The problem of allocating jobs to a set of parallel unrelated machines in a make to stock manufacturing system is studied. The items are subdivided into families of similar products. ...Sequence-dependent setups arise when products belonging both to the same family and to different families are sequenced. Restrictions on the number of available setups should be considered. The availability of planning batch production exists. Nevertheless, batch size is not known a priori. Hence, a solving approach considering both a pre-assignment procedure and a scheduling algorithm is proposed. Specifically, the focus of the article is on the pre-assignment methodology: a pre-assignment model (solved by a commercial solver) and two heuristics are presented and compared, in order to minimise the average idle residual capacity during the planning horizon, while considering pejorative factors related with the split volumes of the same product on different machines, unsatisfied demand along with demand produced in advance in each time period. The application to a case study is finally described in order to assess the performance of the proposed approach.
Upon treatment of 1‐bromo‐2‐(trifluoromethoxy)benzene with lithium diisopropylamide (LIDA) at −100 °C, 3‐bromo‐2‐(trifluoromethoxy)phenyllithium is generated. It can be trapped as such, but ...isomerizes to afford 2‐bromo‐6‐(trifluoromethoxy)phenyllithium when the temperature is raised to −75 °C. The latter intermediate can be directly obtained from 1‐bromo‐3‐(trifluoromethoxy)benzene. 1‐Bromo‐4‐(trifluoromethoxy)benzene gives 5‐bromo‐2‐(trifluoromethoxy)phenyllithium at −100 °C, but at −75 °C it slowly eliminates lithium bromide, thus setting free 1,2‐dehydro‐4‐(trifluoromethoxy)benzene. In the same way, 1,2‐dehydro‐3‐(trifluoromethoxy)benzene can be generated from 1‐bromo‐3‐(trifluoromethoxy)benzene. Both “arynes” can be intercepted in situ with furan. The resulting 4+2 cycloadducts can be reduced with zinc powder, giving 1‐ and 2‐(trifluoromethoxy)naphthalenes, they may be submitted to acid‐catalyzed isomerization to produce trifluoromethoxy‐1‐naphthols, or they may be brominated to afford vic‐dibromo derivatives. Base‐promoted dehydrobromination of the latter compounds produces 2‐ or 3‐bromo‐1,4‐epoxy‐1,4‐dihydro‐5‐ or −6‐(trifluoromethoxy)naphthalenes, which undergo regioselective ring‐opening in acidic media and halogen/metal exchange when treated with butyllithium.
Judged by its capacity to promote a hydrogen/metal permutation at an ortho position, the trifluoromethoxy group is superior to both the methoxy and trifluoromethyl groups. Moreover, like CF3 and ...unlike OCH3, OCF3 exerts a long‐range effect that still considerably lowers the basicity of arylmetal compounds when located in a more remote meta or even para position. As a consequence, 4‐(trifluoromethoxy)anisole is deprotonated by sec‐butyllithium mainly, and by tert‐butyllithium exclusively, at a position adjacent to the OCH3 group rather than next to the strongly electron‐withdrawing CF3O group. 1,3‐Benzodioxole undergoes ortho lithiation only six times faster than anisole, whereas 2,2‐difluoro‐1,3‐benzodioxole reacts about 5000 times faster, as evidenced by competition experiments. The structure and distance dependence of substituent effects can be rationalized by assuming superposing σ‐ and π‐polarizing interactions.
4‐(Trifluoromethoxy)anisole is deprotonated ortho to the OCH3 group rather than ortho to the strongly electron‐withdrawing CF3O group. The trifluoromethoxy group can exert a long‐range effect, as shown here, that considerably lowers the basicity of arylmetal compounds even when it is located in a remote position. The structure and distance dependence of substituent effects can be rationalized by assuming superposing σ‐ and π‐polarizing interactions.
Retreatment of chronic hepatitis C patients nonresponders to interferon (IFN) alone with the standard dose of IFN 3 million units (MU) thrice weekly (TIW) plus ribavirin for 24 weeks has yielded low ...sustained virological response (SVR), averaging 8%. The aim of the present, open‐labelled, randomized study was to evaluate the efficacy of IFN induction therapy followed by prolonged high dose of IFN plus ribavirin in nonresponders. One hundred and fifty‐one patients were randomized to receive 5 MU daily of IFN alfa‐2b (group 1, n = 73) or 5 MU TIW of IFN alfa 2b (group 2, n = 78) for 4 weeks followed by IFN (5 MU TIW) plus ribavirin (1000/1200 mg/daily) for 48 weeks in both groups. In an intention‐to‐treat analysis, the sustained virological response (SVR) at 24‐week follow‐up was 33 and 23% for group 1 and 2, respectively (P = 0.17). The overall SVR was 52 and 18% in patients with genotype 2/3 and 1/4, respectively. Among genotype 1/4 patients the SVR was 29 and 11% for age younger or older than 40 years. Compared with genotype 2/3 patients, the risk (95% confidence interval) of nonresponse to retreatment was 3.0‐fold (1.17–8.0) in younger genotype 1/4 patients and 8.4‐fold (3.0–23.29) in older genotype 1/4 patients. In conclusion these results suggest that retreatment with a reinforced regimen should be focused in nonresponder genotype 2/3 patients and younger genotype 1/4 patients, who are most likely to benefit. Induction therapy does not improve SVR.
Retreatment of relapser patients with chronic hepatitis C with the standard dose of interferon (IFN) of 3 million units (MU) thrice weekly (tiw) plus ribavirin for 24 weeks achieves a sustained ...response in 30 and 73% of patients with genotype 1 and 2 or 3, respectively. The aim of this study was to evaluate the efficacy and safety of IFN α‐2b induction therapy, followed by prolonged treatment with a high dose of IFN α‐2b plus ribavirin in relapser patients. A total of 119 patients were randomized to receive IFN α‐2b 5 MU daily (Group A: 59 patients) or IFN α‐2b 5 MU tiw (Group B: 60 patients) for 4 weeks followed by IFN (5 MU tiw) and ribavirin (1000–1200 mg/day) for 48 weeks in both groups. The primary end point was hepatitis C virus (HCV)‐RNA clearance at week 24 after the end of treatment. A sustained virological response (SVR) was achieved in 68 and 60% of Group A and B patients, respectively (P = 0.37). Logistic regression analysis identified genotype 2 or 3 as the only independent factor associated with response, whereas induction regimen and baseline viraemia levels did not affect the response. The overall SVR was 53 and 72% in patients with genotype 1 or 4 and 2 or 3, respectively. In conclusion, induction IFN therapy does not enhance the SVR to a 48‐week combination therapy. Our study suggests that relapsed patients with genotype 1 or 4 may achieve significant response rates of approximately 50%, if retreated with 5 MU tiw IFN plus ribavirin for 48 weeks.
Trifluoromethoxy-substituted anilines undergo hydrogen/lithium permutation (“metalation”) with optional site selectivity depending on the N-protective group employed. N-tert-Butoxycarbonyl-2- and ...−4-(trifluoromethoxy)aniline react with tert-butyllithium at the nitrogen-adjacent 6- and 2-position affording, after electrophilic trapping, products 1−6. In contrast, deprotonation of the para isomer occurs at the oxygen-neighboring 3-position, giving rise to the acid 12, when the amino group is carrying two trimethylsilyl groups. sec-Butyllithium attacks 3-trifluoromethoxy-N-mono(trimethylsilyl)aniline at the 2-position, but 3-trifluoromethoxy-N,N-bis(trimethylsilyl)aniline at the 4-position to provide respectively the acids 10 and 11 after carboxylation. The synthesis of two new benzodiazepines illustrates (19 and 22) the preparative potential of the aniline functionalization mediated by organometallic reagents.
Consecutive treatment of (trifluoromethoxy)benzene with sec‐butyllithium and electrophilic reagents affords previously inaccessible ortho‐substituted derivatives in generally excellent yields. ...2‐(Trifluoromethoxy)phenyllithium acts as the key intermediate. The 3‐ and 4‐isomers can readily be generated from the corresponding 3‐ and 4‐bromo precursors by halogen‐metal interconversion with butyllithium or tert‐butyllithium. Upon trapping of the 2‐, 3‐ and 4‐(trifluoromethoxy)phenyllithiums with 11 different electrophiles the expected products were formed in generally high yields. Only the attempted nucleophilic addition of 2‐(trifluoromethoxy)phenyllithium to oxirane did not succeed. This failure is tentatively attributed to a lowering of the nucleophilicity by fluorine‐lithium interactions. Conformationally restricted analogs — i.e., 2,2‐difluoro‐1,3‐benzodioxol‐4‐phenyllithium and its 5‐fluoro‐ and 5‐bromo‐substituted congeners — did indeed react smoothly with oxirane, affording the adducts in ordinary yields.
A retrospective multicentre survey was conducted to evaluate, in patients with chronic hepatitis C, the long‐term liver histological changes induced by interferon (IFN). A total of 112 patients (mean ...age 46.4 years) were studied. All patients had received a 6–12‐month IFN‐α course (6–18 MU/week) and had successively undergone clinical, biochemical and virological follow‐up for at least 36 months (range: 36–76). In each patient, two liver biopsies had been performed: 1–6 months before treatment and, 12–76 months after its completion. In 87 patients with biochemical and virological sustained response persisting for 12 months after therapy, post‐treatment liver necroinflammation and fibrosis mean(±SD) scores (Knodell index) were significantly lower than pretreatment scores (2.9 ± 2.2 vs 6.8 ± 2.9 and 0.8 ± 1.0 vs 1.2 ± 1.1, respectively; P < 0.01) . In 25 patients who relapsed within 1 year, necroinflammation and fibrosis post‐treatment mean scores were similar to pretreatment scores (7.4 ± 3.2 vs 6.9 ± 3.1 and 1.8 ± 1.3 vs 1.6 ± 1.2, respectively; P > 0.05). On an individual basis, necroinflammation decreased in 87% of sustained responders but only in 36% of relapsers (P < 0.001), whereas fibrosis decreased in 44% of sustained responders but only in 14% of relapsers (P < 0.001). In sustained responders with biopsies performed 12–23 months (n=34), 24–35 months (n=26) or more than 36 months (n=27) after treatment, a progressive decrease of mean necroinflammatory score was observed (−2.6 ± 2.1, −4.1 ± 3.4 and −5.2 ± 3.7 points, respectively; P < 0.01). A similar pattern was observed in fibrosis score (−0.3 ± 0.6, −0.3 ± 0.7 and −0.7 ± 0.9 points, respectively; P < 0.05). Hence, among chronic hepatitis C patients treated with IFN, those with a 12‐month sustained response, unlike those who relapse, have a long‐term progressive reduction and, in some cases, a complete regression of liver histological damage.
In this paper the problem of allocating and scheduling jobs on parallel unrelated machines is studied. Jobs are grouped in families of similar items. A sequence dependent setup is required between ...batches of jobs belonging to the same and different families, even if in the first case lower time is required. The size of batches is not known a-priori, hence the problem is divided in two different sub problems: a) the allocation of volumes of work on each machine and b) subsequently the scheduling of each item. The focus of the paper is on the first step and consequently on the pre-assignment problem. Three different solving approaches are implemented in several real-life case studies.
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