Organic Process Research & Development 1997, 1, 407−410
Preparation of 9,9-Disubstituted 4,5-Diazafluorenes Useful as Cognitive Enhancers Timothy D. Costello,† James H. Jensen,*,† Christopher A. Teleha,‡ and Matthew E. Voss*,‡ Chemical Process Research and DeVelopment, Chambers Works, The DuPont Merck Pharmaceutical Company, Deepwater, New Jersey 08023, and Chemical and Physical Sciences, Experimental Station, The DuPont Merck Pharmaceutical Company, Wilmington, Delaware 19880
Abstract: A novel synthesis of symmetric and nonsymmetric 9,9-disubstituted 4,5-diazafluorenes has been developed. These compounds have activity in both an in Witro acetylcholine release assay and in WiWo rodent models of learning and memory. Preparation of these compounds involves a unique aldol condensation between 4,5-diazafluoren-9-one (4) and 4-picoline. Reduction of aldol product 5 (5-(4-pyridinylmethylene)-5Hcyclopenta[2,1-b:3,4-b′]dipyridine) provides monoalkylated diazafluorene 6 (5-(4-pyridinylmethyl)-5H-cyclopenta[2,1-b:3,4b′]dipyridine) which proved to be a key intermediate for synthesis of nonsymmetric analogs.
Scheme 1 N O
CH3 AcOH
+ N
N
Ac2O
N
5 N
N
H 5
R Base
5% Pd on C
Electrophile
H2, ethanol
N
N
N
†
Chemical Process Research and Development, Chambers Works. Chemical and Physical Sciences, Experimental Station. (1) (a) Nickolson, V. J.; Tam, S. W.; Myers, M. J.; Cook, L. Drug DeV. Res. 1990, 19, 285-300. (b) Cook, L.; Nickolson, V. J.; Steinfels, G. F.; Rohrbach, K. W.; DeNoble V. J. Drug DeV. Res. 1990, 19, 301-314. (c) Tam, S. W.; Rominger, D.; Nickolson, V. J. Mol. Pharmacol. 1991, 40, 16. (2) Earl, R. A.; Myers, M. J.; Johnson, A. L.; Scribner, R. M.; Wuonola, M. A.; Boswell, G. A.; Wilkerson, W. W.; Nickolson, V. J.; Tam, S. W.; Brittelli, D. R.; Chorvat, R. J.; Zaczek, R.; Cook, L.; Wang, C.; Zhang, X.; Lan, R.; Mi, B.; Wenting, H. Bioorg. Med. Chem. Lett. 1992, 2, 851-854. ‡
N 7 1: R = 4-picolyl
6
Introduction The development of agents to treat Alzheimer’s disease is one of the most critical problems facing the pharmaceutical and medical community. Our efforts center on the development of compounds that increase endogenous stimulusinduced acetylcholine release.1 Agents with this profile are expected to provide a palliative treatment by improving the cognitive abilities of Alzheimer’s patients. Previous work on the structure-activity relationship (SAR) has allowed for the division of our cognition enhancers into two portions, a heteroaromatic core and pendant or side-chain substituents.2 Compound 1 (EXP-9121) was a crucial lead showing good activity both in Vitro and in ViVo with a core chemically distinct from that of our former clinical candidate linopirdine (2, DuP996).
N
N
4
In order to support preclinical development, an efficient and economical synthesis of 1 was needed. The inclusion of an intermediate that would allow rapid SAR development of unsymmetrical pendant groups would be beneficial to the development of future clinical candidates. Discussion Initial preparation of 1 involved gem-dialkylation of 4,5diazafluorene (3)3 (eq 1). NaH
N
N
1
(1)
4-picolyl chloride
3
Several complications were identified in the direct scaleup of the initial route. First, the reduction of 4 to 3 required a large excess of hydrazine (10 equiv), resulting in handling and waste disposal problems. Second, the use of sodium hydride as a base requires strictly anhydrous conditions. Third, a fairly large excess (10-20%) over the 2 mol stochiometric amount of picolyl chloride was required. In addition, the picolyl chloride had to be prepared from the commercially available hydrochloride salt in a separate step and was unstable as the free base. These considerations increased the cost of the final drug significantly. A longer but overall more efficient route to 1 was developed through intermediate 5 (Scheme 1). Treatment of 4,5-diazafluoren-9-one (4)4 with picoline in a mixture of (3) (a) Kloc, K.; Młchowski, J.; Szulc, Z. Heterocycles 1978, 7, 849-852. (b) Młochowski, J.; Szulc, Z. Pol. J. Chem., 1983, 57, 33. (4) Kloc, K.; Młochowski, J.; Szulc, Z. J. Prakt. Chem. 1977, 319, 959-967.
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Vol. 1, No. 6, 1997 / Organic Process Research & Development
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Table 1. Unsymmetrical analogs of compound 1 electrophile 1
4-picolyl chloride
7a
2-cyclohexen-1-one
R
base
N
O
7b
3-picolyl chloride
N
7c
acrylamide
O
% yield
NaOH
68
Triton B
84
NaH
67
Triton B
72
NaH
88
NaH
93
NaH
88
NH2
7d
ethyl bromoacetate
7e
bromobutanenitrile
7f
2-bromoethyl ethyl ether
O OEt CN OEt
AcOH/Ac2O (4:1) provided aldol product 5 in 77% yield.5,6 Reduction of 5 succeeded with NaBH4, but catalytic hydrogenation proved more efficient at larger scales, affording 6 in 88% yield. Conversion of 6 to 1 was accomplished using 4-picolyl chloride hydrochloride (1.3 equiv) with NaOH in 2-propanol (68%). This scheme reduces the expensive picolyl chloride by half and eliminates the preliminary free base step. In addition, 6 could be transformed into a wide selection of unsymmetrical analogs by alkylation or Michael addition with several different substrates, demonstrating the utility of 6 as a key intermediate in our cognition program (see Table 1 for representative examples). The chemistry outlined has successfully provided >10 kg of GMP (good manufacturing practices) 1 for preclinical development and supported an intensive analog program. Details of a large-scale preparation of 1 and representative procedures for preparing unsymmetrical analogs shown in Table 1 are included in the Experimental Section. The addition of 5% NaOCl during workup and recrystallizations of 6 was key to obtaining high yields. After pH adjustment, the solution was black and visibly “oily”. The slow addition of NaOCl produced a bright yellow solution and increased the yield by 10-15%. The exact nature of the oily phase was not determined. However, this phase did (5) Only a few examples of aldol condensations with 2- or 4-picoline and ketones exist. These conditions have proved useful for a number of reactive ketones. For a general discussion of condensation of picolines with aldehydes, see: Tenenbaum, L. E. In The Chemistry of Heterocyclic Compounds; Abramovitch, R. A., Ed.; John Wiley and Sons: New York, 1961; Vol. 14, Part 2, p 192. (6) For additional examples using aldehydes and ketones, see: (a) Klemm, L. H.; Severns, B.; Wynberg, H. J. Heterocycl. Chem. 1991, 28, 61. (b) Efange, S. M. N.; Michelson, R. H.; Remmel, R. P.; Boudreau, R. J.; Dutta, A. K.; Freshler, A. J. Med. Chem. 1990, 33, 3133. (c) Williams, J. L. R.; Adel, R. E.; Carlson, J. M.; Reynolds, G. A.; Borden, D. G.; Ford, J. A. J. Org. Chem. 1963, 28, 387. (d) Sharp, W.; Sutherland, M. M. J.; Wilson, F. J. J. Chem. Soc. 1943, 5. (e) Bryant, W. M., III; Huhn, G. F. U.S. Patent 4,806,651, 1989. (f) Bryant, W. M., III; Huhn, G. F.; Jensen, J. H.; Pierce, M. E.; Stammbach, C. Synth. Comm. 1993, 23, 1617. 408
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contain a significant amount of product which was released as a crystalline material just when the color disappeared. The effect was very dramatic. Copious crystals formed and the temperature increased at the instant the solution changed from black to yellow. Hydrogen peroxide was much less effective. Other reagents were not tried since NaOCl was effective and inexpensive. Conclusions We have developed an efficient, scalable synthesis of disubstituted diazafluorene 1. The optimized route provided an important intermediate 6 by an aldol condensation between 4-picoline and ketone 4 followed by reductive hydrogenation. The isolation of 6 was useful for preparing unsymmetrical analogs. A process improvement of using bleach in the workup after neutralization may have practical benefit in other reactions involving 4-picoline. Experimental Section7 5-(4-Pyridinylmethylene)-5H-cyclopenta[2,1-b:3,4-b′]dipyridine (5). 4,5-Diazafluoren-9-one (4) (667.4 g, 3.66 mol) dissolved in 743.1 g of acetic anhydride, 1328.4 g of 4-picoline, and 1560 g of acetic acid was heated for 7 h at 120 °C (
