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Synthesis of some aromatic prostaglandin analogs
PROSTAGLANDINS SYNTHESIS OF SOME AROMATIC PROSTAGLANDIN ANALOGS Carl D. Perchonock* and Bernard Loevl Research and Development Division, Smith Kline & French Laboratories, Philadelphia, Pennsylvania 19101
ABSTRACT Some aromatic prostaglandin analogs, having a benzene (2a, 2&) and a dimethoxybenzene (&) ring in place of the cyclopentane moiety, have been synthesized. The key intermediates in the syntheses were lactols 2 and 2, which were elaborated to the final products via two olefination reactions. Compound> was twice as potent as phenylbutazone and nine times as potent as aspirin in inhibiting prostaglandin synthetase activity. INTRODUCTION Many reports on the synthesis and biological activity of the natural prostaglandins and their close analogs have appeared in the recent literature.[l] Since these studies have focused mainly on modifications of the side chains and on the oxidation state of the ring, the synthesis of "prostaglandins" in which the cyclopentane moiety is replaced by an aromatic ring appeared an attractive goal. Such analogs should display significantly different profiles of absorption and metabolism, and might therefore show a greater selectivity and/or duration of action. Furthermore, through a suitable choice of substituents the facile conversion to a variety of new types of prostaglandin analogs would be possible. There have been a few reports of aromatic prostaglandin analogs, with the aromatic ring being benzene [2], m-dimethoxybenzene [3], and thiazole [4]. In neither of the first two cases, however, did the analogs possess the side chains present in the natural prostaglandins. We now report the synthesis of some aromatic prostaglandin analogs (l.,2a, 2b) all having the side chains found in the PGl series.
1.
Present Address: U.S.V. Pharmaceutical Corporation Tuckahoe, New York 10707
APRIL 1978 VOL. 15 NO. 4
623
OCH3
+ 83
OCH3
OH 1
OH 2,” R = CH3
ZbR-H
METHODS AND RESULTS The key intermediate in the synthesis of compound 1 was lactol 5, prepared from 2,3-dicyanohydroquinone(a), as shown i';; Scheme I.[57 Methylation of 2 (CH31, K2CO DMF) afforded a 95% yield of 3,6-dimethoxyphthalonitrile(m.p. 280-1' 83'), which was hydrolyzed (NaOH) to the diacid and dehydrated (Ac20) to ftin 83% yield; m.p. 265-268' (lit. [6] 264"). Reduction to 4,7_dimethoxyphthalide(92%; m.p. 168-170'; ir 5.70~) was achieved with NaBH4 [7], and further reduction with diisobutylaluminumhydride (CH2C12, -60") yielded lactol 2 (93.5%; m.p. 156-158"; ir 3.00~). Wittig reaction with the ylide derived from 5carboxypentyltriphenylphosphonium bromide (DMSO, 66 hr) gave the cisolefin 6+ (z. 45%), as judged by the 9 Hz coupling of the vinyl pz tons. Esterification (CH2N2, Et20, 0') and catalytic hydrogenation (1 atm. H2/Pt02, EtOH) produced in 80% yield the saturated hydroxyester 3 (ir 2.85, 5.78u), which was oxidized to the aldehyde (87%; ir 5.78, 5.92u; nmr (CC14) 6 9.89 (lH,s)) with the Jones reagent [8]. Reaction with dimethyl (2-oxoheptyl)-phosphonate[9] (NaH, DME, 85', 18 hr) afforded an 81% yield of enone $ (ir 5.75, 5.92, 6.02, 6.22, 6.33~; nmr (CC14) 6 6.75 (lH, d, J=15), 7.59 (lH, d, J=15>), and reduction with KBH4/CH30H then afforded I+ (96%; ir 2.85, 5.76, 6.23~; nmr (CC14) 6 0.7-1.8 (19H, m), 2.0-2.8 (5H, m), 3.57 (3H, s), 3.66 (3H, s), 3.70 (3H, s), 4.26 (lH, m), 5.88 (lH, d of d, J-6, 15>, 6.36 (lH, d, J=15), 6.50 (2H, s)). For the synthesis of the ring-unsubstitutedanalogs 2,"and 22 (Scheme II), lactols [lo] was reacted with the ylide derived from 4-carboxybutyltriphenylphosphoniumbromide (DMSO, 40 hr), giving a 57% yield of 13 (m.p. 92-94.5"; ir 2.98, 3.08, 5.89, 10.3~; nmr (CDC13) 6 6.0 (lH, m), 6.6 (lH, d, J=15)). The position and stereochemistryof the double bond, which must arise through an isomerizationprocess, were indicated by the ir and nmr data. Reduction of the olefin (1 atm. H2/ pt02, EtOH) afforded an 80% yield of the saturated hydroxy acid (m.p. 75-77"; ir 2.98, 3.08, 5.91u), and esterification (H+/CH30H) gave 2
624
APRIL
1978 VOL. 15 NO. 4
PROSTAGLANDINS
Scheme I OH 1) CH31
1) NaBH4 2) DIBAL-H
b 2) NaOH 3) Ac20 OH 3 IV CH30
OH -
Ph3P = CH(CH2>4C02
/ \ w CH30
C02H
0
I
CH20H
+ CH30
5 hl
6 CH30 CO2CH3
1) CH2N2 2) H2/Pt =
Q& CH30 7 CH30
1) Cr03-H2S04 ?;
2)
)
h3
(CH30)2PCH2cc5H11 CH30
0
NaH si
APRIL
1978 VOL. 15 NO. 4
625
PROSTAGLANDINS
(98.5%; ir 2.89, 5.78~; nmr (CC14) 6 3.52 (3H, 6)). Oxidation with Mn02 yielded the corresponding aldehyde (98.5%; ir 5.74, 5.90; nmr (CC14) 6 3.58 (3H, s), 10.00 (lH, s)), which was converted with dimethyl (2-oxoheptyl)-phosphonate(DME, 25", 3hr) to enone 12 (79%; ir 5.70, 5.89, 5.98, 6.18, 6.22~; nmr (CC14) 6 3.58 (3H, s), 6.50 (U-I,d, J=16), 7.70 (lH, d, J=16)). Reduction with KRH4jCH30H then afforded b in 74% yield (ir 2.85, 5.75~; nmr (CC14) 6 0.7-1.9 (19H, m), 2.2 (3H, m) 2.6 (2H, m), 3.58 (3H, s), 4.15 (lH, m), 5.95 (lH, d of d, J=6, 15), 6.70 (lH, d, J=l5>, 7.0 (4H, m)). Finally, basic hydrolysis (K2C03/CH30H-H20,25', 24 hr) produced acid 2,b(93%; ir 2.98, 5.9Ou). Scheme II
Ph3P=CH(CH2)3CO2- / ‘, 7'"" 9
1) H2/Pt 2) H+/CH30H +
rco2cH3
:; ;;0)2!CH2!,,: 2
KRR4
K2C03 +
626
2a
APRIL
t
1978 VOL. 15 NO. 4
2b
PROSTAGLANDINS
Compounds L 23, and ?;bshowed weak prostaglandin antagonist activity in the PGE2-induced diarrhea test in mice [11,12]. Compound 2> was twice as potent as phenylbutazone and nine times as potent as aspirin in inhibiting prostaglandin synthetase activity [13]. It had marginal activity in decreasing the spontaneous tracheal tone of the guinea pig [I41 * ACKNOWLEDGEMENTS We thank Mr. G. Roberts for the mass spectra, Dr. E. R. White for HPLC studies, and Mr. W. Groves, Ms. L. Sofranko, Dr. J. Horodniak, and Ms. E. Matz for the pharmacological testing. REFERENCES
111 For example, see R. A. Mueller and L. E. Flanders, Annual Reports -in Medicinal Chemistry,2, 162 (1974), and references therein.
[21 A. Collet and J. Jacques, Chim. E.,
5, 163 (1970).
[31 S. A. Sandoz, Belgium Patent 774,784, November 2, 1970; S. A. Sandoz, U.S. Patent 3,804,883, November 22, 1971; S. A. Sandoz, U.S. Patent 3,819,694, November 22, 1971; S. A. Sandoz, U.S. Patent 3,824,278, March 23, 1972. [41 G. Ambrus and I. Barta, Prostaglandins, 1,0,661 (1975). 151 Satisfactory spectral data were obtained for all compounds (chromatographically homogeneous on silica gel or alumina). Confirmation of identity was provided by mass spectra or combustion analysis. 161 V. C. Farmer, J. Chem. =.,
3600 (1956).
[71 D. M. Bailey and R. E. Johnson, J. Org. Chem., 32, 3574 (1970). [81 K. Bowden, I. M. Heilbron, E. R. H. Jones, and B. C. L. Weedon, 2. Chem. %., 39 (1946). [91 E. J. Corey, N. M. Weinshenker, T. K. Schaaf, and W. Huber, 2. Amer. Chem. *., 92, 5675 (1969). -[lOI
G. Kraiss, M. Povdrny, P. Scheiber, and K. Nbdor, Tetrahedron s., 2359 (1973).
[Ill
J. H. Sanner, Intra-Science Chem. Rept., 2, 1 (1972).
[I21
A. Bennett and B. Fleshler, Gastroenterology,53,
1131 C. Takeguchi and C. ‘J. Sih, Prostaglandins,3
794 (1970).
169 (1972).
Arch. Int. Pharmacodyn., l22, 201 (1959). [I41 A. Akcasu, -APRIL 1978 VOL. 15 NO. 4
627
ABSTRACT Some aromatic prostaglandin analogs, having a benzene (2a, 2&) and a dimethoxybenzene (&) ring in place of the cyclopentane moiety, have been synthesized. The key intermediates in the syntheses were lactols 2 and 2, which were elaborated to the final products via two olefination reactions. Compound> was twice as potent as phenylbutazone and nine times as potent as aspirin in inhibiting prostaglandin synthetase activity. INTRODUCTION Many reports on the synthesis and biological activity of the natural prostaglandins and their close analogs have appeared in the recent literature.[l] Since these studies have focused mainly on modifications of the side chains and on the oxidation state of the ring, the synthesis of "prostaglandins" in which the cyclopentane moiety is replaced by an aromatic ring appeared an attractive goal. Such analogs should display significantly different profiles of absorption and metabolism, and might therefore show a greater selectivity and/or duration of action. Furthermore, through a suitable choice of substituents the facile conversion to a variety of new types of prostaglandin analogs would be possible. There have been a few reports of aromatic prostaglandin analogs, with the aromatic ring being benzene [2], m-dimethoxybenzene [3], and thiazole [4]. In neither of the first two cases, however, did the analogs possess the side chains present in the natural prostaglandins. We now report the synthesis of some aromatic prostaglandin analogs (l.,2a, 2b) all having the side chains found in the PGl series.
1.
Present Address: U.S.V. Pharmaceutical Corporation Tuckahoe, New York 10707
APRIL 1978 VOL. 15 NO. 4
623
OCH3
+ 83
OCH3
OH 1
OH 2,” R = CH3
ZbR-H
METHODS AND RESULTS The key intermediate in the synthesis of compound 1 was lactol 5, prepared from 2,3-dicyanohydroquinone(a), as shown i';; Scheme I.[57 Methylation of 2 (CH31, K2CO DMF) afforded a 95% yield of 3,6-dimethoxyphthalonitrile(m.p. 280-1' 83'), which was hydrolyzed (NaOH) to the diacid and dehydrated (Ac20) to ftin 83% yield; m.p. 265-268' (lit. [6] 264"). Reduction to 4,7_dimethoxyphthalide(92%; m.p. 168-170'; ir 5.70~) was achieved with NaBH4 [7], and further reduction with diisobutylaluminumhydride (CH2C12, -60") yielded lactol 2 (93.5%; m.p. 156-158"; ir 3.00~). Wittig reaction with the ylide derived from 5carboxypentyltriphenylphosphonium bromide (DMSO, 66 hr) gave the cisolefin 6+ (z. 45%), as judged by the 9 Hz coupling of the vinyl pz tons. Esterification (CH2N2, Et20, 0') and catalytic hydrogenation (1 atm. H2/Pt02, EtOH) produced in 80% yield the saturated hydroxyester 3 (ir 2.85, 5.78u), which was oxidized to the aldehyde (87%; ir 5.78, 5.92u; nmr (CC14) 6 9.89 (lH,s)) with the Jones reagent [8]. Reaction with dimethyl (2-oxoheptyl)-phosphonate[9] (NaH, DME, 85', 18 hr) afforded an 81% yield of enone $ (ir 5.75, 5.92, 6.02, 6.22, 6.33~; nmr (CC14) 6 6.75 (lH, d, J=15), 7.59 (lH, d, J=15>), and reduction with KBH4/CH30H then afforded I+ (96%; ir 2.85, 5.76, 6.23~; nmr (CC14) 6 0.7-1.8 (19H, m), 2.0-2.8 (5H, m), 3.57 (3H, s), 3.66 (3H, s), 3.70 (3H, s), 4.26 (lH, m), 5.88 (lH, d of d, J-6, 15>, 6.36 (lH, d, J=15), 6.50 (2H, s)). For the synthesis of the ring-unsubstitutedanalogs 2,"and 22 (Scheme II), lactols [lo] was reacted with the ylide derived from 4-carboxybutyltriphenylphosphoniumbromide (DMSO, 40 hr), giving a 57% yield of 13 (m.p. 92-94.5"; ir 2.98, 3.08, 5.89, 10.3~; nmr (CDC13) 6 6.0 (lH, m), 6.6 (lH, d, J=15)). The position and stereochemistryof the double bond, which must arise through an isomerizationprocess, were indicated by the ir and nmr data. Reduction of the olefin (1 atm. H2/ pt02, EtOH) afforded an 80% yield of the saturated hydroxy acid (m.p. 75-77"; ir 2.98, 3.08, 5.91u), and esterification (H+/CH30H) gave 2
624
APRIL
1978 VOL. 15 NO. 4
PROSTAGLANDINS
Scheme I OH 1) CH31
1) NaBH4 2) DIBAL-H
b 2) NaOH 3) Ac20 OH 3 IV CH30
OH -
Ph3P = CH(CH2>4C02
/ \ w CH30
C02H
0
I
CH20H
+ CH30
5 hl
6 CH30 CO2CH3
1) CH2N2 2) H2/Pt =
Q& CH30 7 CH30
1) Cr03-H2S04 ?;
2)
)
h3
(CH30)2PCH2cc5H11 CH30
0
NaH si
APRIL
1978 VOL. 15 NO. 4
625
PROSTAGLANDINS
(98.5%; ir 2.89, 5.78~; nmr (CC14) 6 3.52 (3H, 6)). Oxidation with Mn02 yielded the corresponding aldehyde (98.5%; ir 5.74, 5.90; nmr (CC14) 6 3.58 (3H, s), 10.00 (lH, s)), which was converted with dimethyl (2-oxoheptyl)-phosphonate(DME, 25", 3hr) to enone 12 (79%; ir 5.70, 5.89, 5.98, 6.18, 6.22~; nmr (CC14) 6 3.58 (3H, s), 6.50 (U-I,d, J=16), 7.70 (lH, d, J=16)). Reduction with KRH4jCH30H then afforded b in 74% yield (ir 2.85, 5.75~; nmr (CC14) 6 0.7-1.9 (19H, m), 2.2 (3H, m) 2.6 (2H, m), 3.58 (3H, s), 4.15 (lH, m), 5.95 (lH, d of d, J=6, 15), 6.70 (lH, d, J=l5>, 7.0 (4H, m)). Finally, basic hydrolysis (K2C03/CH30H-H20,25', 24 hr) produced acid 2,b(93%; ir 2.98, 5.9Ou). Scheme II
Ph3P=CH(CH2)3CO2- / ‘, 7'"" 9
1) H2/Pt 2) H+/CH30H +
rco2cH3
:; ;;0)2!CH2!,,: 2
KRR4
K2C03 +
626
2a
APRIL
t
1978 VOL. 15 NO. 4
2b
PROSTAGLANDINS
Compounds L 23, and ?;bshowed weak prostaglandin antagonist activity in the PGE2-induced diarrhea test in mice [11,12]. Compound 2> was twice as potent as phenylbutazone and nine times as potent as aspirin in inhibiting prostaglandin synthetase activity [13]. It had marginal activity in decreasing the spontaneous tracheal tone of the guinea pig [I41 * ACKNOWLEDGEMENTS We thank Mr. G. Roberts for the mass spectra, Dr. E. R. White for HPLC studies, and Mr. W. Groves, Ms. L. Sofranko, Dr. J. Horodniak, and Ms. E. Matz for the pharmacological testing. REFERENCES
111 For example, see R. A. Mueller and L. E. Flanders, Annual Reports -in Medicinal Chemistry,2, 162 (1974), and references therein.
[21 A. Collet and J. Jacques, Chim. E.,
5, 163 (1970).
[31 S. A. Sandoz, Belgium Patent 774,784, November 2, 1970; S. A. Sandoz, U.S. Patent 3,804,883, November 22, 1971; S. A. Sandoz, U.S. Patent 3,819,694, November 22, 1971; S. A. Sandoz, U.S. Patent 3,824,278, March 23, 1972. [41 G. Ambrus and I. Barta, Prostaglandins, 1,0,661 (1975). 151 Satisfactory spectral data were obtained for all compounds (chromatographically homogeneous on silica gel or alumina). Confirmation of identity was provided by mass spectra or combustion analysis. 161 V. C. Farmer, J. Chem. =.,
3600 (1956).
[71 D. M. Bailey and R. E. Johnson, J. Org. Chem., 32, 3574 (1970). [81 K. Bowden, I. M. Heilbron, E. R. H. Jones, and B. C. L. Weedon, 2. Chem. %., 39 (1946). [91 E. J. Corey, N. M. Weinshenker, T. K. Schaaf, and W. Huber, 2. Amer. Chem. *., 92, 5675 (1969). -[lOI
G. Kraiss, M. Povdrny, P. Scheiber, and K. Nbdor, Tetrahedron s., 2359 (1973).
[Ill
J. H. Sanner, Intra-Science Chem. Rept., 2, 1 (1972).
[I21
A. Bennett and B. Fleshler, Gastroenterology,53,
1131 C. Takeguchi and C. ‘J. Sih, Prostaglandins,3
794 (1970).
169 (1972).
Arch. Int. Pharmacodyn., l22, 201 (1959). [I41 A. Akcasu, -APRIL 1978 VOL. 15 NO. 4
627