CAS Registry numbers: i l l . 6591-05-5; /hi. 14100-30-2: (3bi, 14516-54-2: i 3 c ) . 14879-42-6; / l a ) , 54751-04-1 : 14h). 54751-05-2: ( 4 c j . 54751-06-3; (5~). 54751-03-0; i 5 h i . 42593-43-1 ; i S c i . 54751-07-4
K . Susar in: Methoden der organischen Chemie (Houben-Weyl-Miiller), 4th Edit., Vol. Xlljl. Thieme. Stuttgart 1955, p. 212. [2] L . Muirr, Helv. Chim. Acta 49, 1249 (1966): references cited therein. [3] E. Lindnrr and W-P. Meirr, J. Organometal. Chem. 67, 277 (1974). [4] L. Mairr, Top. Phosphorus Chem. 2, 43 (1965). [I]
hydrogenolysis of the 5-carbonyl group takes place as side reaction. The quoted ring coupling in the hydrogenated sulfone (3) is proven by chemical correlation with the hydrogenated sulfone /9)"], whose structure is confirmed by the chemical shift and coupling constant of the proton at C-I (6 = 3.48, broad triplet, 5=8 Hz) (Table 1). From the positive Cotton effect ( A E * ~ ~ 1.64)it = would appear that the phenylsulfonylmethyl group is R, i. e. in an equatorial position.
+
Synthesis of D-Norgestrel"' By Gerhard Sauer, UIrich Eder, Gregor Haffer, Giinter N e d and Rudolf Wiechert"] D-Norgestrel[2s31 (17cc-ethynyl-18-methyl-19-nortestosterone ( 8 ) is a clinically proven, extraordinarily strong progestational and ovulation inhibiting steroid. The regioselective sulfonylmethylation of optically active 7a P-ethyl-6H-7,7a-dihydroindan-1,5-dione (/)I4]opens the possibility of a new, technically simpler synthesis of D-norgestrel.
Table 1. Prepared compounds 121, (3). and ( 9 )
+
(2). m.p. 124--125°C (CCI,): [x]u= 198" ( I '% in CHCI,): IR (KBr): 1750 (5-ring ketone). 1675 (unsat. ketone), I140 and 1300/1310 c m - ' (SO.): U V ICHJOH): E Z I ~ = 1 1 700, E Z ~ I = 10400: CD (dioxane): A E , s , = -34.9. A E ~ O Z+=1 1 . 8 , A ~ . j 1 = 1 +12.5: 'H-NMR (CDCIj):6=0.98(3H, t, J = 7 . 5 H z , CHJ-CHZ), 4.09 and 4.36 (2H. AB, J = 1 3 H z , C H z - S O z ) , 7.82 (2H, dd, J = 8 H z , J = 2 H z . a r o m . H). 7.4-7.7 (3H. m a r o m . H). 13). m.p. 16&161'C (ethyl acetate): [ X I , = +82 (l';*,in CHCI,); IR ( K B r ) : 1732 (5-ring ketone), 1715 (6-ring ketone). 1310/1315 and 1 1 4 5 / 1 1 5 5 c m ~ ' +4.19: 'H-NMR (CDCI,): 6=0.94 (3H. t. (SO,); CD (dioxane): J = 7 . 2 Hz.CH,-CH2).2.Y8(l H.AB-X. J = 4 Hz. J = 1 6 Hz.CH-CH:SO,). 3.23 (1 H, m, W , ,=23Hz, CH-CH,-SO,). 4.06 ( I H. AB-X. J = 4 . 6 Hz. J = 16 Hz. CH-CH,-SO,), 7.55-7.59 (3 H. m. arom. H). 7 M 7.98 (2 H. m, arom. H). f9), m.p. 138--139°C (ethyl acetatejdiisopropyl ether): [XI"= +41" ( I 'Y, in CHC1,); 1R (KBr): 1715 (6-ring ketone), 1140 and 1300 c m - ' (SO,); CD (dioxane): 1.64; 'H-NMR (CDCI,): 6= 1.12 (3H. t. J = 7 H z . C H I CH2). I.l2(9H,s,(CH,),C), 2.R9 (1 H, AB-X, J = 2 . 8 Hz, J = 14 Hz, C H z S 0 2 ) . 3.10(1 H.m, Wl,=24H2.CH--CH,--S0,).3.48(1 H.t,J=XHz.CH-OC(CH,),), 3.96 ( I H, AB-X, J z 5 . 8 Hz. J = 1 4 Hz. CHI-SO,), 7.48-7.62 ( 3 H. m, arom. H). 7.82-7.97 (2 H. m, arom. H).
181
171
91e = C'1I3, IZt = C2T15, t R u = C[C1I3l3. PI1 = C 6 f 1 5
Reaction of the (+)-enedione ( I ) with paraformaldehyde and benzenesulfinic acid in a mixture of nitrilotriethanol (triethan~lamine)[~] and acetic acid[61at 50°C affords the sulfone (2) in 85 % yield (Table 1). Other bifunctional bases such as N,N,N',N'-tetramethylethylenediaminecan be used ; essential, however, is that base and acetic acid are used in a volume ratio of about 3 : 1. Presence of a larger amount of acetic acid accelerates the reaction, but the regioselectivity is thereby reduced, and considerable amounts of doubly alkylated products of varying structure are formed. In acid solution (ethanol with 1 % aqueous 1 N hydrochloric acid) with 6% palladium on charcoal (10%) as catalyst. the sulfone (2) is hydrogenated to the trans-fused sulfone (3) (Table 1). The yield of crystalline product is 75 %. Some [*] Dr. G. Sauer, Dr. U. Eder, Dr. G. Haffer, Dr. G. Neef, and Prof. Dr R. Wiechert Schering AG. Berlin/Bergkamen 1 Berlin 65, Miillerstrasse 170-178 A n q r w . Chum. infernal. Edir.
(Germany)
/ Vol. 14 (1975) i No. 6
In non-polar solvents (pentane/benzene) (3) reacts with the anion prepared from ethyl 7,7-ethylenedioxy-3-oxooctanoate (4)18' and sodium hydride to give high yields of the ester ( 5 ) . This crude product is then cyclized. hydrolyzed, and decarboxylated. The tricyclic compound (7) (cf. H u j m et u ~ . [ ~ I ) was isolated as an oil and for this reason a more detailed characterization was not carried out. Subsequent hydrogenation, ketal cleavage, and cyclization afford 18methyl-19-norandrostenedione(7) in an overall yield of 35':,, (from ( / I ) . D-Norgestrel (8)I2l can be obtained from (7) by ethynylation; its structure, like that of (7), is confirmed by comparison with authentic material. Received: February 5, 1975 [ Z 195 IE] German version: Angew. Chem. 87, 413 (1975) CAS Registry numbers: ( 1 ), 33878-95-4; ( 2 ) , 54832-84-7: (3). 54832-85-8; ( 4 ) , 27428-41-7: ( 5 ) . 54851-83-1; (6). 24894-31-3; ( 7 ) . 21800-83-9: (8). 797-63-7: (9). 54832-86-9 [I]
[2]
[3]
[4]
[S] [6] [7] [X]
Total Synthesis of Optically Active Steroids, Part 12.-Part 1 1 : U . Edrr, G . Sauer, J . Rupprrr, G. Hufler. and R . Wiecherr, Chem. Ber., in press. H . Smith. G. A. Hughes. G . H . Douglas, G. R . Wendr, G . C. Buzby. j u i i . , R . A. E d g r m . J . Fisher, 7: Foell. B. Gadsby, D. H u r r l q , D. Hrrbsr, A . B. A. Jansen. K . Ledig. B. J . McLoughlin. J . McMenamin. T W Pattison. P. C. Phillips. R . Rees. J . Siddall, J . Siuda, L . L . Smirh. J . T o k o l i m and D . H . P. Wcirson, J. Chem. SOC.1964. 4472. C . Ruftr, H . Kosmol, E . Schrlidur, K . Kieslich, and H . Gihian. Liebigs Ann. Chem. 702, 141 (1967). a ) U . Edrr. G. Sauer, and R . Wtechrrr, Angew. Chem. 83, 492 (1971); Angew. Chem. internat. Edit. 10, 496 (1971); b) Z . G. Hajos and D. R . Parrish, J. Org. Chem. 39, 1615 (1974). D. H . Kirk and !I Perrow. J. Chem. Soc. 1962, 1091. H. Hellmann and K. Miiller. Chem. Ber. 98, 638 (1965). Preparation of / Y ) : G. Sauer er a / . , to be published. 2. G. Hujos and D. R. Purrish, J. Org. Chem. 38, 3239. 3244 (1973).
417
K . Susar in: Methoden der organischen Chemie (Houben-Weyl-Miiller), 4th Edit., Vol. Xlljl. Thieme. Stuttgart 1955, p. 212. [2] L . Muirr, Helv. Chim. Acta 49, 1249 (1966): references cited therein. [3] E. Lindnrr and W-P. Meirr, J. Organometal. Chem. 67, 277 (1974). [4] L. Mairr, Top. Phosphorus Chem. 2, 43 (1965). [I]
hydrogenolysis of the 5-carbonyl group takes place as side reaction. The quoted ring coupling in the hydrogenated sulfone (3) is proven by chemical correlation with the hydrogenated sulfone /9)"], whose structure is confirmed by the chemical shift and coupling constant of the proton at C-I (6 = 3.48, broad triplet, 5=8 Hz) (Table 1). From the positive Cotton effect ( A E * ~ ~ 1.64)it = would appear that the phenylsulfonylmethyl group is R, i. e. in an equatorial position.
+
Synthesis of D-Norgestrel"' By Gerhard Sauer, UIrich Eder, Gregor Haffer, Giinter N e d and Rudolf Wiechert"] D-Norgestrel[2s31 (17cc-ethynyl-18-methyl-19-nortestosterone ( 8 ) is a clinically proven, extraordinarily strong progestational and ovulation inhibiting steroid. The regioselective sulfonylmethylation of optically active 7a P-ethyl-6H-7,7a-dihydroindan-1,5-dione (/)I4]opens the possibility of a new, technically simpler synthesis of D-norgestrel.
Table 1. Prepared compounds 121, (3). and ( 9 )
+
(2). m.p. 124--125°C (CCI,): [x]u= 198" ( I '% in CHCI,): IR (KBr): 1750 (5-ring ketone). 1675 (unsat. ketone), I140 and 1300/1310 c m - ' (SO.): U V ICHJOH): E Z I ~ = 1 1 700, E Z ~ I = 10400: CD (dioxane): A E , s , = -34.9. A E ~ O Z+=1 1 . 8 , A ~ . j 1 = 1 +12.5: 'H-NMR (CDCIj):6=0.98(3H, t, J = 7 . 5 H z , CHJ-CHZ), 4.09 and 4.36 (2H. AB, J = 1 3 H z , C H z - S O z ) , 7.82 (2H, dd, J = 8 H z , J = 2 H z . a r o m . H). 7.4-7.7 (3H. m a r o m . H). 13). m.p. 16&161'C (ethyl acetate): [ X I , = +82 (l';*,in CHCI,); IR ( K B r ) : 1732 (5-ring ketone), 1715 (6-ring ketone). 1310/1315 and 1 1 4 5 / 1 1 5 5 c m ~ ' +4.19: 'H-NMR (CDCI,): 6=0.94 (3H. t. (SO,); CD (dioxane): J = 7 . 2 Hz.CH,-CH2).2.Y8(l H.AB-X. J = 4 Hz. J = 1 6 Hz.CH-CH:SO,). 3.23 (1 H, m, W , ,=23Hz, CH-CH,-SO,). 4.06 ( I H. AB-X. J = 4 . 6 Hz. J = 16 Hz. CH-CH,-SO,), 7.55-7.59 (3 H. m. arom. H). 7 M 7.98 (2 H. m, arom. H). f9), m.p. 138--139°C (ethyl acetatejdiisopropyl ether): [XI"= +41" ( I 'Y, in CHC1,); 1R (KBr): 1715 (6-ring ketone), 1140 and 1300 c m - ' (SO,); CD (dioxane): 1.64; 'H-NMR (CDCI,): 6= 1.12 (3H. t. J = 7 H z . C H I CH2). I.l2(9H,s,(CH,),C), 2.R9 (1 H, AB-X, J = 2 . 8 Hz, J = 14 Hz, C H z S 0 2 ) . 3.10(1 H.m, Wl,=24H2.CH--CH,--S0,).3.48(1 H.t,J=XHz.CH-OC(CH,),), 3.96 ( I H, AB-X, J z 5 . 8 Hz. J = 1 4 Hz. CHI-SO,), 7.48-7.62 ( 3 H. m, arom. H). 7.82-7.97 (2 H. m, arom. H).
181
171
91e = C'1I3, IZt = C2T15, t R u = C[C1I3l3. PI1 = C 6 f 1 5
Reaction of the (+)-enedione ( I ) with paraformaldehyde and benzenesulfinic acid in a mixture of nitrilotriethanol (triethan~lamine)[~] and acetic acid[61at 50°C affords the sulfone (2) in 85 % yield (Table 1). Other bifunctional bases such as N,N,N',N'-tetramethylethylenediaminecan be used ; essential, however, is that base and acetic acid are used in a volume ratio of about 3 : 1. Presence of a larger amount of acetic acid accelerates the reaction, but the regioselectivity is thereby reduced, and considerable amounts of doubly alkylated products of varying structure are formed. In acid solution (ethanol with 1 % aqueous 1 N hydrochloric acid) with 6% palladium on charcoal (10%) as catalyst. the sulfone (2) is hydrogenated to the trans-fused sulfone (3) (Table 1). The yield of crystalline product is 75 %. Some [*] Dr. G. Sauer, Dr. U. Eder, Dr. G. Haffer, Dr. G. Neef, and Prof. Dr R. Wiechert Schering AG. Berlin/Bergkamen 1 Berlin 65, Miillerstrasse 170-178 A n q r w . Chum. infernal. Edir.
(Germany)
/ Vol. 14 (1975) i No. 6
In non-polar solvents (pentane/benzene) (3) reacts with the anion prepared from ethyl 7,7-ethylenedioxy-3-oxooctanoate (4)18' and sodium hydride to give high yields of the ester ( 5 ) . This crude product is then cyclized. hydrolyzed, and decarboxylated. The tricyclic compound (7) (cf. H u j m et u ~ . [ ~ I ) was isolated as an oil and for this reason a more detailed characterization was not carried out. Subsequent hydrogenation, ketal cleavage, and cyclization afford 18methyl-19-norandrostenedione(7) in an overall yield of 35':,, (from ( / I ) . D-Norgestrel (8)I2l can be obtained from (7) by ethynylation; its structure, like that of (7), is confirmed by comparison with authentic material. Received: February 5, 1975 [ Z 195 IE] German version: Angew. Chem. 87, 413 (1975) CAS Registry numbers: ( 1 ), 33878-95-4; ( 2 ) , 54832-84-7: (3). 54832-85-8; ( 4 ) , 27428-41-7: ( 5 ) . 54851-83-1; (6). 24894-31-3; ( 7 ) . 21800-83-9: (8). 797-63-7: (9). 54832-86-9 [I]
[2]
[3]
[4]
[S] [6] [7] [X]
Total Synthesis of Optically Active Steroids, Part 12.-Part 1 1 : U . Edrr, G . Sauer, J . Rupprrr, G. Hufler. and R . Wiecherr, Chem. Ber., in press. H . Smith. G. A. Hughes. G . H . Douglas, G. R . Wendr, G . C. Buzby. j u i i . , R . A. E d g r m . J . Fisher, 7: Foell. B. Gadsby, D. H u r r l q , D. Hrrbsr, A . B. A. Jansen. K . Ledig. B. J . McLoughlin. J . McMenamin. T W Pattison. P. C. Phillips. R . Rees. J . Siddall, J . Siuda, L . L . Smirh. J . T o k o l i m and D . H . P. Wcirson, J. Chem. SOC.1964. 4472. C . Ruftr, H . Kosmol, E . Schrlidur, K . Kieslich, and H . Gihian. Liebigs Ann. Chem. 702, 141 (1967). a ) U . Edrr. G. Sauer, and R . Wtechrrr, Angew. Chem. 83, 492 (1971); Angew. Chem. internat. Edit. 10, 496 (1971); b) Z . G. Hajos and D. R . Parrish, J. Org. Chem. 39, 1615 (1974). D. H . Kirk and !I Perrow. J. Chem. Soc. 1962, 1091. H. Hellmann and K. Miiller. Chem. Ber. 98, 638 (1965). Preparation of / Y ) : G. Sauer er a / . , to be published. 2. G. Hujos and D. R. Purrish, J. Org. Chem. 38, 3239. 3244 (1973).
417
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