BE631242A - - Google Patents

Description

       

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     new process for the preparation of lactones <tt4! * oM not .atur '.. If.
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  The present invention relates to a new process
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 of lactone preparation and unsaturated and more particularly of 14 etones of the following general formula 1
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 0 <-f 0 in which R # <14 * is located at position 16 or l of the steroid cal.



  It is known that * Until now for the construction of a leton * endowed steroid * of ant1aldoat'roniqu8 activity. at the start
 EMI2.2
 part of a 16 or 17-o6to corresponding unsaturated steroid we were
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 forced to go through the 6thynyl 'derivatives, which subsequently necessitated recourse to a reduction by catalytic hydrogenation and consequently had the drawback of affecting the other unsaturated functions of the radical, t'roide.



  On the other hand * according to the new process @ object of the invention the use of an otton1de of 1.a-d1h1droX1 4bro) M butane
 EMI2.4
 makes it possible to avoid this drawback and makes possible the condensation of the future side chain, liable as a result of providing the desired lactone without needing to take account of the functions
 EMI2.5
 unsaturated with the etérotdet radical In a particular embodiment of the new prood- dis, the 1,2-dihydroxy bromo butant ketonide is 1.a-1.opro- p, yl1d'nl dioxy 4-bromo butant (as) .
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  This process is essentially characterized in that
 EMI2.7
 the ketone function in 3 of 3-oxo AS 16 or 17-oxo androstene is selectively blocked in real time, in the form of 4nMdn <t dense on the carbonyl in 16 or 17 of the corresponding enamine III by a reaction from Grignard, a 1,2-dihydroxy 4-bromo butane ketonide converted beforehand into an organo-ugnésient derivative obtains the citonide of 3 ** enanino 160 or 17p-hydroxy 16a or 17cm (3 '<4'-dihydroxybutyl), .S -andro.tad1ina, IV, which is released at
 EMI2.8
 by means of an acid the ketone function in 3 and the alcohol functions
 EMI2.9
 blocked as the k6tonide either simultaneously or successfully degraded by means of an oxidant the side chain with simultaneous cyclization of 3-oxo 16p or 17p-hydroxy 16 or 17om (31 # 1-d, hydxaxrbuEy.

   p * -sndroet, irer Va resulting, and which leads to 3-oxo II * 16p or 17 "'PO oc or 17a- (1 ± -hydroxypropyl) d 4-androltene. VI. elsewhere already gifted himself

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 EMI3.1
 antialdont6ronic activity, which is isolated if desired, in the form of its epiracs A and / or 9H according to the usual methods subjects it to the action of an oxidizing agent and obtains final-
 EMI3.2
 ment the lactone of ea - (3-oxo 16P or 17p-hydroxy A 4-andro. stene lba or 17 (1-yl) propionic acid. I.



  According to another characteristic of the present invention, instead of proceeding in two stages, that is to say by periodic cleavage with cyclization in the hemiketal and sulfochromic oxidation of 3-oxo 16p or 17p-hydroxy 16a or 17a- (3 '4'-dihydroxybutyl) IJ 4-androstene. V, in lactone, the compound V is subjected to a vigorous oxidation in particular by means of chromic anhydride or of the sulphochromic mixture and the desired lactonic derivative is obtained directly.



   Thanks to this variant of the method of the invention, it
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 it is possible to obtain higher yields * l of apr a more industrial reagent,
In its = execution times, the above process can still be characterized by the following points! :)
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 the blocking of the ketone function of 3-oxo A 4 16 or 17-oxo an- drostene, II $ is carried out by means of a secondary amine chosen from the group of lower alkylated amines of pyrrolidine, from piperidine or morpholine, and in particular pyrrolidine in methanol;

   - 1,2-dihydroxy 4-bromo butane ketonida used ** t lut2 <'1sopropy11dttne dioxy 4-bromo butane (A) - condensation of the magnesium derivative of 1,2-1aopropylidene dioxy is carried out 4-bromo butane on 3-enamino 16 or 17-oxo 4 "S. Androstadiëhe, III, in the ethelbenzene mixture; - the simultaneous release of the blocked 3-ketone function in the form of enamine and of the blocked alcohol functions in the form de, ketonide, is carried out using acetic acid and in the presence of sodium acetate;

   

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 - the successive release of the alcohol functions blocked in the form of ketonide, is carried out by means of a hydrochloric acid solution and that of the ketone function in 3 blocked in the form of enamine of the same compound by means of acetic acid in the presence of sodium acetate; - the degradation of the side chain of 3-oxo 14b or 17p-hydroxy
 EMI4.1
 16a or 17a- (3 ', 4'-dihydroxybutyl). 14-androstene, V, with cycli. simultaneous nation, is carried out by means of periodic acid in aqueous t-butanol or in 50% methanol, and in the presence of sodium hydroxide or lithium carbonate;

   
 EMI4.2
 - the oxidizing agent used for the oxidation of 3-oxo 1 ', 16p or'. ' 17P-1.OXY 16a or 17a- (s -hydroxypropyJ.) 114 ... androatene, VI, is the sulfochromic mixture in aqueous acetone.



  - oxidation by chromic anhydride of the 3-axis 16p or 17p hydro- xy 16a or 17a (: P, 4'-dihydroxybutyl) 4 ... androstene, V. is carried out in aqueous ae4tqVe medium 1 - in the case where the oxidizing agent of 3-oxo 16p or 17p-hydroxy 16a or 17a- (3 '4' - <iihydroxybutyl} 44-androstèneg Ve is the aultochromic mixture, it is advantageous to operate in the presence of acetone.



  The invention also extends to the lactone of GJ - (3-oxo 16p-hydroxyA "-androstene x6ayljprapionic acid (I, with R # 0 in position 16), which it aims to titrate again. industrial*
On the other hand, the invention also extends to the intermediate products obtained during the execution of the present process that it is also aimed at as new industrial products, namely;
 EMI4.3
 - 3-pyrrolidyl 16-oxo.c13 ".. androstadiene, IIIa, - 1 t acetone of 3-pyrrolidyl l6p-hydroxy 16a- (3 '4'" 'M.hydï'oxy "butyl) II 3.S. ..andrl) stadiene.

   IVa, - 3-pyrrolidyl 17p-hydroxy acetonide 17a- (3 ', 4' "dihydroxy'-butyl) 395-androctadienet IVb, - 3-pyrrolidyl 17/6-hy <;. roxy 17- (3 ', 4'-dihydraaybutyl A'- endrostadiene, IV'b,

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 - 3-uxo 16g-hydroxy 16a- (3 '# 4'-dihydroxybutyl) A * -androstene
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 Goes
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   3-oxo 17hydroXY '17a- (3 4f-dlhydroxybutyl) A 4-androstene,
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 Vb,
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 The following compounds as epimer mixtures, or as epimer A and / or B - 3-oxo 1. 16p epoxy I6ā (l * f ..hydroxypropyl) 4..andro8têne, Via! in the form of the mixture of epimers A and B, F. # 150 * 0 CaJ o. / 57. :

   (c - 0.5%, dioxane); - 3-oxo l'f 17P-epoxy 17 - (1 '5 -hydroxypropy1) A 4..androstene, VIb, in the form of the mixture of epimers A and B, F .. 160 and 19U'Gt / "cc -7 d * # * 29 6 (o # 1%, dioxane) and in the 4'epimer A form.



  F .. 2.0 C 'ā7' d "+ 1 $ (c - 1, &, dioxane) ## le 3" oxo 1 *, 17p-epoxy 17a- (1! J -methoxypropyl) A 4..androlStàne ,? IIb, in the form of the mixture of epimeres A and B, F. # 134 - 135 # C * ± "vJ d" * .32 (o - 0.6%, dioxane)), in the form of epimer B.



  1.. + 3 ra.,% "+ 140 '1.5 (c - 0.7 jS dioxane), as epimer A, F. - 125.0,' oj '- .. 25.: 2 (9 ... 0.65%. Dioxane), and in the form of the mixture of epimers A and B at 50 9r F <"123 - 124'C, -a-7 o" + 52 ': 1 (c - 1 9r dioxane); # 3-oxo 1 'l7p-epoxy 17a- (1'! -benzyloxypropyl) .c 4..andro8tne in the form of a mixture of epimers A and B and in the form of the monomer A, F. - $ 15 Q, Ca-7 O .... 350 t 1.5 (c # 0.7 st dioxane).



  - 3-oxo 1'-, 17p-epoxy 17a- (S -aoetoxypropyl) IJ 4..androstene. in the form of a mixture of epimers A and B, F. * 132 - 133 * 0 -a-7 j0 "+ Sl. t 1.5 (c 0.7%, dioxane) in the form of epimer A, F. * #, 5nC. "'" A ", 7 p" 7': 1, r5 (o - 0.7% dioxane), and in the form of epimer B, F. - 1) 6.C, - a-7 20 "+ 10 ï 1.5 I o c3,%. dioxane), 1J 5 .. ether oxide of 3-oxo 1 'J, 17p-epoxy 17 (1 5-hydroxypropy1) A4-androstene in the form of ep1mero A, F. 3.5'r Z "<ï- 7 O a? 36 '1 (0 - 1, dioxane).

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   The following examples, illustrated by the accompanying diagrams, will give a better understanding of the invention; they are in no way limiting. The general formulas indicated on the formula sheets have substituents whose meanings are as follows
 EMI6.1
 SU is a lower dialuoylamlno, pyrrolidyl, piperidyl or morpholinyl radical; and R3 and R4, equal or different, represent an alkyl radical having from 1 to 10 carbon atoms. id
 EMI6.2
 1,2-isopropy²ne dioxy 4-bromo butane (A) used. in the course of carrying out the new process as a side chain condensing reagent, was prepared according to the method described in patent application (n) 718 B).
 EMI6.3
 



  In what follows, we call the epimer An 1 epimer with low rotational power, and "epimer B" the one with high rotational power.



   Preparation of 1,2-isopropylidene dioxy 4-bromobutane (A)
 EMI6.4
 Stage 1 s Pre aratian of 1 2-iao ra lidene dio h dro butane
The following reaction mixture is prepared - 1, 2, 4-trihydroxy butane ............ 250 gr - Acetone ................... ........... 3 L - 65% perchloric acid ..........,. 25 cm3
The mixture is left at room temperature under nitrogen and with stirring for about two hours, then add 65 g of sodium carbonate, continue stirring for one hour, filter, add to the filtrate 1, 5, cm3 of triethylamine, then drive l acetone under slight vacuum and rectify under a vacuum of 20 mm.



  252 gr of a fraction distilling us 20 mm at 107- are collected.
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 109 C (compound 0). Boiling point under 760 mm - 207009 re0 1.439.

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   The product is soluble in alcohol and acetone insoluble in water and dilute aqueous alkalis; dilute aqueous acids break it down.
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  2tadē¯ ± 2! T2! ± !! 2U.Y¯! Ê! L !! ¯! ¯ * l!: !! 22 ± 2Ele! .Fie! T: bg ± 2.! D! 100 g of compound 0 are dissolved in 125 c% 3 of wr: l.- diria, the solution z "'40'0 is cooled and slowly introduced, 54 or} of mesyl chloride then allowed to rise between -10 and - 5 C and stir for two hours.

   The mixture is then brought back to room temperature and then water is added, extracted with ether, the extract is washed successively with a solution of sodium bicarbonate, a normal solution of sodium hydroxide and leaves overnight with stirring with a solution of baking soda in the presence of triethylamine. We then wash with salt water! dries over magnesium sulfate, concentrates under nitrogen and obtains 140 g of a liquid which is crude compound D,
It is soluble in water insoluble chloroforms and dilute aqueous alkalis; dilute aqueous acids break it down.



   On the other hand, one can also easily prepare, in a similar way, 1,2-isopropylidene dioxy 4-hydroxy butane acetate, by reacting 1,2-isopropylidene dioxy 4-hydroxy butane (c) with acetic anhydride in pyridine. A liquid is thus obtained whose boiling point at 760 mm is
 EMI7.2
 20 C, n u 1.430.



   It is soluble in chloroform, sparingly soluble in ether, insoluble in water and dilute alkalis xqusux; dilute aqueous acids break it down.
 EMI7.3
 



  Stage 3 Pryrat3, we du x ..i.aoroxidno dioxr trbroma JtBht'Mt.!, '! M ".tOh tHMXMMMt * e * M'MM' * '<** buttaneAl We introduce 2 (gr of lithium bromide in ..5a,

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 EMI8.1
 of acetone, then adds 140 g of 1,2-isopropylidene dioxy 4-hydroxy butane mesylate and 7.5 cm 3 of triethylamine (D).

   The reaction mixture is brought to reflux with stirring for approximately 5 hours and then 1.500 cm3 of water are added, the organic phase is separated,
 EMI8.2
 then extract the hydro-ac'tonic phase with ether, dry the ethereal extract and concentrate under nitrogen. The residue of the ethereal extract is then joined to the organic phase and the solution is left on potassium carbonate in the presence of triethylamine. Then filtered, then rectified under vacuum to obtain 55 g of compound a.
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 Boiling point (under 18 - 19 mm Hg) "89. 90 C, n2 - 1.462.



   The product is soluble in acetone and the chloroform insoluble in water and dilute aqueous alkalis; dilute aqueous acids break it down.
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  Agalyge C7R130aBr. 209.09 Calcula a% 40.20 H% 6.26 Br% 3 ', 22 Found 40.3 6.1 37.9 Compound A can be readily hydrolyzed, if desired, by the action of an acid such as hydrochloric acid.
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 There is thus obtained 1,2-dihydroxy 4-bromo butane, n6. 1,475, soluble in chloroform, alcohol and water.



     EXAMPLE 1.
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 fÈ! t! 2S..2! ¯ !! ¯! 22! ¯22¯ !!! 2 !! ¯¯¯: i: 2! 2¯2n: blg ± 2! l¯Jl: nrrl1 rrwwwsrblrwrwrwer, rrwsrwrrvsw, rrnw, nww.nrwr I3 aw / II! nS ± 2e! D! .. 2e: l1..Et2P2e9Y! (1, with R "<" in position 16).



  Sû3S22 ± èSâJS :: ï2: Lfi ± 2ì2ï & SlîS tel with <j position 16), tade t frepl1r, ation of i31 "Pyriripll.dy.l.,) Rl! 6" Oxori.ijtt.ni ± * ii "androst '' dienet IIIa. (with 5ï> N # -NCZ3) We dissolve?, key? ' gr of 3,16-dioxo 6 'androat8ns, IIa, in 140 cm3 of methanol, then added with stirring and under nitrogen 3, $ cm' of pyrrolidinet The reaction mixture is maintained under nitrogen, with stirring and at room temperature for 15 - About 20 minutes, then wring the precipitate formed, the late metha-
 EMI8.7
 nol and dry * 6.76 g of crude compound 1111 are obtained.

   From

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 cil..aux "'' '' ', one obtains by crystallization a" 008 \ 4 jet of 685 Il * # products one pur1t11 the product by dissolution in bons4n # himself of precipitation in methanols t # 193 - 19400 * il is soluble in btnaônt tt la ohloroto: .. e louse soluble in alcohol. and in water insoluble ethers and aqueous dilute alkalis the aqueous dilute acids l.l1t18nt.



  Analysis 1 1231.33ON a 339050 Calculated s 0 e 81 # 36 H - 9080 il * 4 U Found 9 81 2 9 # 6 44 This compound is not described in the literature. The starting compound Ha was prepared according to the method described by J. PAJKOS et collet Che .. L1, ty, 47t 1207 (19-3). tady \ Aod ..006-d .tl'-djhyiy bfy) 4-zindrggli! Dµ- # 'Via * We introduce IF, 04 go of magnesium in 30 on) d # 4ther bitch add lentemonts loua *% Qt $ $ 80 and with stirring a few milliliters of a solution of 16 # 7Z gr of 1 # 2-isopropylid4n # dioxy 4-Urooo butting (A) in 80 = 3 ethers Once the reflux is common- ci * one makes arrive .111. \ 1tan-iment in about an hour 10 all of the solution indicated and-donous and the solution of 7 # 22 gr of this placed Illa in do om3 of bonsene, The) a41ango 'reaction is maintained under stirring and at room temperature for on time..

   Then add 100 or 100% saturated ammonium chloride with stirring, the organic phase is washed with water, dried over magnesium sulfate and concentrated to 30%. - te the product crilt.all1a .. The last traces of benzene are entrained in methanol and a methanol suspension is obtained which is cooled to 0.0. The crystals formed are drained lay6a with methanol and dried. 3.56 g of tac'tonide of 3-pyrrolidyllop-hydroxy 16 << - '(3'4' "dihydrexybutyl) 4 3 .S ... andro.tld.1n .. ira, crude (with jpN "-K d3 and n 3 and R4 a -0113).

   A second throw of

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 EMI10.1
 0 # 48 Gold produced * and obtained From $ Obrois liqueur. him together is rooristali1 .. in Ilither 1.oproPl11quo .. which doane a product,,. towards 204'Ct which one wsploit as is for the following stage / of the synthesis.



   This compound is not described in the literature *
 EMI10.2
 The fictitious A is prepared as described c1-d, .. ua.



  1 # 5 g of compound IVa is dissolved in 15 tadtique z 30 water then added 3 g of loclua states and the reaction mixture is heated with stirring and under atom in an oil bath at 100 C for a period of time. around hour. Then cooled by an ice bath neutralized with lye.
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 de # add 15 en3 of methanol * then continue aloal1n1.atlon until pH 10.,

     neutralize the solution by adding hydrochloric acid and the reverse side in salted water. The pre-
 EMI10.4
 precipitate formed by the ethyl acetate washed the extract and concentrated salt water # takes up the stiffness with the bons4n * -ethylacdtate mixture and leaves the solution At crystallization We obtain 691 lam of 3'-oxo 16 ..hydroX) 'l6oi- (3' <4 '' - dihyd <'0! itybutyl) 4 It.and.ro- Ittno, Vas crude, which is dissolved 4 boiling in the blndnl the solution is cooled . 1 abandons 4 the crystallization boom * and hold We obtain a product 1,.

   140 142 * CU It is soluble in the alcoholate chloroformal ethyl acetate louse soluble in 1 * insinst insoluble in 1 '@ AU # 6DOlzma Hg <' 376.52 Calculated; 0 if 73.36 H% 9.64
 EMI10.5
 Found 4 at 73 iO 9.6 This compound was not described due to the litt4r * tuy <t alliftnift LriRntélî2n. du 1-232? # 'f 169-ân2a la (3, *, f -ydroay "urgrzli, Vlas
150 mg of compound Va are dissolved in 10 cm3 of tbutanol, then the following solution is added;

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 - Periodic acid ............... 300 ut - WATER #tlllltMItMIMMMtlMMIl 10 ox - Lithium carbonate ## * * ## ** # 73 08
Stirring is carried out at room temperature for about three hours;

   then add water, wring out * the critaux to the water
 EMI11.2
 formed the washes / and dries * One obtains US 111% of crude compound Ma which can be purified by recriatallitation in aqueous t-butanol #: ##; , .. 150 * 0 (not very sharp), O / ID4 57- - 2 (o 0.3 dio-xane).



   This compound is soluble in alcohols and the chloroforms insoluble in water. acids and alkalis aqueous dilute.
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  Analysis,! 22H320 ,. 344e4g Calculated 0% 76.70 H% 9.36 Found; 76.9 9.4 This compound is not described in the literature. He introduces himself
 EMI11.4
 we form a mixture of epimers A and B.



  Stage D 1 preparation of a.cidf laotcnc (* J, -1 J-2X2 Igim! \ Yd: r9XY 4 4-aX1drostne 6-y. 1 with R- in position 16.



   140 mg of compound Via are suspended in 10.3cm3
 EMI11.5
 of acetone and 3.5 OM3 of water, cooled. 06 # then add with stirring 0.15 om3 of aulochromic solution 1 - Chromic acid., ....,, ... * # 135 gr - Sulfuric acid.,., .., ...., .. 115 cm- '- Water t * ........ t ..... ..fsp * 500 enr
Allowed to return to room temperature and continued stirring for one hour then added 1 cm3 of methanol in order to destroy the excess oxidant, poured into water, the precipitate extracted with methylene chloride, washed. extracted with water, dried and concentrated.

   The residue is taken up in ether, crystallizes @ 0
 EMI11.6
 and obtains 75 mg of compound 1, (with R oc-, 0 in position 16)

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 crude, which is recrystallized from a mixture of benzene-ether iso-
 EMI12.1
 propyl, Y m 168-0, / a / 20 o + 390 (o o 0 5%. dioxane).



   This compound is aoluble in alcohols, acetone, benzene and chloroform, sparingly soluble in ether, insoluble in water, acids and dilute aqueous alkalis.
 EMI12.2
 



  MftlyM 1 C223O 3 "342 46 Calculates 10 $ 77813 N 8 * 83 Found 76.9 gag fl spectre I.ft it shows a γ -lactone band & 1,766 cà" lo This compound is not described in the literature.



    EXAMPLE 2.
 EMI12.3
 



  Preparation of the acid lactone Q - (3-oxo 178-hydroxy ± -! DS ± 2 !! D! .Zg: l! 1¯22E2D! 9t with R *> <** T in position 17) Itadg & Preparation of 3-pyrrolidyl 17-oXO 4 35-adrolti4tàn ', IIIb (with 5r> N - N = CH3) n2
 EMI12.4
 Noue nitrogen is introduced 10 g of 3 # 17-dioxo to 4-androutenes IIb, in 200 em3 of methanol and we add 5om3 of pyrrolidinb with stirring. We keep the solution obtained nitrogen and we stir at room temperature for 15 to 20 minutes, then filter the precipitate formed, paste it with methanol and dry @ We obtain 11.6 g of crude compound 111b which is used as is
 EMI12.5
 for the next stage of the synthesis, F m 22400 * The product is soluble in benzene,

   insoluble in water and alcohol.



   The starting compound 11b is prepared according to the method
 EMI12.6
 de described by RUZICKA and WTITSTEIN # He1v. Ch1m. Acta., 18, 986 (193µ) * to.de.1 Preparation u ..oxo 17e-hYdroJÇ, '(17-At', '- dihrdro ..



  &bl;! Y to -androstene Vb., We introduce 5 # 5 gr of magnesium in 40 OM3 of 6th.I ', then we introduce dry nitrogen and stir slowly a few milliliters of a solution of 47 gr of 1 # 2-loopropylidene-

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 EMI13.1
 dioxy 4 * bmw bute CA) in 200 m 3 of ether * Once the reflux oomon, 048 we add..1..1tan '.. nt tn approximately 50 minutes the solution indicated o1-d ... ua and the solution of 11 # 7 and cext- pos IIIb in 200 µl of benzene * The reaction .61.anp is kept in a t8 ”vessel, with stirring and at room temperature for 65 hours.



  Then cooled to a * t <Mp4r * <mr <located between 0 and + 10'0, introduced 50 or of a saturated * solution of 4118Onl \ & 11 chloride. Acts * for about 30 minutes then add 3. (tau and decant * t The solution is separated off. The wick is washed at Ileaus over mgnate sulphate, an addition of 50 μl of hydroquinone is added against under nitrogen, * 30 gr of ta4 <tonid <of 3-pyrrolidyl l? p hydroxy 17 (3l # 4l-dihydroxybutyl | at 3 lvbe (with | ±> H - - M <3 # tt 3 M R4 - Raw, which is used as is for the next stage of synthesis and This compound is not described in the literature.



  Cn introduced the crude compound IVb in 200 011 'of hydrochloric acid II and stirred under alote for one hour * The undissolved part is separated in the washing A several times ** with 4hlow relorm containing% 4thonol # extract the washing solutions combined $ by 50 in hydrochloric acid li. The aqueous phases are combined with the alaAl1D1a. all * sot * and we agitation by addition of sodium hydroxide solution # separates the precipitate formed the extract by chloroform washes the chlorine solution for mi that With water until a new rate of rise, dries over sulfate do magnesium and concentrate us # cote * This gives 12 g of 3-pyrrolidyl 170-hydroxy 17ft- (3 '4l-dihydroxybutyl) 4), S.andt08tad1no. IV 'b.

   (with 5: 0'M # 2 brutl that we use as is for the next stage
 EMI13.2
 synthesis*
 EMI13.3
 This compound is not described in the literature.The crude compound IV'b is taken up by the following nélangt

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 EMI14.1
 m Acetic acid iimmmu 36 est - Water # # *, ### * ## * # * ### * * # ## * 3v 00 - Sodium acetate #### ## la gr We stir * the solution obtained for 30 a1nu '.. at room temperature # then addition of 70 o * 3 of sodium hydroxide solution and $ 00 oit) dt fine methanol of ú1800ud & "' 8 the precipitate formed and MU" treated * by addition of 20 because approximately of hydrochloric acid Controlled, we then continued until the appearance of a precipitate, which was extracted with methylene chloride, washed with the extract and dried over magnesium sulfate and concentrated. * We obtain <t4 g of crude compound Vb.



  The product is purified by chromatography on mIn silicate, .1ulD eluting with methylene chloride at 8% of mdthanol # crystallizations then recrystallization from ethers. 206 g of compound Vbe are obtained. A further purification is carried out by roortatalo Itettîon in 1eopropanol. 980 III of compound Vbe P m 191t'O are obtained. A second spray of 840 ttg of product can 8t1'8 obtained from dom liqueur m'r.8.



  This compound is soluble in alcohol # louse soluble in btnsônt t5 chloroforma insoluble in <tUt ethers
 EMI14.2
 dilute acids and alkalis. aqueous.
 EMI14.3
 



  6palzoit 1 2 '"' 6 4.376.5a calculated 0% 73036 H% 9 # 64 Found 9 73 # 1 985 This compound has not been described in the document.



  S <! preparation, from 1-o3e le @ 7ft LéP0> y 7ff (* x -bidon- pr, opy | j 4, 4 - nadMgtènt, Vlbo 700 ml of compound Vb clan are dissolved. 70 ox3 of t-butanol and 1 # 3 em3 from above then add with stirring the following solution
 EMI14.4
 boasts

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 EMI15.1
 - Periodic acid ....., ......... 104 and m Water # ** # * ## # ** ## * ## ***. *. ** 70 car Soda solution NOT  * . ** ### * # 6 cm3
The reaction mixture is left in a closed container, we stirred for about two hours, then water is added and the precipitate formed is extracted with chloroform. The organic solution is washed with brine, dried over sodium sulfate, filtered and concentrated.

   The residue is taken up in ether @ crystallizes and sounds The crystals obtained are then dissolved in benzene, the solution filtered, concentrated! then added
 EMI15.2
 isopropyl ether is left to crystallize *
The crystals formed are then filtered off and dried. 430 mg of crude compound VIb is obtained which is purified by chromatography on magnesium silicate eluting with methylene chloride at 5% ether then by recrystallization from ether,
 EMI15.3
 Po m 160 and 192oc # / a / 20 + 29 '<6 (o m 1%, dioxane).

   It occurs as a mixture of epimaries in which form A is largely predominant,
This compound is soluble in alcohol, benzene and
 EMI15.4
 chloroform, sparingly soluble in ether and ether: s.lopropyl1quo, insoluble in water, dilute aqueous acids and alkalis, Analysis 8 22H3203. 344 # 48 Calculated C% 76.69 H% 9.36 Found 76.6 9.4
This compound is not described in the literature.
 EMI15.5
 



  By slow re-crystallization of the above epimer mixture in bonlone. the epimetric form As y is isolated. 0 210 0, ra. 7 20 a + lg * (o "54 dioxane), On the other hand, in the case where one proceeds to the 4'11 '' 'dation of the butyl chain and & the cyclization in the mdthao nols we get 3-oxo 1 ', 17P "" poxy 17a- (11 1 -m6thoIiVProP11) A 4.on <lroat'ne, VlIbe

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 Depending on the procedure used, 300 mg are dissolved
 EMI16.1
 of compound Yb in 10 cm3 of methanol, added 450 mg of periodic acid and left to stir at room temperature for about 90 minutes, The reaction mixture is then poured into a dilute solution of sodium bicarbonate, the precipitate formed is extracted by ether, wash the extract with water,

     the dry concentrate, takes up the residue in heptane and crystallizes. We thus obtain
 EMI16.2
 compound VII! gross, f "13200 *
This compound is not described in the literature.



   On the other hand, the same compound VIIb can be obtained from compound VIb. The procedure is as follows;
 EMI16.3
 Grohau's under reflux for one hour the following reaction mixture; - Compound VIb ............... 100 mg
 EMI16.4
 .. Methanol ######## * # * # 2.5 car - Normal solution of sulfuric acid ................ 0.0g cm 3
Then slowly add water until the solution begins to cloud, cool and mechanically crystallize. The crystals formed are then filtered off.
 EMI16.5
 and dry. 84 mg of crude compound VIII, F * "130-13200 are obtained.



  The product Viii can be purified by recrystallization from cllohexane, F .. 134 - 13; .0, .7 o. + 1328S (0 * 0.6 fla 5rü iXân II, as well as the product VIIb of the pre-
 EMI16.6
 yield * preparation, in the form of a mixed mixture, in which form B predominates,
It is soluble in ether, benzene and chloroform, sparingly soluble in cyclohexane, insoluble in water, dilute aqueous acids and alkalis.
 EMI16.7
 kaalmag 02311 3403 "" 8.50 Crumbled! 0% bzz5 H% 9 # 56 Found 1 77 i2 906

 <Desc / Clms Page number 17>

 
 EMI17.1
 This compound has not been described in the literature. By washing with ethanol and fractional crystallization of the mixture of dtdpiobres oi-daasus damna la) tt4thanol or hot and cold, the fors * 'p1IÚr1qu was isolated.

   143 * 0 20 140 t 1.5 (oo 0.7. Dïoxane) o By crystallization from l1queura <t <th * no3dqn in lava, $ # 'from the mixture df4pl ir a A and B, A strong pr' doll1l1lnoe de la fora a, on isol * a mixture of said. 'pīNI "50% de)' - ûjt0 jto 17, - 'pox, 11c (11 J -aéthoj <yppopyl) A'-tndrowttnw, Vllbe F, # U3-'ia4 * C, òj 1' '* de (c $ 4, dioxM).



  By chromatography. on gel of .il101 with elution with bantftnt at 2 # 5 and 2 μl of tacitonte From the mixture of 4pi 4 ron A and BA 50% (above), for A is isolated from 3-ow Ite 17 $ -6poxy 17ca- (1-methoxypropyl) Alt.andre.tine. VÏIbt] Po 25 # C LV 2 "" -25 - 2 (o - Oo65. D1o: .c & nl).



  To isolate the said 6pi "ree, we proceeded as described further in the example Y * t, 1 3 * oxo a 17p-4poxy 17 - (Il 1 -hJdroqproPJ1) 4 - androstene can hearth etx '* ct4pit4 all tome d'6th, r, or dienterte COIII88 it is indicated further afield in examples VI, VII, VIII. ad <.MM. la 4 'Vaoj-df ri} m9M..X7Hm ,, A 4 ... 170 -.Xll- avow R - in M poxition 17).



  We dissolve 100 III of compound VIb due to the 61% of 4 0% 3 d ** e4toM and 1 # 5 or 3 of water, then add slowly with stirring 0.1 car * of the following solution 1 - Chronic acid ## # *. *. ** 133 gr - Lultur1que acid ## # * ## ##### 115 car #Sau ######## * ######## ** ## ## q * aï p 500 CI) After 30 minutes, we added 1 on 'da!)) 4th <UMl to destroy the oxidant excta, then 500 8 & soda ash to neutralize.

   The reaction mixture is then checked.

 <Desc / Clms Page number 18>

 
 EMI18.1
 nel in water, then extracted with ethar, wash the extract A l'waa until the washing water is neutral, keep it concentrated A $ te and cause the resulting residue to criatalliaer with a little ether from the water.
 EMI18.2
 oil,
 EMI18.3
 The product is taken up in methylene chlorite * in the solution, the concentrate # added with a little bit of petroleum, gives up crystallization and then wrings off the crystals obtained. 70 ng of compound I (with a t * -0 in position 17) are obtained crude which is purified by recrystallization from tthtp ieoptopyliqua with a little mithylene chloride.



  <"$ 16 'C.



  It is soluble in water-soluble chloroform due to water-insoluble co-propyls. ent2rs la & it presents a y -laotona band at 1,765 e! t "\ KXBKPM 3.



  BEE5SSJS.SSaS.Sti2: 6 = EµS tSëESSaS.2 = XLBE2B653MA R in position 16).



  30% of 3-oxo 36p-hydroxy 16a- (3't4 '"dihydroxybutyl) A 4-androutene is dissolved in 0 μm of to4tiau << then added with stirring, 084 because of a solution of! # chromic anhydride ww .. *. *. e 1 4 gr 0 water # ## # ### µ # # * ## ###### 5 ON acetic acid ### ... ###### # qs * p 50 en) and keep us stirring for about five hours at ambient temperature One then adds to this level with methanol #
 EMI18.4
 water and ammonia to neutralize most of the
 EMI18.5
 tie of acetic aoida. Extracted with methylene chloride,
 EMI18.6
 wash the extracts with baking soda solution and
 EMI18.7
 water, dry and concentrate to aeo # -a vacuum.
 EMI18.8
 



  The residue is taken up in acetone with a drop of sulfuric acid. Water is added to the solution. The prayed ..

 <Desc / Clms Page number 19>

 
 EMI19.1
 This extract, dried and crystallized from inopropyl ether. The crystals are filtered off and dried to give 13 III of lactone (3-oxo 16g-hydroxy to 4.androat'ne 16ct-yl) propioniquoo (1) Y. a 169 * Ct / a / * 0 - + 39 '(c - 0 "% # d10Xlftl), identical to the product described in Example 1.



     EXAMPLE 4.
 EMI19.2
 t ± éS! E !! gQ¯9! .. e ...! 2in! ¯9! ¯ !!. 219! ¯.¯1: e! 2. * 21: bl4E21l.JL:! ns! # lèn ! .. Zi: l1¯E2E122! Q \ !! '. eo R "<J in position 17).
 EMI19.3
 



  750 mg of 3-oxo 17p-hydroxy 17o- (3 '4' dihydroxybutyl) are dissolved! J 4 ... andro: stene in 12 = 3 of acetic acid ro- troidit the solution obtained to '' '$ 1' C and add 10 <m 'of an 80- aceto-chromic solution consisting of chromic anhydride 4 gr water tt ** t * o <tt * t <tt <t * tt * t <* t <t 5 ON acetic acid ............... q.8.p.50 cm '
The reaction mixture is stirred for about overnight at room temperature, then 1.5 cc of methanol and water are added.

   extracted with methylene chloride, washed the extracts with an aqueous solution of sodium bicarbonate and with water, dried over magnesium sulphate and evaporated to dryness under vacuum,
The residue is taken up in 10 because of acetone containing a drop of concentrated sulfuric acid, the solution obtained is left to stand for about forty minutes at room temperature, then water is added, the precipitate formed is filtered off and washed with l. aqueous and dry acetone.

   441 mg of lactone are obtained
 EMI19.4
 ta (3-oxo 170-hydroxy III.4..andro.t6ne 17a-yl) propionic acid (1) Pu m 16500 # identical to the product described in example 2 *

 <Desc / Clms Page number 20>

 EXAMPLE 5.
 EMI20.1
 iirriSlewirrpwrrrfvt.TP, '"", raiG, iwFwEüüwiw; errwârirrüGGlmTi'YGIrw www * aµsssitè52 We dissolve 1.00 gr of 3-oxo 17p''epoxy 17a- (l $ - hydroxyprop3 dehanol),' wandrastyl methanol 25 , add 0.5 cm3 of a normal solution of sulfuric acid, bring the whole to reflux for one hour. then slowly add water until crystallization begins. The crystals formed are then further washed, washed with water, dried and 957 mg are obtained.
 EMI20.2
 crude 3-oxo 17P-opoxy 1 to 1-methoxypro pyl) A-androstene.



   1900 mg of the above product are washed several times with methanol. then dissolved in hot methanol, then allowed to cool the solution obtained and left to crystallize. The crystals obtained are filtered off, washed with a small amount of methanol and dried. The crude product obtained is recrystallized by hot and cold in methanol, the crystals are filtered off.
 EMI20.3
 forms, dries and obtains 322 mg of 3-oxo, .7-3pay 17a- (lt 1 metthoxypropyl) A 4androstènc ép1mre B. P, - 143 "Ct / 20 +140 t., 5 (0 m 0.7% # dioxane).



   The product is soluble in ether and chloroform, sparingly soluble in cyclohexane and methanol, somewhat soluble in alcohol, insoluble in water, dilute aqueous acids and alkalis,
 EMI20.4
 Analysis! 023H3493 "" 350.50 Calculated! 0 ± 77.0 $ H 9.56 Found: 76.8 9.5
 EMI20.5
 The methanolic liquors from the washes of 1900 mg of crude 3-oxo, 17a ... epoxy (1'1-methoxypropyl) A 4-androstene are combined and evaporated.

   The crystalline residue is taken up in hot methanol, then the solution obtained is

 <Desc / Clms Page number 21>

 
 EMI21.1
 cooled and abandoned * to crystallizations
 EMI21.2
 We then wrong the crystals obtained, 'obl, the rtoristailiat by hot and cold in methanols ..ION, dry and obtain 516 III of 3-oxo at 17.'poq 17 .Jll 1 -% 6thoxypropyl) A It-androlt .ne .. 'lani: 1 of spruce A and 8 to 50 "F. # 12) - 121t- / c / 20 5X * 5 - 1 (c - $, dioXIne). the product is soluble in th ..., 10 benzines la oblorotormi sparingly soluble in oyolockant and 1 ... tbanol, sufficiently soluble in alcohols # 1 neoluble in dilute aqueous acids and alkalis.



  AM.M. 'a) HJIt 0, 0u3.4! 0% 77.0, if% 9 * 56 0% 13639 Found 177.0 9i5 1308 Starting from mixtures of 4pi.tAr a rich in forest Do, only fractional crystallizations were isolated from p1.trl. and the mixture above. To and B A $ 0%. On the other hand, the chroutography <tiuggal ct..111c. Separating the drills 4 "pJ." "" A and B starting with a $ 0% mixture of said 4piab- rose is ohrot1ltoraph1e thus 900 III of one. 50% of epi- mates A and B on dt. 1110 salt. eluting with benzene A 2 * 5 # 4'lc6tonl.

   The first 4luatet giving negative optical rotation are collected, again chM) t <! Wthi4 <aur gel de ai "
 EMI21.3
 got
 EMI21.4
 Cllico with elution with 2-acetone bensènt and the product / is recrystallized from pentane. and which gives 53 81 of product whose melting point is T. m 125 * 0 and / a / 20 # 25 * -2 (o * 0.65 * dioxane) which represents the tpixtero A of 3-oxo l ' 17p-epoxy 17tt- (Him 1 -.thoxypropyl) A 4-andmotino.
 EMI21.5
 



  EXAMPLE 6,
 EMI21.6
 Preparation of 3-oxo 1 * 17S-epoxy 17 - (1 \ -beniyloxypropylî && MM <Mm! K) & tW4HAy <& A 4 "IIZ1d.roltène We add stirring to a suspension of 689 III of 3-oxo 1117P..6poxy I7a (l * \ -hydrOXYF0P11) A lt.andro.t'l18

 <Desc / Clms Page number 22>

 
 EMI22.1
 in 7 Bontene gold 002 or * a * dormant solution * of lultwi quo acid and 108 'of bonsyl alcohol and minute the reaction mixture * with stirring and reflux for two hours. Allowed to cool en.u1to, add an exe4a of potassium carbonate # submit 1 stirring $ ta or add about a milliliter of triethylamin # tt concentrate # then remove the rest of the good alcohol) 'l1quo by steaming Ci -.au and gives up crystallization for about forty-eight hours # ** takes out the crystals obtained and lay them '1 * <6h <M' 1.oProp711quO.



  The product obtained is dissolved in hot oyc1oblxane then ori.tll11.t under r.tro1d1110..nt and 214 and 3-oxo 17p-4poxy 170. (1 'T -bontyloxypropyl) are obtained at lt.andzlol, 6nee The repeated crystallization operation gives a product of which t * * 15800 # tG / go ..) 5. : 1 # 5 (o a 0 # 7 es dtoxano). the product is soluble in bonain and obloroforma, sparingly soluble in alcoholate ether and cyclohaxana insoluble in water and thexantt & Balmat 29 "38 3. 43 /" "9 Calculated 9 0 fi 00.14 H% 8081 Found t $ 80.0 te This product is not described in Ut "r & t11l" '.



  It represents the ep1ùre A, with low rotational power of the coopo 6 above, the fA4lant of 6p1.ro. rich in 'p1-re B, with high rotatory power, can be isolated from the mother liquor and recreating liquor * which are combined, then chromatography on magnesium 1111cate with elution with ban-Ibn. At 0 #75% acetone, 4pimer 8 was not crystallized.



  The 3-oxo 17-4p, xy 17 (X- (1 '-benzyloxypropyl) at 4.androeteM can also be obtained by allowing to act at room temperature and in the presence of silver dioxide the bromide of ben - Zyl on 3-oxo 17p-epoxy 17- (1 '-hydroxypropyl) at ** androatene.

 <Desc / Clms Page number 23>

 



    2.064 g of the same starting compound are thus dissolved
 EMI23.1
 in 40 car * of acetone, add 7.44 bones of bemyl bromide and suspends 13.86 g of silver oxide, subject to stirring under a nitrogen atmosphere at room temperature for twenty - four hours, filter and concentrate under vacuum. The 5.3 $ g of crude product obtained by eluting with 1% acetone benzene are purified by training with water vapor and chromatography on magnesium silicate.
 EMI23.2
 



  Recri8allilation in cyclohexane gives 404 95 mg of 3-oxo l 17p¯epoxy 17ex- (l '-benlyloxypropyl) A 4- androstene, Y, m 150 * 0.1 / a / 20 m. 290 t 195 (oa 0 # 8% # dioxuo) # which corresponds to epimer A obtained according to the preparation method described first. On the other hand, it is also possible to obtain the same compound in the following way.
 EMI23.3
 200 mg of 3-oxo 17-epo: x are dissolved;

  y A 'aw t 1 r' methoxypropyl) A-androatene, (anomer a) in 2 car of alcohol
 EMI23.4
 benzyl and added a drop of concentrated hydrochloric acid heats the whole, under nitrogen, by means of an oil bath at 100 ° C. for one hour, then leaves it to cool, subjected to entrainment to the steam of water, then entrained successively with water and benzene, and finally chromatographed the residue on magnesium silicate eluting with benzene at 0.75% acetone, and obtained 211 mg of crude product, which after washing with iso- ether
 EMI23.5
 propyl, has F, - 148 # 0 and / w2o -11- ":!: (0.", dioxane) representing a mixture of A and B #pimers with a strong predominance of A epimer.



  3-oxo l'17P ... epoX² 17ct- (l '-m4thoxyproWl) 4 4 .. androstene was prepared as described in Example 2.



    EXAMPLE 7.
 EMI23.6
 earatan of the axa. lea taw ,. ..aaetax 'tndrostene.

 <Desc / Clms Page number 24>

 
 EMI24.1
 



  689 III of 3-oxo, 17p''epoxy 171- (1 '' \ hydroxypropyl) 14- & ndrontene are introduced into 1 ml of pyridine, stirred and add 1 ml of acetic anhydride. The reaction mixture is stirred at room temperature for about sixty-five hours, then a water-glate mixture and 1 OM3 of pyridine is added. The extract is then extracted with a mixture of methylene chloride-ethanol. The extract is washed with water, dried and concentrated.
 EMI24.2
 



  Traces of pyridine are removed by stripping with toluene and
 EMI24.3
 762 mg of crude 3-oxo-17p-epoxy 17a- (lt -acetoxypropyl) 1 4tllll androntene is obtained which is purified by successive recrystallizations from mixtures of icopropyl ether and benzenes. A first spray of 273 mg is obtained. of product F, or 132. 133 # 0, / / 20 D + 61: 1.5 (0 - 0.7% # dioxane) rich in epimer B, and a second spray of 327 mg of Po at 135 - 13600 # / (1./O. +55 '(c "0.7%, dioxane) representing the mixture at ± 3: 50% # of epimer A and B.



  Analysis of the product of taking, 1e, t, 24H3404. bzz Calculates 1 0% 74o57 H% 9096 Found 74 # 6 dos The second run product (A + B) is soluble in ether, benzene, chloroform, sparingly soluble in cyalohexane, insoluble in water and 110p ether: ropyl1que.
 EMI24.4
 



  This compound is not described in the literature.
 EMI24.5
 



  In order to isolate the epimer B, two recris tallioatione aucconsives of the first draft (F. # 13200 # / a / 20 m + 81-) are carried out in cyclohexane and the propyl ether. 81 mg of a product of F. - 13600 and / a / f3 * lodge is obtained! 1.5 (0 o 0.7, dioxane) corresponding to. 94% epimer B and 6% dfipimer A.



  In order to isolate the A # protein with low optical rotation, the 3-oxo the 17P "epoxy 17 (& - (1" \ .. acetoxypropyl) to 4-androstene) is again prepared according to the method described as

 <Desc / Clms Page number 25>

 
 EMI25.1
 above Mit by changing the proportions of compound 111. you work and obtain From 1.033., of 3-oxo 17p-epoxy 1? a- (1 't -hJ4roQpropyl) A 4-androoqtènou 943 ma de proll1er Jet F. # 126 * 0, / / J * * 41. "1" (c # 0.7 Uoat * nt) ir <tpr <- feeling a 61 & nto of 40 5 dt'4piM <) r B and, 60% epimer A, the pre-jet o1 ... d.IIUI of the product is then NOnl- tailla l tue etMiVtMnt twice in the isopropyl teat containing the bonetne.



  We thus obtain 294 III of a Jet of product of F 14200, IW20 m + 170, and 140 III of a jet of Y. a 134 * 0, ru / 20. e 390.



  We y <crixt * Ui then luco ... 1 YI me nt the jet of the product of Y ,, la 142,00à in the cyolchexant pute dam l'4th <tp tac- propyuquo and obtains 107 III of product of Io te 150 "0 # / 20 -1.5 'Ii5 (oa 0 # 7 z, c110xanl), which represents the 4 | d 4rt A of 3-oxo the 17P-'pox \ y l1ex- (1' -ac ' toX1PrOP11) A 4-anr1ro "ttn.e.



  24H'It Analysis lt. , 86.1 Calculated 10% 74.57 H% 890 Found 74.4 698 It is soluble in thor + benzene and chloroform, sparingly soluble in cyclohexane and opropyl ether. insoluble in water, RIEMPLB 8.



  E ±! E! ±! I29¯¯ !! ¯t¯I. !! ¯ \.: !! b! ± ¯2! L! ¯¯J: e! 2¯! - \ ¯A171:! 221E! 2!: 1 !!.: Bt9 ± 9e ± 2el1.j¯:! Ne !! Dt, 376 ag of 3-oxo 1? '- hydrox; r17 # -U', It'- dibydroxybutyl) d4- are dissolved androctene dama 4 o% 3 of cU.86th11tor8Ud.dl. then add 564 gr of perioclate. of ammonlua, and 10UMt! # together with stirring,, room temperature *, for three exchanges approximately
 EMI25.2
 %'We.

 <Desc / Clms Page number 26>

 
 EMI26.1
 



  Then 50 0 * 3 of water is added # * $ wrongly precipitates it forai washing it with water and aboho. The product is taken up in hot dq benwene. spin, concentrate added dethanol. cools to 0.0, draining * the crystals form4t, washing them with methanol and # * - eh ** 150 III of 11 t 1 '..4thtr oxide of 3-oa <o Ite tl7p <' <poxyl7c6 * (l ' ! -hydroatypropyl) Crude A4-androctene which was purified by rtcrlltlll1lation d * na the good <ta <, with let. dition of methanols Pt 0 315 * 0, / o / J - -36 ± 1 te 0 1. dio- tant) Coluble in bonsene and chloroforma, poorly soluble in alcohols, insoluble in water. methanol
 EMI26.2
 acids and alkalis dilute.
 EMI26.3
 



  An! Lu1 1 (022H, Pa ,,) a. 670.9 "calcd. 0 ± 70 # 75 H% 9.31 Found 7go6,903 This compound has not been described in the literature.



  This product is readily hydrolyzed in the presence of an alcohol as the solvent. the corresponding 8100-xyl6 derivative is obtained.



  Thus prepared from 157% of lt 11% ether oxide of 3-oxo * ltc, 17p-epoxy 17et- (l '-hydroxypropyl) A4-androltn. and 5 cc of methanol in the presence of concentrated sulfuric acid 37 ml of 3-oxo l '<17P- <poxy 17ot- (l'? -m6tboXJ'- propyl) A4 "androltn .. Y. MI - 12,500 # / 20 a +1140 t 1 (c "1% $ dioxane). This corresponds to a mixture of epimers A and De rich in 6p1m6re Bo with high rotatory power.



  The starting compound of 3-oxo 17p-hydroxy 17ex .. (3 ', 4'-dihydroxybutyl) A 4 ... andro8tên. has been prepared according to the method
 EMI26.4
 written in Example II,


    

Claims (1)

EMI27.1 R X VB ND1 ÇA T10 N8. 1 "* A process for the preparation of unsaturated lactonse # terotdts of the following general formula EMI27.2 EMI27.3 in which Z meo being located in position 16 or 17. cl process being characterized essentially in that the ketone function is selectively blocked beforehand in) of a 3-oxo EMI27.4 fa * 16 or 17-oxo anc1rostene. II, we form dtdnaminte condensed on the carbonyl in 16 or 17 of the corresponding tena = 1no III. by a Grignard reaction, an oetonide of 1.I-dihydroq 4- bromo butane converted beforehand into an organo-zagndaiene derivative obtains the oetonide of 3-enamino 160 or 17p-hydroxy 16a or 17 * - () 1 # 41-dihydroxybutyl) .0 "'..androatad1êne. IV, from which the ketone function at 3 and the alcohol functions blocked in the form of the ketonide, either simultaneously or successively, is released by means of an acid, degrades the side chain by means of an oxidant EMI27.5 with simultaneous oyolization of 3-oxo l6p or I? p.hydroxv 16a or 17a - () ', 4' .. c1: Hydroxybutyl) A 4 ... androstên., Y # resulting. and which leads to 3-oxo lt # 16p or 17P'-epoxy 16 or 17 '' (1 ''! -hydroxy-- propyl) A 4-androntênes VI, which is moreover already endowed with activity antialdonteroniquet which one isolates ai desired in the form of these epimeron A and / or B according to the usual methods, submits it to the action of an oxidizing agent and finally obtains the lactone of the acid w - ( 3-oxo 16ss or 17p-hydroxy EMI27.6 A 4..androatêne 16a or 17o {'- yl) propionic I. 2 ". A process according to 1" characterized in that 1 'is subjected alternatively to 3-oxo 16p or 17P-hydroxy 16Ó or 17Ó- EMI27.7 U 1 .l6.t..d.1hydroxybutyl) A 4 ... androflltene to the action of an oq- agent <Desc / Clms Page number 28> energetic and in particular to the action of chromic anhydride EMI28.1 or the sulfonhromic mixture and directly obtains the desired lactone derivative. 3. Execution of the following method 1 and @ characterized by the following points! - blocking the ketone function of 3-oxo ¯4 16 or 17-oxo EMI28.2 androstene, It is carried out by means of a secondary amine selected from the group of amines a1coy1'e8, pyrrolidine. piperidine or morpholine and in particular pyrrolidine in methanol; - the 1,2-dihydroxy 4-bromo butane ketonide used is EMI28.3 1,2-Ieopropylidene dioxy 4-bromo butane (, as; m the condensation of the magnesium derivative of 1.2-i8opropylidene dioxy 4-bromo butane is carried out on 3-enamino 16 or 17-oxo 3, S. androetadi.ne , III, in the mixture éthebtnl'ne. - 'The simultaneous release of the ketone function at 3 blocked in the form of enamine and of the alcohol functions blocked in the form of ketonide, is carried out by means of acetic acid and in the presence of aadiura acetate; - the successive release of the alcohol functions blocked in the form of ketonide, is carried out by means of a hydrochloric acid solution and that of the netone function in 3 blocked in the form of enamine of the same compound by means of acetic acid in the presence of sodium acetate; EMI28.4 - The degradation of the side chain of 3-oxo z or 170-hydre-xy 16a or 17a- (3 '. 4'-dihydroxybuty1) L14.androstane. V. with simultaneous cyclication, is carried out by means of periodic acid in aqueous t-butanol or 50% methanol and in the presence of sodium hydroxide or lithium carbonate; EMI28.5 "the oxidizing agent employed for the oxidation of 3-oxo., 16p or 17p-epoxy 16a or 17" .. (l '-hydroxypropyl} A 4-androoten ,, VI, is the sulfochromic mixture in aqueous acetone ; <Desc / Clms Page number 29> EMI29.1 o the oxidation by chronic anhydride of 3-oxo 169 or 170-bydroxy 16th or 17o (3 ## 4′.dihydroxybutyl) A4-andmotème Vu is carried out in aqueous acetic medium; in the case where the oxidizing agent of 3-oxo 1 '"or 17p-hydroxy 16. or 17o- (3'i ¯'w41hydroxybut, 1) A4.andro.t'nl.'. $ and the sultochromic mixture it is advantageous dtopir a preitn- ce of acetone # 4. * # As an induwtritlw product nouttiux A) lactont acid 4J - (3-oxo 16p-hydroxy A4-androst4n * 16 -yl) ppopionic *; b) the produced intemidialron following 1 3-pyrrolidyl 16-oxo A395-androstadiènt - ac * tonid of 3-pyrrolidyl 16p-hydroxy l6c6- (3't4 '' - dihydM <- xybutyl) 6305-androntadiane - ac4tonide of 3 -pyrrolidyl 179-hydroxY 17 - (3l 4l <"dihydro-xybutyl) A) .5-andro8tad1ne; - 3-pyrrolidyl 17p-hydroxy 17a ... (: p. 4'-dihydroqbutJl) A -andpostadi &M; 3-oxo 16p-hydroxy l6a [- {3't4 '"dihydyoa <ybutyl) A 4.anc1ro- stane 3-oxo 17 @ -hydroxy 17a - (; J8, 4'-dihydrox, buty1) 4 * andro - stene; The following compounds are in the form of a pure α and / or B 1 - 3-oxo l6e- (T-hydroxypropyl) 44.an4ro.tl8ne. sou form of the mixture of epitaeres A and Be la ta 15000 Z "e 20 a +57 X 2. (oo 0.5. dioxane) m le 3-'oxo lit 17-4poxy 170: .. (1 'ç - hydroxypropyl) Alt.an4ro.t'ne, in the form of a mixture of p1m're. A and Bo? * "160 and 192" 0 # La.:! 20 a '+29' (CI. 1% dioxane) , and in the form of epiaere As F. "21000 Cc7 20 a + 10 * (c. 1;, dioxaw) i <Desc / Clms Page number 30> EMI30.1 the 3-Oxo If # 17p- * poxy 1'11- (1 'r ..6thoX7ProWl) A lt-anciro.t6M, under fora * of the mixture "" p1-'r .. A and Do r .. 134 - 135'0, Z- & 710 a +1) 2'8. (o a 0.6 # dioxuo) o all torme dldpimrs B. y * 143'0. ev 2 0 m +1400 + 1 # 5 Ce 0, '1. dionnek under drill (Flats * As F. # 125 "1, feJ - - 5 * * a (0 a 0965 ît d1oxano), ot soue torme du m61anp d." p1MI'I 'A and 8 to 50 ji Po a 123 184g0 # / * aL7 20 a + 52µ5 t 1 (oo 1% # dioxane) 3-oxo It 170-dPOXY 17 <x- (l 'Y -bonsyloxypropyl) A "..andr08t6n, 10UI for-w of a mixture of p1m6r .. A and os and all for = "t'pi- mèrt F, - 150 * 0, ùj J # -35 * 1 # 5 (0 # 0.7 $ t dictate; .. the 3-axis He # 170-epoxy 17th "(the! ..Ao'toXi1propyl A4-androntênet forms a mixture of A and Bs? *" 132-133 * Ci ± ", 7 20 ... 61 '1 # 5 (c 0 0 # 7% o oxane), as epimer A, Y # m 15000 # Cu.7 D -7 * 5 - 1.5 (0 to 0.7. dioxant), and we form ipimer B, Fe 13600 # Caj 20 - +1090 t 1.5 (0 to 0.7% t dioxane); .. the 11-ether oxide of 3-oxo 1 '?, 1 17p-epoxy 17a- (1' ' f -hydroxypropyl) d 4-androstene fuzzy form of ip1.re A, Po 315 * 0, ï J 20 m 36 il, (oa 1%, dîoxane),