Synthesis of a NO-releasing prodrug of rofecoxib

Journal of Organic Chemistry

Volumn 71, Issue 2, 2006, Pages 480-491

  Engelhardt, F Conrad ^a   Shi, Yao Jun ^a   Cowden, Cameron J ^a   Conlon, David A ^a   Pipik, Brenda ^a   Zhou, George ^a   McNamara, James M ^a   Dolling, Ulf H ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ALCOHOLS; BROMINE COMPOUNDS; OLEFINS; SYNTHESIS (CHEMICAL);

CARBOMETALATION REACTION; CHEMOSELECTIVE NITRATION; PRODRUG; SIDE CHAIN;

NITROGEN OXIDES;

3 PHENYL 2 PROPYN 1 OL; ALCOHOL; NITRIC OXIDE DONOR; PHENYL GROUP; PRODRUG; PROPARGYL ALCOHOL; ROFECOXIB; UNCLASSIFIED DRUG;

ARTICLE; DRUG DESIGN; DRUG FORMULATION; DRUG RELEASE; DRUG STRUCTURE; DRUG SYNTHESIS; METALLATION; NITRATION; REACTION ANALYSIS; STRUCTURE ANALYSIS;

CARBON DIOXIDE; CYCLOOXYGENASE INHIBITORS; INDICATORS AND REAGENTS; LACTONES; MODELS, MOLECULAR; MOLECULAR CONFORMATION; NITRIC OXIDE; PRODRUGS; SULFONES;

EID: 30744471678     PISSN: 00223263     EISSN: None     Source Type: Journal    
DOI: 10.1021/jo051712g     Document Type: Article

References (40)

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2. The synthesis of a series of (Z)-2,3-biaryl-4-acetoxybut-2-enoic acids was reported in International Patent Publication WO 96/13483 (1996).
3. Internal communication with Merck Medicinal Chemistry.
4. Fallis, A. G.; Wilson, P. D.; Forgione, P. Tetrahedron Lett. 2000, 41, 17-20.
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6. This method has the advantage of being indigenous to the process and introduces no new chemical entities to the system. Tilstam, U.; Weinmann, H. Org. Process Res. Dev. 2002, 6. 906-910.
7. It has been shown that in the absence of copper iodide (Cul) alkyl Grignard reagents do not readily participate in the carbometalation reaction. See the following: (a) Tessier, P. E.; Penwell, A. J.; Souza, F. E. S.; Fallis, A. G. Org. Lett. 2003, 5, 2989-2992.
8. (b) Douboudin, J. G.; Jousseaume, B.' Saux, A. J. Organomet. Chem. 1979, 168, 1-11.
9. Initially, i-PrMgCl was used as the sacrificial base, but an excess charge of this reagent ultimately led to the generation of a mixed anhydride and the difficult to reject isobutyl ester impurity upon reaction with dianion 15 (see below). This problem was mitigated by substituting methylmagnesium chloride as the sacrificial Grignard reagent. In this case, excess MeMgCl generated acetate upon reaction with carbon dioxide and subsequent reaction with acetic anhydride would simply regenerate acetic anhydride, which would still allow formation of the desired (Z)-4-alkoxybut-2-enoic acid 3 (see below). (Diagram presented).
10. The amount of thioanisole 10 and thioanisic acid 11 byproducts has been reduced significantly by employing an alkylmagnesium chloride reagent (MeMgCl) as a sacrificial base. The only byproduct now is methane gas.
11. Previous investigations have suggested that solvent plays an important role in these carbometalation reactions. Nonpolar solvents such as cyclohexane were essential for the direct condensation of the magnesium chelate intermediate with aldehydes. Toluene/THF mixtures (1:1) have been shown to provide significant improvements in some reactions.
12. Forgione, P.; Fallis, A. G. Tetrahedron Lett. 2000, 41, 11-15.
13. As assayed by quenching into methanol and quantifying trisubstituted alkene 12a.
14. 2 through the reaction mixture while maintaining a slightly elevated temperature range (30-40°C) to afford a reasonable reaction rate. Although lower temperatures facilitate carbon dioxide solubility in THF, incorporation of the carbon dioxide moiety was significantly reduced.
15. (Z)-4-hydroxybut-2-enoic acid 7 cannot be isolated, and it cyclizes upon protic workup to give butenolide 13. The presence of butenolide 13 serves as a viable assay for the presence of (Z)-4-hydroxybut-2-enoic acid in this step.
16. -1).
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19. 2) were added to try to alter the ratio of desired acid 3 to lactone 13. Encouragingly, variability in the ratio of 3/13 was observed under all of these various reaction conditions; unfortunately, the best ratio observed was 2:1, and thus, 30-35% of the product mixture was being lost as the lactone 13 byproduct.
20. The ratio of desired acid 3/butenolide 13 was 2:1. Efforts to increase this ratio were unsuccessful.
21. -1) but amounted to only a 0.7% yield over the course of 14 h in the presence of carbon dioxide.
22. The final amount of butenolide 13 observed at the end of the reaction increased in direct proportion to the length of the carbon dioxide age prior to the acetylation step. Longer carbon dioxide exposures (i.e., > 3 h) had a detrimental effect on the ratio of acid 3 to lactone 13.
23. Gas evolution has been observed upon the addition of acetic anhydride on larger scales supporting the notion of the carbonate protecting group. Longer carbon dioxide exposures prior to the acetate trapping step resulted in an increase in the observed butenolide 13, presumably due to a larger concentration of carbonate 16. Also, free carbon dioxide is observed after acetic anhydride is added to the system.
24. C=O stretching frequency that can be readily distinguished from other reactive intermediates. Note that the carbonyl of both the acid and the acetate protecting group can be used to identify each intermediate. (Diagram presented).
25. 2 in THF at ambient temperature (ca. 0.25 M). Calculations based on the volume of THF and the solubility of carbon dioxide provided the insight to the appropriate amount of KO′Bu (0.5 equiv) that needs to be added.
26. Typical purity was > 98.5% by HPLC analysis at 210 nm.
27. 2 solution), causing thick emulsions. KOH was selected as the base because of its low cost, and having potassium as the counterion introduces no new metal species into the reaction system that could interfere with our isolation of the desired magnesium salt product.
28. 2 solution serves mainly as an aqueous wash for the THF layer, and the high molarity of the solution allows facile separation between the aqueous and THF (organic) layers.
29. Water (3-5% volume) was critical to the success of the crystallization, as the isolated magnesium salt is a highly hydrated species requiring 8-10 water molecules per mole of salt.
30. 2 (5 equiv) in AcOH at 40°C, epoxidation of the Z olefin is possible in the presence of a metal catalyst such us magnesium. Hydrolysis of the formed oxirane followed hy further oxidation can then lead to olefin cleavage products. (Diagram presented).
31. Residual chloride (> 200 ppm) in the sulfide acid salt led to the formation of chlorosulfone.
32. Oxidation of aryl sulfides to aryl sulfones using hydrogen peroxide in acetic acid; Russell, G. A.; Pecoraro, J. M. J. Org. Chem. 1979, 44, 3990-3991.
33. Internal communication with Merck Medicinal Chemistry.
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36. 2 using acetic anhydride and nitric acid and its use in the nitration of an alcohol: Black; Babers Organic Syntheses, 1939; Vol. 19, pp 64-66.
37. 2H, and MeCN.
38. We have not been able to reject either of these impurities by recrystallization without considerable yield losses of the desired final product.
39. 2O), and as long as the addition time was extended to over 30 min. acetylation was completely suppressed.
40. Butler, A. R.; Hendry, J. B. J. Chem. Soc. B: Phys. Org. 1971, 102-105.