Stereoselective syntheses of highly functionalized bicyclo[3.1.0]hexanes: a general methodology for the synthesis of potent and selective mGluR2/3 agonists

[Chemical reaction: See text] A Et3Al mediated intramolecular epoxide opening, cyclopropanation reaction is described. The transformation provided highly functionalized bicyclo[3.1.0]hexane systems in high efficiency and with perfect H or F endo selectivity. Application of this reaction to the synthesis of mGluR2/3 agonist 1 (43% overall yield) and a few intermediates suitable for the synthesis of other bicyclo[3.1.0]hexane mGluR2/3 agonists is discussed.     

Synthesis of a naphthyridone p38 MAP kinase inhibitor

Compound 1 is a p38 MAP kinase inhibitor potentially useful for the treatment of rheumatoid arthritis and psoriasis. A novel six-step synthesis suitable for large-scale preparation was developed in support of a drug development program at Merck Research Laboratories. The key steps include a tandem Heck-lactamization, N-oxidation, and a highly chemoselective Grignard addition of 4-(N-tert-butylpiperidinyl)magnesium chloride to a naphthyridone N-oxide. The N-oxide exerted complete chemoselectivity via chelation in directing the Grignard addition to the alpha position as opposed to 1,4-addition on the ene-lactam. The dihydropyridyl adduct was in situ aromatized with isobutylchloroformate followed by heating in pyridine. Syntheses of Grignard precursor, N-tert-butyl-4-chloro-piperidine, were accomplished via transamination with a quaternary ammonium piperidone or via addition of methylmagnesium chloride to an iminium ion. Utilizing this chemistry, multi-kilogram preparation of compound 1 was successfully demonstrated.     

Structures of three substituted pentacyclo[5.4.0.02, 6.03, 10.05, 9]undecanes and a computational analysis of bond lengths

5-Methyl-2-phenylpentacyclo[5.4.0.0^{2, 6}.0^{3, 10}.0^{5, 9}]undecane-8, 11-dione,5-methyl-2-phenylpentacyclo [5.4.0.0^2,6.0^3,10.0^5,9]undecane-8-one-11-ol,and 5-methyl-2-phenylpentacyclo[5.4.0.0^2,6.0^3,10.0^5,9]undecane-8,11-diol are three cage compounds which differ only in the oxidation state at C(8) and C(11). The three compounds contain a four-membered, a six-membered, and four five-membered rings fused into a cagelike structure. An X-ray structure analysis shows the C(1)-C(7) and C(9)-C(10) bonds in the diketo cage to be 1.606(2) and 1.586(2) Å, which are significantly longer than in the other two molecules. In order to assess the effects of strain, steric, and electronic factors in these compounds, we investigated the unsubstituted parent cage compounds and a series of derivatives by molecular mechanics (MM3), AMPAC (AM1), MOPAC (PM3), and GAUSSIAN 90 calculations. These data suggest that dipolar through space interactions are responsible for the bond elongation and not a _– ^* interaction, which has been postulated in parallel-systems originating from a common bond. A small degree of _– ^* through-bond interaction may contribute to the lengthening in the dimethylene cage analogues.     

An improved preparation of 3,5-bis(trifluoromethyl)acetophenone and safety considerations in the preparation of 3,5-bis(trifluoromethyl)phenyl Grignard reagent

An improved and efficient bromination of 3,5-bis(trifluoromethyl)benzene was developed. A safe and reliable preparation of the potentially explosive 3,5-bis(trifluoromethyl)phenyl Grignard and 3-trifluoromethylphenyl Grignard reagents, from the precursor bromides, is described. Reaction System Screening Tool (RSST) and Differential Thermal Analysis (DTA) studies suggest these trifluoromethylphenyl Grignard reagents can detonate on loss of solvent contact or upon moderate heating. When prepared and handled according to the methods described herein, these Grignard reagents can be safely prepared and carried on to advanced intermediates.     

Development of a new and practical route to chiral 3,4-disubstituted cyclopentanones: asymmetric alkylation and intramolecular cyclopropanation as key C-C bond-forming steps

An efficient and practical asymmetric synthesis of (+)-trans-3-hydroxymethyl-4-(3-fluorophenyl)cyclopentanone (1) is described. An asymmetric Mo-catalyzed alkylation reaction was used to establish the first stereocenter and a Cu-catalyzed intramolecular diastereoselective cyclopropanation reaction was used to set the second stereocenter. The last step involved a one-pot ring-opening/deprotection/hydrolysis/decarboxylation sequence that furnished the desired product in good yield.     

An efficient synthesis of a dual PPAR alpha/gamma agonist and the formation of a sterically congested alpha-aryloxyisobutyric acid via a Bargellini reaction

A practical synthesis of benzisoxazole 1 and its conversion to alpha-aryloxyisobutyric acid 2 using 1,1,1-trichloro-2-methyl-2-propanol (chloretone) was developed. Benzisoxazole 1 was formed in high yields by the action of either methanesulfonyl chloride/base upon intermediate oxime 8 or with thionyl chloride/base, which initially forms cyclic sulfite 10. A highly reactive, short-lived intermediate derived from chloretone was detected by ReacIR and its half-life determined to be approximately 5 min. Reaction conditions for the Bargellini reaction were developed that resulted in a 95% yield of 2 from the reaction of highly hindered phenol 1 with chloretone hemihydrate and powdered NaOH in acetone. Thus highly hindered alpha-aryloxyisobutyric acids can be made in a single step in high yield.     

Synthesis of 3-aminopyrazinone mediated by 2-pyridylthioimidate-ZnCl2 complexes. Development of an efficient route to a thrombin inhibitor

A six-step preparation of thrombin inhibitor drug candidate 1 from pyrazinone 7 in 47% overall yield is described. The problem of low reactivity between weak amine nucleophile 4 and poor electrophile 3-bromopyrazinone 17 was overcome with the use of pyridinylthioimidate 27 in the presence of ZnCl(2) to afford adduct 3 in high yield. Several zinc complexes were characterized by solution and solid-state NMR and X-ray crystallographic analyses, and provided insight into the reaction mechanism. Preparation of pyridine N-oxide amine 4 was accomplished via a selective oxidation of the corresponding pyridinylamine 6. Pyridinylthioimidate 27 was prepared from pyrazinone 7 via a two-step one-pot process in near quantitative yield. Chlorination of the pyrazinone ring in 3 followed by hydrolysis and amide coupling completed the synthesis of 1. This chromatography-free synthesis was used successfully to prepare multikilogram quantities of the drug with reproducibility and high purity.     

Practical synthesis of the new carbapenem antibiotic ertapenem sodium

[reaction: see text] A practical synthesis for the large-scale production of the new carbapenem antibiotic, [4R,5S,6S]-3-[[(3S,5S)-5-[[(3-Carboxyphenyl)amino]carbonyl]-3-pyrrolidinyl]thio]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid monosodium salt (ertapenem sodium, 1), has been developed. The synthesis features the novel use of 1,1,3,3-tetramethylguanidine as base for the low-temperature reaction of a thiol, derived from trans-4-hydroxy-L-proline, with the carbapenem nucleus activated as the enol phosphate. Hydrogenolysis of a p-nitrobenzyl ester is effected using a palladium on carbon catalyst to give an overall yield for the two steps of 90%. The use of bicarbonate in the hydrogenolysis was key in providing protection of the pyrrolidine amine as the sodium carbamate improving both the performance of the reaction and the stability of the product. This discovery made processing at manufacturing scale possible. Experimental evidence for the formation of the sodium carbamate is provided. A remarkably expedient process for the simultaneous purification and concentration of the aqueous product stream relies on ion-pairing extraction for the removal of the water-soluble 1,1,3,3-tetramethylguanidine. Crystallization then affords 59-64% overall yield of the monosodium salt form of the product.