A Practical Synthesis of Tetrasubstituted Imidazole ... - ACS Publications

Downloaded by UNIV OF GUELPH LIBRARY on July 19, 2012 | http://pubs.acs.org Publication Date: November 25, 2003 | doi: 10.1021/bk-2004-0870.ch010

Chapter 10

A Practical Synthesis of Tetrasubstituted Imidazole p38 MAP Kinase Inhibitors: A New Method for the Synthesis of α-Amidoketones Jerry A. Murry, Doug Frantz, Lisa Frey, Arash Soheili, Karen Marcantonio, Richard Tillyer, Edward J. J. Grabowski, and Paul J. Reider Process Research Department, Merck Research Laboratories, Merck and Company, Inc., P.O. Box 2000, Rahway, NJ 07065

In this manuscript we disclose new synthetic methodology to prepare a member of a class of tetrasubstituted imidazole p38 inhibitors. The optimal route involves a thiazolium catalyzed cross acyloin-type condensation of a pyridinealdehyde with an N-acylimine. The pyridinealdehyde was prepared in 3 steps and 68% yield from 2-chloro-4-cyano pyridine. The tosylamide precursor to the N-acyl imine was prepared in two steps and 93% yield from isonipecotic acid. We have demonstrated the scope and some preliminary mechanistic studies concerning this new reaction. The resulting α-keto -amide is then cyclized with methyl ammonium acetate to provide the desired tetrasubstituted imidazole. Cbz deprotection and formation of a pharmaceutically acceptable salt completes the synthesis in 6 steps and 38% overall yield.

© 2004 American Chemical Society In Chemical Process Research; Abdel-Magid, A., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2003.

161

162

Introduction


The pyridinylimidazoles are representative of a class of polysubstituted imidazoles which are potent inhibitors of p38 Mitogen-Activated Protein (MAP) kinase.(i, 2) (Figure 1) These compounds have been indicated for the treatment of inflammatory diseases due to their mode of action which involves upstream regulation of several pro-inflammatory cytokines such as IL-1 (interleukin-1) and TNF (tumor necrosis factor).(3) Effective syntheses for this class of compounds have been described.^, 5)

SB-203,580

1

RWJ-67657

RPR-200765A

Figure 1. Pyridylimidazole p-38 Kinase inhibitors

In this chapter we report new methodology which allows for an efficient, practical synthesis of the p38 MAP kinase inhibitor 1.(6, 7) The key step in this synthesis is a thiazolium catalyzed cross-acyloin coupling reaction of an aldehyde with an acyl imine.(«S) The previously reported syntheses of these compounds have relied on preparing a trisubstituted imidazole and then adding the fourth substituent either by iV-alkylation or metallation of the 2-position and addition of an electrophile. The iV-alkylations may suffer from lack of regioselectivity that usually results in loss of yield and the need for chromatographic separations. However, fiuictionalization of the 2-position has been reported to proceed in high yields. We initiated a program aimed towards an efficient synthesis of this class of compounds that would provide tetrasubstituted imidazoles rapidly and be amenable to large-scale synthesis.

In Chemical Process Research; Abdel-Magid, A., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2003.

163

Route Selection We initially investigated numerous routes towards preparing polysubstituted imidazoles. Four of those routes will be discussed in this section.


Tosylmethyl Isocyanide (TOSMIC) Dipolar Cycloaddition We investigated an approach towards the synthesis of 1 utilizing the tosylmethyl isocyanide (TOSMIC) methodology and the results are outlined in Scheme 1.(9)

Scheme 1. TOSMIC approach to 1 Preparation of the requisite Tosyl formamide 2 using the procedure of Sisko (4, 5) occurred in good yield. Dehydration of 2 with POCl provided the TOSMIC reagent 3 which underwent 1,3 dipolar cycloaddition with methyl imine 4 to provide imidazole 5. However, this procedure proved problematic on larger scale. The reactions turned very dark and formed several unidentified byproducts. Fortunately, the resulting mixture could be purified by silica gel chromatography to provide the desired trisubstituted imidazole in 60% yield. The installation of the piperidine substituent in the 2-position was effected in a 3


164 two-step sequence. Lithiation with w-BuLi followed by addition of iV-benzyl piperidone provided the desired tertiary alcohol 6. Reacting this compound with a-methylbenzylamine under palladium catalysis (10) provided the desired 2amino substituted pyridine 7. Reductive elimination of the tertiary hydroxyl group was accomplished with NaBH in the presence of trifluoroacetic acid. NBenzyl deprotection of the hydrochloride salt with hydrogen and Pd/C provided 1 in 66% yield. Thus using a 1,3-dipolar cycloaddition to provide a trisubstituted imidazole and functionalizing the 2-position had been demonstrated. The route provides the desired compound in 6 linear steps in 18% overall yield. The key step in this route, the TOSMIC cycloaddition to the Nmethyl imine 4, was of serious concern. First the reaction gave variable yields with some significant decomposition. In addition, DSC of the TOSMIC reagent indicated a 180 J/gm exotherm at 80 °C. Both of these factors led us to investigate alternate routes towards the synthesis of desired compound 1.


4

Picolyl Anion Addition to Benzonitrile. The next route involved the addition of the picolyl anion derivedfrom10 to 3-trifluoromethylbenzonitrile, and subsequent cyclization to the tetrasubstituted imidazole (Scheme 2). This route initially appeared very attractive due to its convergency and the apparent ease with which thefragmentscould be prepared. 2-chloro-4-pyridine carboxaldehyde 8 (11) was reduced in the presence of methylamine to provide the desired secondary amine 9. Acylation of amine 9 with isonipecotoyl chloride provided the amide 10 in 60% yield. Treatment of this compound with LiHMDS produced a deep blue solution of the picolyl anion. Treatment of that anion with 3-trifluoromethylbenzonitrile gave, after workup, the tetrasubstituted imidazole 11. This intermediate was converted to the final product by palladium-catalyzed amination followed by Cbz deprotection in 85 and 90% yields respectively. This route provided the desired product 1 in five-steps from 2-chloro-4pyridinecarboxaldehyde in 31% overall yield. Further investigation into the anion reaction revealed that several decomposition products were formed during the anion formation. Indirect evidence for anion decomposition was the isolation of iV-methyl isonipecotamide from the reaction mixture. We attribute the formation of this side product to oxidative degradation of the picolyl anion to cleave the N-C bond. The picolyl degradation fragment was not observed. The apparent instability of this particular picolyl anion coupled with the variable yields of the addition/cyclization reaction led us to investigate other routes towards this target.



Scheme 2. Picolyl Anion Adition to Benzonitrile Approach to 1.


OS


166

CF

>

11

Scheme 3. Nitrilium Ylide Cyclization Approach. 1,3-Dipolar Cycloaddition of a Nitrilium Ylide. We next turned our attention to 1,3-diolar cycloaddition reactions of nitrilium ylides as a direct approach towards the tetrasubstituted imidazole. Nitrilium ylides have been reported to undergo 1,3-dipolar cycloaddition with a number of dipolarophiles including imines.(Z2-i 6) Thus we reasoned that if the nitrilium ylide 14 could be formed, then reacted with the imine 4 derivedfrom2chloro-pyridinecarboxaldehyde 15, it might provide the desired imidazole (Scheme 3). The tosyl amide precursor could be formed from 3trifluoromethylbenzaldehyde, Cbz-isonipecotamide and toluenesulfinic acid following the procedure of Sisko.« 5) Exposing the amide 13 to POCl in the presence of TEA gave a dark solution which was then treated with the iV-methyl imine 4. After warming to ambient temperature, the reaction was treated with DBU and allowed to stir overnight. The resulting mixture was chromatographed to provide the desired tetrasubstituted imidazole 11 in 52% yield. This reaction was examined further and it was found that elimination of toluenesulfinic acid to 3


167 form the Af-acylimine 16 was a major side reaction. Efforts to prevent this side reaction were never completely successful. As a result, we turned our attention towards taking advantage of the apparently facile formation of the JV-acylimine 16.


Acyl Anion Addition to Acyl Imines. Previous work in synthesis of imidazoles has demonstrated that tetrasubstituted imidazoles could be formed from condensation of otamidoketones (such as 17, Scheme 4) with a primary amine. Thus, we envisioned that the desired imidazole (11 or 12) could arisefromthe reaction of the a-amidoketone 17 with methylamine. While a-amidoketone 17 may be prepared according to existing literature procedures; however, we envisioned the addition of acyl anion 18 to the iV-acylimine 16 as a direct and more efficient route. Since we had just recently become aware of the propensity of tosyl amide 13 to eliminate sulfinic acid, we felt this may constitute a new entry into the synthesis of a-amidoketones.

Scheme 4. Retrosynthetic analysis of acyl anion addition approach. a-Amidoketones themselves are an important class of biologically important molecules.(7 7-79) Efforts to prepare diverse arrays of these compounds as enzyme inhibitors are current and extensive. In addition, these substrates represent a subclass of organic building blocks, which can be used to make stereochemically complex targets as well as important heterocycles such as imidazoles.(20)


168 In addition, the use of thiazolium catalyzed processes to prepare compounds which are the result of an acyl anion addition reaction have shown utility in synthetic organic chemistry. The benzoin condensation (21-24) and the Stetter reaction (25-27) represent two of the most powerful examples of these types of transformations (Figure 2.). xG


OH O

AH —

^ v^y

u

Rf

111

Benzoin

OH O

D

O Rf

^

^

^

R

9

Stetter

H R

O

2

O

^ O

2

9

3

r / v

A Kj

X

R ^N^R

n

1

H n

I R

2

Y

R

II O

3

p

0

8

8

- ^ *

(current work)

Figure 2: Thiazolium Catalyzed Acyl Anion Additions In order to expand the existing catalytic methodology towards the synthesis of a-amidoketones, we envisioned trapping the intermediate thiazolium stabilized acyl anion with an iV-aeylimine.(2

so O

O

2

. N

H

DH

Qz\0

3s_ 5 mol% TEA, CH C1 2

2

( r ° :

32

33


93% yield >95% D incorporation Scheme 8. Labeling Experiment If mechanism 1 was operating, then the deuterium should be maintained in the product. However, if mechanism 2 was operating, you would expect to not see any deuterium in the product. The deuterated tosyl amide 32 was easily preparedfromcommercially available deutero benzaldehyde and employed in the reaction. The product a-ketoamide 33 was isolated and characterized. The product was found to have >95% incorporation of the deuterium at the alpha position of the ketoamide. This rules out the possibility of the second mechanism and provides evidence that the product keto-amide 33 is not undergoing epimerization under the reaction conditions. Thus it should be possible to carry out an enantioselective version of this reactions utilizing the appropriate chiral thiazolium salt. To gain further evidence for mechanism 1 we prepared the proposed intermediate aldehyde thiazole adduct 26 (Figure 1) by deprotonating thiazole with LDA and adding the resulting anion to benzaldehyde. Alkylation of this material with methyl iodide provided the corresponding salt, which was isolated and characterized. Employing a catalytic amount of this material in a reaction with a tosyl amide (21, Ar = Ar' = Ph, R = c-hexyl) and benzaldehyde provided the keto-amide product 24 in 83% yield.. Thus the thiazolium salt 26 is a viable intermediate in this reaction and an evidence that supports the first mechanism. (Scheme 9).

^

s

1)LDA,-78°C 2) Ph-CHO 3) Mel, C H C N 3

34

10mol% 26(Ar = Ph,R = Me)

24 (Ar « Af = Ph, R =c-Hex) 83% yield

Scheme 9. Synthesis ofproposed intermediate


177 In order to determine whether the reaction was under kinetic or thermodynamic control we performed a variety of crossover experiments as outlined in Scheme 10. Ar'0 S


2

O

O

H 35

Scheme 10: Crossover experiments Carrying out the reaction of a distinct aldehyde (23) and tosylamide 21 in the presence of a completely differentiated keto-amide 35 provided only the product 24fromcoupling of aldehyde 23 and tosyl amide 21 and not any of the components from the ketoamide 35 added at the start of the reaction. We performed this experiment several times and independently prepared samples of the crossover products and demonstrated that these were not present in these reactions. Finally, in an attempt to determine the rate-determining step of this reaction, we measured the deuterium isotope effect of the aldehydic hydrogen. If the ratedetermining event were addition of the thiazolium salt to the aldehyde, then one would expect to see an inverse isotope effect (K /K < 1). Conversely, if the proton transfer were the rate-detennining event, then a large primary isotope effect would be observed. Finally, if C-C bond formation were in the ratedetennining step, then there would not be an isotope effect since the label has been washed out at this point in the reaction sequence. Careful measurement of this parameter indicated that the K / K for benzaldehyde is 1.3. Because this number is neither

A Practical Synthesis of Tetrasubstituted Imidazole ... - ACS Publications

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