3718
`
`J. Org. Chem. 1989, 54, 3718-3721
`Synthesis of Unsymmetrical Dithioacetals: An Efficient Synthesis of a
`Novel LTD4 Antagonist, L-660,711
`
`J. M. McNamara,* J. L. Leazer, M. Bhupathy, J. S. Amato, R. A. Reamer, P. J. Reider, and
`E. J. J. Grabowski
`Process Research Department, Merck Sharp & Dohme Research Labs, Division of Merck & Co., Inc.,
`P.0. Box 2000, R80Y-240, Rahway, New Jersey 07065
`Received September 27, 1988
`
`An efficient four-step synthesis of the potent LTD4 antagonist L-660,711 (1) is described. The key step involves
`selective conversion of aldehyde 2 to the unsymmetrical dithioacetal 7, via O-trimethylsilyl hemithioacetal 10.
`This specific cleavage of the carbon-oxygen bond of a mixed 0,S-acetal permits the unprecedented synthesis
`of unsymmetrical dithioacetals.
`
`The important biological activity of the slow-reacting
`substance of anaphylaxis (SRS-A) has been attributed to
`the leukotrienes LTC4, LTD4, and LTE4. Their potentially
`important role in the etiology of human asthma and other
`diseases suggests that leukotriene antagonists will offer
`effective new therapy. Thus, extensive efforts have been
`directed toward the discovery and synthesis of such
`agents.1
`L-660,711 (1) [5-(3-(2-(7-chloroquinolin-2-yl)ethenyl)-
`phenyl)-4,6-dithianonanedicarboxylic acid N,N-di-
`methylamide]2 is a potent, orally active, specific LTD4
`antagonist. As part of our efforts on this important clinical
`candidate an efficient synthesis was designed. This paper
`details that synthesis.
`A retrosynthetic analysis of 1 is outlined in Scheme I,
`the key step being the construction of the unsymmetrical
`In order to achieve this
`dithioacetal 1 from aldehyde 2.
`transformation in a selective manner, novel methodology
`was required. The intermediate aldehyde 2 would come
`from the coupling of two readily available fragments:
`7-chloroquinaldine (3)3 and 1,3-benzenedicarboxaldehyde
`(4).4
`
`Results and Discussion
`Aldehyde Synthesis. Aldehyde 2 was prepared by
`condensation of 7-chloroquinaldine (3) with 1.5 equiv of
`1,3-benzenedicarboxaldehyde (4) in the presence of acetic
`anhydride (3 equiv).5 A major byproduct, bis-adduct 5,
`was produced to the extent of ca. 20%. The crude product
`was isolated as a 4:1 mixture of 2:5 in 90% yield by fil-
`tration. Purification was effected by digestion of the crude
`product in hot ethyl acetate, removal of the extremely
`In
`insoluble bis-adduct 5 by filtration, and crystallization.
`>98% pure aldehyde 2 was obtained in 65%
`this manner
`overall yield. Use of less than 1.5 equiv of 1,3-benzene-
`dicarboxaldehyde (4) in the condensation reaction gave
`unacceptably high levels of bis-adduct 5. Conversely, use
`
`(1) Young, R. N.; Guinden, T. R.; Jones, A. W.; Ford-Hutchinson, P.;
`Belanger, P.; Champion, E.; Charette, L.; DeHaven, R. N.; Denis, D.;
`Fortin, R.; Frenette, R.; Gauthier, J.-Y.; Gillard, J. W.; Kakushima, M.;
`Letts, L. G.; Masson, P.; Maycock, A.; McFarlane, C.; Piechuta, H.; Pong,
`S. S.; Rosenthal, A.; Williams, H.; Zamboni, R.; Yoakim, C.; Rokach, J.
`Advances in Prostaglandin, Thromboxane, and Leukotriene Research;
`Raven Press: New York, 1986; Vol. 16, p 37.
`(2) Zamboni, R. J.; Jones, T. R.; Belley, M.; Champion, E.; Charette,
`L.; DeHaven, R. N.; Frenette, R.; Gauthier, J.-Y.; Leger, S.; Masson, P.;
`McFarlane, C.; Pong, S. S.; Piechuta, H.; Rokach, J.; Therien, M.; Wil-
`liams, H. W. R.; Young, R. N.; J. Med. Chem., submitted for publication.
`(3) Leir, C. M. J. Org. Chem. 1977,42, 911. Commercially available
`from Trans World Chemicals, Inc.
`(4) Rosenmund, K. W.; Zetzsche, F. Chem. Ber. 1921,54,2888. Ack-
`erman, J. H.; Surrey, A. R. Organic Syntheses; Wiley: New York, 1973;
`Collect. Vol. V, p 668.
`(5) Benrath, A. J. Prakt. Chem. 1906, 73, 383.
`
`Scheme I
`
`o
`
`CHO
`
`CHO
`
`OHC1
`
`3
`
`4
`
`of more than 2 equiv of 4 improved the ratio of 2:5 but was
`not economically feasible.
`
`6: R1 = R2=OMe
`7: R1=OMe, R2=NMe2
`8: R1 = R2=NMe2
`
`-A OMe
`
`CHO
`
`0022-3263/89/1954-3718$01.50/0
`
`© 1989 American Chemical Society
`
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`

`Synthesis of Unsymmetrical Dithioacetals
`Scheme II
`ox
`
`Ar—C
`
`A
`
`RJSH
`
`R<SH -
`
`Ar—CH
`^SR3
`B
`
`SR4
`
`Ar—CH
`^SR3
`C
`
`Dithioacetal Synthesis. Our initial attempts to pre-
`pare a symmetrical dithioacetal 6 via aldehyde 2 by re-
`action with methyl 3-mercaptopropionate were
`unsuc-
`cessful. Reaction of 2 with 2.0 equiv of methyl 3-
`mercaptopropionate and a catalytic amount of pyridinium
`p-toluenesulfonate (PPTS) in refluxing benzene gave ad-
`duct 9, which arises from conjugate addition of the thiol
`to the unsaturated quinoline. Lewis acids such as zinc
`halides also led to conjugate addition. Boron trifluoride
`etherate, however, was found to be an ideal Lewis acid,
`effecting the desired conversion of aldehyde 2 to dithio-
`acetals without promoting conjugate addition. For exam-
`ple, treatment of 2 with 2.0 equiv of methyl 3-mercapto-
`propionate and 2.0 equiv of boron trifluoride etherate in
`anhydrous methylene chloride at 0 °C gave dithioacetal
`It should be noted that at least 2 equiv
`6 in 87% yield.
`of boron trifluoride etherate were required for this reaction;
`presumably 1 equiv complexes with the quinoline nitrogen
`and is unavailable to activate the aldehyde.6 This result
`also implies that boron trifluoride etherate is less activating
`than protic acids (such as PPTS) for conjugate addition
`to the unsaturated quinoline.
`A modification of this procedure led to a straightforward
`preparation of the required unsymmetrical dithioacetal 7.
`Thus, treatment of 2 with 1 equiv of methyl 3-mercapto-
`propionate, 1 equiv of iVJV-dimethyl-3-mercaptopropion-
`amide7 and 3 equiv of boron trifluoride etherate in an-
`hydrous acetonitrile at 0 °C gave approximately the sta-
`tistical distribution (1:2:1) of diester 6, desired ester amide
`7, and diamide 8 in >95% yield. The analytically pure
`unsymmetrical ester amide 7 was isolated in 49% yield
`after simple silica gel chromatography and crystallization.
`Selective Unsymmetrical Dithioacetal Synthesis.
`Obviously, a selective method to prepare the unsymme-
`trical dithioacetal 7 from aldehyde 2 was desired. To the
`best of our knowledge, no synthetic method to effect this
`transformation has been reported.8 The plan to achieve
`It consists of formation
`this goal is outlined in Scheme II.
`of a mixed 0,S-acetal (B) followed by selective carbon-
`oxygen bond cleavage to produce the unsymmetrical di-
`thioacetal (C).
`Evidence that supports this proposal was obtained as
`follows: Treatment of aldehyde 2 with 1 equiv of methyl
`3-mercaptopropionate and 2 equiv of boron trifluoride
`etherate in anhydrous methylene chloride at -50 °C for
`30 min led to a ca. 50% yield of diester 6 with a recovery
`of ca. 50% of 2. Thus, rupture of the carbon-oxygen bond
`in presumed intermediate B where X = BF3 is relatively
`fast, even at -50 °C. Secondly, treatment of diester 6 with
`1 equiv of AT,N-dimethyl-3-mercaptopropionamide and 3
`equiv of boron trifluoride etherate in either anhydrous
`methylene chloride or ethyl acetate at -50 °C for 12 h gave
`
`(6) For the coordination of boron trifluoride etherate with ¡mines, see:
`Ryan, K. M.; Reamer, R. A.; Volante, R. P.; Shinkai, I. Tetrahedron Lett.
`1987, 28, 2103.
`(7) Durden, J. A. U.S. Patent 4,454,134,1984. See the Experimental
`Section for our modified preparation of this compound.
`(8) For a recently discovered alternative synthesis of unsymmetrical
`dithioacetals, see: Gauthier, J. Y.; Henien, T.; Lo, L.; Therien, M.; Young,
`R. N. Tetrahedron Lett. 1988, 29, 6729. Therien, M.; Gauthier, J. Y.;
`Young, R. N. Tetrahedron Lett. 1988, 29, 6733. See also Young, R. N.;
`Gauthier, J. Y.; Therien, M.; Zamboni, R. Heterocycles 1989, 28, 967 (and
`reference 6 therein).
`
`J. Org. Chem., Vol. 54, No. 15, 1989 3719
`only trace amounts (<5%) of thiol-exchanged compounds
`7 and 8. This implies that cleavage of the carbon-sulfur
`bonds in diester 6 is relatively slow, in contrast to the
`rupture of the carbon-oxygen bond in B.
`Thus, we turned our attention to the preparation of an
`intermediate of type B.
`unsymmetrical hemithioacetal
`Noting earlier reports of O-trimethylsilyl hemithioacetals,
`we chose to investigate the preparation of compound 10.
`However, due to the sensitive nature of substrate 2, pre-
`cisely defined conditions for its conversion to 10 were
`required. Application of Evans’9 and Chan’s10 *conditions
`were unsatisfactory due to competitive conjugate addition
`of the thiol to the unsaturated quinoline (cf. 9 above). This
`problem was averted by a modification of Glass’s proce-
`dure,11 the net result being facile preparation of the desired
`0- trimethylsilyl hemithioacetal 10. Treatment of aldehyde
`2 with 1.06 equiv of N^V-dimethyl-3-mercaptopropion-
`amide and 1 molar equiv of 1,1,1,3,3,3-hexamethyl-
`disilazane in the presence of 10 mol % imidazole in an-
`hydrous methylene chloride with a nitrogen sweep to re-
`the ammonia afforded very clean conversion to 10
`move
`It is interesting
`with <5% remaining starting aldehyde.
`to note that attempted formation of 10 using stoichiometric
`1- (trimethylsilyl)imidazole as the silylating agent led to
`significant 1,2-addition of 1- (trimethylsilyl)imidazole to
`the aldehyde to give the corresponding N, O-trimethylsilyl
`acetal 11.12
`
`The conversion of O-trimethylsilyl hemithioacetal 10 to
`the unsymmetrical dithioacetal 7 was then investigated.
`Treatment of 10 with 1.10 equiv of methyl 3-mercapto-
`propionate and 3.0 equiv of boron trifluoride etherate in
`anhydrous methylene chloride at -55 °C gave 7 with good
`selectivity, the relative distribution of the desired unsym-
`metrical ester amide 7:diamide 8:diester 6 being > 8:1:1.
`In situ   NMR studies showed that at temperatures
`above -40 °C boron trifluoride etherate begins to cleave
`the O-silylated hemithioacetal 10 and produce aldehyde
`2. Under these conditions (with both thiols present) 2 was
`converted to a statistical mixture of dithioacetals 6, 7, and
`8, the result being a compromise of overall selectivity. At
`lower temperatures decomposition of 10 was prevented and
`high selectivity was achieved.
`The key ratio of amide-ester 7 to diester 6 was further
`improved by either direct crystallization of crude 7 or by
`In this way 7 was
`a simple silica gel chromatography.
`isolated with <1% diester 6 present. To our knowledge,
`this is the first report of a practical, selective synthesis of
`unsymmetrical dithioacetals.
`Ester Hydrolysis. Ester-amide 7 was then hydrolyzed
`to L-660,711 (1) under basic conditions. Treatment of a
`tetrahydrofuran solution of 7 with aqueous lithium hy-
`
`(9) Evans, D. A.; Truesdale, L. K.; Grimm, K. G.; Nesbitt, S. L. J. Am.
`Chem. Soc. 1977, 99, 5009.
`(10) Chan, T. H.; Ong, B. S. Tetrahedron Lett. 1976, 319.
`(11) Glass, R. S. Synth. Commun. 1976, 6, 47.
`(12) Ogawa, T.; Matsui, M. Agrie. Biol. Chem. 1970, 34, 969.
`
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`

`3720 J. Org. Chem., Vol. 54, No. 15,1989
`droxide (1.05 equiv, -3 °C to 2 °C, 4.5 h) followed by acidic
`workup produced crystalline 1 in 88% yield. During the
`workup any residual diamide 8 is removed in the neutral
`organic layer leaving >98% pure L-660,711 (1).
`Conclusion
`The selective cleavage of the carbon-oxygen bond of a
`mixed 0,S-acetal has been used to permit the conversion
`of an aldehyde to an unsymmetrically substituted dithio-
`acetal. This novel and practical chemistry has resulted
`in the efficient synthesis (four steps, 34% overall yield)
`of the pharmacologically important LTD4 antagonist L-
`660,711 (1) and will be widely applicable to this exciting
`class of compounds.
`Experimental Section
`Proton NMR spectra were measured on a Bruker WM-250,
`AM-250, or AM-300 spectrometer with 0.5 Hz/Pt digital resolution
`or better. Spectra are referenced to the solvent (CHC13 5 = 7.27
`ppm; DMSO   = 2.50 ppm). Assignments were made by using
`COSY (2D) and NOE difference experiments. Melting points were
`determined on a Thomas-Hoover capillary apparatus and are
`uncorrected. Microanalyses were obtained on a Control Equip-
`ment Model 240X elemental analyzer. 7-Chloroquinaldine (3)
`was obtained from Trans World Chemicals, Inc. (Rockville, MD).
`1,3-Benzenedicarboxaldehyde (4) was obtained from Lancaster
`Synthesis, Ltd. Methyl 3-mercaptopropionate was obtained from
`Aldrich.
`Aldehyde 2. 7-Chloroquinaldine (3) (3000 g, 16.89 mol), 1,3-
`benzenedicarboxaldehyde (4) (3398 g, 25.34 mol), and acetic an-
`hydride (4.69 L, 49.7 mol) were suspended in xylene (16 L) and
`heated to reflux for 7 h with mechanical stirring. The reaction
`mixture was allowed to cool to ca. 40 °C overnight, and hexane
`(16 L, precooled to 5 °C) was added with stirring. After being
`cooled to 21-23 °C, the reaction mixture was filtered, and the
`collected solid was rinsed with hexane (16 L). Overnight drying
`in vacuo gave the crude product (4470 g).
`Half of the crude product was suspended in EtOAc (40 L) and
`heated to reflux. The insoluble bis-adduct 5 was removed by hot
`filtration through a preheated, jacketed, sintered-glass funnel.
`The filtrate was concentrated in vacuo at <40 °C to ca. 15 L,
`heated to reflux, and cooled to ambient temperature overnight.
`The resulting slurry was cooled to 0 °C, stirred for 2 h, and filtered.
`The filter cake was washed with cold EtOAc (ca. 5 L) and then
`dried overnight in vacuo at 45 6C. The other half of the crude
`product was processed as above to afford crystalline aldehyde 2
`(total = 3228 g, 65%). An analytical sample was prepared by
`recrystallization from EtOAc: mp 156-157 °C;   NMR (CDC13)
`  7.46 (d, J = 16.1 Hz, 3'-CH=), 7.48 (dd, J = 8.3, 2.0 Hz, 6-H),
`7.59 (t, J = 7.8 Hz, 5'-H), 7.65 (d, J = 8.3 Hz, 3-H), 7.74 (d, J =
`8.3 Hz, 5-H), 7.80 (d, J = 16.1 Hz, 2-CH=), 7.86 (dt, J = 7.8, 2.0
`Hz, 6'-H), m.90 (dt, J = 7.8, 2.0 Hz, 4'-H), 8.10 (d, J = 2.0 Hz,
`8-H), 8.14 (d, J = 8.3 Hz, 4-H), 8.15 (t, J = 2.0 Hz, 2'-H), 10.08
`(s, CH). Anal. Caled for C18H12CINO: C, 73.59;  , 4.12; Cl, 12.07;
`N, 4.77. Found: C, 73.52;  , 4.17; Cl, 12.25; N, 4.70.
`An analytical sample of the bis-adduct 5 was prepared by
`slurrying 5 (obtained as described above) in hot EtOAc followed
`by filtration and rinsing the filter cake with hot EtOAc: mp
`266-267 °C;   NMR (CDClg)   7.44 (d, J = 16.9 Hz, l'-CH=),
`7.47 (overlapping m, 6-H, 5'-H), 7.62 (b d, J = 8 Hz, 4'-H), 7.67
`(d, J - 9.1 Hz, o-H), 7.77 (overlapping doublets, J =¡ 16, 8 Hz,
`2-CH=, 5-H), 7.93 (b s, 2'-H), 8.10 (d, J = 1.8 Hz, 8-H), 8.14 (d,
`J - 8.1 Hz, 4-H). Anal. Caled for CgAeCW: C, 74.18;  , 4.00;
`Cl, 15.64; N, 6.18. Found: C, 74.02;  , 4.09; Cl, 15.59; N, 6.16.
`Diester 6. To a stirred solution of aldehyde 2 (3.00 g, 10.2 mol)
`and methyl 3-mercaptopropionate (2.26 mL, 20.4 mol) in an-
`hydrous CH2C12 (150 mL) at -5 °C was added BFg-EtjO (2.52 mL,
`20.4 mol) dropwise. After 2 h at -5 to 0 °C, the reaction mixture
`was poured into a stirred solution of 15% aqueous Na2COa (200
`mol) and extracted with CH2C12 (200 mL). The organic layer was
`washed with 10% aqueous Na2C03 (100 mL), dried over Na2S04,
`filtered, and concentrated in vacuo
`to give the crude product,
`which was purified by silica gel (SG) chromatography (60 g SG,
`elution with 25% EtOAc in hexane) to give diester 6 (4.58 g, 87%),
`
`McNamara et al.
`which slowly crystallized on standing. An analytical sample was
`prepared by recrystallization (2X) from hexane-EtOAc: mp 54-56
`°C;   NMR (CDClg) 5 2.6 (t, J = 7.3 Hz, 2 CCH2), 2.86 (m, 2
`SCH2), 3.69 (s, 2 OCHg), 5.04 (s, Ar-CH), 7.39 (d, J = 16.1 Hz,
`3'-CH=), 7.40 (overlapping m, 5'-H, 6'-H) 7.45 (dd, J = 8.8, 2.0
`Hz, 6-H), 7.56 (dt, J = 7.1, 2.0 Hz, 4'-H), 7.65 (d, J = 8.8 Hz, 3-H),
`7.70 (d, J = 16.1 Hz, 2-CH=) 7.72 (d, J = 8.8 Hz, 5-H), m.74 (b
`t, J = 2.0 Hz, 2'-H), 8.07 (d, J = 2.0 Hz, 8-H), 8.11 (d, J = 8.8
`Hz, 4-H). Anal. Caled for CjeHgeClNSA: C, 61.29; H, 5.52; Cl,
`6.70; N, 5.30; S, 12.12. Found: C, 61.30; H, 5.57; Cl, 6.65; N, 5.23;
`S, 12.10.
`jVyV-Dimethyl-3-mercaptopropionamide. N^V-Dimethyl-
`acrylamide (1.24 L, 12.0 mol) was cooled to -5 °C, and thiolacetic
`ca. 2 h with
`acid (0.850 L, 12.0 mol) was added dropwise over
`stirring while the temperature was maintained at <5 °C (exo-
`thermic!). The reaction mixture was allowed to warm to ambient
`temperature over 12 h, and then MeOH (6 L) was added. The
`reaction mixture was cooled to -5 °C, and 3 N aqueous NaOH
`(6 L) was added dropwise with stirring at <5 °C. After 2 h at
`<10 °C the pH was adjusted to 7.5 with concentrated HC1 (ca.
`1.3 L) while the temperature was maintained at <10 °C. The
`reaction mixture was concentrated in vacuo
`in order to remove
`the MeOH, and the residual aqueous concentrate was extracted
`with CH2C12 (4X1L). The combined extracts were washed with
`brine (2 L), dried over MgS04, filtered, and concentrated in vacuo
`to an oil, which was vacuum distilled (bp 101-104 °C at 2.5 mm)
`to give pure jV^V-dimethyl-3-mercaptopropionamide (1342 g, 84%)
`after a ca. 80 g forerun:   NMR (CDClg)   1.77 (t, J = 8.3 Hz,
`SH), 2.65 (t, J = 6.7 Hz, CH2C), 2.81 (m, CH2S), 2.96, 3.00 (2 s,
`N(CH3)2).
`Hemithioacetal 10. A 500-mL three-necked flask was
`equipped with a rubber septum containing a nitrogen inlet needle,
`a mechanical stirrer, and a drying tube containing CaCl2.
`1.1.1.3.3.3- Hexamethyldisilazane (7.2 mL, 17 mmol), NJ4-di-
`methyl-3-mercaptopropionamide (4.51 mL, 36.0 mmol), and im-
`idazole (0.23 g, 3.4 mmol) were added to a suspension of aldehyde
`2 (10.0 g, 34.0 mmol) in anhydrous CH2C12 (100 mL). The reaction
`mixture was stirred under a gentle nitrogen sweep (in order to
`remove NH3), which caused the internal temperature to drop to
`12-14 eC. Additional anhydrous CH2Cl2 was added periodically
`in order to maintain the initial volume of the reaction mixture.
`After 24 h   NMR analysis indicated high conversion to the
`O-silylated hemithioacetal 10 with <5% remaining 2. The reaction
`mixture was filtered and concentrated in vacuo at <25 °C to give
`crude 10 as an oil. Anhydrous CH2C12 solutions of 10 are stable
`  NMR (CDClg)  
`for at least 3 weeks at room temperature:
`0.20 (s, OSi(CHg)g), 2.49 (m, CH2C), 2.85 (m, Ctf2S), 2.90, 2.92
`(i s, N(CH3)2), 6.07 (s, Ar-CH), 7.36 (t, J = 7.5 Hz, 5'-H), 7.38 (d,
`J = 16.1 Hz, 3'-CH=), 7.44 (overlapping m, 6-H, 6'-H), 7.53 (dt,
`J = 7.5,1.5 Hz, 4'-H), 7.65 (d, J = 8.5 Hz, 5-H), 7.72 (d, J = 8.8
`Hz, 3-H), 7.72 (d, J = 16.1 Hz, 2-CH=), 7.75 (b s, 2/-H), 8.06 (d,
`J = 2.0 Hz, 8-H), 8.11 (d, J = 8.8 Hz, 4-H).
`Ester-Amide 7. From Aldehyde 2. To a suspension of
`aldehyde 2 (1200 g, 4.08 mol) in anhydrous CH3CN (9.5 L) was
`added JVJV-dimethyl-3-mercaptopropionamide (533 mL, 4.28 (mol)
`and methyl 3-mercaptopropionate (430 mL, 3.88 mol). The re-
`action mixture was cooled to -10 °C, and BFg-EtgO (1.50 L, 12.2
`mol) was added dropwise with stirring over 1.5 h while the tem-
`perature was maintained at <3 °C. After 2 h at -8 °C to 2 °C
`the reaction mixture was poured into a stirred solution of 15%
`aqueous Na2C03 (38 L). EtOAc (24 L) was added, and after
`mixing and separation the organic product layer was washed with
`5% aqueous Na2C03 (24 L). Concentration in vacuo at <30 °C
`gave the crude product as an oil, which was adsorbed on silica
`gel (1.5 kg) by evaporation of a CH2C12 solution (6 L). The
`resulting “dry pack” of the crude compound on silica gel was
`purified by chromatography on silica gel (8 kg of silica gel, elution
`with a gradient of 25% EtOAc in hexane to EtOAc: R¡ values
`in 1:1 hexane-EtOAc aldehyde 2,0.9; diester 6, 0.85; ester-amide
`7, 0.4; diamide 8, 0.1) to give ester-amide 7, which crystallized
`on standing. Slurrying in warm 2:1 hexane-EtOAc (8 L) followed
`by cooling to 5 °C, filtration, rinsing with hexane (6 L), and drying
`in vacuo for 24 h afforded pure 7 (1058 g, 49%): mp 108-109 °C;
`1H NMR (CDClg)   2.6 (overlapping m, CH2C), 2.85, (overlapping
`m, 2 CH2S), 2.90 (s, N(CH3)?), 3.58 (s, OCHg), 5.06 (s, Ar-CH),
`7.3- S.2 (aromatic and olefinic protons are essentially identical
`
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`3721
`
`J. Org. Chem. 1989, 54, 3721-3726
`(13 L) was added, and the pH was adjusted to 6.0 with concen-
`with assignments for 7). Anal. Caled for C27H29CIN2S2O3: C,
`trated HC1. Seed crystals of 1 (ca. 7 g) were added, and the pH
`61.29; H, 5.52; Cl, 6.70; N, 5.30; S, 12.12. Found: C, 61.30; H,
`was adjusted to 3.5 with 2 N aqueous HC1. After being stirred
`5.57; Cl, 6.65; N, 5.23; S, 12.10.
`From O-Silylated Hemithioacetal 10. The O-silylated
`for 16 h at ambient temperature, the resulting product was filtered,
`rinsed with 2-propanol (7 L), and dried in vacuo at 50 °C overnight
`hemithioacetal reaction mixture as described above (ca. 34 mmol
`to give crystalline 1 (639 g, 88%; >97% pure by HPLC). An
`of 10) was filtered, and the resulting CH2CI2 solution was cooled
`analytical sample was prepared by recrystallization from 2-bu-
`to -50 eC. Methyl 3-mercaptopropionate (4.33 mL, 39.1 mmol)
`tanone: mp 161.5-163 °C;   NMR (DMSO-de)   2.S-3.4 (ov-
`was added followed by dropwise addition of BFg-EtgO (21.0 mL,
`170 mmol) with mechanical stirring at <-45 °C. The reaction
`eralpping multiplets, 4 CH2), 2.79, 2.89 (2 s, N(CH3)2), 5.32 (s,
`Ar-CH), 7.44 (m, 5'-H, 6'-H), 7.47 (d, J = 16.5,3'-CH=), 7.59 (dd,
`mixture was stirred at -50 °C for 16 h and then was quenched
`J = 8.7, 2.3 Hz, 6-H), 7.67 (m, 4'-H), 7.80 (b s, 2'-H), 7.87 (d, J
`by addition to a stirred solution of 15% aqueous Na2COg (200
`= 16.5 Hz, 2-CH=), 7.95 (d, J = 8.6 Hz, 3-H), 8.00, 8.03 (over-
`mL). Additional CH2C12 (100 mL) was added, and the resulting
`lapping doublets, 5-H, 8-H), 8.40 (d, J = 8.6 Hz, j-H), 12.3 (broad,
`organic layer was separated, washed with brine (150 mL), dried
`C02H). Anal. Caled for C26H27C1N2S203: C, 60.63; H, 5.28; Cl,
`over Na2S04, filtered, and concentrated in vacuo at <30 °C to
`give the crude product as a 8:1:1 mixture of 7:8:6. Purification
`6.88; N, 5.44. Found: C, 60.68; H, 5.36; Cl, 6.98; N, 5.35.
`as described above gave ester-amide 7 (10.9 g, 61%).
`Acknowledgment. We would like to express our
`L-660,711 (1). Ester-amide 7 (746 g, 1.41 mol) was dissolved
`in warm THF (8.8 L) and cooled to -3 °C. A solution of 1.00 N
`gratitude to Dr. Robert J. Zamboni for the many useful
`aqueous LiOH (1.48 L, 1.48 mol) was added dropwise with me-
`chemical discussions, to Paul Davis for technical assistance,
`ca. 1.2 h at <0 °C. After an additional 2
`chanical stirring over
`and to Sheila L. Mickle for preparation of the manuscript.
`h at -1 to 1 °C, extra 1.00 N aqueous LiOH (70 mL, 0.070 mol)
`was added. After a total reaction time of 4.5 h at -3 to 2 °C, water
`Registry No. 1,120663-36-7; 2,120578-03-2; 3, 4965-33-7; 4,
`(12 L; precooled to 5 °C) was added and the THF was removed
`626-19-7; 5, 120578-04-3; 6, 120385-96-8; 7, 120663-37-8; 8,
`in vacuo at <20 °C. The resulting aqueous concentrate was
`120578-05-4; 1Ú, 120578-06-5; methyl 3-mercaptopropionate,
`extracted with EtOAc (2 X 4.5 L) and transferred to a round-
`2935-90-2; N^V-dimethylacrylamide, 2680-03-7; N^V-dimethyl-
`bottomed flask equipped with a mechanical stirrer. 2-Propanol
`3-mercaptopropionamide, 5458-01-5; thiolacetic acid, 507-09-5.
`
`Reactivity of Biologically Important Reduced Pyridines. 4. Effect of
`Substitution on Ferricyanide-Mediated Oxidation Rates of Various
`l,4-Dihydropyridinest
`Marcus E. Brewster,* *·*’8 Agnes Simay,*·8·-1- Klara Czako,*·8,11 David Winwood,*·8 Hassan Farag,8·*
`and Nicholas Bodor*·*·8
`Pharmatec, Inc., P.O. Box 730, Alachua, Florida 32615, and Center for Drug Design and Delivery, College of
`Pharmacy, Box J-497, J. Hillis Miller Health Center, University of Florida, Gainesville, Florida 32610
`Received January 27, 1989
`
`The effect of substitution on the rate of ferricyanide-mediated oxidation of various dihydropyridines was
` -Alkyl-, 1-aralkyl-, 1-aryl-, and 6-substituted l-methyl-l,4-dihydronicotinamides, 3-substituted
`examined.
`1-methyl-1,4-dihydropyridines, and quinoline and isoquinoline derivatives were subjected to ferricyanide oxidation.
`Increasing the n-alkyl chain of 1-methyl-1,4-dihydronicotinamide acted to slowly decrease the rate of oxidation.
`The l-cyclopropyl-l,4-dihydronicotinamide was shown to be unusually stable compared to the 1-isopropyl derivative
`due presumably to the electron-withdrawing nature of the  -like substituent.
`l-(4-Substituted phenyl)-1,4-
`the range of  - 02 (  = 0.778) to p-N(CH3)2 (  = 0.83) generated a linear Hammett
`dihydronicotinamides over
`plot (r = 0.9994) with a reaction constant of p = 2.76, consistent with an initial electron removal in the rate-
`determining step of oxidation. When substitutions at the 3-position are considered, the rank order of stability
`was CHO > CN > COCHg > COOCHg > CONHg > CONHR > CONRg and is related to the electron-withdrawing
`potency of the moiety. Finally the 1-methyl-1,4-dihydro-3-quinolinecarboxamide was found to be much more
`stable than the 2-methyl-l,2-dihydro-4-isoquinolinecarboxamide.
`
`Introduction
`of dihydropyridine partial structures in
`The occurrence
`biologically important coenzymes such as NADH and
`NADPH has made these compounds an appealing subject
`for study.1 Of particular importance is the mechanism
`
`tPart 3 of this series: Bodor, N.; Brewster, M.; Kaminski, J.
`Energetics and Mechanism of the Hydride Transfer between 1-
`Methyl-l,4-dihydronicotinamide and the 1-Methylnicotinamide
`Cation J. Molecular Structure (Theochem), in press.
`* Pharmatec, Inc.
`* Center for Drug Design and Delivery.
`x On leave from the Technical University of Budapest, Budapest,
`Hungary.
`1 On leave from the Institute of Drug Research, Budapest, Hun-
`gary.
`* On leave from the University of Assiut, Assiut, Egypt.
`
`of oxidation of substituted dihydropyridines. The classical
`work of Abeles and Westheimer suggested that the oxi-
`dation of various dihydropyridines by thiobenzophenones
`was mediated by concerted hydride transfer.2
`Later,
`discrepancies between kinetic isotope effects and product
`isotope compositions indicated that intermediates existed
`on the reaction coordinate for this process.3 Postulated
`intermediates included radical cations which can be formed
`
`(1) Powell, M. F.; Bruice, T. C. Prog. Clin. Biol. Res. 1988, 274,
`369-385 and references cited therein.
`(2) Abeles, R.; Hutton, R.; Westheimer, F. J. Am. Chem. Soc. 1957,
`79, 712-716.
`(3) (a) Hajdu, J.; Sigman, D. S. J. Am. Chem. Soc. 1976,98, 6060-6061.
`(b) Creighton, D.; Hajdu, J.; Mooser, G.; Sigman, D. S. J. Am. Chem. Soc.
`(c) Shinkai, S.; Tsuno, T.; Manabe, O. Chem. Lett.
`1973, 95, 6855-6857.
`(d) Steffens, J.; Chipman, D. J. Am. Chem. Soc. 1971,
`1981,1203-1206.
`93, 6694-6696.
`
`0022-3263/89/1954-3721$01.50/0
`
`&copy; 1989 American Chemical Society
`
`Page 4
`
`Anacor Exhibit 2019
`Flatwing Pharmaceuticals, Inc. v. Anacor Pharmaceuticals, Inc
`IPR2018-00171
`
`