- New preparation method of febuxostat intermediate
-
The invention relates to a new preparation method of a febuxostat intermediate. The method includes: taking cheap 4-hydroxybenzaldehyde as an initial raw material, firstly preparing aldoxime from 4-hydroxybenzaldehyde and hydroxylamine hydrochloride, then adding a corresponding thio reagent, and preparing a compound 4-hydroxythiobenzamide (152A1-00) by Beckmann rearrangement reaction; utilizing one-pot process, adopting cheap 4-hydroxybenzaldehyde as an initial raw material, carrying out a series of reactions, and then performing cyclization with 2-halogenated ethyl acetoacetate to obtain ethyl 2-(4-hydroxyphenyl)-4-methyl-5-thiazolecarboxylate or different salt forms (152A2x) thereof; and using isobutyl sulfonate (152H1x) with more easily controllable quality to replace bromo-isobutane soas to prepare ethyl 2-(3-formyl-4-isobutoxyphenyl)-4-methyl-5-thiazolecarboxylate (152A4-00). In conclusion, the method provided by the invention is more beneficial to safe, simple and cost-efficientindustrial scale preparation of the febuxostat intermediate with higher purity.
- -
-
Paragraph 0098-0100
(2020/03/06)
-
- PROCESSES FOR MAKING ALKYL HALIDES
-
The invention is directed to processes for producing an alkyl halide, preferably isobutyl bromide. In one embodiment, the process comprises the steps of: (a) contacting an alcohol with a hydrogen halide in a reactor at elevated temperature under conditions effective to form an initial product mixture comprising the alkyl halide, the alcohol, the hydrogen halide and water; (b) cooling the initial product mixture to form a cooled organic phase positioned above a cooled aqueous phase; (c) separating the cooled organic phase from the cooled aqueous phase. The process preferably further comprises a step of: (d) heating at least a portion of the cooled aqueous phase under conditions effective to form additional alkyl halide.
- -
-
Page/Page column 8
(2010/09/18)
-
- Scavenger assisted combinatorial process for preparing libraries of tertiary amine compounds
-
This invention relates to a novel solution phase process for the preparation of tertiary amine combinatorial libraries. These libraries have utility for drug discovery and are used to form wellplate components of novel assay kits.
- -
-
-
- Kinetics and thermochemistry of the R + HBr ? RH + Br (R = n-C3H7, isoC3H7, n-C4H9, isoC4H9, sec-C4H9 or tert-C4H9) equilibrium
-
The kinetics of the reactions of n-C3H7, isoC3H7, n-C4H9, isoC4H9, sec-C4H9 and tert-C4H9 radicals, R, with HBr have been investigated in a beatable tubular reactor coupled to a photoionization mass spectrometer. The reactions were studied by a time-resolved technique under pseudo-first-order conditions, where the rate constants of R + HBr reactions were obtained by monitoring the decay of the radical as a function of time. The radical was photogenerated in situ in the flow reactor by pulsed 248 nm exciplex laser radiation. All six reactions were studied separately over a wide range of temperatures and, in these temperature ranges, the rate constants determined were fitted to an Arrhenius expression (error limits stated are 1σ + Students t values, units cm3 molecule-1 s-1): k(n-C3H7) = (1.6 ± 0.2) × 10-12 exp[+(5.4 ± 0.2) kJ mol-1/RT], k(isoC3H7) = (1.4 ± 0.2) × 10-12 exp[+(6.9 ± 0.2) kJ mol-1/RT], k(n-C4H9) = (1.3 ± 0.2) × 10-12 exp[+(6.4 ± 0.4) kJ mol-1/RT], k(isoC4H9) = (1.4 ± 0.2) × 10-12 exp[+(6.1 ± 0.2) kJ mol-1/RT], k(sec-C4H9) = (1.4 ± 0.3) × 10-12 exp[+(7.5 ± 0.3) kJ mol-1/RT] and k(tert-C4H9) = (1.2 ± 0.3) × 10-12 exp[+(8.3 ± 0.3) kJ mol-1/RT]. The kinetic information was combined with the kinetics of the Br + RH reactions to calculate the entropy and the heat of formation values for the radicals studied. The thermodynamic values were obtained at 298 K using a second-law procedure. The entropy values and enthalpies of formation are (entropy in J K-1 mol-1 and enthalpy in kJ mol-1): 284 ± 5, 100.8 ± 2.1 (n-C3H7); 281 ± 5, 86.6 ± 2.0 (isoC3H7); 329 ± 5, 80.9 ± 2.2 (n-C4H9); 316 ± 5, 72.7 ± 2.2 (isoC4H9); 330 ± 5, 66.7 ± 2.1 (sec-C4H9) and 315 ± 4, 51.8 ± 1.3 (tert-C4H9). The C-H bond strength of analogous saturated hydrocarbons derived from the enthalpy of reaction values are (in kJ mol-1): 423.3 ± 2.1 (primary C-H bond in propane), 409.1 ± 2.0 (secondary C-H bond in propane), 425.4 ± 2.1 (primary C-H bond in n-butane), 425.2 ± 2.1 (primary C-H bond in isobutane), 411.2 ± 2.0 (secondary C-H bond in n-butane) and 404.3 ± 1.3 (tertiary C-H bond in isobutane). The enthalpy of formation values are used in group additivity calculations to estimate Δf H298○ values of six pentyl and four hexyl free radical isomers.
- Seetula, Jorma A.,Slagle, Irene R.
-
p. 1709 - 1719
(2007/10/03)
-
- Functionalization of saturated hydrocarbons by aprotic superacids 4. Ionic bromination of ethane and other alkanes and cycloalkanes with molecular bromine in the presence of systems based on polyhalomethanes and AlBr3 under mild conditions
-
Aprotic organic superacids CBr4 · 2AlBr3, CBr4 · AlBr3, · CCl4 · 2AlBr3, CCl4 · 2AlBr3, and C6F5CF3 · 2AlBr3 efficiently catalyze the bromination of alkanes and cycloalkanes with Br2. Ethane is selectively brominated at 55-65 °C to give mostly 1,2-dibromoethane (stoichiometric reaction). Propane, butane, cyclopentane, cyclohexane, and methyl-cyclopentane react with Br2 at -40 to -20 °C with good selectivity affording monobromides in high yields (catalytic reactions).
- Akhrem,Orlinkov,Afanas'eva,Vol'pin
-
p. 1148 - 1153
(2007/10/03)
-
- Methods for the synthesis of L-leucine selectively labelled with carbon-13 or deuterium in either diastereotopic methyl group
-
A versatile approach is described for the enantioselective synthesis of isotopically labelled L-leucine involving the preparation of 4-methylpentanoic acid labelled selectively with carbon-13 or deuterium in either the pro-R or pro-S methyl group followed by a reductive amination of the ketone catalysed by leucine dehydrogenase. This strategy is applied to the total synthesis of (2S,4R)-[5,5,5-D3]-leucine using CD3I as the source of deuterium.
- Kelly,Kelly, Nicholas M.,Reid,Gordon Reid,Willis,Willis, Christine L.,Winton,Winton, Peter L.
-
p. 8315 - 8318
(2007/10/02)
-
- Ionic Bromination of Ethane and Other Alkanes (Cycloalkanes) with Bromine Catalyzed by the Polyhalomethane*2AlBr3 Aprotic Organic Superacids under Mild Conditions
-
The polyhalomethane*2AlBr3 aprotic organic superacids were shown to effectively catalyze low-temperature ionic bromination of (cyclo)alkanes.Ethane readily reacts with Br2 at 55-65 deg C, affording mainly 1,2-dibromoethane.Propane, butane, and C5-C6 cycloalkanes react at -40 - -20 deg C, resulting in monobromides with high yields and good selectivity.
- Akhrem, Irena S.,Orlinkov, Alexander V.,Afanas'eva, Lyudmila V.,Mysov, Evgenii I.,Vol'pin, Mark E.
-
p. 9365 - 9368
(2007/10/02)
-
- SYNTHESIS OF SOME 2'-C-ALKYL DERIVATIVES OF 9-(2-PHOSPHONOMETHOXYETHYL)ADENINE AND RELATED COMPOUNDS
-
To study the effect of β-substitution in 2'-alkyl derivatives of 9-(2-phosphonomethoxyethyl)adenine (Ia) on the antiviral activity or group specificity, these derivatives were synthesized. 9-(2-Hydroxyalkyl)adenines VIII were prepared by alkylation of adenine with suitably substituted oxiranes XIII or 2-hydroxyalkyl p-toluenesulfonates IV and VI.After protection of the adenine amino group by benzylation (compounds IX) or amidine formation (compounds X), the intermediates were alkylated with bis(2-propyl) p-toluenesulfonyloxymethanephosphonate (XI) in the presence of sodium hydride.After deprotection, the obtained phosphonate diesters XII were converted into phosphoniuc acids I by transsilylation and hydrolysis.This synthetic scheme was used for the preparation of ethyl (Ie), propyl (If), 2-propyl (Ig), 2-methylpropyl (Ih), cyclopropyl (Ii), cyclohexyl (Ij), benzyl (Ik) and phenyl (Il) derivatives.The 2'-trifluoromethyl derivative XXIIa was prepared analogously from 9-(2-hydroxy-3,3,3-trifluoropropyl)adenine (XXa), obtained by alkylation of adenine sodium salt with 2-hydroxy-3,3,3-trifluoropropyl bromide. 2,6-Diaminopurine derivative XXIIb was obtained analogously. 2'-Trimethylsilyl derivative XIXa was obtained by alkylation of adenine with 2-phosphonylmethoxy-3-(4-toluenesulfonyloxy)propyltrimethylsilane (XVII) followed by transsilylation and hydrolysis of diester XVIIIa. 9-(3-Phosphonomethoxybutyl)adenine (XXVIII) and 9-(2-methyl-2-phosphonomethoxypropyl)adenine (XXXV) were prepared from the corresponding hydroxy derivatives XXVIb and XXXII, respectively, by the same reaction pathway as derivatives I.
- Cvorakova, Hana,Holy, Antonin,Rosenberg, Ivan
-
p. 2069 - 2094
(2007/10/02)
-
- Hydrocarbon Functionalization by the (Iodosylbenzene)manganese(IV) Porphyrin Complexes from the (Tetraphenylporphinato)manganese(III)-Iodosylbenzene Catalytic Hydrocarbon Oxidation System. Mechanism and Reaction Chemistry
-
The two types of complexes isolated from the reaction of (tetraphenylporphinato)manganese(III) derivatives, XMnIIITPP, with iodosylbenzene - IVTPP(OIPh)>2O, 1, X = Cl- or Br-, and IVTPP>2O, 2, X = N3- - are capable of oxidizing alkane substrates in good yields at room temperature.Several lines of evidence establish the intermediacy of free alkyl radicals in the reactions of 1 and 2 with alkanes.Oxygen exchange with water in both the iodosyl (Mn-O-I) and μ-oxo (Mn-O-Mn) moieties of 1 suggests the formation of oxo manganese porphyrin complexes from these moieties.Hydrogen abstraction from the alkane substrate by an oxo manganese porphyrin intermediate is postulated to be mechanism for reaction of 1 and 2 with alkanes.Observation of a monomeric manganese(IV) porphyrin intermediate by EPR spectroscopy during the reactions of 1 with alkanes is consistent with the formation of a hydroxymanganese(IV) porphyrin complex resulting from substrate hydrogen abstraction by an oxo intermediate.The formation of RX product from oxidation of RH by 1 has been determined to result from ligand-transfer oxidation of free alkyl radicals by the porphyrin complexes in solution.Through competition reactions and time-dependent product formation studies, ligand-transfer oxidation by XMnIIITPP was found to be the major pathway for RX production.Observation of MnIITPP by EPR spectroscopy during the reactions of 1 with alkanes supports this conclusion.Formation of ROH product may result from ligand-transfer oxidation of free radicals or from the collapse of an intermediate caged radical pair.The mechanism of ROH product formation in the caged radical pair is postulated to be an outer-sphere electron-transfer process due to the expected slow rate of inner-sphere ligand transfer for the high-spin d3 hydroxymanganese(IV) porphyrin complex.Thus the ability of the substrate radical to undergo electron-transfer oxidation determines the ratio of radicals that undergo cage escape to give free radicals to radicals that undergo oxidation and subsequent formation of alcohol product in the caged species.Studies with tertiary substrates support these conclusions.
- Smegal, John A.,Hill, Craig L.
-
p. 3515 - 3521
(2007/10/02)
-
- Silylaminyl Radicals. Part 2. Free Radical Chain Halogenation of Hydrocarbons using N-Halogenobis(trialkylsilyl)amines
-
The liquid-phase halogenation of a number of hydrocarbons and of 1-chlorobutane by N-halogenobis(trialkylsilyl)amines has been studied using product analysis techniques.The reactions take place by free radical chain mechanisms which involve the propagation steps generalised in equations (A) and (B) (X=Br or Cl).At 353 K, the molar reactivities of toluene (benzylic C-H) and cyclohexane towards (R3Si)2N+RH(R3Si)2NH+R (A) R+(R3Si)2NXRX+(R3Si)2N (B) (Me3Si)2N are approximately equal and toluene is 5.2 times more reactive than perdeuteriotoluene.The relative rates of hydrogen abstraction by (Me3Si)2N and (ButMe2Si)2N from the primary, secondary, and tertiary C-H groups in 2-methylbutane show that the silylaminyl radicals are not only highly reactive but also sterically demanding.Thus, at 333 K the average primary C-H reactivity is 0.6 times that of the tertiary C-H towards attack by (Me3Si)2N, but 4.2 times that of the tertiary C-H towards attack by the more bulky (ButMe2Si)2N.Silylaminyl radicals are much more reactive in hydrogen abstraction than are analogous dialkylaminyl radicals and this difference is interpreted in terms of thermodynamic and polar effects which arise because of the ?-donor-?-acceptor nature of the trialkylsilyl substituent.
- Cook, Malcolm D.,Roberts, Brian P.,Singh, Karamjit
-
p. 635 - 644
(2007/10/02)
-
- SELECTIVITIES OF pi - AND sigma -SUCCINIMIDYL RADICALS IN SUBSTITUTION AND ADDITION REACTIONS. APPENDIX: RESPONSE TO WALLING, EL-TALIAWI, AND ZHAO.
-
A new method for studies of pi -succinimidyl (S// pi ) radicals is described, one that makes possible the study of reactions of this radical with a variety of substrates not accessible by the use of Br//2-NBS. NBS systems containing BrCCl//3 at mole fractions greater than 0. 3 show all the characteristics associated with S// pi behavior, and they function in the presence of olefins which serve as Br//2 scavengers. If CCl//4 is substituted for BrCCl//3, the system is clearly S// sigma . The S// pi behavior is contrasted with S// sigma and Br multiplied by (times) reactivities for H abstractions from a variety of substrates and for additions to tert-butylethylene, isobutylene, and 1,3-butadiene. In early-transition-state systems, for H transfer, the strength of the bond being broken and the strength of the bond being made are not the major factors in determining reactivities. The behavior in late-transition-state systems is influenced by both bond strengths. The S// pi radical shows intermediate behavior. These conclusions are supported by primary deuterium isotope effects for methylene chloride and chlororoform. The Appendix addresses a number of questions raised by the preliminary study of NBS reactions by Walling et al.
- Skell,Tlumak,Seshadri
-
p. 5125 - 5131
(2007/10/02)
-
- Reactions of a Graded Set of Radicals with N-Bromosuccinimide; Two Transition States
-
The reactions of N-bromosuccinimide with a series of radicals have been studied.These reactions fall into two categories, the more reactive radicals producing ?-succinimidyl and the less reactive radicals producing ?-succinimidyl.The threshold for the changeover from one reaction domain to the other occurs with radicals less reactive than secondary alkyls.These results are interpreted with two transition states, an in-line transition state for the more reactive radicals and an out-of-plane transition state for the less reactive radicals. An upper limit of 18 kcal/mol is established for the enthalpy difference, HS? - HS?.Two new methods for generating S? radicals are indicated.
- Tlumak, Robert L.,Skell Philip S.
-
p. 7267 - 7274
(2007/10/02)
-
- Relative Bond Dissociation Energies for Two-Ligand Complexes of Cu+ with Organic Molecules in the Gas Phase
-
Ralative two-ligand dissociation enthalpies, δD(Cu+-2L), for Cu+ with 43 organic molecules are determined.A pulsed-laser volatilization/ionization sourse is used to generate Cu+ which reacts with EtCl and/or other molecules to give Cu(ligand)2+ species.Equilibrium constants are measured for the ligand-exchange reactions which occur when pairs of ligand molecules are present.Free energies for two-ligand exchange are obtained from the equilibrium constant for the reaction Cu(A)2+ + 2B ->/+ + 2A.The free-energiy differences are added to give a scale of relative free energies for ligand exchange.These are converted to enthalpies to give δD(Cu+-2L) scale with the assumption that enthropy changes are small and can be neglected except for symmetry corrections which are made in appropriate cases.Dependence of δD(Cu+-2L) on functional group and substituent effects is analyzed.These results for Cu+ are compared to available results for other reference acids: H+, Al+, Mn+, Li+, and CpNi+.These comparisons show that Cu+ is a softer acid than the other reference acids.This is apparent from the relative preference of Cu+ for mercaptans and HCN compared to alcohols and other oxygen bases.
- Jones, Roger W.,Staley, Ralph H.
-
p. 2296 - 2300
(2007/10/02)
-
- Carbon-Halogen Bonding Studies. Halogen Redistribution Reactions between Alkyl or Acetyl Halides and Tri-n-butyltin Halides
-
The equilibrium positions have been determined for the halogen redistribution reactions of tri-n-butyltin halides with a variety of structurally different types of alkyl halides and with acetyl halides.These have been related through the reaction ΔGo values to carbon-halogen bond dissociation energy differences.It is suggested that the trends observed in the latter may provide evidence for the existence of a small steric bond weakening effect in the order C-I > C-Br > C-Cl bonds on going from methyl to primary, secondary, and tertiary alkyl halides.On the other hand, with the 2,3-? bond containing allyl, benzyl, and propargyl halides , α-haloacetones, and haloacetonitriles, there may be some type of electronic carbon-halogen bond strengthening effect which lies in order C-I > C-Br > C-Cl.Finally, for the acetyl halides, the data are in agreement with increases in bond strengths resulting from ? contributions being in the order C-Cl > C-Br > C-I.
- Friedrich, Edwin C.,Abma, Charles B.
-
p. 1367 - 1371
(2007/10/02)
-
