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+{"prompt": "Synthesis step:", "completion": "2-Substituted and 1,2-Disubstituted Piperidines METHYLPHENIDATE (11968) Methylphenidate (3.1.6) (Ritalin) is a commonly prescribed central nervous system (CNS) stimulant. Methylphenidate is used to treat attention deficit disor- der, attention deficit hyperactivity disorder, and narcolepsy, a chronic sleep dis- order. However, a growing number of young individuals misuse or abuse methylphenidate to sustain attention, enhance intellectual capacity, and increase memory [1\u00014]. Side effects of methylphenidate include trouble sleeping, loss"}
+{"prompt": "Synthesis step:", "completion": "of appetite, weight loss, dizziness, nausea, vomiting, and headache. Methylphenidate (3.1.6) has been synthesized via condensation of pheny- lacetonitrile (3.1.1) with a 2-chloropyridin (3.1.2) at 110\u0001112\u0003C in toluene in the presence of NaNH2, which gave 2-phenyl-2-(pyridin-2-yl)acetonitrile (3.1.3). The last was hydrolyzed to corresponding amide (3.1.4), which on treatment with HCl in methanol on heating gave methyl 2-phenyl-2-(pyridin- 2-yl)acetate (3.1.5). Hydrogenation of the pyridine ring to a piperidine ring in the obtained product in acetic acid on the Pt or PtO2 catalyst gave the"}
+{"prompt": "Synthesis step:", "completion": "desired methylphenidate (3.1.6) [5\u00017] (Scheme 3.1). Alternatively, 2-bromopyridine can be used instead of 2-chloropyridine [8]. A huge amount of chemical work is described on the separation and interconversion stereoisomers of methylphenidate [9\u000114]. The absolute (2R,20R; threo) stereochemistry of the most active enantiomer, (2R,20R)-"}
+{"prompt": "Synthesis step:", "completion": "threo-methylphenidate, was proven [15,16]. PERHEXILINE (1216) Perhexiline (3.1.11) was originally developed as an antianginal drug and was launched on the UK market as a racemate in 1975 under the trade name Methylphenidate 3.1.6 NaNH2 Toluene 110\u201312\u00b0C CH3OH H2SO4 3.1.1 3.1.2 3.1.3 3.1.5 3.1.4 H2-Pt SCHEME 3.1"}
+{"prompt": "Synthesis step:", "completion": "Synthesis of methylphenidate. Piperidine-Based Drug Discovery. DOI: http://dx.doi.org/10.1016/B978-0-12-805157-3.00003-X"}
+{"prompt": "Synthesis step:", "completion": "Copyright \u00a9 2017 Elsevier Ltd. All rights reserved. Pexid. It rapidly gained a reputation for efficacy in the management of angina pectoris. However, hepatic and neurological adverse effects in a small proportion of patients led to a marked decline in its use in 1985.The drug was originally classified as a coronary vasodilator, and later as a calcium channel antagonist. Recent data suggests that it acts as a cardiac metabolic agent"}
+{"prompt": "Synthesis step:", "completion": "through inhibition of the enzyme, carnitine palmitoyltransferase-1 [17\u000122]. Perhexiline (3.1.11) consists of a piperidine framework with a 2,2-dicy- clohexylethyl substituent at the 2-position. The synthesis of racemic perhexi- line is based on nucleophilic addition of lithiated 2-picoline (3.1.7) to dicyclohexyl ketone (3.1.8) to give the corresponding tertiary alcohol (3.1.9), which undergoes HCL mediated dehydration forming alkene (3.1.10), the subsequent hydrogenation of which catalyzed by PtO2 gives desired perhexi- line (3.1.11) [23,24]. An alternative approach was demonstrated, using as starting ketone, bezophenone (3.1.12), which on reaction with lithiated 2- picoline gives tertiary alcohol (3.1.13), which after dehydration using hydro- chloric acid gives alkene (3.1.14), the hydrogenation of which catalyzed by PtO2 [25] or in presence Raney-Ni [26] or Rh-Al2O3 [27] gives desired per-"}
+{"prompt": "Synthesis step:", "completion": "hexiline (3.1.11) (Scheme 3.2). Two enantiomers, (1)- and (\u0001)-perhexiline have different pharmacody- namic profiles. It has been suggested that the (\u0001)-enantiomer is primarily responsible for the therapeutic effects, whereas the (1)-enantiomer is primar- ily responsible for the toxic effects [17]. Optically enriched perhexiline has been obtained by resolution of the 1,10-binaphthyl-2,20-diyl(hydrogen)phos-"}
+{"prompt": "Synthesis step:", "completion": "phate diastereomeric salts of perhexiline [28]. Synthesis of both enantiomers of perhexiline in high enantiomeric excess through a stereoselective catalytic hydrogenation of the 2-(oxazolidin-2-one)- substituted-pyridine and the elucidation of the absolute configurations of the"}
+{"prompt": "Synthesis step:", "completion": "two enantiomers of perhexiline which was unknown, was recently reported [29]. PIPRADROL (259) Pipradrol (3.1.17) is a dopamine reuptake inhibitor and norepinephrine reup- take inhibitor, a mild amphetamine type psychostimulant with action similar Perhexiline 3.1.11 BuLi or PhLi H2/PtO2 H2/PtO2, or Raney-Ni, or Rh-Al2O3 3.1.7 3.1.8 3.1.9 3.1.10 3.1.13 3.1.14 3.1.12 SCHEME 3.2"}
+{"prompt": "Synthesis step:", "completion": "Synthesis of perhexiline. Piperidine-Based Drug Discovery to methylphenidate. Pipradrol was developed in the 1950s as an antidepres- sant and was used for treatment of obesity and dementia, but the adverse effects associated with its use and its abuse potential led to its withdrawal"}
+{"prompt": "Synthesis step:", "completion": "and international control [30]. Pipradrol (3.1.17) was synthesized from pyridyl Grignard reagent prepared from 2-pyridyl bromide (3.1.15) and bezophenone (3.1.12), which gave diphe- nylpydinemethanol (3.1.16) reduced catalytically to desired pipradrol (3.1.17) [31,32]. Enantiomers of pipradrol were synthesized from (R)- and (S)- pipecolic acid ethers (3.1.18) and the probable conformation of the base was deduced. All of the central stimulant activity resided in (R)-pipradrol, but both the (R) and (S)"}
+{"prompt": "Synthesis step:", "completion": "isomers possessed anticonvulsant properties [33] (Scheme 3.3). MEFLOQUINE (5370) Mefloquine (3.1.27), sold under the brand name Lariam, is an orally adminis- tered very potent blood schizontocide that has been marketed since 1990 for both malaria prophylaxis and for acute treatment of falciparum malaria. It is a long-acting antimalarial drug known for its efficacy against chloroquine- and SP-resistant Plasmodium falciparum [34\u000137]. Mefloquine can cause"}
+{"prompt": "Synthesis step:", "completion": "serious side effects that include nervous system changes. The synthesis of mefloquine (3.1.27) began with the synthesis quinolin-4- ol (3.1.21) obtained by polyphosphoric acid condensation of the ethyl 4,4,4- trifluoroacetoacetate (3.1.19) with O-trifluoromethylaniline (3.1.20). A further conversion of prepared (3.1.21) by POBr3 into the 4-bromoquinoline (3.1.22) led to the transformation of the last 4-Li derivative (3.1.23) followed by CO2 carboxylation gave cinclioninic acid (3.1.24). Addition of 2-pyridyllithium (3.1.25) gave the pyridyl ketone (3.1.26). Hydrogenation with H2-PtO2 gave a"}
+{"prompt": "Synthesis step:", "completion": "good yield of desired mefloquine (3.1.27) [38,39] (Scheme 3.4). Pipradrol 3.1.17 3.1.15 3.1.12 Mg, EtMgBr Ether or Diethyl cellosolve 3.1.16 H2/PtO2 EtOH MeOOC 3.1.18 Ether PhMgBr SCHEME 3.3"}
+{"prompt": "Synthesis step:", "completion": "Synthesis of pipradrol. 150\u00b0C 140\u00b0C n-BuLi Ether CO2 (dry powdered) Ether 3.1.19 3.1.20 3.1.21 3.1.22 3.1.23 POBr3 Mefloquine 3.1.27 COOH Ether H2/PtO2 EtOH 3.1.24 3.1.25 3.1.26 SCHEME 3.4"}
+{"prompt": "Synthesis step:", "completion": "Synthesis of mefloquine. None of the optically active forms of mefloquine (3.1.27) resolved via its hydrochloride salt with (1)- (\u0001)-3-bromo-8-camphorsulfonic acid ammonium salts showed any significant differences in antimalarial activity"}
+{"prompt": "Synthesis step:", "completion": "[40]. MEPIVACAINE (4176) Many local anesthetics are presently available for clinical use, and among them many derivatives of 2-substituted piperidines. The choice of a particu- lar agent for a particular case is based mainly on its clinical and pharmaco-"}
+{"prompt": "Synthesis step:", "completion": "logical features. Mepivacaine (3.1.31), launched on the market as Carbocaine and Polocaine, is a local anesthetic with a reasonably rapid onset and medium duration of action that became available in the 1960s. Mepivacaine exerts its local anes- thetic effect by blocking voltage-gated sodium channels in peripheral neurons, which creates temporary anesthesia (lack of feeling or numbness). Mepivacaine is used for causing numbness during surgical procedures, labor, or delivery"}
+{"prompt": "Synthesis step:", "completion": "[41,42]. It may cause dizziness, drowsiness, or blurred vision. Two basic methods for the synthesis of mepivacaine are proposed. The first comprises transformation ethyl 1-methylpipecolate (3.1.30) 1-methylpiperidine-2-carboxylic acid amide with magnesium (2,6-dimethylphenyl) amide bromide (3.1.29) under reflux in ether. A magnesium derivative (3.1.29), in turn, was prepared via interaction of 2,6-xylidine (3.1.28) with ethylmagnesium"}
+{"prompt": "Synthesis step:", "completion": "bromide [43\u000145]. In another method, picolinic acid was converted to its amide (3.1.32), hydro- genated over platinum on carbon catalyst, and alkylated at the piperidine ring"}
+{"prompt": "Synthesis step:", "completion": "nitrogen with formalin using palladium on carbon [43,45,46] (Scheme 3.5). (1)-Mepivacaine \u0001 (S)-configuration is a longer-acting local anesthetic"}
+{"prompt": "Synthesis step:", "completion": "than the mixture enantiomers obtained during synthesis [47]. ROPIVACAINE (6847) Ropivacaine (3.1.37) (Naropin) is the pure S(\u0001)-enantiomer of propivacaine released for clinical use in 1996. It is a long-acting, well tolerated local anes- thetic agent and first produced as a pure enantiomer. Its effects and Mepivacaine 3.1.31 NH2 EtMgBr N MgBr Ether Ether Reflux H2/Pt-C EtOH, HCl H2/Pd-C CH2O 3.1.28 3.1.29 3.1.30 3.1.33 3.1.32 SCHEME 3.5"}
+{"prompt": "Synthesis step:", "completion": "Synthesis of mepivacaine. Piperidine-Based Drug Discovery mechanism of action are similar to other local anesthetics working via reversible inhibition of sodium ion influx in nerve fibers. It may be a pre- ferred option among other drugs among this class of compounds because of its reduced CNS and cardiotoxic potential and its lower propensity for motor"}
+{"prompt": "Synthesis step:", "completion": "block in the management of postoperative pain and labor pain [48\u000158]. The synthesis of ropivacaine (3.1.37) was carried out starting with L-pipeco- lic acid (3.1.34), prepared by a resolution of (6)-pipecolic acid with (1)-tartaric acid, which was dissolved in acetyl chloride and converted to acid chloride (3.1.35) with phosphorus pentachloride. The obtained compound (3.1.35) dis- solved in toluene a solution of 2,6-xylidine (3.1.28) dissolved in the mixture of equal volumes of acetone, and N-methyl-2-pyrrolidone was added at 70\u0003C to give (1)-L-pipecolic acid-2,6-xylidide (3.1.36). Reaction of this compound with propyl bromide in presence of potassium carbonate in i-PrOH/H2O gave the"}
+{"prompt": "Synthesis step:", "completion": "desired ropivacaine (3.1.37) [59] (Scheme 3.6). Another approach for the synthesis of ropivacaine (3.1.37) was proposed"}
+{"prompt": "Synthesis step:", "completion": "via a resolution of enantiomers of chiral pipecolic acid-2,6-xylidide [60]. BUPIVACAINE (21293) AND LEVOBUPIVACAINE (1976) Bupivacaine (3.1.41) (Marcaine) is a local anesthetic of great potency and long duration that has been widely used for years, but it has cardio and CNS toxic sideeffects. For many years it was nearly the only local anesthetic appli- cable to almost all kinds of loco-regional anesthetic techniques, and nowa-"}
+{"prompt": "Synthesis step:", "completion": "days, in many occasions, it is still the only alternative available [61\u000164]. Bupivacaine is currently used in racemic form. At high doses, however,"}
+{"prompt": "Synthesis step:", "completion": "the racemate is potentially hazardous due to toxicity problems. Currently, racemic bupivacaine (3.1.41) is produced from picolinic acid (3.1.38) either by reduction to pipecolic acid (3.1.39) and then, after conver- sion to corresponding acid chloride (3.1.40) coupling with 2,6-xylidine to give pipecolic acid-2,6-xylidide (3.1.33), or by reducing the pyridyl amide"}
+{"prompt": "Synthesis step:", "completion": "(3.1.43) prepared from picolinic acid chloride (3.1.42) over platinum oxide. The amide intermediate (3.1.33), which can also be used to prepare the anes- thetics ropivacaine (3.1.37) and mepivacaine (3.1.31), was transformed to desired bupivacaine (3.1.41) either by direct alkylation using butyl bromide and potassium carbonate or by reductive amination using butyraldehyde"}
+{"prompt": "Synthesis step:", "completion": "[45,59,65\u000169] (Scheme 3.7). 3.1.34 Ropivacaine 3.1.37 3.1.28 PrBr K2CO3 AcCl i-PrOH/H2O Toluene, Acetone/NMP 3.1.35 3.1.36 PCl3 SCHEME 3.6"}
+{"prompt": "Synthesis step:", "completion": "Synthesis of ropivacaine. Enantiomers of bupivacaine can be prepared via diastereomeric salt reso- lution with tartaric acid or by resolution of the amide (3.1.33) with O,"}
+{"prompt": "Synthesis step:", "completion": "O-dibenzoyl tartaric acid followed by alkylation [47,70]. One of enantiomers, S(\u0001) isomer of the racemic bupivacaine (levobupiva- caine), has equal potency but less cardiotoxic and CNS effects in comparison with both R(1) bupivacaine and bupivacaine racemate. The reduced toxicity of"}
+{"prompt": "Synthesis step:", "completion": "levobupivacaine (3.1.48) gives a wider safety margin in clinical practice [71,72]. Stereospecific synthesis of levobupivacaine from (S)-lysine have been"}
+{"prompt": "Synthesis step:", "completion": "proposed (Scheme 3.8). Treatment of N-CBZ (S)-lysine (3.1.44) with sodium nitrite in acetic acid yields the acetate (3.1.45). The prepared acetate (3.1.45) was then coupled with dimethyl aniline using N,N0-dicyclohexylcarbodiimide to give the amide (3.1.46) in good yield. The acetate group was then converted into the tosylate (3.1.47), which was deprotected and cyclized stereospecifically in one-pot reaction to give the amide (3.1.33) in high yield. Alkylation is easily"}
+{"prompt": "Synthesis step:", "completion": "achieved using an alkyl bromide and K2CO3 without any racemization. Alkylation can also be carried out using butyraldehyde/formic acid although"}
+{"prompt": "Synthesis step:", "completion": "the former is a much simpler process [73] (Scheme 3.8). Bupivacaine 3.1.41 3.1.38 3.1.43 3.1.39 3.1.40 3.1.42 3.1.28 BuBr K2CO3or PrCHO, HCOOH H2/PtO2 3.1.28 Toluene, Acetone/NMP H2/PtO2 EtOH, AcOH AcCl PCl3 Toluene SOCl2 Reflux 3.1.33 H2O/HCl SCHEME 3.7"}
+{"prompt": "Synthesis step:", "completion": "Synthesis of bupivacaine. NaNO2, NaOAc, AcOH 3.1.28 3.1.44 3.1.45 Levobupivacaine 3.1.48 BuBr, K2CO3or PrCHO, HCOOH 3.1.33 H2/Pd-C 1. K2CO3, MeOH 2. TsCI, Et3N 3.1.46 3.1.47 SCHEME 3.8"}
+{"prompt": "Synthesis step:", "completion": "Synthesis of levobupivacaine. Piperidine-Based Drug Discovery FLECAINIDE (3638) Flecainide (3.1.54), sold under the trade name (Tambocor), is an antiarrhyth- mic drug used to prevent and treat tachyarrhythmias, a wide variety of cardiac arrhythmias including paroxysmal atrial fibrillation, paroxysmal supraventric- ular tachycardia and ventricular tachycardia, and has been used extensively worldwide over the last 25 years. It is a sodium channel blocker that is effec- tive medicine for tachyarrhythmia, for which the other antiarrhythmic medica- tion is not effective. Flecainide is also effective in the treatment of catecholaminergic polymorphic ventricular tachycardia but, in this condition, its mechanism of action is contentious. It can be given either intravenously or orally and its pharmacokinetic properties allow for a relatively long (12 hours) effect. Flecainide is an antiarrhythmic agent that has the potential to be considered an narrow therapeutic index drug that has a narrow window between its effective dose and a dose at which it can produce adverse toxic effects (dizziness, vision problems, shortness of breath, headache, nausea, vomiting, stomach pain, diarrhea, constipation, tremor or shaking, tiredness,"}
+{"prompt": "Synthesis step:", "completion": "weakness, anxiety, depression, numbness, or tingling) [74\u000179]. The original synthesis of flecainide is described on the Scheme 3.9, where a solution of 2,5-dihydroxybenzoic acid (3.1.49) in acetone was added to a suspension of KHCO3 in acetone followed by a solution of 2,2,2-tri- fluoroethyl trifluoromethanesulfonate (3.1.50) and stirred under reflux for 72 hours give 2,2,2-trifluoroethyl 2,5-bis(2,2,2-trifluoroethoxy)benzoate (3.1.51). The key step in this route is aminolysis. For that purpose obtained benzoate (3.1.51) was added to a stirred solution of 2-aminomethylpyridine (3.1.52) in glyme to give (3.1.53). Catalytic hydrogenation of the resultant N-(2-pyridylmethyl)-2,5-bis(2,2,2-trifluoroethoxy)benzamide (3.1.54)"}
+{"prompt": "Synthesis step:", "completion": "carried out in AcOH over PtO2 to give desired flecainide (3.1.54) [80\u000183]. A significant simplification in the synthesis was achieved by the use of"}
+{"prompt": "Synthesis step:", "completion": "2-aminmethylpiperidine (3.1.55) [84] (Scheme 3.9). 3.1.49 Flecainide 3.1.54 Glyme Glyme H2/PtO2 AcOH F3C S KHCO3 Acetone Reflux 72 h 3.1.50 3.1.51 3.1.52 3.1.55 3.1.53 SCHEME 3.9"}
+{"prompt": "Synthesis step:", "completion": "Synthesis of flecainide. ENCAINIDE (682) Encainide (3.1.62), formerly marketed as Enkaid, is an antiarrhythmic drug with class IC activity and has been used in the treatment of life-threatening ventricular arrhythmias, symptomatic ventricular arrhythmias, and supraven- tricular arrhythmias. The most common noncardiac side effects were dizzi- ness and blurred vision and proarrhythmic effects. Encainide was associated with increased death rates in patients who had asymptomatic heart rhythm abnormalities after a recent heart attack and was withdrawn from the US"}
+{"prompt": "Synthesis step:", "completion": "market in 1991 [85\u000189]. The first step in practically all proposed methods for encainide synthesis is based on condensation of picoline (3.1.56) or picolinium salts (3.1.63) (methiodide, methsulfate) with 2-nitrobenzaldehyde (3.1.57). In some patents and papers a mixture of picoline as well as the aforementioned aldehyde was refluxed in acetic anhydride to give 2-[2-(2-Nitrophenyl)ethenyl-2]pyridine (3.1.57) [90\u000193]. In others a mixture of previously prepared picolinium salts (3.1.63) and 2-nitrobenzaldehyde (3.1.57) was refluxed in methanol in the presence of a catalytic amount of piperidine to give product (3.1.64), which was dehydrated on reflux in the mixture of acetic acid, acetic anhydride and"}
+{"prompt": "Synthesis step:", "completion": "potassium acetate to give (3.1.65) [94,95]. A solution of 2-[2-(2-nitrophenyl)ethenyl-2]pyridine (3.1.57) in ethanol was hydrogenated over Pd-C catalyst forming 2-[2-(2-aminophenyl)ethyl-2] pyridine (3.1.58). The obtained product was dissolved in pyridine and acyl- ated with 4-anisoyl chloride (3.1.59) at 70\u0003C to give amide (3.1.60). The last was dissolved in warm acetonitrile, treated with dimethyl sulfate (or methyl iodide), and heated to 70\u0003C. The resulted crystalline salt (3.1.61) was hydro-"}
+{"prompt": "Synthesis step:", "completion": "genated in ethanol using platinum oxide to give desired encainide (3.1.62). In the method started from picolinium salts (3.1.63) (methiodide, meth- sulfate), the salt (3.1.65) obtained after dehydration of (3.1.64) was hydroge- nated over a platinum oxide catalyst to give 2-(2-(1-methylpiperidin-2-yl) ethyl)aniline (3.1.66), which was acylated with 4-anisoyl chloride 4- (3.1.59)"}
+{"prompt": "Synthesis step:", "completion": "in acetone to give desired encainide (3.1.62) (Scheme 3.10). Another interesting method for the synthesis of encainide was proposed, according to which methyl anthranilate (3.1.67) was acylated with 4-anisoyl chloride (3.1.59) in dichloromethane solution to give amide (3.1.68). The obtained product on reaction with 2-pyridyllithium (3.1.69) formed product (3.1.70) underwent one-pot hydrogenation with Pt-C AcOH, followed by addi- tion of Pd-C catalyst, and reductive methylation with formalin in the presence"}
+{"prompt": "Synthesis step:", "completion": "of Pd-C to give encainide (3.1.62) with good yield [96] (Scheme 3.11). THIORIDAZINE (6558) Thioridazine (3.1.73) (Mellaril), is one of the older, first-generation typical antipsychotic oral medications used only management Piperidine-Based Drug Discovery schizophrenia but is also widely used for the relief of anxiety, agitation, mania, manic depressive psychosis, and behavioral problems. However, evi- dence of cardiac complications led to the restriction of its use from 2000 and withdrawal worldwide in 2005 because it caused severe cardiac arrhythmias"}
+{"prompt": "Synthesis step:", "completion": "and excessive death rates associated with its use [97\u0001103]. It has been shown recently that thioridazine has in vitro activity against multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains of Mycobacterium tuberculosis, and is able to cure antibiotic-susceptible and -resistant pulmonary tuberculosis infections. Under proper cardiac evalua- tion procedures, it is safe and does not produce any known cardiopathy"}
+{"prompt": "Synthesis step:", "completion": "[104\u0001107]. The synthesis of thioridazine was achieved through reaction of 2- (methylthio)-10H-phenothiazine (3.1.71) and 2-(2-chloroethyl)-N-methylpi- peridine (3.1.72) in refluxing xylene in the presence of sodium amide to give"}
+{"prompt": "Synthesis step:", "completion": "desired thioridazine (3.1.73) [108\u0001110] (Scheme 3.12). 3.1.56 H2/Pd-C Ac2O Reflux EtOH Pyridine 3.1.57 3.1.58 3.1.59 3.1.62 AcOH, Ac2O, AcONa MeCN H2/PtO2 EtOH Acetone H2/Pt EtOH 3.1.60 3.1.61 Piperidine Methanol EtOH Reflux 3.1.59 3.1.66 3.1.65 3.1.64 3.1.63 3.1.57 Encainide SCHEME 3.10"}
+{"prompt": "Synthesis step:", "completion": "Synthesis of encainide. 2.H2/Pd-C 1. H2/Pt, AcOH 3.1.59 Encainide 3.1.62 COOCH3 COOCH3 3. H2/Pd-C, CH2O 3.1.67 3.1.69 NH O 3.1.70 3.1.68 CH2Cl2 SCHEME 3.11"}
+{"prompt": "Synthesis step:", "completion": "Synthesis of encainide. RIMITEROL (219) Rimiterol (3.1.82) is a third-generation, short-acting selective \u03b22-adrenore-"}
+{"prompt": "Synthesis step:", "completion": "ceptor agonist used for the treatment of bronchospasm. It is not effective by the oral route of administration, but may be of value in the intravenous therapy of severe asthma. Rimiterol is available in pressur- ized aerosols. There have been no reports of significant subjective side effects following the acute administration of rimiterol by aerosol. There are no specific contraindications to rimiterol, but it should be given with care to patients with thyrotoxicosis, cardiovascular disease, diabetes mellitus, renal,"}
+{"prompt": "Synthesis step:", "completion": "or hepatic dysfunction [111\u0001118]. Synthetic routes to rimiterol (3.1.82) are described. For that purpose 3,4- dimethoxyphenyl-2-pyridylcarbinol (3.1.77) prepared reaction between veratraldehyde (3.1.74) and picolinic acid (3.1.75) on reflux in p- cumene, or by treatment of the same aldehyde (3.1.74) with 2-pyridyllithium (3.1.76) prepared from 2-bromopyridine n-butyllithium"}
+{"prompt": "Synthesis step:", "completion": "ether. Obtained carbinol (3.1.77) was oxidized to the corresponding ketone (3.1.80) by potassium permanganate in water at 70\u0003C, or by dimetliylsulphoxide- acetic anhydride mixtures, or by air in boiling nitrobenzene. An alternative approach for the synthesis of ketone (3.1.81) was proposed via acylation of veratrole (3.1.78) with picolinic acid chloride (3.1.79) in nitrobenzene in the"}
+{"prompt": "Synthesis step:", "completion": "presence of aluminum chloride. The protecting methoxy groups in (3.1.80) were changed to hydroxyl groups in boiling hydrobromic acid and the product (3.1.81) hydrogenated in methanol over platinum oxide to give desired rimiterol (3.1.82) [119\u0001122]"}
+{"prompt": "Synthesis step:", "completion": "(Scheme 3.13). LOBELINE (1914) Lobeline (3.1.90) is a plant alkaloid, the main constituent of the 20 known of Lobelia inflata, known as Indian tobacco because native Americans smoked"}
+{"prompt": "Synthesis step:", "completion": "the dried leaves as a substitute for tobacco. Lobeline has a long history of therapeutic use and, and during the 19th century it was prescribed as an emetic or a respiratory stimulant used to treat asthma, collapse, and anesthetic accidents. Lobeline has multiple mechan-"}
+{"prompt": "Synthesis step:", "completion": "isms of action. Thioridazine 3.1.73 NaNH2 Reflux 3.1.71 3.1.72 SCHEME 3.12"}
+{"prompt": "Synthesis step:", "completion": "Synthesis of thioridazine. Piperidine-Based Drug Discovery Lobeline is a high affinity compound for nicotinic acetylcholine recep- tors, and it is considered a promising candidate for pharmacotherapy of addiction and abuse (smoking, cocaine, amphetamines) and is used in tablets"}
+{"prompt": "Synthesis step:", "completion": "as a smoking cessation remedy. It has been classified as a compound having many nicotine-like effects working as both an agonist and an antagonist at nicotinic receptors, having many nicotine-like effects including hypertension, bradycardia and hypoten- sion, anxiolytic effects, enhancement of cognitive performance. Lobeline inhibits the function of vesicular monoamine and dopamine transporters and diminishes the behavioral effects of nicotine and amphetamines. Lobeline"}
+{"prompt": "Synthesis step:", "completion": "binds to \u03bc-opiate receptors, blocking the effects of opiate receptor agonists. Lobeline esters was shown be useful for treating neurodegenerative diseases of the CNS, which include Alzheimer\u2019s disease, Parkinson\u2019s disease,"}
+{"prompt": "Synthesis step:", "completion": "Huntington\u2019s disease, etc. [123\u0001129]. Isolation from plants is uneconomical procedure, and many different"}
+{"prompt": "Synthesis step:", "completion": "routes of synthesis have been considered. The first synthesis of lobeline (3.1.90) started with a Claisen condensa- tion between ethyl glutarate (3.1.83) and acetophenone (3.1.84) to give tetra- ketone (3.1.85). The last on treatment with ammonia was cyclized to piperidine-2,6-diylidene derivative (3.1.86). The carbonyl groups in (3.1.86) were reduced by hydrogenation over platinum oxide giving a mixture of diastereoisomers that were separated crystallization give \u03b2-norlobelanidiene (3.1.87). The double bonds in obtained compound (3.1.87) were reduced with aluminum amalgam to give (3.1.88), which was converted into its methylated derivative (3.1.89) by treatment with methyl tosylate. The produced compound (3.1.89) was converted into (1/\u0001)-lobeline by treatment with an oxidizing agent such as permanganate, or chromium tri- oxide, and then was dissolved by D-tartaric acid giving (\u0001)-lobeline (3.1.90)"}
+{"prompt": "Synthesis step:", "completion": "[130] (Scheme 3.14). 3.1.74 Rimiterol 3.1.82 COOH p-Cumene Ether 3.1.78 COCl Nitrobenzene Ac2O, or Air, Nitrobenzene H2/PtO2 CH3OH 3.1.75 3.1.76 3.1.77 3.1.79 3.1.80 3.1.81 KMnO4/ H2O SCHEME 3.13"}
+{"prompt": "Synthesis step:", "completion": "Synthesis of rimiterol. Another strategy for the synthesis of lobeline (3.1.90) was proposed the same year. For that purpose 2,6-lutidine (3.1.91) was condensed with benzal- dehyde (3.1.92) at high temperature in presence of zinc chloride to give 2,6- distyrylpyridine (3.1.93). Bromination of the last with an excess of bromine rand further dehydrobromination with potassium hydroxide gave dipheny- lethynylpyridine (3.1.95). Hydration of (3.1.95) with concentrated sulfuric acid furnished the diphenacylpyridine (3.1.96). Alkylation of the pyridine ring with methyl tosylate gave a quaternary salt (3.1.97) that was reduced to lobelanidine (3.1.98). A mild oxidation of (1/\u0001)-lobelanidine (3.1.98) by potassium permanganate gave a mixture of the (1/\u0001)-lobeline (3.1.90a)"}
+{"prompt": "Synthesis step:", "completion": "[131] Scheme 3.15. Described synthetic routes might not be implemented for large scale pre-"}
+{"prompt": "Synthesis step:", "completion": "parations as they are of low efficiency. An efficient process for the preparation of (\u0001)-lobeline (3.1.90) from lobelanine (3.1.99) on industrial scale have been developed using asymmetric hydrogenation with a catalyst system consisting of cyclooctadiene rhodium 3.1.83 NaNH2 Ether NH3gas 100\u00b0C 3.1.84 3.1.85 1.H2/PtO2 Al/Hg Amalgam Ether TsMe Pyridine 2. Crystal- lization 3.1.86 3.1.87 3.1.88 Lobeline 3.1.90 1. KMnO4 2. D-tartaric acid 3.1.89 SCHEME 3.14"}
+{"prompt": "Synthesis step:", "completion": "Synthesis of lobeline. KOH/EtOH Benzene ZnCl2 235\u00b0C 3.1.91 3.1.92 3.1.93 3.1.94 CCl4 TsMe H2/PtO2 Methanol Benzene 3.1.95 3.1.96 3.1.97 H2SO4 (+/\u2013)-Lobeline 3.1.90a 3.1.98 KMnO4 SCHEME 3.15"}
+{"prompt": "Synthesis step:", "completion": "Synthesis of (1/-)-lobeline. Piperidine-Based Drug Discovery chloride dimer ([RhCl(COD)]2) and (2R,4R)-4-(dicyclohexyl-phosphino)-2- (diphenylphosphinomethyl)-N-methylaminocarbonyl pyrrolidine [132,133]"}
+{"prompt": "Synthesis step:", "completion": "(Scheme 3.16). The chemical precursor for the biosynthesis of lobeline, 2,6-cis-lobelanine (3.1.99), was easily obtained by an elegant one-pot synthesis which involves Mannich condensation and a Robinson type biomimetic reaction of glutaric dialdehyde (3.1.100), benzoylacetic acid (3.1.101), and methylamine hydro-"}
+{"prompt": "Synthesis step:", "completion": "chloride (3.1.102) in acetone and citrate buffer [134] (Scheme 3.17). Perfect reviews on synthesis and chemistry of lobeline are published"}
+{"prompt": "Synthesis step:", "completion": "[135\u0001138]. ARGATROBAN (2627) Argatroban (3.1.111) (Arganova) is a highly selective direct thrombin inhibi- tor indicated for use as an anticoagulant for the treatment and prophylaxis of thrombosis in patients with heparin-induced thrombocytopenia (HIT), a dev- astating, life-threatening, immune-mediated complication of therapy with heparin and in patients undergoing percutaneous coronary intervention who"}
+{"prompt": "Synthesis step:", "completion": "have, or are at risk for HIT. Argatroban does not generate antibodies, is not susceptible to degradation"}
+{"prompt": "Synthesis step:", "completion": "by proteases and is cleared hepatically. It is a reversible antithrombin agent and therefore exhibits a considerably different pharmacological profile. Its mechanisms of action include several other processes that have not been explored fully to date. These include the inhibition of nonthrombin serine proteases, a direct effect on endothelial cells and the vasculature (generation of nitric oxide), and downregulation of various SCHEME 3.16"}
+{"prompt": "Synthesis step:", "completion": "Synthesis of lobeline. 3.1.100 CH3NH2 Lobelanine 3.1.99 pH4, 25\u00b0C Acetone Citrate buffer 3.1.101 3.1.102 SCHEME 3.17"}
+{"prompt": "Synthesis step:", "completion": "Synthesis of lobelanine. inflammatory and thrombotic cytokines. Argatroban is more effective than heparins and hirudins in the antithrombotic management of microvascular dis- orders (Heparin has historically been used as the anticoagulant of choice in"}
+{"prompt": "Synthesis step:", "completion": "the management of a number of thrombotic diseases.) [139\u0001153]. The improved synthesis of argatroban (3.1.111) started with prepara- tion of racemic ( 6 )-trans-benzyl 4-methyl pipecolic acid ester (3.1.104), which was synthesized via \u03b1-lithiation and further benzyloxycarbonylation sequence of N-Boc-4-methylpiperidine (3.1.103) using for that purpose s-BuLi and tetramethylethylene-diamine in ether followed by addition of"}
+{"prompt": "Synthesis step:", "completion": "benzyl chloroformate, which yielded the afforded compound (3.1.104). After N-Boc deprotection (HCl, AcOEt), the desired benzyl 4-methyl pipe- colic acid ester (3.1.105) was obtained. The condensation of compound (3.1.105) with N\u03b1-Boc-N\u03c9-nitro-L-arginine (3.1.106), two diastereomers (3.1.107a) and (3.1.107b) were obtained and separated by flash chroma- tography on silica gel to afford the desired (3.1.107a). After removal of the Boc group in (3.1.107a) by (HCl, AcOEt), the obtained compound (3.1.108) was transformed to (3.1.110) by treatment with 3-methyl-8- quinoline sulfonyl chloride (3.1.109) in dichloromethane in the presence of trimethylamine. The hydrogenation of the last over Pd/C catalyst in eth- anol/acetic acid mixture effected the debenzylation of the ester group, the cleavage of the nitro group, and the hydrogenation of the pyridine ring affording desired argatroban (3.1.111) [154] (Scheme 3.18). The first patents on the synthesis of argatroban are based on ethyl 4-methyl pipeco-"}
+{"prompt": "Synthesis step:", "completion": "lic acid ester [155\u0001157]. 3.1.103 1. s-BuLi TMEDA, Ether 2. ClCH2COOCH2Ph CH2OOCH2Ph COOH COOCH2Ph COOCH2Ph COCH2Ph Argatroban 3.1.111 CH2OOCH2Ph AcOEt i-BuOCOCl Et3N EtOH, AcOH COOCH2Ph AcOEt Et3N, CH2Cl2 H2/Pd-C COOH 3.1.104 3.1.105 3.1.106 3.1.107a 3.1.107b 3.1.108 3.1.109 3.1.110 SCHEME 3.18"}
+{"prompt": "Synthesis step:", "completion": "Synthesis of argatroban. Piperidine-Based Drug Discovery ASCOMYCIN (752), PIMECROLIMUS (1645), TACROLIMUS (32436), SIROLIMUS (22468), EVEROLIMUS (8972), AND TEMSIROLIMUS (2859) Series Ascomycin (3.1.112) derivatives \u0001 Pimecrolimus (3.1.113), Tacrolimus (3.1.114) as well as Sirolimus (3.1.115) and its derivatives Everolimus (3.1.116) and Temsirolimus (3.1.117) \u0001 can formally be considered"}
+{"prompt": "Synthesis step:", "completion": "1,2-disubstituted piperidines (Fig. 3.1). The 23-membered macrolactam Ascomycin (3.1.112) and 31-membered macrocyclic polyketide Sirolimus (3.1.115) are fermentation products origi-"}
+{"prompt": "Synthesis step:", "completion": "nally isolated from the cultured broth of Streptomyces hygroscopicus. Ascomycin and its derivatives are powerful calcium-dependent serine/ threonine protein phosphatase (calcineurin (CaN), protein phosphatase 2B inhibitors and have been used therapeutically mainly as immunosuppressants in inflammatory skin diseases. Calcineurin inhibitors (CNIs) have been also"}
+{"prompt": "Synthesis step:", "completion": "proposed for the treatment of inflammatory and degenerative brain diseases. Ascomycin and its derivatives may be useful in preventing ischemic brain damage and neuronal death in the treatment of CNS and exhibit anticonvul- sant activity. Nonimmunosuppressant activity of its derivatives as CNS drugs"}
+{"prompt": "Synthesis step:", "completion": "probably should be further explored. Pimecrolimus (3.1.113) prepared by the substitution of 32-hydroxy group in ascomycin with a chlorine with an inversion of configuration and tacroli- mus (3.1.114), which was obtained by using the mutant Streptomyces Pimecrolimus 3.1.113 Tacrolimus 3.1.114 Ascomycin 3.1.112 Temsirolimus 3.1.117 Everolimus 3.1.116 Sirolimus 3.1.115 FIGURE 3.1"}
+{"prompt": "Synthesis step:", "completion": "Ascomycin, pimecrolimus, tacrolimus, sirolimus, everolimus, and temsirolimus. species. These compounds have been successfully introduced in the treat- ment of atopic dermatitis. They inhibit T cell proliferation, mast cell degran- ulation, production, and the release of IL-2, IL-4, IF-\u03b3, and TNF-\u03b1. They do not effect endothelial cells and fibroblasts, so they do not induce skin atro-"}
+{"prompt": "Synthesis step:", "completion": "phy and consequently are well tolerated and safe. They have been used also for treatment of other inflammatory skin dis- eases including psoriasis, lichen planus, seborrheic dermatitis, allergic contact dermatitis, vitiligo, pyoderma gangrenosum, alopecia areata, graft- versus-host disease, akne rosacea, etc. The pharmacology, use, and modifica-"}
+{"prompt": "Synthesis step:", "completion": "tions of Ascomycin and its derivatives are reviewed [158\u0001167]. Sirolimus (3.1.115) also known as Rapamycin, and its derivatives, Everolimus (3.1.116) and Temsirolimus (3.1.117), are a class of immunosup-"}
+{"prompt": "Synthesis step:", "completion": "pressive drugs approved for solid organ transplantation. Sirolimus, a mammalian target of rapamycin (mTOR) inhibitors, are a kind of macrolide antibiotics, producing by Streptomyces hygroscopicus in appropriate fermenting culture had been found to have also potent antiin- flammatory, antineoplasms, antiatherosclerosis, antiaging, neuroprotection"}
+{"prompt": "Synthesis step:", "completion": "properties. Sirolimus and its derivates, everolimus and temsirolimus, have a similar structure that inhibits the proliferation of T cells by interfering with a serine-threonine kinase, called mTOR. By inhibiting the ubiquitous mTOR pathway, they present a peculiar safety profile. Apart from their immuno- suppressive effects, these agents may also inhibit endothelial intimal prolif- eration, the replication of cytomegalovirus, and the development of certain cancers. They are used not only as immunosuppressants after organ trans- plantation in combination with CNIs but also as proliferation signal inhibi-"}
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