, 1093 (1950) discloses the ,Ul~GLiu.. of 17a-cyano-3,17~dillyd.uAy~LuD~5-ene 3-acetyl ester.
~i'elv. Chim. Acta, 29, 1580 (1946) discloses the Ul~.~GlG~iUIl of a mi~rture of17,B-cyano-3,17a-dil yLuAy~LuD~c 3-acetyl and 17a-cyano-3,17~-.... . .
wo 95l30684 2 1 8 7 5 2 2 . ~
Illl.~LvA~ Dl~L 3-acetyl ester6.
l~clu. Chim. Acta, 21, 1317 (1938) discloses 3 . .y~u u"~5-en-17-one to the 17- ~uilull~l~luhl using hydrogen Lvanide.
Ster.oids, 28, 89 (1976) discloses the ,UI~ LiUII of the 17~.~ully Lill of 5 I:IIIVI~ The 1 ' eu~ y ûf the ~.JC~UUlI,~'dl;ll was not ~ ' ...:. (l US Patent 3,496,169 discloses the ~u~ Lull of the a-~...vllyLi l from carbonyl rrTT~ro~lnrl~ using alkylLy~n~ n~inllTn " ~ u". l^
East Cerman Patent 147,669 discloses the pl~y~lliull of a 17a-hydroAy-17~-Lyano steroids by reaLtion of a 17-keto-steroid with an alkanone or a cyrlr~ll 10 ~J~uLyLhl in the presenLe of a base. The steroid had a double bond at 4,5-, 5,6-and 5,10- positions. The 3-position waa a ketone, acetoxy or " ~' - ~l~i,.l.
Japanese Patent J5 7,062,296 discloses ~ iu.. of 17a-lyLUA,~Ul~ ~, ' Ull_ derivatives from 17~-cyano-17a-llyv'.uA~v~ua~4-en-3-one or 17~-L~ano-17a-LyuluAy~Lua~-4,9(11)-dien-3-one in which the 3-carbonyl and 17a-15 hydroA-y groups are proteLtêd.
Japanese Patent J5 7,062,299 disLloses the p, ~ iUII of 17,B-cyano-17a-LyLuA~Lu ' 1~ and 17,B cyano-17a-1.yu~uAy~L. 1,9(11)-diene or their 3-acetal derivatives by use of either hydrogen cyanide or an alkali metal salt thereo Japanese Patent J5 7,062,300 discloses 17~cyano-17a-1.~ul~,A~vluD~en-3-20 one and 17,B-cyano-17a-l~yd~uAy~v'lu~ 4,9(11)-dien-3~ne and the 3-acetals thereo Te~l ' ' u" Letters, 22, 2005 (1971) reported the ~ liul~ of a ~;yullvL~Lhl with a steroid A-ring containing a ~5(1U)-double bond.
US Patent 4,977,255 discloses an important process for the tr.~ rr.~ T~ of 17~-cyano-17a-hydroAy steroids into cu~_.~.;i311y important corticoids or 25 ,u.. " v__L. The 17,B-cyano-17a-hydroAy steroid starting materials were prepared in PREPARATIONS 1 thru 10. Some of the 17-keto steroids used to maAe the 17~-cyano-17a-hydroAy steroids contained methyl ~ : at C6 (PREPARATIONS 3 and 4), methylene cllhn~;tl-t;~Tl at C6 (PREPARATION 8), ~9(11) ~ , in the C-ring (PREPARATIONS 1, 5, 9 and 10) and/or a 3-methoAy-~8~5-"..- -~ d A-ring 30 (PREPARATIONS 1, 2 and 5).
Tel, ' ~i u,. Letters, 313669( 1990) discloses the ~le,u~c~iull of 17~-cyano-3,17a-dil~yu;vAy.lllLu~1~-3,5,9(11)-triene and its conversion to llyulu~ul~v acetate.
US Patent 5,003,063 discloses the conversion of protected ~ .vllyLhls (II) to 35 the ~,ul.~ u.lLIlg protected 21-halo steroid (IV) where the protecting groups are at ~ . n ~ ~ 5(6)
EXAMPLE 2 discloses a process for the l r~ :- . of a ~4~9(~ 3,17-diketo 16 steroid without a~ .. at C6. EXAMPLE 26 disclûses a prûcess for the ., r.. -1:.. of a~ 4-3,17-diketogteroidviithout a~ atC6. EXAMPLE
27 discloses a process for the 1~ r....... - 1 .. of a 6a-methyl-11~-hydroxy-~4-3,17-diketo steroid. EXAMPLE 28 discloses a process for the 1..~ -AF-- "~ of a 6a-methyl-~1~4-3,17-diketo steroid. These patents also disclose 17~-cyano-3,17a-20 dihydroxy-5-ene 3-ethylidine ketal ethers (EXAMPLE 3) and 17~-cyano-3,17a-dihydroxy-3,5-diene 3-rnethyl ethers (EXAMPLE 24). However, in both ca6es the 17-keto steroid was first 1..." r . -~1 to the cu~ ul.L~lG 17-~JGll~l.JLh~ and then the C3 filnrt;~nol;ty in the A-ring was I ,_.. ~I-... ~.l into the ether.
US Patent 4,921,638 discloses 17~-cyano-3,17a-dil.yLuA.~ al.dluD G-3,5,9(11)-25 triene 3-methyl ether (rl~GlGLiUll 1) and 17~-cyano-6-fluoro-3,17a-yLuAy~Lua~a-3,5,9(11)-triene 3-methyl ether (n~,G. ~iu~ 5). In addition, US
Patent 4,921,638 (EXAMPLE 89) discloses the production of 173-cyano-9a,17a-1;1IY~hUAYG~dI uOW-en-3-one from the corresponding 17-keto steroid using potassium cyanide, sulfilric acid, methanol and water.
J. Am. Chem. Soc., 75, 650 (1953) discloses the ~u.. . of the 17-~.~GIIullydli~ of androst^4-ene-3,17-dione and its conver6ion to the cul~ ,uL.L..~ 3-enol etbyl ether, the 3-enol benzyl ether and the 3-ethylene glycol ketal.
h'elu. Chem. Acta, 33, 1093 (1950) discloses the ,Ul~GLiu.. of 17a-cyano-3,17~dillyd.uAy~LuD~5-ene 3-acetyl ester.
~i'elv. Chim. Acta, 29, 1580 (1946) discloses the Ul~.~GlG~iUIl of a mi~rture of17,B-cyano-3,17a-dil yLuAy~LuD~c 3-acetyl and 17a-cyano-3,17~-.... . .
wo 95l30684 2 1 8 7 5 2 2 . ~
Illl.~LvA~ Dl~L 3-acetyl ester6.
l~clu. Chim. Acta, 21, 1317 (1938) discloses 3 . .y~u u"~5-en-17-one to the 17- ~uilull~l~luhl using hydrogen Lvanide.
Ster.oids, 28, 89 (1976) discloses the ,UI~ LiUII of the 17~.~ully Lill of 5 I:IIIVI~ The 1 ' eu~ y ûf the ~.JC~UUlI,~'dl;ll was not ~ ' ...:. (l US Patent 3,496,169 discloses the ~u~ Lull of the a-~...vllyLi l from carbonyl rrTT~ro~lnrl~ using alkylLy~n~ n~inllTn " ~ u". l^
East Cerman Patent 147,669 discloses the pl~y~lliull of a 17a-hydroAy-17~-Lyano steroids by reaLtion of a 17-keto-steroid with an alkanone or a cyrlr~ll 10 ~J~uLyLhl in the presenLe of a base. The steroid had a double bond at 4,5-, 5,6-and 5,10- positions. The 3-position waa a ketone, acetoxy or " ~' - ~l~i,.l.
Japanese Patent J5 7,062,296 discloses ~ iu.. of 17a-lyLUA,~Ul~ ~, ' Ull_ derivatives from 17~-cyano-17a-llyv'.uA~v~ua~4-en-3-one or 17~-L~ano-17a-LyuluAy~Lua~-4,9(11)-dien-3-one in which the 3-carbonyl and 17a-15 hydroA-y groups are proteLtêd.
Japanese Patent J5 7,062,299 disLloses the p, ~ iUII of 17,B-cyano-17a-LyLuA~Lu ' 1~ and 17,B cyano-17a-1.yu~uAy~L. 1,9(11)-diene or their 3-acetal derivatives by use of either hydrogen cyanide or an alkali metal salt thereo Japanese Patent J5 7,062,300 discloses 17~cyano-17a-1.~ul~,A~vluD~en-3-20 one and 17,B-cyano-17a-l~yd~uAy~v'lu~ 4,9(11)-dien-3~ne and the 3-acetals thereo Te~l ' ' u" Letters, 22, 2005 (1971) reported the ~ liul~ of a ~;yullvL~Lhl with a steroid A-ring containing a ~5(1U)-double bond.
US Patent 4,977,255 discloses an important process for the tr.~ rr.~ T~ of 17~-cyano-17a-hydroAy steroids into cu~_.~.;i311y important corticoids or 25 ,u.. " v__L. The 17,B-cyano-17a-hydroAy steroid starting materials were prepared in PREPARATIONS 1 thru 10. Some of the 17-keto steroids used to maAe the 17~-cyano-17a-hydroAy steroids contained methyl ~ : at C6 (PREPARATIONS 3 and 4), methylene cllhn~;tl-t;~Tl at C6 (PREPARATION 8), ~9(11) ~ , in the C-ring (PREPARATIONS 1, 5, 9 and 10) and/or a 3-methoAy-~8~5-"..- -~ d A-ring 30 (PREPARATIONS 1, 2 and 5).
Tel, ' ~i u,. Letters, 313669( 1990) discloses the ~le,u~c~iull of 17~-cyano-3,17a-dil~yu;vAy.lllLu~1~-3,5,9(11)-triene and its conversion to llyulu~ul~v acetate.
US Patent 5,003,063 discloses the conversion of protected ~ .vllyLhls (II) to 35 the ~,ul.~ u.lLIlg protected 21-halo steroid (IV) where the protecting groups are at ~ . n ~ ~ 5(6)
4 2 1 ~ 7 5 2 ~ r~
.
double bond.
CA 106:84943 and CA 109:170717 disclose 3-lly~.A~GIl~LvaLG-3,5,9(11)-trien-17-one 3-etbyl etber whicb does not contsin tbe methyl group at C6 which iB
necessary to produce tbe 6-rnethyl i-,~.... 1~..1.~.
None of tbe above documenti disclose 3-ethoAy-6-1l._~ ' u~
SUMMARY QF lNVENl'ION
Disclosed is 3-hydro~y-6-ll~ lG..~u~G-3,5,9(11)-trien-17-one 3-ethyl ether.
Also discloEed is 17,B-cyano-3,17a-dihydroAy-6 _~IYIGI~ 3,5,9(11)-triene 3-ethyl ether.
Eurther disclosed i8 a process for the ~ :- . of 17~-cyano-3,17a-dihydroAy-6-~_Lllyl~u~uaLG-3,5,9(11)-triene 3-ethyl ether, the compound of formula (Il) CN
~ j~ OH
~ .
J~,W (II) CHt which comprises:
(1) contacting 3-hydroAy-6-1ll_Ll.~lGIldluaLG-3,5,9(11)-trien-17-one 3-etbyl ether, the compound of formula (I) O
~) (I) with hydrogen cyanide (H-C~N) at a pH of about 7 to abûut 11 to produce the 17,~-cyGno-3,17a-dihydroAy-6-methylandrosta-3,5,9(11)-triene 3-ethyl ether (II) and 17a-35 cyano-3,17~-dihydroAy-6-1l..Lll~lGllLuc,~G-3,5,9(11)-triene 3-ethyl ether in the presence of a solvent or solven~ mi-Ature in whicb the 17~-cyano isomer selectively . .
wo 95/30684 2 1 ~ 7 ~ 2 2 r~ 2.-~ iVPQ
I)ETATnF~n DESCRIPl'ION OF T;E~ INVENTION
The process of the present invention is the i ~ of 3-hydroxy-6-lr~Lul~la-3~5~9(11)-trien-17-one 3-ethyl ether (I) to 17~-cyano-3,17a-dihydroxy-6 6-~_:llyl~L. 3,5,9(11)-triene 3-ethyl ether (II) by reaction with cya~ude in the presenoe of an acid and a 6uihble solvent.
The 3~thyl ether starting material, 3-hydroxy-6 ..._~l~yl~ lLuQ~-3,5,9(11)-trien-17-one 3-ethyl ether (I) is prepared from 6a-~ ' ' u_' ~1,9111)-diene-3,20-dione (US Patent 2,842,573, EXAMPLE 2) by reaction with ' ' JlulUlvfull~Q~t~ in a 10 suihblo solvent such as ethanol in the presence of pyridine hydrochloride under a nitrogen ' ' ~. The reaction is heated at about 40 until the reaction is complete as mûnitored by TLC using a methylene c ll~,.;lcta..dt~,.lc (97.5/2.5) solvent system (a L;~ l~u_ quench is neoessary before ~_ ~u.. .~ the TLC). The reaction is complete when only a few percent of starting material is left. When the 15 reaction is complete, the reaction mixture is cooled to 20-25 and the desired 3-ethyl ether crystallizes out. If some 3-hydroxy-6-~_~ 3,5,9(11)-trien-17-one 3-ethyl ether (I) is available, it is preferred to seed the cooled reaction mixture. The 3-ethyl ether (I) must be ~ ~ 11i7r~1 slowly to assure good filtration. If the 3~thyl ether (I) comes out of solution too fast, very fine particles are formed resulting in a 20 poor filtration. To avoid this, cryct~lli7Qt;rm prior to water addition is necessary. It is best induced by seeding. When a thick slurry is obtained, the mixture is cooled further on an ice bath. Water is then added and the mixture is stirred until thehydrolysis of the undesired 17-diethyl ketal is complete as measured by TLC. At this point the reaction mixture is quenched with a slight excess of ~ Q~C
25 over the pyridine hydrochloride. Additional water is added to further precipitate the 3-ethyl ether (I) and the mixture stirred at 5 for one hour. The 3-ethyl ether is obtained by filtration as is known to those skilled in the art, washing with cold methanol. Various rnmrolln~lQ in the mother liquor can be ~v"~_.kv to the ~4-3-keto starting material, if desired, by using hydrochloric acid (1 N).
The 3-hydroxy-6-~_~llyl~Lu~l~-3,5,9(11)-trien-17-one 3-ethyl ether (I) is contacted with hydrogen cyanide at a pH of about 7 to about 11. It is critical to maintain the pH of the reaction mixture in the operable range of about 7 to about 11, preferably from about 8 to about 10, more preferred is from about 9.0 to about 9.5. The pH is ~UIlV~lliwlUy set in this range by using a slight excess of cyanide salt relative to acid (10-25~o). This produces the desired 17~-cyano-3,17a-dihydroxy-6-~_UIyl~vlu~ -3~5~9(11)-triene 3-ethyl ether (II) and the 17a-cyano isomer, 17a-..... , . . . . .. . . .. ... . .... = .. ... .. . . . . . . . _ .. .. _ . .
WO 95/30684 2 1 8 7 ~ 2 2 I ~
cy~no-3,17~-dihydroxy-6 ~ ~llyLu.dl~,DLil-3,5,9(11)-triene 3-ethyl ether. The reaction is performed in the presence of a aolvent or solvent misture in which the 17~-cyano isomer is less soluble than the 17a-cyano isomer 80 that the desired product 7 ,u~G~y;L~L_~. out as the reaction proceeds.
6 The hydrogen cyanide is ~UI~ Uy prepared in sib~ by combining a salt of cyanide amount of an acid with a PKa of less than about 7; it is preferred that the PKa be less than 6. It is preferred that the cyanide initially be either sodium or potasiium cyanide however since it is preferred to add it as an aqueous solution the particular form of the cyanide is not important as long as it is soluble. The acid is 10 necessary to convert the cyanide (C~) to hydrogen cyanide (H-CaN) which is the active species in the formation of the 17-1;y~luullyL;u. It is preferred that the acid be a carboxylic acid. Suitable acids include inorganic acids such as hydrochloric, 1IYdLVb1U11UC~ hydriodic, sulfuric, ~lydlulluul;~, perchloric, nitric and r~
carboxylic acids such as acetic acid, formic, propionic, benzoic, chloroacetic, 15 d;~1IV1I ' LL;II1U1~ ' pivalic, GUIylll~vi~ and other organic acids such as p-TSA, mPt~sln~ lfnni~ and ~ - lf ~ or their equivalent. The particular acid is not important as long as it is DuLc.~ Uy acidic to transform the cyanide(C~) to hydrogen cyanide (H-C-N). AlL~ ~.IL~_~y, the hydrogen cyanide may be l by a labile ~;y~ uullyvlul compound such as acetone ~iy. l vllyvLiu which is 20 ! ";ally available and commonly used for this purpose.
The nature of the solvent or solvent mixture is critical. For the reaction to succeed the 17~-cyano-3,17a-dihydroxy-6-1ll~ llyk~uv uDL~-3,5,9(11)-triene 3-ethyl etber (II) product must precipitate while the 17a-cyano isomer remains in solution.
Therefore, the sûlvent or solvent system must be such that the 17,~-cyano-3,17a-25 dihydroxy-6-~_UIyl~vluD~-3,5,9(11)-triene 3-ethyl ether (II) is less soluble in the reaction mixture than the 17a-cyano isomer. The 3-hydroxy-~ ..._llyl~dluDLu-3,5,9(11)-trien-17-one 3-ethyl ether (I) steroid starting material and cyanide salt must have at least some solubility in the solvent or solvent mixture. To effectuate ~1C~.;,U;L21LUII of 17~-cyano-3,17a-dihydroxy-6-1l.~Ulyl~vluDL~-3,5,9(11)-triene 3-ethyl 30 ether (II) the solvent can be adjusted during the reaction, if necessary, to cause more product to precipitate. It is preferred that the solvent or solvent mixture contain at least 50% of an alcohol. It is preferred that the alcohol be selected from the group consisting of methanol, ethanol, propanol, ;..V,UIU,U~ Ol, butanol, t-butanol, ethylene glycol and propylene glycol. The preferred alcohol is methanol. Suitable non-35 alcoholic solvents include water, methylene chloride, toluene, L~ yv~uîulal~ ormixture thereo
.
double bond.
CA 106:84943 and CA 109:170717 disclose 3-lly~.A~GIl~LvaLG-3,5,9(11)-trien-17-one 3-etbyl etber whicb does not contsin tbe methyl group at C6 which iB
necessary to produce tbe 6-rnethyl i-,~.... 1~..1.~.
None of tbe above documenti disclose 3-ethoAy-6-1l._~ ' u~
SUMMARY QF lNVENl'ION
Disclosed is 3-hydro~y-6-ll~ lG..~u~G-3,5,9(11)-trien-17-one 3-ethyl ether.
Also discloEed is 17,B-cyano-3,17a-dihydroAy-6 _~IYIGI~ 3,5,9(11)-triene 3-ethyl ether.
Eurther disclosed i8 a process for the ~ :- . of 17~-cyano-3,17a-dihydroAy-6-~_Lllyl~u~uaLG-3,5,9(11)-triene 3-ethyl ether, the compound of formula (Il) CN
~ j~ OH
~ .
J~,W (II) CHt which comprises:
(1) contacting 3-hydroAy-6-1ll_Ll.~lGIldluaLG-3,5,9(11)-trien-17-one 3-etbyl ether, the compound of formula (I) O
~) (I) with hydrogen cyanide (H-C~N) at a pH of about 7 to abûut 11 to produce the 17,~-cyGno-3,17a-dihydroAy-6-methylandrosta-3,5,9(11)-triene 3-ethyl ether (II) and 17a-35 cyano-3,17~-dihydroAy-6-1l..Lll~lGllLuc,~G-3,5,9(11)-triene 3-ethyl ether in the presence of a solvent or solven~ mi-Ature in whicb the 17~-cyano isomer selectively . .
wo 95/30684 2 1 ~ 7 ~ 2 2 r~ 2.-~ iVPQ
I)ETATnF~n DESCRIPl'ION OF T;E~ INVENTION
The process of the present invention is the i ~ of 3-hydroxy-6-lr~Lul~la-3~5~9(11)-trien-17-one 3-ethyl ether (I) to 17~-cyano-3,17a-dihydroxy-6 6-~_:llyl~L. 3,5,9(11)-triene 3-ethyl ether (II) by reaction with cya~ude in the presenoe of an acid and a 6uihble solvent.
The 3~thyl ether starting material, 3-hydroxy-6 ..._~l~yl~ lLuQ~-3,5,9(11)-trien-17-one 3-ethyl ether (I) is prepared from 6a-~ ' ' u_' ~1,9111)-diene-3,20-dione (US Patent 2,842,573, EXAMPLE 2) by reaction with ' ' JlulUlvfull~Q~t~ in a 10 suihblo solvent such as ethanol in the presence of pyridine hydrochloride under a nitrogen ' ' ~. The reaction is heated at about 40 until the reaction is complete as mûnitored by TLC using a methylene c ll~,.;lcta..dt~,.lc (97.5/2.5) solvent system (a L;~ l~u_ quench is neoessary before ~_ ~u.. .~ the TLC). The reaction is complete when only a few percent of starting material is left. When the 15 reaction is complete, the reaction mixture is cooled to 20-25 and the desired 3-ethyl ether crystallizes out. If some 3-hydroxy-6-~_~ 3,5,9(11)-trien-17-one 3-ethyl ether (I) is available, it is preferred to seed the cooled reaction mixture. The 3-ethyl ether (I) must be ~ ~ 11i7r~1 slowly to assure good filtration. If the 3~thyl ether (I) comes out of solution too fast, very fine particles are formed resulting in a 20 poor filtration. To avoid this, cryct~lli7Qt;rm prior to water addition is necessary. It is best induced by seeding. When a thick slurry is obtained, the mixture is cooled further on an ice bath. Water is then added and the mixture is stirred until thehydrolysis of the undesired 17-diethyl ketal is complete as measured by TLC. At this point the reaction mixture is quenched with a slight excess of ~ Q~C
25 over the pyridine hydrochloride. Additional water is added to further precipitate the 3-ethyl ether (I) and the mixture stirred at 5 for one hour. The 3-ethyl ether is obtained by filtration as is known to those skilled in the art, washing with cold methanol. Various rnmrolln~lQ in the mother liquor can be ~v"~_.kv to the ~4-3-keto starting material, if desired, by using hydrochloric acid (1 N).
The 3-hydroxy-6-~_~llyl~Lu~l~-3,5,9(11)-trien-17-one 3-ethyl ether (I) is contacted with hydrogen cyanide at a pH of about 7 to about 11. It is critical to maintain the pH of the reaction mixture in the operable range of about 7 to about 11, preferably from about 8 to about 10, more preferred is from about 9.0 to about 9.5. The pH is ~UIlV~lliwlUy set in this range by using a slight excess of cyanide salt relative to acid (10-25~o). This produces the desired 17~-cyano-3,17a-dihydroxy-6-~_UIyl~vlu~ -3~5~9(11)-triene 3-ethyl ether (II) and the 17a-cyano isomer, 17a-..... , . . . . .. . . .. ... . .... = .. ... .. . . . . . . . _ .. .. _ . .
WO 95/30684 2 1 8 7 ~ 2 2 I ~
cy~no-3,17~-dihydroxy-6 ~ ~llyLu.dl~,DLil-3,5,9(11)-triene 3-ethyl ether. The reaction is performed in the presence of a aolvent or solvent misture in which the 17~-cyano isomer is less soluble than the 17a-cyano isomer 80 that the desired product 7 ,u~G~y;L~L_~. out as the reaction proceeds.
6 The hydrogen cyanide is ~UI~ Uy prepared in sib~ by combining a salt of cyanide amount of an acid with a PKa of less than about 7; it is preferred that the PKa be less than 6. It is preferred that the cyanide initially be either sodium or potasiium cyanide however since it is preferred to add it as an aqueous solution the particular form of the cyanide is not important as long as it is soluble. The acid is 10 necessary to convert the cyanide (C~) to hydrogen cyanide (H-CaN) which is the active species in the formation of the 17-1;y~luullyL;u. It is preferred that the acid be a carboxylic acid. Suitable acids include inorganic acids such as hydrochloric, 1IYdLVb1U11UC~ hydriodic, sulfuric, ~lydlulluul;~, perchloric, nitric and r~
carboxylic acids such as acetic acid, formic, propionic, benzoic, chloroacetic, 15 d;~1IV1I ' LL;II1U1~ ' pivalic, GUIylll~vi~ and other organic acids such as p-TSA, mPt~sln~ lfnni~ and ~ - lf ~ or their equivalent. The particular acid is not important as long as it is DuLc.~ Uy acidic to transform the cyanide(C~) to hydrogen cyanide (H-C-N). AlL~ ~.IL~_~y, the hydrogen cyanide may be l by a labile ~;y~ uullyvlul compound such as acetone ~iy. l vllyvLiu which is 20 ! ";ally available and commonly used for this purpose.
The nature of the solvent or solvent mixture is critical. For the reaction to succeed the 17~-cyano-3,17a-dihydroxy-6-1ll~ llyk~uv uDL~-3,5,9(11)-triene 3-ethyl etber (II) product must precipitate while the 17a-cyano isomer remains in solution.
Therefore, the sûlvent or solvent system must be such that the 17,~-cyano-3,17a-25 dihydroxy-6-~_UIyl~vluD~-3,5,9(11)-triene 3-ethyl ether (II) is less soluble in the reaction mixture than the 17a-cyano isomer. The 3-hydroxy-~ ..._llyl~dluDLu-3,5,9(11)-trien-17-one 3-ethyl ether (I) steroid starting material and cyanide salt must have at least some solubility in the solvent or solvent mixture. To effectuate ~1C~.;,U;L21LUII of 17~-cyano-3,17a-dihydroxy-6-1l.~Ulyl~vluDL~-3,5,9(11)-triene 3-ethyl 30 ether (II) the solvent can be adjusted during the reaction, if necessary, to cause more product to precipitate. It is preferred that the solvent or solvent mixture contain at least 50% of an alcohol. It is preferred that the alcohol be selected from the group consisting of methanol, ethanol, propanol, ;..V,UIU,U~ Ol, butanol, t-butanol, ethylene glycol and propylene glycol. The preferred alcohol is methanol. Suitable non-35 alcoholic solvents include water, methylene chloride, toluene, L~ yv~uîulal~ ormixture thereo
-5 -The reaction should be performed in a Lc - y_.~uu~ range of from about 0 to about 70 (in a sealed system); preferable from about 10 to about 45; more preferably from about 20 to about 40. At elevated i ~ a sealed system is necessary to prevent the hydrogen cyanide from being distilled off. It is preferred to 5 run the reaction for about one hour at about 30-35, then reduce the L~,~y_.~lLuuc to about 20-25.
When the reaction is complete, it is preferred to add water and stir for a short period such as 30 min. The desired 17~-cyano-3,17a-dihydroy-6-~ yl~u~L~ 3,5,9(11)-triene 3-ethyl ether (II) product slowly w ~. " out. If 10 some product (II) is available, it is preferred to seed the reaction mixture.Once the reaction is complete as measured by TLC, it is quenched with (acetic) acid to a pH of less than 7. At this point the reaction is warmed to about 50 and THF is added until all the solids dissolve. It is important to note that at this point large amounts of hydrogen cyanide are evolved. When all the solids have 15 dissolved, water is added over a period of about three minutes. If it is added to fast, the crystals wi~l be too small and filtration and washing and drying will be more difficult. The mixture is stirred at 50, then cooled (to about -10) stirred more, filtered, washed and dried to give the desired 17~-cyano-3,17a-dihydroxy-6-~_ l~lG4d~uDL -3,5,9(11)-triene 3-ethyl ether (II) as a hydrate. If the anhydrous 20 form is desired, the compound should be dried at above 50.
17~-Cyano-3,17a-dihydroxy-6-~ L uuuua~-3,5,9(11)-triene 3-ethyl ether (II) is equivaient to hydrates and solvates thereof.
17~-Cyano-3,17a-dihydroxy-6-1.._l,ylal.uluaLa-3,5,9(11)-triene 3-ethyl etber (II) is useful in the production of 6-methyl steroids such as ~ ylyl~d~llovluu_~ see 25 US Patents 4,500,461, 4,548,748 and 4,977,255.
DEFINITIONS AND CON V~;N 11UN~
The definitions and ~ n~t;t~n~l below are for the terms as used Uuuu~ yuL
this entire document including both the a~ and the claims.
DEFINITIONS
All LL~y_~oLuu~"~ are in degrees C~ntigr~
- TLC refers to thin-layer ul.~ y~
HPL~w refers to high pressure liquid THF refers to L~L~ yuluru~
When solvent pairs are used, the ratios of solvents used are ~ulu~w'~ulv~_ 35 (v/v).
When the solubility of a solid in a solvent is used the ratio of the soLid to the
When the reaction is complete, it is preferred to add water and stir for a short period such as 30 min. The desired 17~-cyano-3,17a-dihydroy-6-~ yl~u~L~ 3,5,9(11)-triene 3-ethyl ether (II) product slowly w ~. " out. If 10 some product (II) is available, it is preferred to seed the reaction mixture.Once the reaction is complete as measured by TLC, it is quenched with (acetic) acid to a pH of less than 7. At this point the reaction is warmed to about 50 and THF is added until all the solids dissolve. It is important to note that at this point large amounts of hydrogen cyanide are evolved. When all the solids have 15 dissolved, water is added over a period of about three minutes. If it is added to fast, the crystals wi~l be too small and filtration and washing and drying will be more difficult. The mixture is stirred at 50, then cooled (to about -10) stirred more, filtered, washed and dried to give the desired 17~-cyano-3,17a-dihydroxy-6-~_ l~lG4d~uDL -3,5,9(11)-triene 3-ethyl ether (II) as a hydrate. If the anhydrous 20 form is desired, the compound should be dried at above 50.
17~-Cyano-3,17a-dihydroxy-6-~ L uuuua~-3,5,9(11)-triene 3-ethyl ether (II) is equivaient to hydrates and solvates thereof.
17~-Cyano-3,17a-dihydroxy-6-1.._l,ylal.uluaLa-3,5,9(11)-triene 3-ethyl etber (II) is useful in the production of 6-methyl steroids such as ~ ylyl~d~llovluu_~ see 25 US Patents 4,500,461, 4,548,748 and 4,977,255.
DEFINITIONS AND CON V~;N 11UN~
The definitions and ~ n~t;t~n~l below are for the terms as used Uuuu~ yuL
this entire document including both the a~ and the claims.
DEFINITIONS
All LL~y_~oLuu~"~ are in degrees C~ntigr~
- TLC refers to thin-layer ul.~ y~
HPL~w refers to high pressure liquid THF refers to L~L~ yuluru~
When solvent pairs are used, the ratios of solvents used are ~ulu~w'~ulv~_ 35 (v/v).
When the solubility of a solid in a solvent is used the ratio of the soLid to the
-6 -WO 9~30684 2 1 8 7 5 2 2 r~
solvent is ~. ' ''~,.,lu~ (wt/v).
Hydrogen cyanide refers to HCN (H-C~N).
EXAMPLES
Without further I Ir~ ., it is believed that onc skilled in the art can, 5 using the preceding ~lp~rirtiAn~ practice the present invention to its fullest extent.
The following detailed ex~Aunples describe how to prepare the various ~
and/or perform the various processes of the invention and are to be construed asmerely illustrative, and not limit-l ;rn~ of the preceding disclosure in any way~L_L~u_._.. Al'hose skilled in the art will promptly recognize A~ variations 10 from the procedures both as to reactants and as to reaction conditions and tPrhniTlPI:I
PREPARAAl'ION 1 3-Hydroxy-6-m~U~ ,~ ' 3,5,9(11)-trien-17-one 3-ethyl ether a) 6a `' ' y -1lLu~L-4,9(11)-diene-3,17-dione (US Patent 2,842,573 - EXAMPLE
15 2, 50 g), pyridine hydrocbloride (0.56 g), absolute ethanol (100 ml) and LL;. :I~lulU.ufu.l.,_Le (1.4 eq, 39 ml) are slurried and the vapors are removed under reduced preOsure and replaced with nitrogen. The mixture is heated with stirring at 40 until the reaction is complete, as measured by TLC (methylene chlul;1~ u ._,97 5/2.5) The mixture is cooled to 20-25 and the product is obtOined by seeding20 and slow cry~tAI~ " with the mixture being cooled further with an ice bath.
Water (2 eq, 6 ml) is slowly added and the mixture stirred until the reaction iscomplete as measured by TLC (methylene chlu~id~'hw'u.l.; 97.5/2.5) When complete, the reaction is quenched with LIl~Ulyl_~ (0.04 eq, 1 ml), water (40 ml) is added and the mixture stirred at 5 for one hour. The mixture is filtered rapidly, 25 the c ke is washed with cold (-20) methanol (2 x 50 ml). The filter cake is dried at 40 under reduced pressure overnight to give the title compound, Rf = 0.67 (methylene chlul;W.~ v,lc, 97.5/2.5).
The st_rting material may be recovered by combining the mother liquors and the methanol wa~hes and ~:ull~.lL~rLhlg to reduce the volume to the point that most 30 of the organic solvents are removed. Methanol (25 ml) is added and the mixture is purged with nitrogen. Hydrochloric acid (12 N, 5 ml) is added and the mixture isstirred. The precipitate is filtered and washed witb water and cold methanol. The filter cake is dried in a vacuum oven overnight to give the title compound, HPLC R~t = 4.70 min (-~Pt~nitrilp/water~ 90/10, flow rate 1.5 ml/min, column C18 Nucloesil).5 PREPARATION 2 3-Hydroxy-6-1,~_'',yl~lunL~-3,5,9(11)-trien-17-one 3-methyl ether . .
woss/30684 2 ~ 8 7 522 r~ 6 Following tbe general procedure of PREPARATION 1 and making non-critical variations but starting with methanol dnd L~ ylul ~ the title compound is obtsined, Rf = 0.71 (methylene . 1 ~ t -- .r, 97.512/5); HPLCRt =
5.56 min (a~tnrlitr~ water~ 90/10, flow rate 1.5 mVmin, column C18 Nucloesil). r PREPARATION 3 3-Hydroxy-6--1..21lyl~uul. 3,5,9(11)-trien-17-one 3-propyl ether Following the general procedure of PREPARATION 1 and making non-critical variations but starting witb propanol and L~ u~uylu~ r~ , the title compound i8 obtsined, HPLC Rt = 8.52 min (~. _~.. I, il. ~wd~ 90110, flow rate 1.5 ml/min, 10 column C18 Nucloesil).
EXAMPLE 1 17~-Cyano-3,17a-dibydroxy-6-~ ".y., .u ui.L~-3,5,9(11)-triene 3-ethyl etber (II) 3-Hydro~cy-6-~_:l~l~Lu ,L,l-3,5,9(11)-trien-17-one 3-ethyl ether (I, PREPARATION 1, 50 g), potassium cyanide (19.95 g) and metbanol (120 ml) are 15 combined and purged witb a uiL. urJ_../~cl,.~ ed pressure system (3 x) and heated to 35-40 in a sealed system. The vapors are removed under reduced pressure and acetic acid (14 ml) is added via a syringe. The vacuum i5 slowly reledse to nitrogen and once ambient pressure is reached the vessel is sealed. The reaction mixture is stirred for one hour at 35 and then at 20-25. The reduced pressure is ag_in 20 replaced by nitrogen until ambient pressure is reached. Water (9 ml) is added and the mixture stirred for 30 min. If no solids are out of solution, the mixture isseeded. The flask is resealed and stirred at 25 until less than 3% starting material is observed by HPLC (usually overnight). When the reaction is complete, the reaction mixture is vented with nitrogen and quenched with acetic acid (4 ml). The 25 reaction is warmed to about 50 and THF (about 45 - 50 ml) is slowly added until all the solids are dissolved. Care must be exercised as large amounts of hydrogen cyaDide are evolved. When all the solids are dissolved water (33 ml) is added over at least three minutes. The mixture is stirred for five min at 50 and then cooled slowly over a period of a couple of hours to - 10. The mixture is stirred at - 10 for 30 a couple of hours and filtered. The filtered cake is washed with aqueous methanol (50%, 2 Y 50 ml) cooled to 10. The filter cake is dried overDight on the nitrogen press. At this point the product is the hydrate. Drying L~,u~ UI I,~ of greater than 50 are required to remove the water of hydration and give the title compound, HPLC = 6.70 min (~ I.".,l."lr!~L_" 8W20); yield (chemical) 92.4%; HPLC indicates35 about 1% starting material remains. Upon IO~ ~ " the starting material is removed.
wo g~;/306~^~4 2 1 ~ 7 ~ 2 2 EXAMPLE 2 17~-Cyano-3,17a-dihydroxy-6-1.._:l.yL~L. 3,5,9(11)-trienG 3-methyl ether 3-Hydroxy-6 ~l~LuDL,--3,5,9(11)-trien-17-one 3-methyl ether (PREPARATION 2, 9.3 g), potassium cyanide (4.2 g) and methamol (18 ml) are mixed5 nd heated to 35. The mixture is purged v~ith nitrogen and subjected to reduce pressure. Acetic acid (3.0 ml) is added using reduced pressure in the flask. Thereaction is ...-~ d at 45-48. After 1 hr 45 min, the mixture is seeded v~ith the desired ~ul~yLi7 obtained from previous ~
After a total of four hours, the mixture is cooled. One hr later, the mixture is10 at 27 and a sample is taken. Analysis discloses about 9% of the starting material remains im the mixture. The ,, 1 . ~ is checked at the same time. Very little ofthe starting material is seen, indicating that the starting material CUI~IC . ' ' viith the product.
The slurry is heated back up to 35 and stirred overnight. No change is 15 noticed after the overnight stirring. The reaction is then quenched with acetic acid (1.5 ml) and the mixture is cooled to 25. The solids are filtered off and washed with cold methanol. The crystals are analyzed by HPLC and found to contain about8% starting material. The solids are then recrystallized by dissolving them im Luh~ l. The methanol is removed by distillation and the resulting 20 crystals are filtered off, Rf = 0.3 (&~ /n~ chloride, 2/98) . The assay on the crystals imdicates that about 5-6% of starting material is still present.
Recry~ 7^-~;^n does not remove the starting material.
EXAMPLE 3 17,~-Cyano-3,17a-dihydroxy-6-~. LLyl_lLua~,--3,5,9(11)-triene 3-propyl ether 3-Hydroxy-6-~_~llyl~ul, 3,5,9(11)-trien-17-one 3-propyl ether (PREPARATION 3, 10.0 g), potassium cyanide (4.7 g) and methamol (15 ml) are combined and purged. The mixture is heated to 45. Acetic acid (3.5 ml) is charged with nitrogen and then subjected to reduced pressure. The reduced pressure is then released to nitrogen and the flask again subjected to reduced pressure. When the30 mixture is 1,,"~J114. water (4 ml) is added and the mixture is seeded. After 30 r~in, a slurry is observed. After additional 30 min stirring, the mixture is cooled to 32. An hour later, water (4 ml) is added. After 45 min additional stirring, the mixture is quenched with acetic acid (1.5 ml). T~ Lur~ is added (10 ml) and the mixture is heated to 40. Water is added to precipitate the product but an oil is 35 observed. Methanol and seed crystals are added following which crystals are obtained. The mixture is stirred slowly overnight, cooled and filtered. After g wo 95/30684 2 1 8 7 5 2 2 washing (~_th~ul/~. ' ) and drying, the title compound ia obtained, 6.5 g yields.
EXAMPLE 4 3-Hydroxy-6 ~_~l~.,.'." -l 3,5,9(11)-trien-17-one S-ethyl ether a) 6 r~ '' yl~Lu;,~4,9(11)-dieno-3,20-dione (US Patent 2,842,573, Example 2, B 60 g) is mixed with ethanol (130 ml) and purged with nitrogen. Pyridine Lul llu~;d~ (0.56 g) iB dissolved in ethanol (20 ml) and added to thc I mixture. The reaction mixture is kept at 35-40 and stirred until the reaction is complete (as monitored by TLC). When the reaction is complete, the mixture is cooled to 0-5. Water (6 ml) is added and the mixturo stirred at 0-510 until the back hydrolysis is complete (as measured by TLC). When the back hydrolysis is complete, IAI;-I.~YI~iII- (1.2 ml) is added.
The mixture is refluxed at 55 to 60 under nitrogen witb stirring. When the steroid is in solution, the water bath is removed and the reaction mixture is allowed to cool to 20-25. Water (60 ml) is added over 30 minutes. When complete the 15 mixture is cooled to 0 to 5 and stirred for 60 minutes. The mixture is filtered, washed with Ll;_U.yl~L.~ (2% in cold (-5 to -10) methanol, 60 ml) and dried to give the title compound.
EXAMPLE 5 17~-Cyano-3,17a-dihydroxy-6-m~UIy.. .~L. 3,5,9(11)-triene 3-ethyl ether (II) 3-Hydroxy-6-~_:llyl~ -3,5,9(11)-trien-17-one 3-ethyl etber a, EXAMPLE 4, 40 g), potassium cyanide (17.6 g) amd methanol (96 ml) are mixed - under nitrogen and stirred at 20-25. Acetic acid (12.35 ml) is added and the mixture warmed to 35 with stirring. The reaction mixture ia stirred at 35-40 for 45 minutes then cooled to 20-25. Water (10.8 ml) is added and the mixture stirred 25 until the reaction is complete (as measured by HPLC). When the reaction is complete, the mixture is quenched with acetic acid (3.85 ml). When the reaction IA ~U_.C.~U~ is 20-25, THF (20 ml) followed by water (20 ml) water is added andthe mixture stirred for 5 min at 20-25 then cooled to -10 for 1-2 hr. The mixture is then filtered, washed with aqueous methanol (50%, 2 x 40 ml) at 10 and dried to30 give the title compound which because it is a Itl~ o.iu e sensitive hydrate, is stored at ~ 0.
wogs/30684 21 ~7 5~ r ~ 6 CHART A
5 ~ (I) l". OH ( ) ~' CH3--CH2--o
solvent is ~. ' ''~,.,lu~ (wt/v).
Hydrogen cyanide refers to HCN (H-C~N).
EXAMPLES
Without further I Ir~ ., it is believed that onc skilled in the art can, 5 using the preceding ~lp~rirtiAn~ practice the present invention to its fullest extent.
The following detailed ex~Aunples describe how to prepare the various ~
and/or perform the various processes of the invention and are to be construed asmerely illustrative, and not limit-l ;rn~ of the preceding disclosure in any way~L_L~u_._.. Al'hose skilled in the art will promptly recognize A~ variations 10 from the procedures both as to reactants and as to reaction conditions and tPrhniTlPI:I
PREPARAAl'ION 1 3-Hydroxy-6-m~U~ ,~ ' 3,5,9(11)-trien-17-one 3-ethyl ether a) 6a `' ' y -1lLu~L-4,9(11)-diene-3,17-dione (US Patent 2,842,573 - EXAMPLE
15 2, 50 g), pyridine hydrocbloride (0.56 g), absolute ethanol (100 ml) and LL;. :I~lulU.ufu.l.,_Le (1.4 eq, 39 ml) are slurried and the vapors are removed under reduced preOsure and replaced with nitrogen. The mixture is heated with stirring at 40 until the reaction is complete, as measured by TLC (methylene chlul;1~ u ._,97 5/2.5) The mixture is cooled to 20-25 and the product is obtOined by seeding20 and slow cry~tAI~ " with the mixture being cooled further with an ice bath.
Water (2 eq, 6 ml) is slowly added and the mixture stirred until the reaction iscomplete as measured by TLC (methylene chlu~id~'hw'u.l.; 97.5/2.5) When complete, the reaction is quenched with LIl~Ulyl_~ (0.04 eq, 1 ml), water (40 ml) is added and the mixture stirred at 5 for one hour. The mixture is filtered rapidly, 25 the c ke is washed with cold (-20) methanol (2 x 50 ml). The filter cake is dried at 40 under reduced pressure overnight to give the title compound, Rf = 0.67 (methylene chlul;W.~ v,lc, 97.5/2.5).
The st_rting material may be recovered by combining the mother liquors and the methanol wa~hes and ~:ull~.lL~rLhlg to reduce the volume to the point that most 30 of the organic solvents are removed. Methanol (25 ml) is added and the mixture is purged with nitrogen. Hydrochloric acid (12 N, 5 ml) is added and the mixture isstirred. The precipitate is filtered and washed witb water and cold methanol. The filter cake is dried in a vacuum oven overnight to give the title compound, HPLC R~t = 4.70 min (-~Pt~nitrilp/water~ 90/10, flow rate 1.5 ml/min, column C18 Nucloesil).5 PREPARATION 2 3-Hydroxy-6-1,~_'',yl~lunL~-3,5,9(11)-trien-17-one 3-methyl ether . .
woss/30684 2 ~ 8 7 522 r~ 6 Following tbe general procedure of PREPARATION 1 and making non-critical variations but starting with methanol dnd L~ ylul ~ the title compound is obtsined, Rf = 0.71 (methylene . 1 ~ t -- .r, 97.512/5); HPLCRt =
5.56 min (a~tnrlitr~ water~ 90/10, flow rate 1.5 mVmin, column C18 Nucloesil). r PREPARATION 3 3-Hydroxy-6--1..21lyl~uul. 3,5,9(11)-trien-17-one 3-propyl ether Following the general procedure of PREPARATION 1 and making non-critical variations but starting witb propanol and L~ u~uylu~ r~ , the title compound i8 obtsined, HPLC Rt = 8.52 min (~. _~.. I, il. ~wd~ 90110, flow rate 1.5 ml/min, 10 column C18 Nucloesil).
EXAMPLE 1 17~-Cyano-3,17a-dibydroxy-6-~ ".y., .u ui.L~-3,5,9(11)-triene 3-ethyl etber (II) 3-Hydro~cy-6-~_:l~l~Lu ,L,l-3,5,9(11)-trien-17-one 3-ethyl ether (I, PREPARATION 1, 50 g), potassium cyanide (19.95 g) and metbanol (120 ml) are 15 combined and purged witb a uiL. urJ_../~cl,.~ ed pressure system (3 x) and heated to 35-40 in a sealed system. The vapors are removed under reduced pressure and acetic acid (14 ml) is added via a syringe. The vacuum i5 slowly reledse to nitrogen and once ambient pressure is reached the vessel is sealed. The reaction mixture is stirred for one hour at 35 and then at 20-25. The reduced pressure is ag_in 20 replaced by nitrogen until ambient pressure is reached. Water (9 ml) is added and the mixture stirred for 30 min. If no solids are out of solution, the mixture isseeded. The flask is resealed and stirred at 25 until less than 3% starting material is observed by HPLC (usually overnight). When the reaction is complete, the reaction mixture is vented with nitrogen and quenched with acetic acid (4 ml). The 25 reaction is warmed to about 50 and THF (about 45 - 50 ml) is slowly added until all the solids are dissolved. Care must be exercised as large amounts of hydrogen cyaDide are evolved. When all the solids are dissolved water (33 ml) is added over at least three minutes. The mixture is stirred for five min at 50 and then cooled slowly over a period of a couple of hours to - 10. The mixture is stirred at - 10 for 30 a couple of hours and filtered. The filtered cake is washed with aqueous methanol (50%, 2 Y 50 ml) cooled to 10. The filter cake is dried overDight on the nitrogen press. At this point the product is the hydrate. Drying L~,u~ UI I,~ of greater than 50 are required to remove the water of hydration and give the title compound, HPLC = 6.70 min (~ I.".,l."lr!~L_" 8W20); yield (chemical) 92.4%; HPLC indicates35 about 1% starting material remains. Upon IO~ ~ " the starting material is removed.
wo g~;/306~^~4 2 1 ~ 7 ~ 2 2 EXAMPLE 2 17~-Cyano-3,17a-dihydroxy-6-1.._:l.yL~L. 3,5,9(11)-trienG 3-methyl ether 3-Hydroxy-6 ~l~LuDL,--3,5,9(11)-trien-17-one 3-methyl ether (PREPARATION 2, 9.3 g), potassium cyanide (4.2 g) and methamol (18 ml) are mixed5 nd heated to 35. The mixture is purged v~ith nitrogen and subjected to reduce pressure. Acetic acid (3.0 ml) is added using reduced pressure in the flask. Thereaction is ...-~ d at 45-48. After 1 hr 45 min, the mixture is seeded v~ith the desired ~ul~yLi7 obtained from previous ~
After a total of four hours, the mixture is cooled. One hr later, the mixture is10 at 27 and a sample is taken. Analysis discloses about 9% of the starting material remains im the mixture. The ,, 1 . ~ is checked at the same time. Very little ofthe starting material is seen, indicating that the starting material CUI~IC . ' ' viith the product.
The slurry is heated back up to 35 and stirred overnight. No change is 15 noticed after the overnight stirring. The reaction is then quenched with acetic acid (1.5 ml) and the mixture is cooled to 25. The solids are filtered off and washed with cold methanol. The crystals are analyzed by HPLC and found to contain about8% starting material. The solids are then recrystallized by dissolving them im Luh~ l. The methanol is removed by distillation and the resulting 20 crystals are filtered off, Rf = 0.3 (&~ /n~ chloride, 2/98) . The assay on the crystals imdicates that about 5-6% of starting material is still present.
Recry~ 7^-~;^n does not remove the starting material.
EXAMPLE 3 17,~-Cyano-3,17a-dihydroxy-6-~. LLyl_lLua~,--3,5,9(11)-triene 3-propyl ether 3-Hydroxy-6-~_~llyl~ul, 3,5,9(11)-trien-17-one 3-propyl ether (PREPARATION 3, 10.0 g), potassium cyanide (4.7 g) and methamol (15 ml) are combined and purged. The mixture is heated to 45. Acetic acid (3.5 ml) is charged with nitrogen and then subjected to reduced pressure. The reduced pressure is then released to nitrogen and the flask again subjected to reduced pressure. When the30 mixture is 1,,"~J114. water (4 ml) is added and the mixture is seeded. After 30 r~in, a slurry is observed. After additional 30 min stirring, the mixture is cooled to 32. An hour later, water (4 ml) is added. After 45 min additional stirring, the mixture is quenched with acetic acid (1.5 ml). T~ Lur~ is added (10 ml) and the mixture is heated to 40. Water is added to precipitate the product but an oil is 35 observed. Methanol and seed crystals are added following which crystals are obtained. The mixture is stirred slowly overnight, cooled and filtered. After g wo 95/30684 2 1 8 7 5 2 2 washing (~_th~ul/~. ' ) and drying, the title compound ia obtained, 6.5 g yields.
EXAMPLE 4 3-Hydroxy-6 ~_~l~.,.'." -l 3,5,9(11)-trien-17-one S-ethyl ether a) 6 r~ '' yl~Lu;,~4,9(11)-dieno-3,20-dione (US Patent 2,842,573, Example 2, B 60 g) is mixed with ethanol (130 ml) and purged with nitrogen. Pyridine Lul llu~;d~ (0.56 g) iB dissolved in ethanol (20 ml) and added to thc I mixture. The reaction mixture is kept at 35-40 and stirred until the reaction is complete (as monitored by TLC). When the reaction is complete, the mixture is cooled to 0-5. Water (6 ml) is added and the mixturo stirred at 0-510 until the back hydrolysis is complete (as measured by TLC). When the back hydrolysis is complete, IAI;-I.~YI~iII- (1.2 ml) is added.
The mixture is refluxed at 55 to 60 under nitrogen witb stirring. When the steroid is in solution, the water bath is removed and the reaction mixture is allowed to cool to 20-25. Water (60 ml) is added over 30 minutes. When complete the 15 mixture is cooled to 0 to 5 and stirred for 60 minutes. The mixture is filtered, washed with Ll;_U.yl~L.~ (2% in cold (-5 to -10) methanol, 60 ml) and dried to give the title compound.
EXAMPLE 5 17~-Cyano-3,17a-dihydroxy-6-m~UIy.. .~L. 3,5,9(11)-triene 3-ethyl ether (II) 3-Hydroxy-6-~_:llyl~ -3,5,9(11)-trien-17-one 3-ethyl etber a, EXAMPLE 4, 40 g), potassium cyanide (17.6 g) amd methanol (96 ml) are mixed - under nitrogen and stirred at 20-25. Acetic acid (12.35 ml) is added and the mixture warmed to 35 with stirring. The reaction mixture ia stirred at 35-40 for 45 minutes then cooled to 20-25. Water (10.8 ml) is added and the mixture stirred 25 until the reaction is complete (as measured by HPLC). When the reaction is complete, the mixture is quenched with acetic acid (3.85 ml). When the reaction IA ~U_.C.~U~ is 20-25, THF (20 ml) followed by water (20 ml) water is added andthe mixture stirred for 5 min at 20-25 then cooled to -10 for 1-2 hr. The mixture is then filtered, washed with aqueous methanol (50%, 2 x 40 ml) at 10 and dried to30 give the title compound which because it is a Itl~ o.iu e sensitive hydrate, is stored at ~ 0.
wogs/30684 21 ~7 5~ r ~ 6 CHART A
5 ~ (I) l". OH ( ) ~' CH3--CH2--o
Claims (11)
1. 3-Hydroxy-6-methylandrosta-3,5,9(11)-trien-17-one 3-ethyl ether.
2. 17.beta.-Cyano-3,17.alpha.-dihydroxy-6-methylandrosta-3,5,9(11)-triene 3-ethyl ether.
3. A process for the preparation of 17.beta.-cyano-3,17.alpha.-dihydroxy-6-methylandrosta-3,5,9(11)-triene 3-ethyl ether, the compound of formula (II) (II) which comprises:
(1) contacting 3-hydroxy-6-methylandrosta-3,5,9(11)-trien-17-one 3-ethyl ether, the compound of formula (I) (I) with hydrogen cyanide (H-CN) at a pH of about 7 to about 11 to produce the 17.beta.-cyano-3,17.alpha.-dihydroxy-6-methylandrosta-3,5,9(11)-triene 3-ethyl ether (II) and 17.alpha.-cyano-3,17.beta.-dihydroxy-6-methylandrosta-3,5,9(11)-triene 3-ethyl ether in the presence of a solvent or solvent mixture in which the 17.beta.-cyano isomer selectively crystallizes.
(1) contacting 3-hydroxy-6-methylandrosta-3,5,9(11)-trien-17-one 3-ethyl ether, the compound of formula (I) (I) with hydrogen cyanide (H-CN) at a pH of about 7 to about 11 to produce the 17.beta.-cyano-3,17.alpha.-dihydroxy-6-methylandrosta-3,5,9(11)-triene 3-ethyl ether (II) and 17.alpha.-cyano-3,17.beta.-dihydroxy-6-methylandrosta-3,5,9(11)-triene 3-ethyl ether in the presence of a solvent or solvent mixture in which the 17.beta.-cyano isomer selectively crystallizes.
4. A process for the preparation of 17.beta.-cyano-3,17.alpha.-dihydroxy-6-methylandrosta-3,5,9(11)-triene 3-ethyl ether according to claim 3 where the hydrogen cyanide is formed in situ by contacting a cyanide salt (CN?) and an acid with a PKa of less than 7.
5. A process for the preparation of 17.beta.-cyano-3,17.alpha.-dihydroxy-6-methylandrosta-3,5,9(11)-triene 3-ethyl ether according to claim 4 where the cyanide salt is either sodium or potassium and the acid is selected from the group consisting of inorganic and organic acids.
6. A process for the preparation of 17.beta.-cyano-3,17.alpha.-dihydroxy-6-methylandrosta-3,5,9(11)-triene 3-ethyl ether according to claim 3 where the hydrogen cyanide is contributed by a labile cyanohydrin compound.
7. A process for the preparation of 17.beta.-cyano-3,17.alpha.-dihydroxy-6-methylandrosta-3,5,9(11)-triene 3-ethyl ether according to claim 3 where the solvent contains at least 50% of an alcohol.
8. A process for the preparation of 17.beta.-cyano-3,17.alpha.-dihydroxy-6-methylandrosta-3,5,9(11)-triene 3-ethyl ether according to claim 7 where the alcohol is selected from the group consisting of methanol, ethanol, propanol, isopropanol, butanol, t-butanol, ethylene glycol and propylene glycol.
9. A process for the preparation of 17.beta.-cyano-3,17.alpha.-dihydroxy-6-methylandrosta-3,5,9(11)-triene 3-ethyl ether according to claim 8 where the alcohol is methanol.
10. A process for the preparation of 17.beta.-cyano-3,17.alpha.-dihydroxy-6-methylandrosta-3,5,9(11)-triene 3-ethyl ether according to claim 3 where the solvent contains some water.
11. A process for the preparation of 17.beta.-cyano-3,17.alpha.-dihydroxy-6-methylandrosta-3,5,9(11)-triene 3-ethyl ether according to claim 3 where the pH is maintained in the range of about 7 to about 11 with an acid which has a PKa less than 7.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US24003694A | 1994-05-09 | 1994-05-09 | |
| US240,036 | 1994-05-09 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2187522A1 true CA2187522A1 (en) | 1995-11-16 |
Family
ID=22904843
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002187522A Abandoned CA2187522A1 (en) | 1994-05-09 | 1995-05-02 | Synthesis of 17.beta.-cyano-3-ethoxy-17.alpha.-hydroxy-6-methylandrosta-3,5,9(11)-triene |
Country Status (9)
| Country | Link |
|---|---|
| EP (1) | EP0759928A1 (en) |
| JP (1) | JPH10500946A (en) |
| KR (1) | KR970702873A (en) |
| CN (1) | CN1147816A (en) |
| AU (1) | AU684946B2 (en) |
| CA (1) | CA2187522A1 (en) |
| HU (1) | HUT75517A (en) |
| MX (1) | MX9605428A (en) |
| WO (1) | WO1995030684A1 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112898365B (en) * | 2021-03-08 | 2023-02-28 | 营口德瑞化工有限公司 | Synthesis method of 17 beta-cyano-17 alpha-hydroxyandrost-4-en-3-one |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2468617A1 (en) * | 1979-10-26 | 1981-05-08 | Roussel Uclaf | NOVEL CHLORINATED ACETYLENIC DERIVATIVES OF ANDROST-4-ENE, THEIR PREPARATION PROCESS, AND THEIR APPLICATION AS MEDICAMENTS AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
| EP0153001B1 (en) * | 1984-02-03 | 1992-03-11 | The Upjohn Company | Steroids having an enamide or enimide group and their preparation |
| DE3427486A1 (en) * | 1984-07-23 | 1986-01-30 | Schering AG, Berlin und Bergkamen, 1000 Berlin | METHOD FOR PRODUCING 6 (ALPHA) METHYLSTEROIDS |
| DE3434448A1 (en) * | 1984-09-17 | 1986-03-27 | Schering AG, 1000 Berlin und 4709 Bergkamen | METHOD FOR PRODUCING PREGNAN DERIVATIVES |
| DD281394A5 (en) * | 1984-12-10 | 1990-08-08 | Jenapharm Veb | METHOD FOR PRODUCING STEROID C-17 ALPHA CARBONITRILES |
| US5352809A (en) * | 1986-10-10 | 1994-10-04 | Gist-Brocades N.V. | 9-alpha-hydroxy steroids, process for their preparation, process for the preparation of the corresponding 9(11)-dehydro derivatives and pharmaceutical preparations containing such steroids |
| CA1317283C (en) * | 1986-11-05 | 1993-05-04 | Douglas Alan Livingston | Steroidal 17-silyl ethers and process to corticoids and progesterones |
-
1995
- 1995-05-02 WO PCT/US1995/005026 patent/WO1995030684A1/en not_active Application Discontinuation
- 1995-05-02 AU AU23628/95A patent/AU684946B2/en not_active Expired - Fee Related
- 1995-05-02 HU HU9603110A patent/HUT75517A/en unknown
- 1995-05-02 MX MX9605428A patent/MX9605428A/en unknown
- 1995-05-02 CN CN95192975A patent/CN1147816A/en active Pending
- 1995-05-02 EP EP95917651A patent/EP0759928A1/en not_active Withdrawn
- 1995-05-02 JP JP7528991A patent/JPH10500946A/en active Pending
- 1995-05-02 CA CA002187522A patent/CA2187522A1/en not_active Abandoned
-
1996
- 1996-11-08 KR KR1019960706331A patent/KR970702873A/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| KR970702873A (en) | 1997-06-10 |
| WO1995030684A1 (en) | 1995-11-16 |
| HU9603110D0 (en) | 1997-01-28 |
| EP0759928A1 (en) | 1997-03-05 |
| MX9605428A (en) | 1997-12-31 |
| AU2362895A (en) | 1995-11-29 |
| AU684946B2 (en) | 1998-01-08 |
| JPH10500946A (en) | 1998-01-27 |
| CN1147816A (en) | 1997-04-16 |
| HUT75517A (en) | 1997-05-28 |
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