BE626046A - - Google Patents

Description

       

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 EMI1.1
 The present invention relates to a process "for the preparation of '-iritosar-1,2,3,4.4a. ,, 4,10a-oota-4drophdnanthrbne having an efarbmyl or oarbunyl group substituted in position 2.



  The process for the preparation of compounds ausdita characterized in that reacting a halide of rider *
 EMI1.2
 of the general formula
 EMI1.3
 
 EMI1.4
 in which 1 represents a bblogene atom, with ammonia or a primary or secondary amine such as mines @ the compounds of the general view are preferably used
 EMI1.5
 
 EMI1.6
 in which a and Ri represent a <ttott <of hydrogen

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 EMI2.1
 or a group. al ,, lower 01lo, by eX.

   Il.thJJ.:e, 'Í' 6.: 4 '; ethyl or isopropyl, the hydroxyethyl group or
 EMI2.2
 a di (int4r1eur alkyl) group u.1no4thl: J .., e.g. dimethyl- or diethylaminoethyl, only one of the "substituents R and t, which can represent hydrogen or R, and R2 together with the nitrogen atom to which they are attached can form a heterocyclic ring of 5-8 atoms, whose nitrogen atom is the only atom
 EMI2.3
 hetero, such as for example the p1per1dnic nucleus. The compounds obtained by this process have asymmetric carbon atoms and can thus be in different atereoisomeric forms.



   The starting substances of the general formula 1 can be prepared from the corresponding free acids,
 EMI2.4
 or their alkal salts: 1J1ometallic. by reaction with a halide of oxalic acid or an inorganic acid, e.g. with phosphorus trihalide, phosphorus pentahawlogenide, phosphorus oxyhalide or thionyl halide, the preferred halides being chloride or bromide, e.g. phosphorus trichloride,
 EMI2.5
 phosphorus tribromide, phosphorus pentaoblorides, phosphorus oxychloride, thionyl chloride, etc ,. '"*' '# The conversion of the acid into an acid halide can be carried out advantageously in the presence of an inert solvent, such as
 EMI2.6
 that the bin.'ne, x "3: ae;

  .haa, elne, ether, chloroform, petroleum ether, etc., advantageously within a temperature limit ranging from room temperature to

 <Desc / Clms Page number 3>

 reflux temperature of the mixture. After this reaction, the acid halide can be isolated in the usual way, without however this isolation being compulsory. Advantageous
 EMI3.1
 Usually, ozalt or de thionyl chlorura + is used, the reaction mixture is evacuated to dryness in vacuo and then added to a healthy solution in an organic solvent.



  The organic solvent is then separated from the reaction mixture and the desired product is obtained, when in the above reaction is used as
 EMI3.2
 starting substance i 'ac, ide? -aethazy- ,, 2,, 4, day, 30, I4a- octahyd * ophenanthrene 2¯carboxylic with trans configuration of the B / C rings, one obtains passing through the halide of corresponding acid 2-carbaayl-7- & ethoxy-1,2,3,4 4a, 9, 10, 10a-octahydrophenanthrene, the rings of which also exhibit the trans configuration.

   Starting from the higher melting point (hereinafter referred to as isomer 1) of -pt6thaty-1, 2, 3 N 4, a, '$, 1C1, is started. oetst.ydrophénantbrrne2-aarbo xylique, in which the B / 0 rings have the c1s configuration, the corresponding stereoisomeric 2-carbamyl-7-methoxy- lr2,3,4,4a, 9 10,10a-octahydrophénantrfene is obtained as final product, of which B / C nuclei also exhibit the
 EMI3.3
 geese configuration.

   When the low melting point isomer (referred to as isomer 2) of Z-aethar - 1,2.r4ya, yiU, IQa-actabrdro-phenanthrene-2-carboxylic acid is used as the starting material , whose B / 0 rings have the cis configuration. we obtain the corresponding isomer of
 EMI3.4
 -carbamyl-7-metoxy -., 2,, 4,4a, 9,10,1t) a-aotahyrdraphénantrne, the B / C rings of which have the -ils configuration. In

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 EMI4.1
 In general, the above stereoisomers are used in the form of their rac4matte. however, if desired, we can also
 EMI4.2
 
 EMI4.3
 obtain the desired optical isomer, ie the drctro form. are or levorotatory ,, using the corresponding optical isomer
 EMI4.4
 of the starting material.

   When, for example, we use
 EMI4.5
 as starting material 7-mdthoqr-.l, 2, 3! 4, a,, 10,10a.ootahydrophenanthrene-2-'carboxylic (B / C trme rings), we thus obtain d-2-carbamyl-7-mdthoxr-1,2,, 4.4a, 3,10,10e - octahydrophénanthreue (lioyùiu B / C trana).



  Example 1 Preparation of the high melting point iacmer of 2-cartamyl- -mdt a 1 2-oCtah dr0 henarrthrne o C ci) as a solution of 50 g of the high melting point of? -Methoxy acid. I, 2, ° 4,4a. 9 ... 10aoatahydroph6s, - antirene-2-carboxylic (B / C rings) in 2500 ml of benzene, 170 Bl of thionyl chloride are added and the solution is slowly heated to reflux for 2 hours. The solution
 EMI4.6
 benzene is then concentrated to dryness, the residue taken up
 EMI4.7
 in benzene and the reconcentrated solution in order to remove
 EMI4.8
 the balance of thionyl chloride. The acid chloride obtained
 EMI4.9
 ootMae.substance can be used directly
 EMI4.10
 without further purification.
 EMI4.11
 



  In a solution of 500 ml of ether and 3.9 g of ammonia is added slowly and with stirring at 0 a solution of 6t4 of the acid chloride in 50 ml of benzene. The mixture is

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 EMI5.1
 then stirred for 18 hours at room temperature * and
 EMI5.2
 then poured into a liter of water, after which the aouebonqui not forcing are separated. The ethereal layer was washed well with 1N sodium hydroxide, 2% hydrochloric acid, water and sodium chloride solution. After
 EMI5.3
 drying and elimination of solvents by evaporation, one obtains
 EMI5.4
 holds by crystallization from acetonitrile 3.9 g of the high melting point isomer of 2-carbatayl <* 7-wethoxy-1,2,3,4,4a, 9,10,10a-octahydrophënanthreoe (nucleus * B / C and *) fondant
 EMI5.5
 204.5-205.5.
 EMI5.6
 



  Wpe preparation of the isomer of - h-meth 1-cb 3. - -met 1 4 a 1 (ï 14aoctah dr henanthre e (nuclei B / C rr cia 1 eorreapondant etereepiaomeri ually at llit3omègle, high melting point of l 7-mtboxy-12.3j, 4.4atl010a-oetahyrophéna.-thrne-2-csrbozylic acid (B / C cia rings), In a mixture ie 500 μl of ether and 9p6 g of methylamine, slowly added to 0 a solution of 9 g of the acid chloride obtained in Example 1 in 100 ml of benzene. The mixture is stirred for 18 hours.
 EMI5.7
 1 liter of water and separates the layers that form. Layer
 EMI5.8
 ethereal is washed with water and with sodium chloride solution.

   Checking and removal of organic solvent
 EMI5.9
 by evaporation, crystallization is obtained from
 EMI5.10
 benzene 1.6 g of 2- {ï-methylcarbamyl) -7-methoxy-1,2,5,4,4a, (B / C rings) melting 195-
 EMI5.11
 195.5.

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 EMI6.1
 etll1'le, Preparation of. The isomer of 2- (N.! L-dimethyl-carbamyl) -7-ethox-1f2, '4.4a, 2.10,10a-octahYdr enanthrene (' B / C cis rings) corresponding atereoisomerically to the high melting point isomer of methor 1 2 4a lff ï (apctahydrophenanthrene-2-carboxylic (Ble ci8 rings) To a mixture of 1000 ml of ether and 91.2 g of dimethylamine, add slowly to 0 a solution of 25.6 g of
 EMI6.2
 acid chloride obtained in Example 1 in 200 ml of benzine.



  The mixture is stirred for 18 hours at room temperature. Then add 2 liters of water and separate the
 EMI6.3
 flies that form. The ethereal layer is washed successively with IN sodium hydroxide, hydrochloric acid, water and sodium chloride solution. After drying and removing the organic solvents by evaporation, crystallization is obtained from J ae ton1tl'ile z. 4.6 g of 2- (N;, t-dlméttyl-carbsrarl-i-mgthaxy-1,2,3r4na , 9x.r10aoctahydrophenanthrene (cis B / C rings) trimming. 130-131.



  IXEltIl, El ,,, - i é aratlo d 'eots e 4e 2- N- ra 1-cs: ^ h .. mé or 1.2't4,4a.lO, 1' t-9c1ah²drophénhrèr. () 'Olnu.x B / r; .s1Il corresponding steret) 18mériqêent to 1 of ". Of high fusion of the acid -methox -1 2 A Oa..drophenanthrene-2-carboxylic (rings B / Çj ois).

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 EMI7.1
 



  . r. #: G .... '. - WA A mixture of 500 ml of ether and 13.5 g of n-propyl- bring oh slowly add to 0 and stirring a solution of 6.4 g of the acid chloride obtained in Example 1 in 50 ml of
 EMI7.2
 benzene. The mixture is stirred for 18 hours at room temperature. Then the solution is poured into a liter of water and the layers that form are separated. The ethereal layer is then washed successively with IN scdium hydroxide, 2N hydrochloric acid, water and a solution of sodium chloride.

   After drying and evaporation of the organic solvent, crystallization is obtained from acetoni-
 EMI7.3
 trile 2.7 g of 2- (N-propyl-carbamyl) -7-mthoxy-1,2,3,4,4a, 9,10,10a-octahydrophenanthrene (cis Ble rings) melting 127-128.5. example 5
 EMI7.4
 Preparation of the 2- -cieth laminoeth-a rb isomer. -mvthox- -1 2 4 a 10 l0 l0a-actah droheranthr e (Bie cie-correi3 nucleus. Btereoiaomeric high melting point isomer of acid-methox -1 2 4 ai0 10 ", octahydrophênanthrene-2- carboxylic cores BC cie4 In a mixture of 500 ml of ether and 8.5 g of p-diethylamino-ethylamine, there is slowly added to 0 a solution of 10 g of the acid chloride obtained in Example 1 in 100 ml of benzene The mixture is stirred for 18 hours at
 EMI7.5
 ambient temperature.

   Lk-desousq is added 1 liter of water to the solution obtained and separates the layers which form.



  The ethereal layer is washed successively with the hydroxide

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 EMI8.1
 of sodium 1NO of water 8t an edition of sodiua chloride.
 EMI8.2
 After drying and evaporation of the organic solvent, one obtains
 EMI8.3
 by crystallization from acetone 6.2 g of 2 (.- di41ih11- 8l.inoethyl-oarbl4t. '"7iti0l, j, 3, 4, s .0 s 301-ootahydrophenanthrene (B / 0 rings) melting at 101-3.t3. X 3 .. preparation of the chlorudrigue acid salt of 2- (K-di <thylinoeth.-Carbaaa 1 - -. Ethox -1 2 to 10 3.Oa-octah draphenanthrene (M cores melting sky 101-10309 To a solution of 4.7 g of the product obtained in Example 5 in 100 ml of methanol is added 30 ml of ethanolic hydrochloric acid 4.7.

   After removal of methanol by eva-
 EMI8.4
 'poration and crystallization from acetone, 3.2 g of the hydrochloride are obtained, melting at 148-150.
 EMI8.5
 



  Example y Preparation of the low melting isomer of 2-carbaayl- -meto -l. 2 to 10 11a-actah dro hnanthràne (C Ois rings) To a solution of 31 of the low melting point isomer of. Mdthor-1., 2,, 4a, 3,10,14a-ootahydraphiaxtthrsre -carboar3ique (nuclei 'bic cis) in 1700 ml of benzene, 100 al of thionyl chloride are added and the solution obtained is heated for 2 hits * under reflux. . t, 1t14.1

 <Desc / Clms Page number 9>

 
 EMI9.1
 benzene is then concentrated to dryness. the residue is taken up in benzene and the solution evaporated a further
 EMI9.2
 times in order to remove the thionyl chloride jolde.

   The acid chloride obtained as an intermediate can be used directly without further purification.
 EMI9.3
 A mixture of 750 ml of ether and 4.9 6 of aaimoniao is added slowly to 0 a solution of 8 g of acid chloride in 75 ml of benzene. The mixture is stirred for 18 hours at room temperature. Then, 1 liter of water is added to the mixture and the layers that form are separated. The ethereal layer is washed with water and a solution of hydrogen chloride. After drying and evaporation of the organic solvent, 5.5 g is obtained by crystallization from acetonitrile.
 EMI9.4
 low melting point isomer of 2-carbamyl -? - methoxy 1,2 # 3,4,4a, 9,10glOa-octahydrophenanthrene (B / C ois rings) melting at 170-171.5.



   Example 8
 EMI9.5
 Preparation of 2- T Hdi- -h drox eth 1carb -metho - 1 2 a 10 10a-octah dro henanthrne (B / C nuclei trans A a solution of 37 g of 7-methoxy-1,2,3,4 acid , 4a, 9,10, ICa-octahydrophinanthrbne-2-carboxylique (B / C trans rings) in 2 'liters of benzene, 140 ml of thionyl chloride are added and the mixture is heated for 2 hours at reflux. then concentrated, the residue taken up in benzene and the solution thus obtained concentrated to

 <Desc / Clms Page number 10>

 
 EMI10.1
 siccite to remove the balance of thionyl chloride. The acid chloride obtained as an intermediate can be used directly without further purification.



   Has a mixture of 500 ml of ether and 11.3 g of diethanol--
 EMI10.2
 amine # a solution of 9.9 g of the acid chloride in 100 ml of benzene is slowly added to 0. The mixture is
 EMI10.3
 then stirred for 18 hours at room temperature. on top of this, 1 liter of water is added and the layers which are not formed are separated. The ethereal layer and washed with water and a. sodium chloride solution. After drying and evaporation of the organic solvents, one obtains by crystallization in
 EMI10.4
 benzene 4.5 g of 2- (Di, N-di - hYdraxy-dtky3..caràamy.i--. methoxy-1, 2, 3, 4, 4a,, .t3, lta-oatatydrophénaiathrue (B / rings C trans) melting at 111.5-1130.



    Example 9
 EMI10.5
 ar tion of 2- N 8-dirth 1-aarbam. - cdtho =. 3. has 9010a-octahydrohenanthrene (Ble trartB rings).



  To a mixture of 500 ml of ether and 7.8 g of thyllamine, a 90% solution of the chloride obtained in Example 8 is slowly added to z. The mixture is stirred at room temperature for 18 hours. Above, add 1 liter of water and separate the layers that form.

   Layer
 EMI10.6
 ethereal is washed with sodium hydroxide 11 '= water' and sodium chloride solution. After drying and

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 evaporation of the solvent, one obtains by crystallization in
 EMI11.1
 acetone 5, 9 g of 2- (X, Niethyl-carbamyl) -7-methoxy-.l, 2,3, 4,4a, 9,10,10a-octahydrophenanthrene (Bzz10 trane rings) melting at 81-820 . temple 10
 EMI11.2
 Preparation of piperidine 7-methoxy-l.2.3.4.4a..10lOa-octahydroDhanthrene-2-carboxylate (Bie true rings) Sanb a mixture of 500 such of ether and 9.1 g of piperidine, slowly added to 00 a solution of 999 g of the acid chloride obtained in Example 8.

   The mixture is stirred for 18 hours at amà3ante.L: -deaeue, 1 liter of water is added and the layers which form are separated. The ethereal layer is washed with 1H sodium hydroxide, ' water and sodium chloride solution. After drying and evaporation of the solvent, one obtains by crystallization in
 EMI11.3
 acetone 5.7 g of piperidine 7-metboxy-1,2,3 4,4a, 9,10,10a-octahydro-phenanthrenē2-carboxylate (B / C trane rings) melting at 100-1010.



    Example 11
 EMI11.4
 repair of 2-fy¯fl¯d4ethylamlncëthyl-jarbamlyl) -7¯lBethoxy¯ 1,2. ? 4 4a 9.10 .lOactahydrophenanthrène (trans BJ2 rings), Without a mixture of 500 ml of ether and 8.5 s of 0-didthyl-

 <Desc / Clms Page number 12>

 
 EMI12.1
 am1no'ihllamin. is slowly added to or a solution of 10 g of the acid chloride obtained in Example 8 in 100 ml of benzene.



  The mixture is stirred at room temperature for 18 hours.



  On top, we add 1 liter of water and separate the layers that form. The ethereal layer is washed with sodium hydroxide 18, water and sodium chloride solution.



  After drying and evaporation of the solvent, one obtains by
 EMI12.2
 crystallization from acetone 8.6 g of 2- (Np-diethylamino-dthyl-carbamy.? -methoay -. ,, 2, â.4, a, 9 r .. .t? a-actabtdropienw anthrene (B rings / C trans) melting at 137-1380.



   Example 12
 EMI12.3
 Preparation of 2-carb yl-1-méthôxg-1.2.3.4.ia, 2,10 * 10a-ottahydrophenanthrene (nuclei trans wheat) il 500 ml of ether containing 4.0 g of ammonia, slowly added to 0 4 , 75 g of the chloride obtained in Example 8 in 150 ml of benzene. The mixture is stirred for 18 hours at room temperature. Then add 1 liter of water and separate the layers that form.

   The ethereal layer is washed with 1N sodium hydroxide, 2N hydrochloric acid, water and sodium chloride solution. After
 EMI12.4
 drying and evaporation of the solvent, by crystallization in ethanol 3 g of fluxing 2.ac.rtamyl- ^ .methaxy-1,2,3,4,4a, 9,10 are obtained (Ble nuclei). to 196-197.5.

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 Example 13
 EMI13.1
 Fré aration da 2-- l-meth Z-.carbsm 1 -? - méthox¯v-1,2. "3 4.4a.9.¯ 10.10a-octahXdrophénanth.rène (H rings tr A a mixture of 250 ml 4 Ether and 5.08% of 4-ethylacin, a solution of 4.75 g of the acid chloride obtained in Example 8 in 150 ml of benzene is slowly added to 0.

   The mixture.
 EMI13.2
 is stirred for 11 hours at room temperature. Ù-4th.80, add 1 liter of water. The substance that did not dissolve *
 EMI13.3
 is then removed by filtration. ? .d-deosub, the ethereal layer is separated and washed with 1N sodium hydroxide, 2N hydrochloric acid and sodium chloride solution, After drying and evaporating the solvent, the residue is combined with the undissolved substance (separated beforehand) and the combined substances are crystallized in benzene}
 EMI13.4
 we thus obtain 3 g of 2- (H-methyl-carbamy:) -? - méthoxy.-1,2,3, 4,4a, 9,10,, 10a-oetahydrophenanthrene (B / 0 trana rings) melting at 187 -: 88.



     The above examples relate to the preparation of racemic isomers, the starting substances in each case being racemic mixtures. When we want to prepare the optical antipodes of these compounds we simply use
 EMI13.5
 as the starting material for optically active isc.Area.
The acid halides used as starting substances in the process of the invention can be prepared
 EMI13.6
 from the corresponding free acids. These free steels, in turn, can be obtained tlujvri ... '1.t. 9 e5. gtuvdbr-5

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 Example 14
 EMI14.1
 Preparation of acida, d,? -Methox -1 3 4 4a 9 10 14a octahydrophenanthrene-2-carboxylic acid (Ble trana rings):.

   A mixture of 35.74 g of 2-acetyl-7- # ethoxy-1,2,3,4 9,10-hexahydrophenanthrone, 17 ml of ethylene glycol and 0.25 g of p-toluene sulfontic acid monohydrate in 240 ml of benzene is heated under reflux for 5 hours with a water repairer. The solution is washed twice with 50 ml of sodium carbonate and twice with 50 ml of water. After drying over sodium sulphate, the aqueous layer is freed from the solvent under vacuum; the residual viscous oil consists of 1 '
 EMI14.2
 2-acetyl-7-ffiethoxy-1,2,3t4 9-cyclic ethylene acetal 10-hexahydrophenanthrene.
 EMI14.3
 



  A solution of 3Q-1 g of 2-acetyl -? - methoxy-12, 4,911-hexahydrophenaathrene - ethylene acetal in 300 ml of anhydrous ether is added, with stirring, at a rate of ablution of 13.8 g of potassium in 900 ml of ammonium
 EMI14.4
 niac liqaide at -40. After the solution has been stirred for 45 minutes, 23 g of ammonium chloride is added and the ammonia is allowed to evaporate while continuing to stir.



   The residue is treated with ice, with water and with an additional 200 ml of ether. The ethereal layer is separated and washed with water. The

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 aqueous layers are washed with 100 ml of ether. The ethereal layers are combined, dried over sodium sulfate and the solvent is removed in vacuo.



     To the residue, dissolved in 300 ml of methanol, is added
 EMI15.1
 7.5 g of oxalic acid and 75 ml of water and the mixture is heated under reflux for 1 hour. The methanol is removed under vacuum, then the residue is diluted with 100 ml of water and extracted with 300 ml of ether. The organic layer is separated and washed with water. The aqueous layers are washed with 100 ml of ether. In combined organic layers are dried with sodium sulfate and the solvent is removed under
 EMI15.2
 empty. The residue, d ,, t.-2-acetyl-'T-méthxy-1,2,, 4y4a, 9,10,10a-octahydrophénar4thréne (B / C trans rings) and crystallized in a small volume of ethanol, then recrystallized from petroleum ether; melting point 83-85 C.
 EMI15.3
 



  A solution of sodium hypobromite is prepared from 109 g (2.73 mol) of sodium hydroxide and 160 g (1.06 mol) of bromine in 1500 ml of water. to this cooled solution (ice-freezing mixture) Ron adds, with stirring, Y 'T8; (0.302 mol) (the additional amount is prepared as described above) of d / -2-acetya -? - 1,2-methoxy ", 4,4ar9,14Y1Ga-octrxhydrophrnanthrëne (B / C trans nuclei) dissolved in the, 00 ml of dioxane, one
 EMI15.4
 speed such that the temperature does not exceed 100. When the addition is complete, the cooling bath is removed and the resulting solution is stirred.

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 for 1 hour at room temperature.

   It is then concentrated empties us down to about 1/4 of its original volume, after which it is diluted with 3 liters of water. This aqueous solution is extracted twice with ether, then it is cooled to 0 ° C. and acidified with Congo red by means of approximately 600 ml of acid. hydrochloric acid 3N. The precipitated product is filtered, washed with water and dried, so that 78.2 g of crude product are obtained. This crude solid product is dissolved in 1 liter of hot chloroform, filtered through Celite, after whereby the solution is concentrated to a volume of about 250 µl. slowly adding acetone.

   The substance crystallizes in the boiling solution, which gives 65.8 g of acid
 EMI16.1
 d, w? -methoxy1,2,3,4, a, 9,10,1Ca-octahydrophdnanthrèns-2-car4oxylique (B / C trans rings), boiling point at *. 241-243 C. By further concentrating the mother liquors, 6.17 g of material is obtained, melting at 235-240 Total yield; 74.27 g, (92%).
 EMI16.2
 



  B. Has 38 g of 2.-acet ,, 1.-? - methoZy-Iy2v3,4,9,10-haxa. h1drQhenanthene in 150 ml of purified dioxane, a solution of 2.84 ml of bromine in 150 ml of 1N aqueous sodium hydroxide is added. The mixture is left to stand for 3 hours at room temperature, after which it is concentrated in vacuo to a small volume, then diluted with 60 ml of water, then extracted twice with 500 ml of ether.
 EMI16.3
 



  The aqueous layer is acidified with aulforic acid 59 and the precipitate is separated by filtration, without water.

 <Desc / Clms Page number 17>

 
 EMI17.1
 and dried. Yields 3.17 g of 7-aethOZl-1,2, ', 4.9, lo-hexahydrophenanthrene-2-carboxylic acid. After two recrystallizations from acetone, the melting point is about 184-1880.



   In a 1 liter flask cooled with dry ice and acetone, equipped with an efficient stirrer and two drying towers (potassium hydroxide), 400 ml of liquid ammonia are introduced, then 5.0 g potassium. After stirring for 5 minutes, a solution of 2.58 g of acid
 EMI17.2
 7mehoxy-1,2,3,4,9.10-hexahydrophdnanthrne-2-carboxylique in 125 ml of dioxane is added over 5 minutes, the mixture is stirred for 25 minutes and the blue color is then removed by adding 10 g of ammonium chloride. The ammonia is allowed to evaporate and the remaining solvent is removed in vacuo. The residue is treated with 100 ml of 2N hydrochloric acid and the mixture is extracted three times with a 2.5: 1 mixture of ether and methylene chloride.

   The organic layers are washed twice with water and are then extracted twice.
 EMI17.3
 taken in a total of 100 ml of IN potassium hydroxide solution. The combined basic layers are cooled and acidified with Congo red using 3N hydrochloric acid. The precipitate obtained is filtered off, washed with water and dried, so that 2.44 g of a colorless solid, melting point 208-2220, is obtained.



   The above colorless solid is dissolved

 <Desc / Clms Page number 18>

 
 EMI18.1
 in 50 ml of hot ethanol and the solution obtained is added with 1.1 ml of morpholine in 5.6 ml of ethanol. The resulting mixture is concentrated to a volume of 40 ml, after which it is cooled to room temperature and inoculated with a small amount of the morpnoline salt of the acid prepared by method A. The mixture is
 EMI18.2
 left to stand overnight at room temperature, then cooled and filtered, yielding 1.41 g of crude morpholine salt of d ", '- i-mdthocy-1,2,3,4 , 4ay3,10,10a-octaliydrophenantitrene-2-carboxylic (BIC trane rings);

   melting point 136.5-144,
A solution of the above-mentioned morpholine salt in 60 ml of methylene chloride is washed twice with 50
 EMI18.3
 ml of 2H HCl and once with water. The organic layers (washed once with water) are combined, chopped over anhydrous sodium sulphate and evaporated, to give 1.09 g of crude product; melting point 233-2390. By crystallization from methanol, 0.22 g is obtained.
 EMI18.4
 (3., Si) trans acid as a colorless solid, melting point about 239-242.5.

   Further exposure to methanol gives 0.680 g of product mp 240-243.5, this melting point not undergoing a decrease, when the product is mixed with a sample of product prepared as described in A. higher up.
 EMI18.5
 fopapleiiiM 15 Resolution of acld.7 ethox-1, 2 4 4a '.Oa..oc'-

 <Desc / Clms Page number 19>

 
 EMI19.1
 tahsdropb9nanthrane-2-carboxylic nuclei (Ble trace). 30 g decides d,? -Aethoxy -., 2,3,, a, 9..OrlOa-octahydro. phenanthrene-2-carboxylic (B / C trans rings) in 175 ml of benzene are treated with 100 ml of thionyl chloride and the mixture obtained is heated at reflux for 1 hour.



  The mixture is then cooled and concentrated to dryness but empty. The residue is evaporated twice in the presence of benzene, to remove the last traces of thionyl chloride. The crude acid chloride obtained with the addition of 75 ml of benzene is added rapidly to a solution of 18.5 g of -menthol in 50 ml of anhydrous pyridino and the solution obtained is left to stand overnight at room temperature, in a nitrogen atmosphere. The solution is then diluted with 700 ml of water and extracted three times with a 2.5: 1 mixture of methylene chloride and ether.

   The organic layers are washed three times with 2N hydrochloric acid, twice with IN sodium hydroxide solution and finally once again with water. The combined organic layers are dried over anhydrous sodium sulfate and evaporated to dryness, so that a yellow solid is obtained.
 EMI19.2
 a) BaterJ- # enthy11qu8 of the acid to -? - methoxy-1,2r, t ,, 4a, 9,10,10a-octahydrophenanthrene-2-carboxylic (b / C trana rings).



     By fractional crystallization of the aforementioned crude product

 <Desc / Clms Page number 20>

 in ethanol, 7.62 g (33%) of the ester 1-
 EMI20.1
 .enihl, l1que dextrorotatory acid as a solid, mp 121-122.50 [a] 25D = +24.90 +2 (in dioxane). Further crystallization from ethanol gives a pure sample, mp 122-123, [a] 25D = +25.4 ¯2 (c = 1.08 in dioxane).
 EMI20.2
 b) d-7-methozy-1,2,3 * 4,4a, 9,10,10a-octahydro-phenanthrene-2-carboxylic acid (B / C trans rings).



   A solution of 6.65 g of the ester precipitated in .83.5 ml of a 5% ethanolic solution of sodium hydroxide is heated under reflux for 2 hours in a nitrogen atmosphere. The solution obtained is then cooled and evaporated to dryness. The residue is diluted with 700 ml of water and washed twice with ether. The aqueous layer is then acidified in Congo by means of 3N hydrochloric acid and the precipitate obtained is filtered, dried and crystallized in methanol (charcoal), so that 3.25 g (75%) of dextrorotatory acid as a colorless solid, melting point 248-
 EMI20.3
 249.5. [] 6. +94.8 +2 (c m 1.06 in chloroform).



  Further crystallization from a mixture of chloroform and acetone gives a pure sample; melting point
 EMI20.4
 246-248, @ (a] 26 m +94.00 2 <c # in the abloroforet). c) Acid-menthyl ester. i-Cnethoxy-1r2,3,4r 4a, 9flO, 10a-octahydrophenanthrene-carboxylic (r. \). 7! L, u B / C trf <.9)

 <Desc / Clms Page number 21>

 The filtrates from ester crystallization
 EMI21.1
 Dextrocyanic acid, (* anal "ae) oat oon- centers. By fractional crystallization of the solids in acetonitrile, 5, S 9 (24.5%) of the solids are obtained. Levorotatory acid e-monthyl ester as a colorless solid, melting point $ 105.10, [#] 5.



  -93.2 +20 (c - 1.11 in dioxane). Two outraged
 EMI21.2
 crystallizations from acetonitrile give a pure sample, melting point 108-109.5, (a] 5. -95, t 20 (c # 1.00. in dioxane),
 EMI21.3
 d) Acid. ? -Methoxy-1, ',, 4,4a, 9,10.10a-octahydro-phenanthrene.-2-cariozyl (H / O trans rings).



   A solution of 5.108 g of the aforementioned ester (part "c") in 64.0 ml of a 5% ethanolic solution of potassium hydroxide is heated under reflux for 2¸ hours in a nitrogen atmosphere. The solution is then cooled and evaporated to dryness. The raidu is diluted with water and washed twice with ether. The aqueous layer is then acidified with Congo red with 3N hydrochloric acid. The precipitate obtained is crystallized once in methanol (wood charcoal) and once in chloroform, in which way 1.832 g of levorotatory acid are obtained in the form of a colorless solid; Fusion point
 EMI21.4
 247.5-249.5. [<* 3p6 -94.4 +2 (c. 1.034 in chloroform).

   An additional fraction of 0.429 gg tu8ion point 246.5-249.5, [a] 4. -93.1 +2 (c = 1.06 in the

 <Desc / Clms Page number 22>

 
 EMI22.1
 chloroform), and recovered from liqueura-nères. Total yield 2.26 g (6.11. Crystallization again from a mixture of chloroform and acetone gives a pure sample; ¯ melting point 247-248.500 Col 25 m -95, ao +20 (o # 1, 03 in chloroform).



   Example 16
 EMI22.2
 eradication of! . 2-acdt - -.metho - a 3ü bt. oetahydronhenanthrene (S / C cores isomers 1 and 2.



  AT. A solution of 102.5 g of 2-ac, ethyl - '. Metho-i, 2s3 4,9,10-hexahydrophënanthrene in 3000 ml of ethyl acetate is hydrogenated at room temperature and under atmospheric pressure, over 10, 0 g of 10% palladium on carbon.
 EMI22.3
 After absorption of one mole of hydrogen, 1: rate of hydrogenation decreases appreciably and the reaction stops. The mixture is filtered through colitis and evaporated to dryness, in order to obtain a colorless oil.



   The oily residue is crystallized from ether of
 EMI22.4
 petroleum, which gives 75 6 g of d, ", -2 aaitrl .-- athoxy- 1., y 3, 4, is,, .0, 3.t - octb, drophinarrshrin (closed isomeric B / 0 rings 2 days melting at 4.5-g'tot. Tar concentration of li Qurura-rrrs, we obtain 21 g of d, .1 (2-acetxi.? Ithoxr. In, 3, d, 4a, 9, iQ, 1Qaoctrthrdrophins , nthrna (3/0 rings, shade 1) melting point 65-66oC, 3.

   3pimerisomer of isomer 2 under acidic conditions

 <Desc / Clms Page number 23>

 
To a solution of 12.05 g of isomer 2 in 350 µl of glacial acetic acid is added 12.0 ml of a 30% solution of hydrogen bromide in glacial acetic acid and the mixture is mixed. obtained is left to stand overnight at room temperature.

   It is then varnished in 2000 ml of water, and extracted with ether, washed twice with brine twice again with a 5% solution of sodium bicarbonate and finally once again. with water, after which he nestled had? anhydrous sodium sulfate.



  Removal of the solvent gives an oil which crystallized from a mixture of ether and hexane to give 8.92 g (74%) of crude isomer; melting point 60-660.



  Further crystallization from methanol gives 6.02 g of product melting point 66-67. By crystallization from an ether-hexane mixture, a pure sample melting point 64.5-660 is obtained. The semicatbazone of the product melts at 226-228 C.



   0. Epimerization of isomer 2 under basic conditions.



   To a solution of 500 ml of isomer 2 in 15 ml of anhydrous methanol, 250 mg of sodium methoxide are added and the resulting solution is heated under reflux for 2 hours. The solution is then concentrated in the vacuum until a vacuum is reached. volume of about 5 ml and the residue is diluted with 25 ml of water.

   The product is isolated with a 2.5 µl mixture of methylene chloride and ether, washed with water, dried over sulfate.

 <Desc / Clms Page number 24>

 of anhydrous sodium and evaporates, resulting in an oil which is crystallized from a mixture of ether and hexane.



  In this way 302 mg (60%) of crude isomer 1 is obtained, melting point 60-65.
 EMI24.1
 



  <"'Pl ?. fxeaple" ##': '"i'> y,, ..



  8t30 $ Clda d, T m. t! 4a 71 LQO Cta-. h dr ¯ bn threna-2-oerbox li ue (B / C rings, isomer 1).



   A solution of sodium hypobromite is prepared from 7.0 g of sodium hydroxide and 3.5 ml of bromine in 100 ml of water. To this cooled solution (mixture
 EMI24.2
 glaca.ael, 5.0 g of d, -2 * ace "tyl-7-metaoxy-1,2,3,4,4a, 9,10,10a-oetahydrophenanthrene (rings B / Sky, isomer 1), dissolved in 100 ml of dioxane, at a rate such (about 20 minutes) that the temperature does not exceed 10 C. When the addition is complete, the cooling bath is removed and the resulting solution is stirred for hours at room temperature.

     It is then concentrated under vacuum to about 1/3 of its original volume and diluted with 500 ml of water. This solution is extracted twice with ether, then acidified with Congo red with 3N hydrochloric acid. the precipitate obtained is filtered, washed with water and dried, which gives
 EMI24.3
 4 <98 g of a colorless solid, mp 218.5 ° 2C20. Crystallization from acetonitrile gives 4.25 g (84%) of the product mp 222-223.

 <Desc / Clms Page number 25>

 



    Example 18
 EMI25.1
 Resolution of d, .-? - mtthox -i 2 4 4a 1Q lCjacetah, vdrophenanthrene-2-ca2boxylic (BC rings ci., 18om A. Ester of d-7-methoxy-1,2,3 acid , 4,4a, 9,10,1Ooctahydrophenanthrene-2-carboxylic (B / C rings five isomer 1) with 2. Mandelic acid. To a solution of the dg-1 acid prepared in Example 17, in 260 ml of benzene - 160 ml of thionyl chloride are added and the resulting solution is heated under reflux for 1 hour, then cooled and concentrated to dryness in vacuo. The residue is evaporated twice in the presence of benzine, to remove the last traces of thionyl chloride.

   With crude acid chloride
 EMI25.2
 obtained dissolved in 0 ml of anhydrous acetonitrile, a solution of 28.0 g of mandelic acid in 110 ml of anhydrous asetonitrile is added and the solution is left in repca overnight at room temperature. The resulting precipitate was filtered off and recrystallized from acetonitrils (once) and from ethanol (twice) with charcoal to give 12.77 g of the acid-mandelic acid ester. dextrorotatory forms us of a colorless solid! point
 EMI25.3
 of fusion 24p-2ü3o, a. 54.3 20 (o m 1.21 in dioxane). An additional 1.63 g fraction, mp 199-202, (4125. ¯52.8 +20 (o w 1.19 in dl.oxaae), is recovered from the mother liquor.

   Total yield 14.60 g

 <Desc / Clms Page number 26>

 
 EMI26.1
 (43%) Crystallization from ethanol gives a pure sample, mp 202-203.5, -53.90 (c - 1.12 in dioxane).



  B. D-7-methoxy-1,2., 4,4a, 9.10,1C1a-octahyàra-phenanthrene-2-carboxylic acid (B / O rings goose, isomer 1).



   A solution of 12.1 g of the aforementioned ester (part "A") in 200 ml of a 5% ethanolic solution of potassium hydroxide is heated under reflux for 2 hours in a nitrogen atmosphere. The solution is then cooled and evaporated to dryness. The residue is diluted with 600 ml of water and washed twice with ether. The aqueous layer is acidified to Congo red with 3N hydrochloric acid.

   The precipitate obtained is crystallized once in aoetonitrile, then also once in ethanol (charcoal), so that 6.10 g is obtained.
 EMI26.2
 (76.5%) of the dextrorotatory acid forms a colorless solid; mp 243.5-2460, [a 3 - +23.9 (6 1.18 in chloroform). Further crystallization from ethanol gives a pure sample, melting point
 EMI26.3
 243-245, 23 r + 5.0 2a (o - 1.21 in chloroform).



  C. Baking "wadthoxy '., R", 4arZr0 octahydrophenanthrene-2-c * rboxylic acid (B / 0 rings and $ isomer 1) with d-moddlîqu * 4 acid. The filtrates from the crystallization of l 'ester

 <Desc / Clms Page number 27>

 
 EMI27.1
 dextrorotatory acid emandelic acid (part * 10) are collected and evaporated to dryness. By hydrolysis of the residue obtained with a 5% alcoholic solution of potassium hydroxide, as described above, 21.6 g of crude solid are obtained. Crystallization from acetonitrile gives 16.19 g of crude levorotatory acid; Fusion point
 EMI27.2
 233-238, [] 5. -18.8 +20 (c .. 1.1 in chloroform).



  To a solution of 15.2 g of the abovementioned crude levorotatory acid in 88 ml of benzene, 53 ml of thionyl chloride is added and the mixture obtained is heated under reflux for 1 hour. It is then cooled and concentrated to dryness under vacuum. The residue is evaporated twice, in the presence of benzene, to remove the last traces of thionyl chloride. To the crude acid chloride obtained in 30 ml of anhydrous acetonitrile, a solution of 9.50 g of d-mandelic acid in 38 ml of acetonitrile is added and the solution is left to stand overnight at room temperature. .

   The precipitate obtained this
 EMI27.3
 filtered and crystallized once in .eo6tonitrila, in the aorta which gives 14.98 g (44%) of the d-mandelic acid ester of levorotatory acid melting point 200-2030,
 EMI27.4
 a D 54, 24 +20 (a 1, ü5 in dioxane). Oriat.3 .. sation in ethanol gives a pure sample, melting point 2Ct2. 200 0 [124 at z40 (0 m 1.04 in d, 4yr).



  D. 1-i-Mithoxy-x, 2,, 4, 4 .U, 10aoctahrdrophit anthrene-2-carboxylic acid (B / C cis rings, isomer 1).

 <Desc / Clms Page number 28>

 



  A solution of 14.98 g of the aforementioned ester (parity "C")
 EMI28.1
 in 250 ml of R4 * 4 ethanolic solution at 5i and heated under reflux for 2 hours in a nitrogen atmosphere.



  The solution is then cooled and evaporated to dryness,
The residue is diluted with 300 ml of water and washed twice with ether. The aqueous phase is acidified with Congo red with 3N hydrochloric acid. The precipitate obtained is
 EMI28.2
 crystallized from acitonitrile (1 time) and from ethanol (1 liver) with animal charcoal to give 7.09 g (71.5%) of the levorotatory acid as a colorless solid ;
 EMI28.3
 melting point 243-245.5. (aJ4. -24 +2 (c - 1.12 in chloroform) Crystallization again from 1 '
 EMI28.4
 ethanbl gives a pure sample; mp 243-24, [12, m -23.9 t20 (c = 1.27 in chloroform).



  Example 12 Preparation of d, - -methox i 2 to 14 10a-octahydrophenanthrene-'2-carbo] [yliQue (B / O rings ai ieb-mer 2).



   A. By oxidation using hypobromite of 2-acetyl-
 EMI28.5
 T-methoxy-1,2,3ry 4a, 9,10,10a-oatabyàrophenanthrene (cis B / C rings, isomer 2).



   A solution of sodium hypobromite is prepared from 30.8 g of sodium hydroxide and 47.6 g (15.4 ml) of bromine in 425 ml of water. To this cooled solution (ice bath) is added, with stirring, 22.0 g of d, @ -2-
 EMI28.6
 acetl-7-methoxy-Î, 2.3,4,4a, 9,1fl; 10aoctaàydraphén.nthz $ be

 <Desc / Clms Page number 29>

 
 EMI29.1
 (Ble oia nuclei, isomer 2). dissolved in 425 Si of dioxane, at such a rate (about 20 minutes) that the temperature does not exceed 10. When the addition is complete, the cooling bath is removed and the mixture is stirred at room temperature for 2 mud, it is then
 EMI29.2
 concentrated in vacuo to about 1/3 of its original volume, after which it is diluted with 1800 ml of water.

   The solution is extracted twice with ether, then cooled and acidified with Congo red using 3N hydrochloric acid. The precipitate obtained is filtered off, washed with water and dried, which gives 14.85 g of yellow solid; melting point 139-1520. Two recrystallizations from acetonitrile gave 10.0 g of crude product; melting point 145-162. #
To 8.8 g of this crude product in 90 ml of glacial acetic acid, 24 g of -zinc is added and the mixture is heated under reflux for 1 hour. The mixture obtained is filtered, evaporated to dryness and the product is isolated with a 10% solution of potassium hydroxide.

   This solution is acidified and the precipitate obtained is filtered and recrystallized from acetonitrile, which gives 6.16 g (31%).
 EMI29.3
 d, -? - 1,2,4-methoxy, 4,4a, 9,10,10a-octahydropheaanthrene-2-carboxylic acid (B / O cis rings, 2 isomer) formed a colorless solid; melting point 161-164. By crystallization from acetonitrile a pure sample is obtained, melting point 162-164.
 EMI29.4
 



  B. By catalytic hydrogenation of 7-c <! Thoxy- acid

 <Desc / Clms Page number 30>

 
 EMI30.1
 1 2 # 3 4 # 9 10-haxahydrophénanthrfcne-2-carboxyiiqut A suspension of 1400 g of 7-methomy-1 2 # 3 # 4 # 9,1-.heaahydrophénanthrfcne-2-aarbotyi3gue acid in 18 liters of acetate of ethyl, 155 g of 10% palladium on carbon are added. The cbtenu mixture is hydrogenated at room temperature and under atmospheric pressure, until. until the absorption of hydrogen ceases, The mixture is filtered and the catalyst is washed well with methylene chloride.



  The filtrate is concentrated to dryness giving a crude product which is as a colorless solid melting at about 141-1670. The crude product is dissolved in 16 liters of hot ethanol and the solution obtained is added with 600 ml of morpholine in 2 liters of ethanol. The product which crystallizes on standing filtered to give 1241 g of the morpholine salt, melting point 142-145. (By condensation of the liqueurs-merea, a further 55.3 g of product are obtained; melting point 143-146).
 EMI30.2
 



  Total yield; 1306 g (69.5l) By crystallization from ethanol. a pure sample is obtained, melting point 143-1460.



   A solution of the above salt of morpholine (1240 g) in 12 liters of methylene chloride was washed twice with a total of 12 liters of 3N hydrochloric acid, as well as with water (once). The organic layer is dried over anhydrous sodium sulfate and evaporated to dryness, yielding a solid which is crystallized from ethyl acetate. This gives 837 g of acid

 <Desc / Clms Page number 31>

 
 EMI31.1
 ,, -aithoxy-1,2y, 4,4a, 9,10,10a-ootahydropaenanthrae-2-carboxylic (B / C cis rings, isomer 2); Fusion point
 EMI31.2
 162.5-164.5.

   Total yield ae5. g (yield 4.95%, based on corpholine sol and overall yield of 6bai relative to 7-methomy-1,2,3,4 # 9910-hezahydro-2phenanthroic acid).



  The mother liquors from the morpholine salt are concentrated to alcohol and the residue is dissolved in 8 liters of methylene chloride. The resulting solution is washed three times with a total of 3 liters of acid.
 EMI31.3
 hydrochloric acid 39. The organic layers are washed with water, combined, dried over anhydrous sodium sulfate and evaporated to dryness. The solid material obtained is crystallized twice from ethanol, which gives 156 g of acid.
 EMI31.4
 d, '- Methoxy-1,2,3.4,4a, 9,10,10a-octahydrophenanthrno2-carboxylic (cis B / C rings, isomer 1), mp 221-2230.



   Example 20
 EMI31.5
 ReBOlutioq of d -methox acid -1 2 4a 9 0 10 ooct dro heriaathré e-2-carbox li ue (B / 0 felsf iso- rings, re 2 h.



  A. Cinchonidine sol of α-7-methoxy-1,2 ', 4,4a, 9,10,10a-octahydrophenanthrene-2-carboxylqua (cis B / C rings, 2 isomer).

 <Desc / Clms Page number 32>

 
 EMI32.1
 



  To a solution of 40.0 g of d "-? - mdthaxy-1,2,3,4,4a ,, 14,10a-ôotahydrophdnaaathrne.-2..aarboxrliq acid, us (nuclei
B / C goose, isomer 2) in 3 liters of boiling acetone, 45.25 g of cinchonidine are added and the solution is concentrated to a volume of about 2 liters. The product which crystallizes on standing is filtered. , which gives 36.05 g of colorless solid; melting point 143-155. Several subsequent crystallizations in acetone give 23.53 g
 EMI32.2
 cinchonidine salt; melting point 148.5-150.50, a5 -77.9 +20 (o m 1.01 danel'étbana). Another 3.28 g fraction, melting point 147-149, [a] 4. -79.8 ¯20 (c = 1.002 in ethanol), is recovered in the mother liquors.

   Total yield 26.81 g (63%). A pure sample crystallizes in acetone as a solid
 EMI32.3
 colorless; mp 148.5-15Q, 5 rac4 = -78.3 +2 (c. 1.01 in ethanol), B., cide, '- mdthoxyl, ... 4a, 9,10,10a. octhahydra. y phenanthrene2-carboz, ylicue (DIa alia nuclei, isomer 2).



   A solution of the above-mentioned salt of cinchonidine (26 g) in 900 ml of methylene chloride is washed twice with 500 ml of 2N hydrochloric acid and once with water. The organic layer is dried over sodium sulfate. anhydrous sodium, evaporated to dryness and the residue obtained is crystallized from ethyl acetate, which gives 7.25 g of colorless product! melting point 157-158.5,
 EMI32.4
 [CI} 4. -6y.94 +20 (c 1.01 except chloroform). A fraction

 <Desc / Clms Page number 33>

 
 EMI33.1
 additional 2.51 g, melting point a.5â, 5-158.5, [a] 5. -59.7 t2 (o # 1.02 in chloroform), is recovered from the mother liquors. Total yield of levorotatory acid, 9.76 g (81%).

   Crystallization from acetonitrile gives a pure sample, melting point 16.5-158.5
 EMI33.2
 [a) 4. -59.4 +20 (c - 1.01 in chloroform).



  C. d-7-methoxy¯l, 2,3,4.4ft, d, 10,10a-oetahydrophenanthrene-2¯carboxylic acid ephedrine salt (closed B / C rings isomer 2).
 EMI33.3
 



  The filtrates from crystallization go to levorotatory acid "cinchonldine salt" (part "A '*), combined and concentrated to dryness. By acidification of the salt obtained with 2N hydrochloric acid, as described above, 16.5 g of brat dextrorotatory acid are obtained, point
 EMI33.4
 mp 150-153, [EO] 24 * 49.4o '(c = 1.01 in chloroform). To a solution of 15.7 g of the crude textrorotatory acid in 300 ml of hot ethyl acetate, 11.17 g of ephedrine is added. The product which crystallizes on standing is filtered, which gives 21.8 g of colorless solid; melting point 158.5-161.5. By crystallization in acetate
 EMI33.5
 of ethyl, 19.83 t (63.7%) of the α-ephedrin salt is obtained. dextrorotatory acid; melting point 159-162, [a] '.



  # 23.9 +20 (o to 1.00 in ethanol). Further crystallization in ethyl acetate gives a pure sample; melting point 159.5-162.5p · a] p3 +22.70 +2 (0.11 in ethanol).

 <Desc / Clms Page number 34>

 
 EMI34.1
 



  D. d-7-mithozy-12 # 3 # 4 # 4 * # 910olOa-octabYdrophen-anthrene-2-carboxylic acid (B / O rings, oombre 2).



    '' A solution of the above-mentioned ephedrine salt (19.2 g) in
 EMI34.2
 500 al of methylene chloride * and washed twice with 250 ml of hydrochloric acid '2, then once with water. The organic layers are dried over anhydrous sodium sulfate, evaporated to dryness, then the crystalline material obtained is crystallized from ethyl acetate, so that 7.57 g of painless product is obtained,
 EMI34.3
 melting point 15T - 1580, [] 4. +59.9 2 (c is 1.01 in chloroform). An additional 2.45 g fraction, melting point 155-157, C 3J to 3 * +60.5 +2 (o m 1.01 in chloroform) is recovered from the mother liquors.

   Total yield a dextrorotatory acid: 10.02 g (88%). By crystalli-
 EMI34.4
 satation in acetonirrile, a pure sample is obtained, melting at 156.5-1530; ± J5. +60.60 (o - 1.01 in chloroform).

 <Desc / Clms Page number 35>

 



   The composa obtained according to the process of the invention have to the monk one of the following properties ... lowering the level of cholesterin in the. blood serum. anti-gonadotropic and estrogenic activity. They can therefore be used as active medicaments, in one or more of these directions, and this in the form of medicamentous preparations containing the active substance in admixture with a pharmaceutical vehicle which can be organic or inorganic, solid or liquid, suitable for oral or parenteral administration,
As pharmaceutical carrier, substances which do not react with the new compounds, for example water, gelatin, etc., can be used.

   lactose, starch, magnesium stearate, talc, gums, polyalkylene glycols, petrolatum, and other vehicles of use in medicinal preparations. These preparations can be presented in the form of tablets, dragees, suppositories, capsules or solutions, suspensions or emulsions. Where appropriate, the preparations can be sterilized and / or can contain auxiliary substances, for example. preservatives, stabilizers, wetting or emulsifying agents. They can also contain osmotic pressure regulating salts or buffer compounds, and be combined with other therapeutically useful substances.



   In the following example, a few pharmaceutical compositions are described containing as active substance a representative of the class of compounds covered by the invention,

 <Desc / Clms Page number 36>

 
 EMI36.1
 or dr-2 /! -, I-dtttéthglcarblreylj? -mdthaxy.lrr3rr4tr 9.10 r ZOa-actahdroghéranthrbne. example him "A) An injection solution contains the following sur- stances:

   
 EMI36.2
 2f- (N, 1-diethyl-csrbamy.) -? - 7-methoxy. * 2 * 3 * 4 r 4as 9.1 *, Oa-cctahydraphenanthrene 1.0 m8 ses-difethyl-acetayid 0.1 as
 EMI36.3
 
<tb> ethanol <SEP> 0.1 <SEP> ml
<tb>
<tb>
<tb> benzyl alcohol <SEP> <SEP> 0.015 <SEP> ml
<tb>
<tb> water <SEP> ad <SEP> 1.0 <SEP> ml
<tb>
 B) One gelatin capsule contains the following substances
 EMI36.4
 2- (N r 1-dlmethyl-çart amytl) -7lriethoxy-1, 2, 3 r x 4evD, 1, IQa-octahydrophénantrne 1 ma
 EMI36.5
 
<tb> lactose <SEP> 167 <SEP> mg
<tb>
<tb> starch <SEP> 37 <SEP> mg
<tb>
<tb> talc '<SEP> 5 <SEP> mg
<tb>
<tb> total <SEP> weight <SEP> 210 <SEP> mg <SEP>:
<tb>
 C) A 100 mg tablet contains the following substances *
 EMI36.6
 2- (.;

  N-d1mth11-carbamyl) -7-mthox1-1.2. '. 4.4. ,, 9,10.10ap- J .1
 EMI36.7
 octahydroph4nantrne 1.0 mg '
 EMI36.8
 
<tb> lactose <SEP> 50.0 <SEP> mg
<tb>
<tb> starch <SEP> 42.0 <SEP> mg
<tb>
 
 EMI36.9
 Latinized preg starch "5.0 mg
 EMI36.10
 
<tb> <SEP> calcium <SEP> stearate <SEP> 2.0 <SEP> mg
<tb>
 
D) Suppositories with a total weight of 1.3 g contain the following substances}
 EMI36.11
 2p- (lfi.N-dimethylcarbamrlj -? - methoxy.l, 2,, 4.4, 9.10āoctahydrophéna.nthrrte pJ'0. Oiled with hydrogenated coconut A., 149 -i,
 EMI36.12
 
<tb> wax <SEP> petal <SEP> 0.050
<tb>



    

Claims (1)

Claims 1. Process for the preparation of 7-methoxy-1,2,3,4,4a, 9,10,10a-octahydrophenanthrene derivatives, carrying in position 2 a carbamyl or substituted carbamyl group, '. characterized in that an acid halide of EMI37.1 the general formula <C - X has CH3O in which X represents a halogen atom, with ammonia or a primary or secondary amine. 2.Procédé claimed in claim 1, characterized in that the ost reaction carried out with an amine of EMI37.2 general formula H # S il, Ri dace in which R and R1 represent a hydrogen atom or a lower alkyl, hydroxyethyl or di (lower alkyl) aminoethyl group, only one of the substituents R and R being able to represent hydrogen, or he and R2. together with the nitrogen atom to which they are attached, can form a heterocyclic ring <Desc / Clms Page number 38> to 5-8 atoms, the nitrogen atom being the only hetero atom. 3. Method according to claims 1 or 2, charac- EMI38.1 ized in that methylamine, n-propylamine or dl6thylaminoethylaaine is used as the primary amine. 4. Process according to claims 1 or 2, characterized in that dimethylamine, diethylamine, diethanolamine or piperidine are used as secondary amine. 5.Process according to claims 1 to 4, characterized in that as starting material an acid halide of the formula I, wherein the B / C rings have the cis configuration. 6. Method according to claims 1 to 5, characterized in EMI38.2 this is used as the starting material: the acid halide of the high-functional isomer of octahydrophenanthrene-2-carboxylic acid (cis B / C ring). 7. Process for the preparation of 7-methoxy- derivatives EMI38.3 1,2,, 4,4a, 9, lp, lfla-oaahydrophenanthrene bearing in position 2 a carbamyl or substituted carbamyl group, as described above, in particular in the examples. 8. the products obtained according to the process of claims 1 to 7. <Desc / Clms Page number 39> 9.- A phenanthrene derivative of the general formula EMI39.1 wherein R and R1 represent a hydrogen atom or a lower alkyl, hydroxyethyl or di (lower alkyl) aminoethyl group or, together with the nitrogen atom to which the island is attached, a 5-8 membered heterocycle, the nitrogen atom being the only hetero atom. 10. A compound according to claim 9, wherein R and R1 represent hydrogen. 11. A compound according to claim 9, wherein R represents hydrogen and R1 represents methyl. 12. A compound according to claim 9, wherein R and R1 represent an ethyl group, 13. A compound according to claim 9, wherein R represents hydrogen and R1 an n-propyl group, <Desc / Clms Page number 40> 14 A compound according to claim 9, in which R and R 1 represent a methyl group, 15. A compound according to claim 9 wherein EMI40.1 R represents hydrogen and Rl a d1ethylamine group. ethyl* 16. A compound according to claim 9, wherein EMI40.2 R and Rl represent a P-hydrox $ -êthvle group. 17. A compound according to claim 9, wherein R and R1, together with the nitrogen atom to which they are attached, represent a piperidino group. EMI40.3 18. The isomer of 2- (DT-methyl-carbamyla? -Methoxy-1,2 * 3, 4.4a, 9,1010a-octahydrophenthrene (B / C rings ci @) corres- aponding stereoieaadrically with I1 the high isomer. melting point of 7-methoxy-, 2,3,4,4a, 9,1Qlps-.actahydro-phenanthrene-2-carboxylic acid "(B / C key rings), 19. The 2- isomer (1.-propyl-carbamyl) iT-tethaxy-1,2,, 4r4ar9, .0, laa-actahydraphenanthrene (B / C rings eîn) corresponding etereoomerically to the high melting point of the acid Tmdthax y - 1 v 2 e ', d 4a n, l0a-octahydrophenanthrene-2-carboxylic (cis B / C rings). 20. The high melting point isomer of 2-carbamyl-7-ebthaty.1,2, r4,4a, 9, .ü, la-octahydrophenaathrene (cis B / C rings). <Desc / Clms Page number 41> EMI41.1 21. The isomer of 2- (NfN-dimethyl-carbaoyl) -7¯me'thoxy- 1.2,3,4,4a, 9,10,10a-octahydrophinanthrene (B / C key rings) corresponding stereo1somrically to the isomer high melting point of? -methoxy ..., 2, .4., Aa, 9,1Qr10a-octahydrophenanthrene-2-carboxylic acid (B / O rings). 22. The low melting point isomer of 2 * carbamyl-7-mthoxy-1,2,3,4,4a ,, 1 (1,14a-octahydrophenanthrena (rings EMI41.2 B / C cia). EMI41.3 23. The isomer of 2- (H-diéthyaminaéthy.-Ca, rbfnayi) -? - tuétl'oxy-1,2,3r.4a, 9y14,1Ca-octahydrophénanthr & ne (Bic cia rings) corresponding atérdoloomerically to the isomer of high melting point of β -atethox ;, I-1,2, ', d, 4a, 9 w 1C y 1 (3a-octahydrophenanthrene..2-carbaxel (B / Cc rings). <Desc / Clms Page number 42> 24. Exposures having blood serum cholesterin-lowering action, and / or antigonadotropic and / or estrogenic, characterized in that they comprise a compound according to claims 8-23, as well as a pharmaceutical vehicle or carrier. 25. Compositions according to claim 24, characterized in that they are in the form of dosage units containing 0.1 to 10 mg of active substance per dosage unit. 26. Compositions according to claim 25, characterized in that they are in the form of tablets, capsules, cachets, suppositories, ova, ampoules, and the like.