Synthesis of Pyridopyrazine-1,6-dione Î³-Secretase Modulators via

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Synthesis of Pyridopyrazine-1,6-dione #-Secretase Modulators via Selective 4-Methylimidazole N1- Buchwald Arylation Longfei Xie, Christopher W. am Ende, Martin Pettersson, Danica A Rankic, Neil Sach, Subas Sakya, and John M. Humphrey J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02953 • Publication Date (Web): 08 Jan 2019 Downloaded from http://pubs.acs.org on January 10, 2019

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The Journal of Organic Chemistry

Synthesis of Pyridopyrazine-1,6-dione γ-Secretase Modulators via Selective 4-Methylimidazole N1Buchwald Arylation Longfei Xie, a Christopher W. am Ende, a Martin Pettersson,b Danica A. Rankic, a Neal Sach,c Subbas Sakya,a John M. Humphreya* aPfizer

Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340, USA

bPfizer

Worldwide Research and Development, 1 Portland Street, Cambridge, Massachusetts 02139,

USA cPfizer

Worldwide Research and Development, 10770 Science Center Drive, San Diego, CA, 92121,

USA. TOC Graphic: for Table of Contents use only NH

O

N O

N

Br O

O

Xantphos Pd G4

toluene/dioxane

O

KHCO3 4 Å mol seives 71%

N

N O

N

sole regiomer

ABSTRACT

ACS Paragon Plus Environment

The Journal of Organic Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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An efficient synthesis of pyridopyrazine-1,6-dione -secretase modulators (GSMs) is described. Our route features the construction of a crystalline lactone intermediate via a selective palladiumcatalyzed 4-methylimidazole N1- arylation using the Buchwald Xantphos Pd G4 precatalyst, which does not require a pre-activation step. The weak inorganic base KHCO3 was employed to minimize saponification of a particularly sensitive lactone substrate. Additional key transformations include DABAL-Me3-mediated lactone aminolysis and a mild TBD/ethyl trifluoroacetate mediated lactam ring closure to afford a representative GSM in high yield. Alzheimer’s disease (AD) is a fatal debilitative neurodegenerative disorder that is characterized by progressive cognitive impairment and a loss of motor function.1 AD represents a significant unmet medical need given the lack of therapeutic agents that can halt or slow progression of the disease. A possible cause of AD is the aberrant accumulation of neurotoxic amyloid 42 (A42) peptides that aggregate to form amyloid plaques. These A peptides are formed via sequential processing of the amyloid precursor protein (APP) by the aspartyl protease enzymes β-secretase and γ-secretase.2 As a result, suppression of amyloid plaque formation through inhibition or modulation of these enzymes is an area of considerable interest in the search for effective AD therapies. A promising therapeutic strategy for the treatment of AD involves modulation of γ-secretase activity through the application of small molecule γ-secretase modulators (GSMs).3 Compounds of this class do not inhibit γ-secretase but rather shift the cleavage site of APP to reduce formation of neurotoxic Aβ42 peptide in favor of shorter, more benign species. Maintenance of γ-secretase activity vs. total enzyme inhibition is critical to avoid serious side effects resulting from inhibition of Notch signaling.4 Several classes of GSMs have emerged, with most being loosely derived from an A, B, C, Dtype ring framework as exemplified by compounds 1-4 (Figure 1).5 A key structural facet of these


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compounds is the presence of a 5-methyl-3-imidazolyl motif (ring A, structure 1), which plays a critical role in GSM activity. Figure 1. Representative heteroaryl GSMs.

N

O

D

HN

N C S

N

B

N AN

F

N

F O E2012 (2) Eisai

NGP-555 (1) Neurogenetics

CF3

CF3 O

N N N

N

N

N

N

N N

N O

O H

O E2212 (3) Eisai

Pfizer (4)

We have recently reported on the discovery of compound 4 and related chromene derivatives, that are structurally defined, in part, by a pyridopyrazine-1,6-dione bicyclic core that was critical for the alignment of potency with metabolic stability and CNS exposure.6 The GSM 4 afforded robust reduction of brain A42 when dosed orally in rat at 10 and 40 mg kg-1, thus establishing the series as a promising direction for our research. As other members of this series progressed through preclinical studies, we sought to streamline the synthetic route to support anticipated bulk demands.



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Our initial synthesis of the pyridopyrazine-1,6-dione GSMs featured a novel HATU-mediated coupling/cyclization reaction to form the desired compounds (5) from the pyridone carboxylic acid (6) and various substituted amino alcohols (7) (Figure 2A).7 This approach enabled early evaluation of structure-activity relationships and provided material to support preclinical in vivo studies. However, the synthesis had a number of drawbacks including the requirement for >2 equivalents of the high-energy coupling reagent HATU (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate),8 low yields (20-30%) with sterically hindered amines,7a and challenging product isolation. Furthermore, the poor solubility and amorphous nature of the solid pyridone carboxylic acid 6 made isolation, purification, and employment of this intermediate cumbersome. Each of these issues were effectively addressed by preparation of the highly crystalline lactone intermediate 8 (Figure 2B), and development of a facile amidation / lactamization sequence that was amenable to the incorporation of hindered amines.9 One notable challenge in each of these approaches centered on differentiation between the two nitrogen atoms (N1/N3) of the asymmetrical 4-methylimidazole substituent. Figure 2. Original and revised lactam strategies CO2H (2A) Original Approach: 1-Pot HATU-mediated coupling/cyclization.

N

O

N

HCl

+ OH

R 7

6 amorphous, poor organic solubility

O N

NH

N

HN

R

N

N

O

O 5

(2B) Revised Approach: Amidation followed by alcohol activation and cyclization.

O N

N

N

+ H 2N 9

O 8 crystalline, moderate organic solubility


R

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Our first route to the key lactone 8 is illustrated in Scheme 1 and has been reported.10 The simple structure of the starting 3-aminopyridine (10) vs. the relatively complex product 8 necessitated a number of functionalization steps. Imidazole N1/N3 differentiation was achieved through stepwise construction of the imidazole by elaboration of the pyridyl 3-amino group, which further added to the length of the sequence. Scheme 1. Original route to pyridone carboxylic acid 6 and lactone 8.

N

H 2N

Br

NBS DMSO H2O

N

H 2N

Br

Na

N

H 2N

MeOH, dioxane

Br

O

KI,Cs2CO3,DMF

Br

N

N O

NH4OAc N

AcOH

O 14

O 13

CO2Me

Pd(dppf)Cl2, DCM

N

N

N

HN O

12

Br

O

Cl

HCOOH

O

11

10

Br

Ac2O

TEA, CO, MeOH

O

N

N

N O 16

15 O CO2H

HCl, dioxane 150 °C, quant

N

NH

N

. HCl

O 6

Br

Br

Cs2CO3, DMF 90 oC

O N

N

N O

8

For a more direct path we chose the commercial pyridone carboxylic acid 17 as an ideally functionalized feedstock for conversion into 8 through a bromination/N1-arylation strategy (Scheme 2). This tactic would require exquisite regioselectivity in the N1-arylation reaction to avoid trace isomeric contaminants in the final active substance – a problem that plagued us previously in a related system.11 As detailed in a report by Buchwald et al., high selectivity is not generally achievable through SNAr or



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Ullmann-type arylation but can be obtained through a pre-activated Me4tBuXPhos palladium catalyst system. According to Buchwald et al., steric hindrance induced by the imidazole methyl substituent within the palladium complex strongly favors reaction intermediates leading to the desired N1-arylation product.12 The pyridone acid 17 can be brominated regioselectively, but the product of the reaction is an intractable amorphous solid with poor organic solubility. In a more scalable process, initial bisalkylation with 1,2-dibromoethane gave the crystalline lactone 18,13 and subsequent bromination afforded the crystalline aryl bromide 19 in two steps without chromatography (Scheme 2). Isomeric bromine derivatives were not observed. Application of the Buchwald procedure,12 employing Me4tBuXPhos palladium and potassium phosphate in toluene-dioxane, afforded complete imidazole N1arylation selectivity for the conversion of the bromide 19 into the target lactone 8 in 76% crystallized yield. Consistent with the Buchwald report, this transformation was best achieved through a 120 °C preactivation of the catalyst and ligand prior to imidazole introduction. Subsequent to this result, our internal reaction screening and optimization efforts (See Supporting Information) revealed that commercially available Xantphos Pd G4 precatalyst gave the target lactone in comparable yield (71%). Employment of the G4 precatalyst system is operationally simpler with no need for preactivation vs. the reported method.12 In subsequent optimization work with the G4 precatalyst system, we found that KHCO3 provided superior results to other bases (e.g. K2CO3, K3PO4) in minimizing saponification of the lactone 8 to the corresponding hydroxy-acid. Molecular sieves were essential in maintaining an anhydrous environment to further minimize hydrolysis of this particularly susceptible lactone.


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Scheme 2. Improved route to the key lactone template 8. O OH NH O

O N

Cs2CO3 DMSO, 85 °C

17

O

85% O

Br2/MeOH 91%

O

Br

Br

N

O

Xantphos Pd G4

toluene/dioxane

N

Br

NH

18

8

KHCO3

O

4 Å mol seives

19

71%

Conversion of the lactone 8 into the representative GSM 22 was accomplished via lactone amidation with the requisite amine 20, followed by activation of the resultant primary alcohol intermediate 21, and base catalyzed intramolecular SN2 cyclization (Scheme 3). The amidation could be accomplished via direct amine addition in a polar solvent such as methanol or DMF, but this transformation required a large excess of the amine component to drive the reaction beyond ~60% conversion. To incorporate the complex, precious amines present in our most advanced GSMs, we turned

instead

to

the

air-stable

Lewis

acid

DABAL-Me3

(bis(trimethylaluminum)-1,4-

diazabicyclo[2.2.2]octane adduct),14 which provided yields in excess of 90% utilizing only stoichiometric amine.



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Scheme 3. DABAL-Me3 amidation and TBD/ethyl trifluoroacetate cyclization sequence. CF3 CF3

O 8

H 2N

N

DABAL-Me3

O

N

93%

20

N O

N H OH

O 21

CF3 TBD CF3CO2Et

O N

N THF, 93% (or DMF)

N

N

N

O

O

N H

N TBD

22

The intermediate 21 afforded us with numerous opportunities for activation and SN2 ring closure, some of which we have reported previously.6,

9, 13

In order to achieve improved and more consistent

yields we initiated a base / solvent screen on a related chloride intermediate utilizing the 3-aminopentane derived amide as a relatively hindered amide nucleophile (see Supporting Information). In this study, the strong organic bases TBD (1,5,7-Triazabicyclo[4.4.0]dec-5-ene) and BEMP (2-tert-Butylimino-2diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine)

provided

superior

results

vs.

both

inorganic and weaker tertiary amine bases, and DMF provided faster reaction rates over THF. We also examined a variety of activation methods including Mitsunobu, sulfonate, and trifluoroacetic anhydride activations. Each of these methods suffered from drawbacks ranging from by-product generation, imidate formation, elimination reaction, and the need for careful attention to stoichiometry during the activation step. We ultimately developed a remarkably mild in situ activation system comprised of ethyl trifluoroacetate and TBD,13 the latter of which provided superior results to DBU with respect to rate of


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reaction and purity profile. The reaction catalyzed by TBD could be conducted in THF or DMF, with the latter solvent providing significantly faster reactions. For the specific case of intermediate 21, treatment with 5 equivalents of ethyl trifluoroacetate and 2.2 equivalents of TBD in THF provided complete conversion to the target 22 within 4 h at room temperature in 93% crystallized yield after aqueous workup. The moderate excess of ethyl trifluoroacetate conveniently acted as a water scavenger such that strictly anhydrous conditions were unnecessary. In conclusion, we have demonstrated a succinct synthetic route to the pyridone-1,6-dione class of GSMs, represented by the chromene derivative 22. The method features a selective N1-imidazole arylation with the commercially available Xantphos Pd G4 Buchwald precatalyst performed on the key crystalline lactone intermediate 8. Catalyst pre-activation is not necessary for this system, which presents an ease-of-use advantage over the literature method. We have optimized conditions for the mild, room temperature conversion of this lactone into target - secretase modulators via DABAL-Me3 mediated amidation and subsequent base catalyzed ring closure with TBD and ethyl trifluoroacetate. All products depicted in Schemes 2 and 3 were isolated as crystalline solids without chromatography, which facilitated work on multi-gram quantities.

EXPERIMENTAL SECTION Reagents and starting materials were obtained from commercial sources and used without purification unless otherwise indicated. The Xantphos Pd G4 precatalyst was obtained from SigmaAldrich. Potassium bicarbonate was dried under vacuum overnight at 130 °C. All products were isolated and purified as crystalline solids. Silica gel chromatography, used in one instance to assess the amount of product 8 remaining in the mother liquor after crystallization, was performed via through a glass column hand-packed with JT Baker 40 µM flash silica gel. 1H and


13C

NMR spectra are presented as


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chemical shifts (ppm) relative to the solvent with multiplicities reported as s (singlet), bs (broad singlet), d (doublet), t (triplet), q (quartet), m (multiplet), comp (complicated pattern of overlapping resonances), app (apparent), and obsc (obscured peaks). Fluorine NMR spectral data are presented as chemical shifts relative to trifluoroacetic acid (-75.4 ppm). Products were shown to be >97% by 1H NMR analysis and by HPLC (Waters Acuity instrumentation, CSH C18 1.7 µM 2.1 x 50 mm column, mobile phase A: 99.9 acetonitrile/ 0.1 formic acid; mobile phase B: 99.9 water/0.1 formic acid. Elutions were effective via a 1.5 min gradient beginning at 5:95 A/B and ending with 100% B) with compound identified by UV = 215 nM and ESI positive ion mass spectrometry. 7-bromo-3,4-dihydropyrido[2,1-c][1,4]oxazine-1,6-dione (19).

A round bottom flask

equipped with an over-sized stir bar was charged with 3,4-dihydropyrido[2,1-c][1,4]oxazine-1,6-dione (18) (2.00 g, 14.4 mmol)13 and the solid was dissolved by the addition of hot methanol (30 mL). The solution was allowed to cool slightly. Prior to commencement of starting material precipitation, bromine (4.22 g, 26.4 mmol) was added rapidly dropwise (exothermic). Analysis by 1H NMR indicated that the reaction was complete within 45 min. Near the end of the addition, a thick flocculent precipitate formed. The amorphous solid was stirred vigorously overnight to afford a granular slurry. The slurry was cooled in an ice bath for 30 min, and the precipitate was collected via filtration and rinsed with ether to afford 2.57 g (87%) of the title compound as a white powder. The mother liquor was concentrated and partitioned between 1 M sodium thiosulfate (1x) and ethyl acetate (3x). The organic portion was washed with brine, dried over MgSO4, and concentrated to afford an additional 96 mg for a combined yield of 2.67 g (91%). Mp 200.9-204.4 °C (dec); IR (thin film) 1727, 1244, 1051, 742 cm-1; 1H NMR (400 MHz, DMSO-d6)  8.11 (d, J = 7.8 Hz, 1H), 7.00 (d, J = 7.4 Hz, 1H), 4.66 (t, J = 5.7 Hz, 2H), 4.22 (t, J = 5.7 Hz, 2H); 13C{1H} NMR (100 MHz, DMSO-d6) 158.8, 155.9, 140.6, 132.8, 121.2, 110.7, 65.6, 40.1); MS m/z (ion) 244 (M + 1); HRMS (ESI-TOF) m/z: [M + H]+ calcd for C8H6BrNO3, 243.9604; found,


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243.9603; Analysis calcd. for C8H6BrNO3: C, 39.37; H, 2.48; N, 5.74; Found: C, 39.38; H, 2.33; N, 5.65. 7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydropyrido[2,1-c][1,4]oxazine-1,6-dione (8). To 7bromo-3,4-dihydropyrido[2,1-c][1,4]oxazine-1,6-dione (19) (5.00 g, 20.5 mmol), 4-methylimidazole (3.36 g, 41.0 mmol) potassium bicarbonate (4.10 g, 41.0 mmol) and activated 4 Å molecular sieves (40 g) in toluene (100 mL) and dioxane (33 mL) under a nitrogen atmosphere was added Xantphos Pd G4 precatalyst (304 mg, 0.31 mmol). The mixture was heated at reflux for 16 h, at which point it was cooled to rt and filtered through a silica gel pad, rinsing with 1:9 MeOH/CH2Cl2 (200 mL). The solvent was removed under vacuum and the residue was partitioned between EtOAc (50 mL) and 1 N HCl (100 mL). The organic layer was extracted with water (1 x 10 mL). The combined aqueous material was basified with saturated NaHCO3 and extracted with CH2Cl2 (3 x 50 mL). The combined extracts were dried over anhydrous Na2SO4 and concentrated to afford 3.69 g of the title compound as a yellow solid. The material was recrystallized from a solution of methyl tert-butyl ether (50 mL) and CH2Cl2 (30 mL) to afford 3.51 g (70%) of the title compound as a pale yellow solid. Silica gel chromatography of the mother liquor, eluting with a 0 – 10% gradient of methanol in CH2Cl2, afforded an additional 46 mg for a combined yield of 3.56 g (71%). Spectral and physical data for this compound are consistent with that previously reported.9 N-((2,2-dimethyl-6-(trifluoromethyl)-2H-chromen-4-yl)methyl)-1-(2-hydroxyethyl)-5-(4methyl-1H-imidazol-1-yl)-6-oxo-1,6-dihydropyridine-2-carboxamide

(21).

To

7-(4-methyl-1H-

imidazol-1-yl)-3,4-dihydropyrido[2,1-c][1,4]oxazine-1,6-dione (8) (2.65 g, 10.8 mmol) and (2,2dimethyl-6-(trifluoromethyl)-2H-chromen-4-yl)methanamine (20) (2.25 g, 8.73 mmol), in THF (20 mL) at rt was added DABAL-Me3 (2.68 g, 10.5 mmol). The mixture was stirred at rt for 18 h, and was then cooled in an ice bath and quenched via the dropwise addition of water (10 mL) followed by 5 N NaOH



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(10 mL). The mixture was partitioned between 1 N NaOH (1 x 300 mL) and EtOAc (2 x 300 mL). The combined organic extracts were washed with brine, dried over MgSO4, and concentrated to a thick slurry. The slurry was stirred overnight, and then cooled for 20 min in an ice bath. The solids were collected via filtration and rinsed with ethyl ether to afford 4.07 g (93%) the title compound as a white powder: mp 200.8 - 201.4 C; IR (thin film) 3224 (br), 2980, 2923, 1644, 1280 cm-1;

1H

NMR (400

MHz, DMSO-d6)  9.26 (t, J = 5.6 Hz, 1H), 8.15 (s, 1 H), 7.70 (d, J = 7.4 Hz, 1H), 7.58 (s, 1H), 7.51 (d, J = 8.6 Hz, 1H), 7.34 (s, 1H), 6.97 (d, J = 8.2 Hz, 1H), 6.41 (d, J = 7.8 Hz, 1H), 5.93 (s, 1H), 4.90 (t, J = 5.1 Hz, 1H), 4.27 (comp, 6.2 Hz, 4H), 3.60 (q, 2 H), 2.14 (s, 3H), 1.41 (s, 6 H);

13C{1H}

NMR (100

MHz, DMSO-d6)  163.0, 156.9, 155.6 (app d, 4JCF = 1.5 Hz), 142.0, 136.9, 136.3, 129.3, 128.5, 127.6, 126.5, 126.4 (q, 3JCF = 3.7 Hz), 124.5 (q, 1JCF = 270.7 Hz), 121.4 (q, 2JCF = 32.3 Hz), 120.7, 120.2 (q, 3J CF

= 3.7 Hz), 116.8, 115.2, 105.4, 77.2, 58.2, 47.6, 39.3, 27.7, 13.5;

19F

NMR (376 MHz, CDCl3) 

61.3 (s). HRMS (ESI-TOF) m/z: [M + H]+ calcd for C25H25F3N4O4, 503.1901; found, 503.1892. 2-((2,2-dimethyl-6-(trifluoromethyl)-2H-chromen-4-yl)methyl)-7-(4-methyl-1H-imidazol-1yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione (22). To a slurry of N-((2,2-dimethyl-6(trifluoromethyl)-2H-chromen-4-yl)methyl)-1-(2-hydroxyethyl)-5-(4-methyl-1H-imidazol-1-yl)-6-oxo1,6-dihydropyridine-2-carboxamide (21) (1.66 g, 2.30 mmol) in THF (13 mL) was added ethyl trifluoroacetate (2.34 g, 16.5 mmol) followed by 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) (964 mg, 6.92 mmol). The white slurry turned yellow and dissolved within a few minutes. After 4.5 h, the solution was diluted with water and extracted twice with ethyl acetate. The combined extracts were washed with brine, dried over MgSO4, and concentrated. The residue was recrystallized from EtOAc/heptane with cooling in an ice bath for 1 h to afford 1.48 g (93%) of the title compound. Mp 198.0-198.5 °C (Lit. 196.5-197.0 °C6);

19F

NMR (76 MHz, CDCl3)  61.6 (s). Other spectral and physical data for this

compound are consistent with that previously reported.6


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Supporting Information: Experimental procedures for Buchwald reaction conditions screening; solvent and base screening methods for optimization of the SN2 cyclization; 1H, 13C,

and 19F NMR spectra.

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Synthesis of Pyridopyrazine-1,6-dione Î³-Secretase Modulators via

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