- Continuous-Flow Multistep Synthesis of Cinnarizine, Cyclizine, and a Buclizine Derivative from Bulk Alcohols
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Cinnarizine, cyclizine, buclizine, and meclizine belong to a family of antihistamines that resemble each other in terms of a 1-diphenylmethylpiperazine moiety. We present the development of a four-step continuous process to generate the final antihistamines from bulk alcohols as the starting compounds. HCl is used to synthesize the intermediate chlorides in a short reaction time and excellent yields. This methodology offers an excellent way to synthesize intermediates to be used in drug synthesis. Inline separation allows the collection of pure products and their immediate consumption in the following steps. Overall isolated yields for cinnarizine, cyclizine, and a buclizine derivative are 82, 94, and 87 %, respectively. The total residence time for the four steps is 90 min with a productivity of 2 mmol h-1. The incredible bulk: Bulk alcohols are converted continuously into chlorides using HCl in a microflow. A reaction network that consists of four steps and two inline separations leads to the continuous preparation of cinnarizine, cyclizine, and a buclizine derivative with yields of 82, 94, and 87 %, respectively. The total residence time for the four steps is 90 min with a productivity of 2 mmol h-1.
- Borukhova, Svetlana,Nol, Timothy,Hessel, Volker
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- Hydrogen Chloride Gas in Solvent-Free Continuous Conversion of Alcohols to Chlorides in Microflow
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Chlorides represent a class of valuable intermediates that are utilized in the preparation of bulk and fine chemicals. An earlier milestone to convert bulk alcohols to corresponding chlorides was reached when hydrochloric acid was used instead of toxic and wasteful chlorinating agents. This paper presents the development of an intensified solvent-free continuous process by using hydrogen chloride gas only. The handling of corrosive hydrogen chloride became effortless when the operating platform was split into dry and wet zones. The dry zone is used to deliver gas and prevent corrosion, while the wet zone is used to carry out the chemical transformation. The use of gas instead of hydrochloric acid allowed a decrease in hydrogen chloride equivalents from 3 to 1.2. In 20 min residence time, full conversion of benzyl alcohol yielded 96 wt % of benzyl chloride in the product stream. According to green chemistry and engineering principles, the developed process is of an exemplary type due to its truly continuous nature, no use of solvent and formation of water as a sole byproduct.
- Borukhova, Svetlana,No?l, Timothy,Hessel, Volker
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supporting information
p. 568 - 573
(2016/03/04)
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- Indium triiodide catalyzed direct hydroallylation of esters
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The InI3-catalyzed hydroallylation of esters by using hydroand allysilanes under mild conditions has been accomplished. Many significant groups such as alkenyl, alkynyl, cyano, and nitro ones survive under these conditions. This reaction system, provided routes to both homoallylic alcohols and ethers, in which either elimination of the alkoxy moiety or of the carbonyl oxygen atom could be freely selected by changing the substituents on the alkoxy moiety and on the hydrosilane. In addition, the hydroallylation of lactones took place without ring cleavage to produce the desired cyclic ethers in high yields.
- Nishimoto, Yoshihiro,Inamoto, Yoshihiro,Saito, Takahiro,Yasuda, Makoto,Baba, Akio
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supporting information; experimental part
p. 3382 - 3386
(2010/08/19)
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- Assessment of heat-sensitive thiophosphate protecting groups in the development of thermolytic DNA oligonucleotide prodrugs
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Heat-sensitive thiophosphate protecting groups derived from the alcohol 4 or 10 have provided insights in the design of DNA oligonucleotide prodrugs. Indeed, functional groups stemming from the alcohol 9, 15, 16 or 22 may be applicable to thiophosphate protection of immunostimulatory CpG DNA motifs, whereas those originating from the alcohol 3, 5, 12, 13, 18, 20 or 22 offer adequate protection of terminal phosphodiester functions against ubiquitous exonucleases that may be found in biological environments. Functional groups derived from the alcohol 9, 15, 16, 19 or 23 are suitable for the protection of phosphodiester functions flanking the CpG motifs of immunomodulatory DNA sequences.
- Ausín, Cristina,Kauffman, Jon S.,Duff, Robert J.,Shivaprasad, Shankaramma,Beaucage, Serge L.
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experimental part
p. 68 - 79
(2010/03/04)
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- Design, synthesis, and biological activity of isophthalic acid derivatives targeted to the C1 domain of protein kinase C
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Protein kinase C (PKC) is a widely studied molecular target for the treatment of cancer and other diseases. We have approached the issue of modifying PKC function by targeting the C1 domain in the regulatory region of the enzyme. Using the X-ray crystal structure of the PKC δ C1b domain, we have discovered conveniently synthesizable derivatives of dialkyl 5-(hydroxymethyl)isophthalate that can act as potential C1 domain ligands. Structure-activity studies confirmed that the important functional groups predicted by modeling were indispensable for binding to the C1 domain and that the modifications of these groups diminished binding. The most promising compounds were able to displace radiolabeled phorbol ester ([3H]PDBu) from PKC α and δ at Ki values in the range of 200-900 nM. Furthermore, the active isophthalate derivatives could modify PKC activation in living cells either by inducing PKC-dependent ERK phosphorylation or by inhibiting phorbol-induced ERK phosphorylation. In conclusion, we report here, for the first time, that derivatives of isophthalic acid represent an attractive novel group of C1 domain ligands that can be used as research tools or further modified for potential drug development.
- Af Genn?s, Gustav Boije,Talman, Virpi,Aitio, Olli,Ekokoski, Elina,Finel, Moshe,Tuominen, Raimo K.,Yli-Kauhaluoma, Jari
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supporting information; experimental part
p. 3969 - 3981
(2010/01/16)
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- Synthesis and reactivity of novel α,α,β- and α,α,δ-trichlorinated imines
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A variety of different N-(2,2,3-trichloropropylidene)amines, N-(2,2,3-trichlorobutylidene)amines, and N-(2,2,5-trichloropentylidene)amines were synthesized for the first time, and their reactivity with regard to hydride reagents was investigated. In this way, N-(2,2,5-trichloropentylidene)amines were evaluated as substrates for the synthesis of piperidines, and N-(2,2,3-trichloropropylidene)amines and N-(2,2,3-trichlorobutylidene)amines were reduced efficiently into the corresponding novel β,β,γ- trichloroamines by means of sodium cyanoborohydride in methanol in the presence of acetic acid. Furthermore, N-(2,2,3-trichloropropylidene)amines were transformed into 2-(chloromethyl)aziridines by lithium aluminium hydride in Et2O, and N-(2,2,5-trichloropentylidene)acetamide was used for the first time as a suitable substrate for the addition of oxygen, nitrogen, and sulfur nucleophiles in good yields. Georg Thieme Verlag Stuttgart.
- D'Hooghe, Matthias,De Meulenaer, Bruno,De Kimpe, Norbert
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scheme or table
p. 2437 - 2442
(2009/04/08)
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- Oxidation of monohydric and dihydric alcohols with CCl4 catalyzed by molybdenum compounds
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Mo(CO)6 catalyzed oxidation of alcohols and diols with tetrachloromethane. Primary oxidation products in reaction of alcohols with CCl4 are alkyl hypochlorites, and final products depending on the structure of initial alcohol are aldehydes (as acetals), ketones, chloroketones, and esters.
- Khusnutdinov,Shchadneva,Burangulova,Muslimov,Dzhemilev
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p. 1615 - 1621
(2007/10/03)
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- Design, synthesis, and evaluation of new chemosensitizers in multi-drug-resistant Plasmodium falciparum
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A series of new chemosensitizers (modulators) against chloroquine-resistant Plasmodium falciparum were designed and synthesized in an attempt to fabricate modulators with enhancing drug-resistant reversing efficacy and minimal side effects. Four aromatic amine ring systems phenothiazine, iminodibenzyl, iminostilbene, and diphenylamine-were examined. Various tertiary amino groups including either noncyclic or cyclic aliphatic amines were introduced to explore the steric tolerance at the end of the side chain. The new compounds showed better drug-resistant reversing activity in chloroquine-resistant than in mefloquine-resistant cell lines and were generally more effective against chloroquine-resistant P. falciparum isolates from Southeast Asian (W2 and TM91C235) than those from South America (PC49 and RCS). Structure-activity relationship studies revealed that elongation of the alkyl side chain of the molecule retained the chemosensitizing activity, and analogues with four-carbon side chains showed superior activity. Furthermore, new modulators with phenothiazine ring exhibited the best chemosensitizing activity among the four different ring systems examined. Terminal amino function has limited steric tolerance as evidenced by the dramatic lose of the modulating activity, when the size of substituent at the amino group increases. The best new modulator synthesized in this study possesses all three optimized structural features, which consist of a phenothiazine ring and a pyrrolidinyl group joined by a four-carbon alkyl bridge. The fractional inhibitory concentration (FIC) index of the best compound is 0.21, which is superior to that of verapamil (0.51), one of the best-known multi-drug-resistant reversing agents. Some of the analogues displayed moderate intrinsic in vitro antimalarial activity against a W-2 clone of P. falciparum.
- Guan, Jian,Kyle, Dennis E.,Gerena, Lucia,Zhang, Quan,Milhous, Wilbur K.,Lin, Ai J.
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p. 2741 - 2748
(2007/10/03)
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- Transformation of OH-adduct of 1-chloro-4-iodobutane into intra-molecular radical cation in neutral aqueous solution
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The iodine centered OH-adduct formed on reaction of OH radicals with 1-chloro-4-iodobutane in neutral aqueous solution transforms (k=5.4×105 s-1) to an intra-molecular radical cation (). The unfavorable structural conformation of solute radical cation generated on reaction of OH radicals with 1-chloro-5-iodopentane does not allow the transformation of OH-adduct into an intra-molecular radical and instead a dimer radical cation () is formed.
- Mohan, Hari,Maity,Chattopadhyay,Mittal
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p. 493 - 498
(2007/10/03)
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- An efficient Fischer indole synthesis of avitriptan, a potent 5-HT(1D) receptor agonist
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An efficient synthesis of antimigraine drug candidate avitriptan (1, BMS 180048) is reported. The key step is a two-phase Fischer indolization reaction between hydrazine 6 and 5-chlorovaler-aldehyde, 20, to give the chloropropylindole 35, which is susceptible to acid-catalyzed degradation under the reaction conditions required for its formation. Sequential coupling of 35 with piperazine, 26, and 4-chloro-5-methoxypyrimidine, 24, gives the title compound in 40-45% overall yield. Significant improvements in the syntheses of the known starting materials, hydrazine 6, 5- chlorovaleraldehyde, 20, and 4-chloro-5-methoxypyrimidine, 24, were also achieved.
- Brodfuehrer,Chen,Sattelberg T.R.,Smith,Reddy,Stark,Quinlan,Reid
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p. 9192 - 9202
(2007/10/03)
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- Anti-androgenic cyclo and bicyclo alkenes
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Compounds having the formula (i), (ii) and (iii), STR1 where R is H, alkyl of 1 to 6 carbons, or CO--R 2 where R 2 is alkyl of 1 to 6 carbons; R 1 is H, CH 3, or (CH 2) m --CH 3 ; n is an integer having the values of 2 to 10, m is an integer having the values of 1 to 6, have anti-androgen activity on secondary androgen receptor sites. The compounds are useful for treating mammals, including humans afflicted with acne, male pattern baldness, adhesions and keloids. The compounds are also effective for treating other diseases or conditions which are related to androgen receptors, such as undesirable formation of breast capsules in females after breast augmentation surgery, osteoarthritis and symptoms of Alzheimer''s disease. The compounds also have inhibitory effect on the metabolism of certain microorganisms and fungi of the kind, the metabolism of which is normally known to be controllable by anti-androgen compounds.
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- 19→nor→steroids
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Novel 19-nor-steroids of the formula STR1 wherein the A and B rings have a structure selected from the group consisting of STR2 having hormonal properties and their preparation and intermediates.
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- ω-HYDROXY-1-ALKANESULFONYL CHLORIDES
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The general synthesis of hydroxyalkanesulfonyl chlorides is illustrated by the preparation of 6-hydroxy-1-butanesulfonyl cloride (2e) and 5-hydroxy-1-pentanesulfonyl chloride (2d) as fairly stable, only liquids (of ca. 95percent purity) charecterized by Hmr, Cmr and infrared spectra, and by conversion both to the corresponding sultones (3) and to crystalline acetoxy-piperidides (6); 2d and 2e form apparent polymers, very slowly on standing at room temperature and more rapidly on heating, but on reaction with triethylamine yield the sultones (3d and 3e).A sample consisting mostly (>70percent) of 4-hydroxy-1-butanesulfonyl chloride (2c), prepared and charecterized similarly, was found to form the sultone (3c) slowly in non-polar solvents, much more readily in polar media (t1/2 ca. 20 min in water), and very rapidly in the presence of triethylamine.Effective concentrations for the spontaneous cyclization of 4-hydroxy-1-butanesulfonyl chlorides (2c) and the tertiary-amine induced cyclizations of 2d and 2e are estimated at roughly 3x102, 0.1, and 0.05 M, respectively.The mechanism of the chlorination reaction and the origins of the different products with different substrates and reaction conditions are discussed.
- King, J. F.,Webster, Michael R.,Chiba, Naoki,Allen, Julie K.,Parker, Kenneth J. M.,et al.
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p. 161 - 176
(2007/10/02)
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- OXIDATIVE CLEAVAGE OF SILICON-CARBON BOND WITH TRIMETHYLAMINE-N-OXIDE. NEW ACCESS TO PRIMARY ALCOHOLS AND ALDEHYDES FROM TERMINAL ALKENES AND ALKYNES
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Oxidative cleavage of carbon-silicon bond of organosilanes with trimethylamine-N-oxide is achieved under mild conditions.The reaction occurs chemoselectively irrespective of the presence of amino and thio groups to give formally anti-Markovnikov hydration product of 1-alkenes and 1-alkynes via hydrosilylation.
- Sakurai, Hideki,Ando, Masatomo,Kawada, Nobuo,Sato, Kazuhiko,Hosomi, Akira
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- Metal-assisted Reactions. Part 17. Ring-opening and Dimerization of Cyclic Ethers by Titanium Halides
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Reaction of TiCl4 or TiBr4 with a variety of cyclic ethers gives, predominantly, products resulting from simple ring-opening or from ring-opening with simultaneous condensation to dimeric species.The variations in yields of these two kinds of products might be correlated qualitatively with an initial formation of the complex TiX4*2E (X = Cl or Br; E = cyclic ether) in which the ethers were held in a cis or trans relationship.Although such a correlation might suggest that TiCl4 but not TiBr4 exerts a template effect on the condensation, stereochemical considerations of the reaction products indicate otherwise.TiCl3 and VCl3 do not give similar results and TiF4 gives no reaction.
- Delaney, Paul A.,Johnstone, Robert A. W.,Entwistle, Ian D.
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p. 1855 - 1860
(2007/10/02)
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- WITTIG-HORNER REACTION IN HETEROGENOUS MEDIA VII. A NEW STRATEGY FOR THE TOTAL SYNTHESIS OF THE ROYAL JELLY ACID AND THE QUEEN SUBSTANCE OF HONEY-BEE
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A new general scheme for the preparation of Royal Jelly acid and Queen Substance of honey-bee, including, as the key steps, copper I catalyzed addition of functional (protected alcohol and ketone) Grignard reagents to acrolein diethylacetal, and the Wittig-Horner reaction of unprotected 8-hydroxyoctanal and 7-oxo-octanal with triethylphosphonoacetate in water, in the presence of potassium carbonate.
- Villieras, J.,Rambaud, M.,Graff, M.
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p. 569 - 580
(2007/10/02)
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- Cyclodehydration and Chlorination of Simple Diols with Triphenylphosphine and tert-Butyl Hypochlorite
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The reagent triphenylphosphine-tert-butyl hypochlorite converts 1,4-diols into the corresponding tetrahydrofurans and 1,2-diols into a mixture of the regioisomeric chlorohydrins and the epoxides at -78 deg C followed by warming to ambient temperature (ca. 30 deg C).Symmetrical diols give largely chlorohydrins and dichlorides.
- Barry, Carey N.,Evans, Slayton A.
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p. 2825 - 2828
(2007/10/02)
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- VINYL CATIONS. 40. pi - AND sigma -ROUTES TO VINYL CATIONS. SOLVOLYSES OF 2-METHYLCYCLOHEXENYL, CYCLOPENTYLIDENEETHYL, HEX-5-YN-1-YL, AND RELATED TRIFLATES.
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Three triflates were solvolyzed at various temperatures in water-alcohol mixtures, in TFE-water mixtures, in TFA, in TFIP, in HFIP, and in 100% TFE in the presence of various buffers and the resulting products were determined. The three reactants were also solvolyzed in a standard mixture (1:100:100 equals triflate:TFE:Na//2CO//3) at various temperatures, and the yields of products were compared. The solvolysis products were shown to be under kinetic control.
- Hanack,Fuchs,Collins
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p. 4008 - 4017
(2007/10/12)
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- SYNTHESIS OF 8E,10E-DODECADIEN-1-OL FROM METHYL 2,5-HEPTADIENOATES
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A method is proposed for the synthesis of 8E,10E-dodecadien-1-ol (the pheromone of the codling moth) from methyl 2Z,5E-heptadienoate and from a mixture of 2E,5Z- and 2Z,5Z-heptadienoic esters.Prototropic isomerization of the methyl esters of the 2Z,5E- and of the mixture of 2E,5Z- and 2Z,5Z-heptadienoic acids takes place quantitatively with the formation of methyl 3E,5E-heptadienoate and methyl 3E,5Z-heptadienoate respectively.
- Zakharkin, L. I.,Babich, S. A.
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p. 1995 - 2000
(2007/10/02)
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- Hydroboration. 57. Hydroboration with 9-Borabicyclononane of Alkenes Containing Representative Functional Groups
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The hydroboration of alkenes containing representative functional groups was examined with 9-borabicyclononane (9-BBN) in order to extend the hydroboration reaction for the preparation of functionally substituted organoboranes.Terminal alkenes containing a remote functional group are hydroborated with a remarkable regioselectivity (>=98percent terminal), producing the corresponding stable organoboranes. 9-BBN hydroborates the allylic derivatives so as to place boron essentially on the terminal carbon atom (>=97percent).The directive effect is further enhanced (>=99percent) in the case of β-methylallyl derivatives.The hydroboration of crotyl derivatives attaches boron predominantly at the 2-position, followed by an elimination-rehydroboration sequence.However, crotyl alcohol can be protected against elimination as the tert-butyl or tetrahydropyranyl ethers.The hydroboration-oxidation of ethyl crotonate involves a series of elimination, hydroboration, and condensation processes.In the vinyl, crotyl, and isobutenyl systems, the mesomeric effect of the substituent favors the placement of boron at the β-position, while the inductive effect favors the α-position, with the former effect predominating in most cases.Acyclic β-substituted organoboranes undergo rapid elimination.Nonpolar solvents and lower reaction temperatures decrease the rate of elimination.However, those derived from cyclic vinyl derivatives are relatively stable under neutral conditions, undergoing facile elimination in the presence of a base.
- Brown, Herbert C.,Chen, Jackson C.
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p. 3978 - 3988
(2007/10/02)
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- SYNTHESIS OF HIGHER ACETYLENIC ALCOHOLS
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The alkylation of 1-alkynes in various solvents was investigated, and the optimum conditions for the production of acetylenic alcohols were obtained.
- Kovalev, B. G.,Matveeva, E. D.,Stan, V. V.,Vovk, G. A.,Yudin, L. G.,Kost, A. N.
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p. 1728 - 1733
(2007/10/02)
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