First-generation process synthesis

Initial efforts to prepare benzoic acid 28 from methyl or ethyl 4-aminobenzoate and biphenyl-2-carboxylic acid (27) afforded poor yields of 28 (48% and 7%, respectively). However, acylation of 4-aminobenzoic acid with biphenyl-2-carbonyl chloride was found to provide 28 in excellent yield (95%) when DMAP was employed as a base. Selective acylation of the anilinic nitrogen of 26 with benzoic acid 28 was accomplished in analogy with the first-generation process synthesis by conversion of 28 to the corresponding acid chloride (SOCl2, CH3CN) followed by acylation of 26 in acetonitrile. Subsequent addition of ethanolic hydrogen chloride to the reaction mixture resulted in the precipitation of conivaptan HCl (1), which was isolated in 90% yield. 

Through their refinements to the synthesis of 1, the Astellas process group ultimately developed a multikilogram-scale process for the production of 1, which both decreased the cost and increased the safety of the synthesis relative to earlier discovery and process routes.34 The resulting process additionally provided conivaptan HCl (1) in 56% overall yield from cyanobenzazepinone 19, representing a four-fold increase in yield relative to the first-generation process synthesis and sixfold increase in yield relative to the initial discovery route. 

Scheme 5. First-generation process synthesis of P2 fragment 24.

The first generation process started with the chemical synthesis of the (R,S)-amide. There were several possible synthetic routes (Fig. 8) via the (R,S)-nitrile or (R,S)-acid [19, 20], A microbial screening program resulted in the isolation of several bacterial strains containing amidases that could specifically hydrolyze the (R)-amide. One of these strains, Comomonas acidivorans A 18 was particularly effective [21]. After the hydrolysis of the unwanted isomer the product (S)-2,2-dimethylcy-clopropane carboxamide was isolated from the bio-solution using a combination of salting-out and solvent extraction. This process had some intrinsic problems ... 

SCHEME 5.17 First-generation process pyrrolidine acid synthesis. 

Feynman s vision of miniaturization and the Drexler-versus-Smalley debate on feasibility of mechanosynthetic reactions using molecular assemblers were discussed. Fullerenes are the third allotropic form of carbon. Soccer-ball-structured Cgo with a surface filled with hexagons and pentagons satisfies Euler s law. Howard patented the first generation combustion synthesis method for fullerene production. The projected price of the fullerenes has decreased from 165,000 per kg to 200 per kg in the second-generation process. Fullerenes can also be synthesized using chemical methods, a supercritical extraction method, and the electric arc process. Applications of fullerenes include high temperature superconductors, bucky onion catalysts, advanced composites and electromechanical systems, synthetic diamonds. 

The second category of coal Hquefaction iavolves those processes which first generate synthesis gas, a mixture of CO and by steam gasification of coal... 

RCM of a dienyne was also a key step in Mori s recent total synthesis of the alkaloid erythrocarine (447) [183]. The tetracyclic framework of447 was elaborated in the penultimate step, by exposing the hydrochloride of metathesis precursor 445 (1 1 diastereomeric mixture at the carbinol center) to first-generation catalyst A. The tandem process occurred smoothly within 18 h at room temperature leading to tetracycles 446 (1 1 mixture) in quantitative yield. Deprotection of the a-acetoxy isomer 446a led to 447 (Scheme 88). 

Hoveyda and coworkers [227] used a domino process to give chromanes 6/3-8 by treatment of 6/3-7 in the presence of ethylene. One of the first-generation Grubbs catalyst 6/3-9 and one of Blechert s [228] early examples allowed the synthesis of bicyclic compounds of different sizes, depending on the length of the tether thus, the reaction of 6/3-10 led to 6/3-11 using 30 mol% of the Schrock Mo complex 6/3-12. 

AGB stars constitute excellent laboratories to test the theory of stellar evolution and nucleosynthesis. Their particular internal structure allows two important processes to occur in them. First is the so-called 3(,ldredge-up (3DUP), a mixing mechanism in which the convective envelope penetrates the interior of the star after each thermal instability in the He-shell (thermal pulse, TP). The other is the activation of the s-process synthesis from alpha captures on 13C or/and 22Ne nuclei that generate the necessary neutrons which are subsequently captured by iron-peak nuclei. The repeated operation of TPs and the 3DUP episodes enriches the stellar envelope in newly synthesized elements and transforms the star into a carbon star, if the quantity of carbon added into the envelope is sufficient to increase the C/O ratio above unity. In that way, the atmosphere becomes enriched with the ashes of the above nucleosynthesis processes which can then be detected spectroscopically. 

A comparison of the amount of waste produced per kilogram of sitagliptin manufactured by the two processes demonstrates the improved efficiency of the new route (Figure 5.6). Overall, the new route reduces the total waste output of the process by approximately 80%. This will result in over 220000 kg less waste per 1000 kg of sitagliptin produced. While the first-generation synthesis produced over 60 L of aqueous waste per kg of 1, the new route produces no aqueous waste only 2 liters of water per kg of sitagliptin is now required for its preparation. 

The second-generation synthesis of (S,S)-TaDiAS 1 is summarized in Scheme 6.1 [16], This process requires only common and inexpensive reagents under operationally simple reaction conditions. When using the first-generation synthesis (a five-step process from diethyl tartrate) [4a] or the second-generation synthesis (a four-step process from tartaric acid), a variety of catalysts with versatility on the acetal moieties (R1 and R2) and aromatic parts (Ar) were synthesized (over 100 derivatives) [18]. A large-scale reaction (>20g) can also be performed with the same efficiency. 

The photooxygenation of cyclopentadiene with Rose Bengal as photosensitizer was performed using a falling-film microreactor in methanol [317]. The endoperoxide is first generated and then reduced to 2-cyclopenten-l,4-diol, which is used as an intermediate in pharmaceutical drug synthesis. This route is not easily possible by batch processing because the explosive endoperoxide intermediate is formed in substantial amounts. 

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