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Our teams have recently completed scale-up campaigns for two structurally similar H3 receptor antagonists. The first and second generation processes were developed for the synthesis of 107 and 125 ...

An efficient process to produce kilogram quantities of a key argininylbenzo[d]thiazole intermediate was developed for the preparation of the tryptase inhibitor RWJ-56423. A variety of activated arginine esters and benzo[d]thiazole nucleophiles were evaluated as coupling partners. Our work led to the selection and optimization of an argininyl imidazolide ester and benzothiazol-2-yl MgCl nucleophile. This paper focuses on the preparation, use, and stability of the benzothiazol-2-yl Grignard reagents.

The microreactor technology is an efficient tool for kilogram-scale syntheses in continuous mode and is particularly effective for hazardous reactions that do not allow scale-up in conventional reactors. Applications to several classes of reactions including highly exothermic reactions, high-temperature reactions, reactions with unstable intermediates, and reactions involving hazardous reagents are described herein.

Elarofiban is a novel, nonpeptide, orally active fibrinogen receptor antagonist useful for the treatment of platelet mediated thrombotic disorders (Costanzo, M. J.; Hoekstra, W. J.; Maryanoff, B. E. WO, 97/41102, 1997). Herein we describe the process research that was carried out for the synthesis of elarofiban that eventually led to the development of a safe and cost-effective commercial scale process.

Preparation of methyl (S)-3-amino-3-(3‘-pyridyl)propionate dihydrochloride in high enantiomeric purity by selective crystallization of a diastereomeric salt of a carboxylic acid precursor (N-BOC-pr...

A new synthesis of the methyl-branched sugar axenose is described. Axenose is found in the antibiotics axenomycin, dutomycin, and polyketomycin. The synthesis is based on additions of organometallic reagents to pentodialdo-1,4-furanosides and allows the preparation of derivatives of methyl α- l -axenoside which are protected at the tertiary C-3 hydroxyl group. Conversion to thioglycoside derivatives for use in oligosaccharide synthesis was carried out directly from the methyl glycoside by treatment with phenylthiotrimethylsilane and trimethylsilyl trifluoromethanesulfonate.

Methyl (S)-3-amino-3-(3-pyridyl)propanoate (2) is a key starting material in the synthesis of RWJ-53308 (1), an orally active antagonist of the platelet fibrinogen receptor (GP IIb/IIIa antagonist). Herein, we describe an efficient stereoselective synthesis of 2 by the hydrogenation of enantiomeric enamine 8 with Pd(OH)2C, followed by the removal of the chiral auxiliary under mild conditions, a novel procedure that employs the combination of formic acid and triethylsilane.

RWJ-51204, the lead compound in our pyrido [1,2-a] benzimidazole (PBI) series, was shown to exhibit anxiolytic efficacy in animal models at doses which did not cause central nervous system side effects commonly observed with other anxiolytic agents. To prepare supplies of drug substance for early toxicological and clinical studies, we needed to develop a safe and scaleable synthesis. Our main focus was to improve the last two steps of the process which involved formation of the penultimate carboxamide intermediate followed by alkylation using potentially toxic chloromethyl ethyl ether. Due to safety issues concerning storage and handling of this reagent during the large scale synthesis, we investigated alternate routes to minimize potential exposure risks. The process research carried out for the final steps that led to the safe and cost-effective multi-kilogram synthesis of RWJ-51204 is described herein.

6-Methoxy-1,2,3,4-tetrahydroisoquinoline (1) or its hydrochloride salt (4) is an expensive chemical with limited commercial availability. We report an improved and practical synthesis of 4 from ine...

Tetrabutylammonium hydroxide is effective in hydrolysis of polypeptide esters to the corresponding acids with minimum racemization of the stereogenic centers at the α-positions. It is especially effective in hydrolysis of non-polar polypeptide esters that are insoluble in most common solvents.

Three methods for the synthesis of the deoxy sugar amicetose (2,3,6-trideoxy- d - erythro -hexopyranoside) are described. All three utilize the known dihydropyran 2-isobutoxy-6-methyl-2,3-dihydro-4 H -pyran as an intermediate. Asymmetric hydroboration of the dihydropyran with IpcBH 2 gave enantiomerically enriched isobutyl α and β-amicetosides. Hydroboration with borane–tetrahydrofuran followed by derivatization of the major product (β-anomer) with R -(−)-1-(1-naphthyl)ethylisocyanate gave diastereomeric carbamates which were separated and converted to isobutyl β- d and β- l -amicetosides having high optical purity. Racemic isobutyl β-amicetosides were also resolved by enzymatic transesterification using lipase and an acyl transfer reagent. Porcine pancreatic lipase and lipases from Candida rugosa and Pseudomonas sp. were evaluated in the presence of either vinyl acetate, vinyl butyrate, or trifluoroethyl butyrate as acylating agents. A GC-based method for determining enantiomeric purity of amicetose derivatives was developed.

A study of β-turn peptide mimetics, related to the C-terminal γ-chain of fibrinogen and containing a nipecotic acid scaffold, led to RWJ-50042 (1), an interesting fibrinogen receptor (GPIIb/IIIa) antagonist. To enhance potency, we employed solid-phase parallel synthesis for the preparation of over 200 analogues in a protocol of optimization cycles. This strategy produced several promising nipecotamide analogues, such as 25, which is 35 times more potent than 1 in vitro.

Tetrabutylammonium hydroxide is effective in hydrolysis of polypeptide esters to the corresponding acids with minimum racemization of the stereogenic centers at the α-positions. It is especially effective in hydrolysis of non-polar polypeptide esters that are insoluble in most common solvents.

The minor component observed in aqueous proton (1H) and carbon (13C) NMR spectra of oxymorphone HCl and oxycodone HCl is produced by the reaction of these salts with water forming gem-diols and not due to the axial N-methyl isomer.

We have continued to explore spirobenzazepines as vasopressin receptor antagonists to follow up on RWJ-339489 (2), which had advanced into preclinical development. Further structural modifications were pursued to find a suitable backup compound for human clinical studies. Thus, we identified carboxylic acid derivative 3 (RWJ-676070; JNJ-17158063) as a potent, balanced vasopressin V(1a)/V(2) receptor antagonist with favorable properties for clinical development. Compound 3 is currently undergoing human clinical investigation.

From a series of amide analogs of the histamine H1 antagonist, azatadine, a potent, orally active, dual platelet-activating factor (PAF) and histamine antagonist, Sch 37370, namely 1-acetyl-4-(8-chloro-5,6-dihydro-11H-benzo- [5,6]cyclohepta[1,2-b]pyridin-11-ylidine)piperidine, was discovered. Sch 37370 selectively inhibits PAF-induced aggregation of human platelets in vitro (IC50 = 0.6 microM), and in vivo inhibits PAF- and histamine-induced bronchospasm in guinea pigs with ED50 values of 6.0 and 2.4 mg/kg p.o., respectively. Sch 37370 is expected to be more efficacious than single mediator antagonists in allergic diseases, such as asthma.

Three different classes of compounds were isolated in the reaction of Grignard reagents with 5-H[1]benzopyrano[2,3-b]pyridin-5-one, commonly called 1-azaxanthone. The formation of (a) 4-substituted 1,4-dihydro-1-azaxanthones (II), (b) 5-substituted-5-hydroxy-1-azaxanthenes (III) or (c) 4,5-disubstituted-1-azaxanthenes (IV) is dependent on the solvent used in the preparation of the Griganrd reagent (i.e. ether or tetrahydrofuran), the steric properties of the reagent and on the temperature. The isolated compounds were characterized by chemical derivatives and/or spectroscopic analyses.

The preparation and properties of four isomeric azadibenzoeycloheptenones 3 and their 10,11-dihydro derivatives 2 are described. The ketones 2 were prepared by cyclization of appropriately substituted phenethylpyridine carboxylic acids and dehydrogenated to 3. Four monochloro derivatives 24 of the 4-azaketone 2d are also described.

Dialkylaminoalkylether derivatives of a variety of aromatic, heterocyclic, and steroidal ketone oximes were prepared and examined for their antiandrogenic effects. The compounds were prepared by two general methods. The diethylaminoethyl ether of 2-benzoylpyridine oxime exhibits interesting antiandrogenic activity in rats but the effective dose is very close to the toxic dose. In the course of this investigation other pharmacological properties of the compounds were noted.

An improved synthesis of the title compound is described. The base catalyzed condensation of 4-methylnicotinonitrile with benzaldehyde resulted in the isolation of trans-4-styrylnicotin-amide (2a) in high yield. Hydrolysis to the acid and heating the acid 3a with polyphosphoric acid (ppa) gave the title compound 1a in good yields. Even higher yields of 1a were obtained in the presence of catalytic quantities of selenium. Also described are two other syntheses of the title compound as well as the preparation of a series of compounds related to 2a (Table I).

The title compounds were prepared by the condensation of a series of β-keto esters with 2-benzylimidazoline. A mechanism is proposed wherein the dienamine 4 undergoes an intramolecular acylation with the elimination of ethoxide and subsequent hydride shift.

6,7-Benzo-12H-5,6,7,12-tetrahydrocycloocta[1,2b]pyridine-12-one (III) and 5,6-benzo-5,6,11,12-tetrahydrocycloocta[1,2b]pyridine-11-one (IV) were prepared. Wolff-Kishner reduction gave the corresponding azahydrocarbons (VIIa and IX). Alkylation of 6,7-benzo-12H-5,6,7,12-tetrahydrocycloocta[1,2b]pyridine, using potassium amide and liquid ammonia, gave the corresponding 12-dialkylaminoalkyl derivatives (VIIb and VIIc). The dehydration of 12- hydroxy - 12 - (1 - methyl - 4 - piperidyl) - 6,7 - benzo - 12H-5,6,7,12-tetrahydrocycloocta[1,2b]pyridine (V), prepared by two methods, gave 4-aza-4b-(1-methyl-4-piperidyl)-9,10-dihydroindeno[1,2a]indene (VI). The compounds were without significant biological activity.