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This paper describes the development and validation of a high temperature gas chromatography flame ionization detection (HTGC-FID) method for the purity evaluation of arene substituted regioisomers in a key starting material of a pharmaceutical candidate in Phase 3 studies. The chromatographic conditions of the method employ a (5%-phenyl)-methylpolysiloxane packed column (30 m × 0.25 mm) at a constant flow of 1.0 mL min −1 with a gradient temperature program from 150 °C to 400 °C with injector and detector temperatures of 300 °C and 340 °C, respectively. The calibration curve for the desired product ( r = 0.9999) was assessed for five points in the range from approximately 1.0 μg mL −1 to 40 μg mL −1 . The precision (% RSD) of the method was calculated for six replicate injections and found to be 0.81%. The limits of detection and quantitation were determined to be 0.06 and 0.20 μg mL −1 , respectively.

A practical synthesis of SGLT2 inhibitor candidate ertugliflozin (1) has been developed for potential commercial application. The highly telescoped process involves only three intermediate isolations over a 12-step sequence. The dioxa-bicyclo[3.2.1]octane motif is prepared from commercially available 2,3,4,6-tetra-O-benzyl-d-glucose, with nucleophilic hydroxymethylation of a 5-ketogluconamide intermediate as a key step. The aglycone moiety is introduced via aryl anion addition to a methylpiperazine amide. High chemical purity of the API is assured through isolation of the crystalline penultimate intermediate, tetraacetate 39. A cocrystalline complex of the amorphous solid 1 with l-pyroglutamic acid has been prepared in order to improve the physical properties for manufacture and to ensure robust API quality.

This is the first in a series of three papers describing the identification and development of a commercial synthesis of filibuvir (1). This contribution describes development of an Evans aldol reaction to control the tertiary alcohol stereocenter, a challenging variant of that strategy in that both reacting partners were nonstandard (acetate enolate and ketone electrophile). A sequence consisting of Sonogashira coupling, acylation and hydrogenation delivered acetate 24, and Dieckmann cyclization provided β-keto lactone 2.

This paper describes an improved sequence for the conversion of an oxazolidinone (3) to a β-keto lactone (5). The primary drivers behind this change were the modest and variable yields observed in the intramolecular cyclization to generate the β-keto lactone. Changing the cyclization substrate from oxazolidinone to alkyl ester offered a significantly improved cyclization, as well as improvements in the alkyne hydrogenation. Selection of the optimal substrates for methanolysis and intermediate salt formation are also described.

An efficient synthesis of chloromethyl 2-ethoxy-2-methylpropanoate from 2-bromoisobutyric acid is reported. Four developments were key to this route: (i) a mild, base-mediated ethanolysis of a tertiary alkyl bromide, (ii) a sodium bisulfite purge of 2-methylacrylic acid, (iii) preparation of a thiomethyl ester via a formal Pummerer process with DMSO, and (iv) improved conversion of a thiomethyl ester to a chloromethyl ester through suppression of a competing chlorination pathway.

CE-178,253 benzenesulfonate (1) is a CB1 antagonist discovered by Pfizer medicinal chemists. Two syntheses of this compound are described. The first, based on the discovery synthesis, involves assembly of an aryl-substituted pyrazolotriazine core onto which the second aryl moiety is installed by a Suzuki coupling; this route has been scaled to provide up to 6 kg of API. A second, more convergent route is also described, which installs the pyrazolotriazine containing both aryl substituents by condensation of a bromoketone with a substituted thiosemicarbazide. This route has been demonstrated on laboratory scale and is viewed as the preferred bond-forming sequence.

Development of an efficient bond-forming sequence and optimization of reaction conditions are described for the synthesis of CP-945,598-01 (1·HCl), a CB1 antagonist in clinical studies for the treatment of obesity. Reordering of the bond-forming sequence provided a more efficient synthesis and avoided the use of phosphorous oxychloride. A telescoped reaction sequence (4 → 9) was developed to avoid a problematic isolation. Product isolations were developed so as to provide efficient throughput by minimizing solvent volumes and avoiding slow filtrations.

A review of reactions scaled in the GMP facilities at the Pfizer-Groton site was undertaken. Reactions were categorized into one of seven categories: carbon−carbon bond formation, carboxylic acid derivative interconversion, carbon−nitrogen bond formation, carbon−oxygen bond formation, red-ox, salt formation/resolution, and other. Reactions scaled from 1997 to 2002 were compared to chemistry scaled from 1985 to 1996 to look for changes in the nature of chemistry being scaled between the two time periods. Reactions were further subcategorized within those categories, and some interesting trends were noted.

A practical, readily scaleable synthesis of N,N-dimethyl-propanediamide (1) is reported. The utility of this bis-amide is demonstrated in the preparation of several 2,4-disubstituted ox-azoles from α-bromoketones.

The synthesis of 6-ethoxy-4-oxo-1,4-dihydro-[1,5]naphthyridine-3-carboxylic acid benzylamide (1) on multikilogram scale is described. The major challenge for the synthesis of this quinolone GABA partial agonist was in the isolation of product of acceptable purity for clinical studies due to the insolubility of this compound. Also described are efforts to circumvent a high-temperature cyclization required for the synthesis of the quinolone ring system.

The multihundred-gram synthesis of [2-(3-methyl-3H-imidazol-4-yl)-thieno[3,2-b]pyridin-7-yl]-(2-methyl-1H-indol-5-yl)-amine (1) is described utilizing a Stille cross-coupling of an iodothienopyridine (3) with 5-(tributylstannyl)-1-methylimidazole (11). Several cross-coupling methods were evaluated for the conversion of thienopyridine 3 to imidazole−thienopyridine 2, but only two were effective: the Stille coupling and a Negishi cross-coupling of the organozinc reagent derived from 2-(tert-butyldimethylsilyl)-1-methylimidazole and iodothienopyridine (3). The latter procedure worked well on laboratory scale (

Novel pyrazolinone-piperidine dipeptide derivatives were synthesized and evaluated as growth hormone secretagogues (GHSs). Two analogues, capromorelin ( 5 , CP-424391-18, hGHS-R1a K i =7 nM, rat pituicyte EC 50 =3 nM) and the des-methyl analogue 5c (hGHS-R1a K i =17 nM, rat pituicyte EC 50 =3 nM), increased plasma GH levels in an anesthesized rat model, with ED 50 values less than 0.05 mg/kg iv. Capromorelin showed enhanced intestinal absorption in rodent models and exhibited superior pharmacokinetic properties, including high bioavailabilities in two animal species [ F (rat)=65%, F (dog)=44%]. This short-duration GHS was orally active in canine models and was selected as a development candidate for the treatment of musculoskeletal frailty in elderly adults.

Several routes to bisulfite adduct 2 were explored, the most efficient of which involved vinyl Grignard addition to 2-indanone followed by ozonolysis and workup with aqueous NaHSO3 to effect reduction and bisulfite formation in a single pot. The safety and calorimetry of this ozonolysis reaction was studied, and the safe scale-up to 3 kg of olefin is described. The utility of bisulfite adduct 2 as an aldehyde surrogate in a reductive amination reaction is also described.

New tert -butyl, picolyl and fluorinated analogues of capromorelin ( 3 ), a short-acting growth hormone secretagogue (GHS), were prepared as part of a program to identify long-acting GHSs that increase 24-h plasma IGF-1 levels. Compounds 4c and 4d (ACD LogD values ≥2.9) displayed extended plasma elimination half-lives in dogs, primarily due to high volumes of distribution, but showed weak GH secretagogue activities in rats (ED 50 s>10 mg/kg). A less lipophilic derivative 4 (ACD LogD=1.6) exhibited a shorter canine half-life, but stimulated GH secretion in two animal species. Repeat oral dosing of 4 in dogs for 29 days (6 mg/kg) resulted in a significant down-regulation of the post dose GH response and a 60 and 40% increase in IGF-1 levels relative to pre-dose levels at the 8- and 24-h post dose time points. Compound 4 (CP-464709-18) has been selected as a development candidate for the treatment of frailty.

A practical synthesis of 4-hydroxymethyl-2-methylpyridine has been developed which makes use of Evans' regioselective lithiation of readily available 2,4-lutidine and trapping with dimethylformamide.

Growth hormone secretagogues (GHSs) represent attractive therapeutic alternatives to recombinant growth hormone (GH), given their ability to amplify pulsatile hormone secretion in a relatively physiologic manner. CP-424,391 (391) is a novel, orally active pyrazolinone-piperidine GHS. In rat pituitary cell cultures, 391 stimulated GH release with an EC50=3 nM. The addition of 391 to rat pituitary cells activated intracellular calcium signaling but did not elevate intracellular cyclic adenosine monophosphate (cAMP). 391 also modulated the effects of GH-releasing hormone and somatostatin on pituitary cell GH-release and intracellular signaling. In nonpituitary cell lines, the ability of 391 to stimulate intracellular signaling was dependent on the expression of recombinant human GHS receptor. Acute administration of 391 to anesthetized rats or to conscious dogs induced pulsatile release of GH in a dose-dependent manner. Plasma insulin-like growth factor-1 (IGF-1) was elevated progressively over a 5-d course of daily oral dosing in dogs. Chronic oral administration of 391 augmented body weight gain in rats and dogs. Thus, the peptidomimetic GHS 391 has potential utility for the treatment of clinical conditions that could benefit from systemic augmentation of GH and IGF-1 levels.

The effect of P 1 ′ C α gem-disubstitution in a series of succinamide hydroxamate inhibitors of MMP-1 has been investigated. While in all cases P 1 ′ gem-disubstitution led to loss of potency relative to the corresponding P 1 ′ isobutyl and phenyl compounds 1 and 3 , respectively, the loss of activity was less pronounced in certain instances, e.g., the P 1 ′ gem-cyclohexyl analogue 12 IC 50 = 0.15 μM).

Electron-deficient pyrrole (1) was derivatized by diazotization with p-nitrobenzene diazonium chloride. Reduction of the diazo intermediates gave 2- and 1-aminopyrroles (3 and 4). The 2-aminopyrrole (3) was determined to be the process impurity formed during a furan−pyrrole heteroatom exchange reaction. An oxidative mechanism for the impurity formation was hypothesized. Nitrogen sparging of the reaction mixture prior to heating eliminated formation of 3.

Biosynthetic proposal for the pentacyclic skeleton of the Daphniphyllum alkaloids is put forth (Scheme I) and various ramifications are examined experimentally. proto-Daphniphylline (II), the putative product of this hypothetical biogenesis, has been prepared by a convergent synthesis that starts with amide 14, α,β-unsaturated ester 15, and homogeranyl iodide (Scheme II) and employs a highly efficient tetracyclization process previously used for the synthesis of (±)-methyl homosecodaphniphyllate (30) (Scheme III)

3,3'-Diaminodipropylamine 2-(tert-Butoxycarbonyloxyamino)2-phenylacetonitrile Cyanuric chloride N-(tert-Butoxycarbonyl)-piperazine N,N-Diisopropyl ethylamine 2-[3,3'-Di-(tert-butoxycarbonyl)-aminodipropylamine]-4,,6-dichloro-1,3,5-triazone 1,3,5-[Tris-piperazine]-triazine Keywords: melamine dendrimers; s-triazine; one-pot procedure; substitution; waste disposal; safety

O. This solution is left to stir at 0 °C for 30 min. The resulting aqueoussolution is added in a dropwise fashion to the acetone solution at 0 °C over a period of 2 h. Thewhite suspension obtained after complete addition is left to stir at 0 °C for 2.5 h before warminggradually to 21 °C, and then stirred for an additional 20 h (Note 6). The white solid is collectedby filtration on a 15 cm-diameter Buchner funnel. The reaction vessel is rinsed with 500 mLwater, which is subsequently used to wash the filter cake (Notes 7 and 8). The wet solids aretransferred back to the rinsed reaction vessel and dissolved in CH

Cycloheptane 1-Trimethylsilyloxybicyclo[3.2.0]heptane-6-one 1-Trimethylsilyloxy-7,7-dichlorobicyclo[3.2.0]hepta-6-one Dichloracetyl chloride 1-Trimethylsilyloxycyclopentene Acetic acid Keywords: cycloheptane-1,3-dione; reduction; diketones; desilylation; chlorine atom; cyclopentanone; tranfer hydrogenolysis; sodium formate

[Structure: see text] The development of a concise enantioselective synthesis of nicotinic alkaloid 1 is presented. The route features the synthesis and use of a "stable" aliphatic triflate 21 in an alkylation step to generate Heck precursor 24 and an enantioselective cyclization to establish a compound with the key [3.2.1]-bicyclic core, 29.