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23Na magic-angle spinning and double-rotation NMR study of solid forms of sodium valproate
Sodium valproate is a pharmaceutical with applications in the treatment of epilepsy, bipolar disorder, and other ailments. Sodium valproate can exist in many hydrated and acid-stabilized forms in the solid state, and it can be difficult to obtain precise structural information about many of these. Here, we present a 13C and 23Na solid-state NMR study of several forms of sodium valproate, only one of which has been previously structurally characterized by single-crystal X-ray diffraction. 23Na magic-angle spinning (MAS), double-rotation (DOR), and multiple-quantum magic-angle spinning (MQMAS) NMR spectra are shown to provide useful information on the number of molecules in the asymmetric unit, the local coordination geometry of the sodium cations, and the presence of amorphous phases. Two previously identified forms are shown to be highly similar, or identical, according to the 23Na NMR data. The utility of carrying out both DOR and MQMAS NMR experiments to identify all crystallographically unique sites is demonstrated. 13C cross-polarization MAS NMR spectra also provide complementary information on the number of molecules in the asymmetric unit and the crystallinity of the sample.
Dicaire, Nuiok M.,Perras, Frederic A.,Bryce, David L.
p. 9 - 15
(2014)
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Michael reaction of nitroalkanes with β-nitroacrylates under a solid promoter: Advanced regio-and diastereoselective synthesis of nitro-functionalized ββ-unsaturated esters and 1,3-butadiene-2-carboxylates
A new class of nitro-functionalized α,β-unsaturated esters has been prepared by a regio-and diastereoselective Michael addition of nitroalkanes to βnitroacrylates, performed at room temperature, under carbonate on polymer as promoter, and in the presence
Palmieri, Alessandro,Gabrielli, Serena,Ballini, Roberto
p. 1485 - 1492
(2010)
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Novel method for preparing valproic acid
The invention discloses a novel method for preparing valproic acid. According to the novel method, the valproic acid is prepared by taking 2-cyano-2-propyl valeric acid as a starting material through a one-pot method. According to the method disclosed by the invention, the valproic acid is prepared at 120-160 DEG C by taking the 2-cyano-2-propyl valeric acid as a raw material and the sulfuric acid aqueous solution as a catalyst, the reaction yield can reach 80%, and the purity of the valproic acid product can reach 99%; the preparation process is simple, the steps are short, and the manpower and equipment cost input for intermediate center control and preparation in the industry is greatly reduced. According to the method disclosed by the invention, a sulfuric acid hydrolysis mechanism of 2-cyano-2-propyl valeric acid is adopted, and compared with a traditional mechanism that amide is oxidized into carboxylic acid by nitrous acid, the situation that sodium nitrite is converted into nitrous acid in an acid environment and the nitrous acid is further converted into nitric oxide and nitrogen dioxide gas under an acid condition to pollute atmosphere and water is avoided; meanwhile, the operation safety of operators is improved, and corrosion of nitric oxide and nitrogen dioxide to equipment is avoided.
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Paragraph 0018; 0027-0051

(2021/08/06)

Preparation method of sodium valproate
The invention discloses a preparation method of sodium valproate, which comprises the following steps of by taking 2-cyano-2-propyl valerate as a raw material and a sulfuric acid aqueous solution as a catalyst, obtaining a mixture of valproic acid and valproate at 120-160 DEG C, then hydrolyzing by using an alkali solution to obtain a valproate aqueous solution, and extracting, acidifying and rectifying to obtain valproic acid. The reaction yield can reach 76%, and the purity of valproic acid can reach 99%. Compared with the traditional mechanism of oxidizing amide into carboxylic acid by nitrous acid, the method provided by the invention avoids the pollution to the atmosphere and the water body caused by the conversion of sodium nitrite into nitrous acid in an acid environment and the further conversion of nitrous acid into nitric oxide and nitrogen dioxide gas under an acid condition, and improves the operation safety of operators at the same time; and corrosion of nitric oxide and nitrogen dioxide to equipment is avoided.
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Paragraph 0044-0049; 0052-0057; 0060-0065; 0068-0073; ...

(2021/08/06)

Preparation method and application of Grignard reagent
The invention relates to a preparation method and application of a Grignard reagent, the Grignard reagent is obtained by treating a halide with a structural formula as a raw material with magnesium inan organic solvent, X is a halogen atom and is selected from Cl, Br and I, R2 is an alkyl or aryl group containing 2-9 carbon atoms. The Grignard reagent is mainly applied to a synthetic process of dimopidol and hydrochloride thereof, and is used for introducing an alkyl side chain. The whole synthetic process of dimopidol and hydrochloride thereof is safe and efficient, each step of reaction operation is simple and safe, and the reaction yield is high so that industrial production can be realized.
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Paragraph 0053; 0056; 0057

(2020/12/29)

Method for recovering 2-propylmalonic acid and preparing valproic acid from 2-propylmalonic acid
The invention discloses a method for recovering 2-propylmalonic acid and preparing valproic acid from 2-propylmalonic acid, and the method for recovering 2-propylmalonic acid and preparing valproic acid from 2-propylmalonic acid includes the following steps: (1) collecting acid water after centrifuging dipropylmalonic acid, adding ether, ester, chlorinated hydrocarbon and an alcohol (immiscible with water) solvent, stirring, extracting, layering, and drying to obtain dipropylmalonic acid with the recovery rate of more than 90%; and (2) performing esterification, propylation, hydrolysis and acidification on the 2-propylmalonic acid to obtain dipropylmalonic acid, and performing decarboxylation to obtain high-purity valproic acid (the content is greater than or equal to 99.5%). Through recovery and comprehensive utilization of the 2-propylmalonic acid, the production cost of the 2-propylvaleric acid is reduced, and the pressure of subsequent environmental protection treatment is greatlyreduced.
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Paragraph 0015-0030

(2021/01/15)

Synthesis of Acyclic Aliphatic Amides with Contiguous Stereogenic Centers via Palladium-Catalyzed Enantio-, Chemo- and Diastereoselective Methylene C(sp3)?H arylation
The enantioselective desymmetrizing C?H activation of α-gem-dialkyl acyclic amides remains challenging because the availability of four chemically identical unbiased methylene C(sp3)?H bonds and increased rotational freedoms of the acyclic systems add tremendous difficulties for chemo- and stereocontrol. We have developed a method for the synthesis of acyclic aliphatic amides with α,β-contiguous stereogenic centers via PdII-catalyzed asymmetric arylation of unbiased methylene C(sp3)?H, in good yields and with high levels of enantio-, chemo- and diastereoselectivity (up to >99 % ee and >20:1 d.r.). Successive application of this method enables the sequential arylation of the gem-dialkyl groups with two different aryl iodides, giving a range of β-Ar1-β′-Ar2-aliphatic acyclic amides containing three contiguous stereogenic centers with excellent diastereoselectivity.
Deng, Yao-Ting,Ding, Yi,Han, Ye-Qiang,Kong, Ke-Xin,Shi, Bing-Feng,Wu, Le-Song,Yang, Xu
supporting information
p. 20455 - 20458
(2020/09/07)

Achiral Derivatives of Hydroxamate AR-42 Potently Inhibit Class i HDAC Enzymes and Cancer Cell Proliferation
AR-42 is an orally active inhibitor of histone deacetylases (HDACs) in clinical trials for multiple myeloma, leukemia, and lymphoma. It has few hydrogen bond donors and acceptors but is a chiral 2-arylbutyrate and potentially prone to racemization. We report achiral AR-42 analogues incorporating a cycloalkyl group linked via a quaternary carbon atom, with up to 40-fold increased potency against human class I HDACs (e.g., JT86, IC50 0.7 nM, HDAC1), 25-fold increased cytotoxicity against five human cancer cell lines, and up to 70-fold less toxicity in normal human cells. JT86 was ninefold more potent than racAR-42 in promoting accumulation of acetylated histone H4 in MM96L melanoma cells. Molecular modeling and structure-activity relationships support binding to HDAC1 with tetrahydropyran acting as a hydrophobic shield from water at the enzyme surface. Such potent inhibitors of class I HDACs may show benefits in diseases (cancers, parasitic infections, inflammatory conditions) where AR-42 is active.
Tng, Jiahui,Lim, Junxian,Wu, Kai-Chen,Lucke, Andrew J.,Xu, Weijun,Reid, Robert C.,Fairlie, David P.
supporting information
p. 5956 - 5971
(2020/06/05)

Derivatization of valproic acid using ferrocene derivatives: Synthesis, characterization and investigation of optical and electrochemical properties
New ferrocenyl-based valproic acid (VPA) ester derivatives were designed and synthesized according to the reaction of appropriate haloalkylferrocene derivatives with VPA in the presence of K2CO3 and a catalytic amount of 18-crown-6 ether. Elemental analyses and Fourier transform infrared, 1H NMR, 13C NMR and mass spectra all well confirmed the predicted molecular structure. This is the first report in which ferrocene has been applied in derivatization of VPA as a chromogenic group. The electrochemical properties of the synthesized compounds were studied using cyclic voltammetry measurements, and energies of the frontier molecular orbitals were determined. In addition, the solubilities of the final compounds were studied in distilled water, phosphate buffer (pH?=?7.4) and 0.9% (w/v) NaCl solution.
Rahimpour, Keshvar,Jouyban, Abolghasem,Teimuri-Mofrad, Reza
(2019/07/03)

NCP ligand, [...] complex, synthesis method, intermediate and application
The invention discloses an NCP ligand, iridium complex, synthetic method, intermediate and application thereof. The invention provides an NCP ligand and an NCP ligand iridium complex, wherein R1, R2, R3, R4, R5, R6 and R7 separately represent hydrogen atom or C1-C30 alkyl, R' and R'' independently represent C1-C30 alkyl. The invention provides the application of the NCP ligand iridium complex to the catalysis of alkane dehydrogenation reaction, olefin isomerization reaction, alcohol dehydrogenation reaction, ester alpha alkylation reaction, and amide alpha alkylation reaction. The NCP ligand provided by the invention contains dialkyl substituted phosphine, which has strong electron donating ability and can form a NCP ligand iridium complex by complexing with iridium. The NCP ligand iridium complex uses pyridine to replace a conventional alkyl phosphate electron donor, and has the advantages of good stability, high selectivity on alkane dehydrogenation reaction, mild reaction conditions, good catalytic effect, and industrial production prospect.
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Paragraph 0122; 0214-02176

(2018/07/30)

Three-component 1D and 2D metal phosphonates: structural variability, topological analysis and catalytic hydrocarboxylation of alkanes
Herein, we report the use of diphosphonate building blocks and chelating auxiliary N,N-ligands to generate novel polymeric architectures. Specifically, we report new 1D and 2D coordination polymers incorporating three components: transition metal ions (Co2+, Cu2+, Mn2+ or Zn2+), diphosphonate ligands (methane-diphosphonate, MDPA, or 1,2-ethanediphosphonate, EDPA) and N,N-heterocyclic chelators (1,10-phenanthroline, phen, or 2,2′-bipyridine, bpy). Six compounds were isolated under mild synthesis (ambient temperature) conditions: [Cu2(phen)2(EDPA)2(H2O)4]∞ (1), [Co(phen)(EDPA)(H2O)2]∞ (1a), {[Cu(phen)(MDPA)]·H2O]}∞ (2), [Mn(bpy)(EDPA)(H2O)2]∞ (3), [Zn(bpy)(EDPA)]∞ (4), and, lastly, a discrete Ni2+ molecular derivative [Ni(phen)(H2O)4](EDPA) (5). Synthetic details, crystal structures, and intermolecular interactions (π-π stacking and hydrogen bonding) in 1-5 are discussed. Topological analyses and classification of the underlying metal-organic networks in 1-4 were performed, revealing the uninodal 1D chains with the 2C1 topology in 1-3 and the binodal 2D layers with the 3,4L13 topology in 4. In 1-3 and 5, multiple hydrogen bonds lead to the extension of the structures to give 3D H-bonded nets with the seh-4,6-C2/c topology in 1 and 3, 2D H-bonded layers with the 3,5L52 topology in 2, and a 3D H-bonded net with the 6,6T1 topology in 5. The catalytic activity of compounds 1 and 1a was evaluated in a single-step hydrocarboxylation of cyclic and linear C5-C8 alkanes to furnish the carboxylic acids with one more carbon atom. These reactions proceed in the presence of CO, K2S2O8, and H2O at 60 °C in MeCN/H2O medium. Compound 1 showed higher activity than 1a and was studied in detail. Substrate scope was investigated, revealing that cyclohexane and n-pentane are the most reactive among the cyclic and linear C5-C8 alkanes, and resulting in the total yields of carboxylic acids (based on substrate) of up to 43 and 36%, respectively. In the case of cycloalkane substrates, only one cycloalkanecarboxylic acid is produced, whereas a series of isomeric monocarboxylic acids is generated when using linear alkanes; an increased regioselectivity at the C(2) position of the hydrocarbon chain was also observed.
Demadis, Konstantinos D.,Anagnostou, Zafeiria,Panera, Aggeliki,Mezei, Gellert,Kirillova, Marina V.,Kirillov, Alexander M.
p. 17788 - 17799
(2017/03/30)

Divalproex sodium method for the recovery and use of the crystallization mother liquor
The invention provides a recycling method of divalproex sodium crystallization mother liquor. The method comprises the following steps: 1) concentrating the divalproex sodium crystallization mother liquor to obtain a solid-state mixture containing divalproex sodium; 2) mixing the solid-state mixture obtained in the step 1) with an alkaline solution to dissolve the solid-state mixture to further obtain a mixed solution; 3) mixing the mixed solution obtained in the step 2) with an inorganic salt to produce a valproate precipitate, and separating to obtain the valproate precipitate; 4) mixing the valproate precipitate obtained in the step 3) with an acid solution to obtain an organic layer, and performing fractionation on the organic layer to obtain valproic acid. Through the method provided by the invention, the yield of obtained valproic acid can be as high as 93%, the purity is not lower than 99.6%, and valproic acid can meet medicinal requirements; the method provided by the invention has the advantages of simplicity, easiness in operation, easiness in control of reaction process and effect of reducing actual production cost, and is in line with requirements of industrial mass production.
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Paragraph 0073; 0074; 0075

(2017/02/24)

A composition for treating dermatopathy neurocyte and method (by machine translation)
The invention relates to the compounds of formula (I) or its pharmaceutical acceptable salts, as well as polymorphs, solvates, enantiomers, stereoisomers and hydrates thereof. The pharmaceutical compositions comprising an effective amount of compounds of formula (I), and methods for treating or preventing neurological disorders may be formulated for oral, buccal, rectal, topical, transdermal, transrnucosal, intravenous, parenteral administration, syrup, or injection. Such compositions may be used to treatment of epilepsy, bipolar disorder, migraine, schizophrenia, depression, Alzheimer's disease, cancer, HIV and familial adenomatous polyposis.
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Paragraph 0197; 0198; 0199

(2016/12/12)

A General and mild catalytic α-alkylation of unactivated esters using Alcohols
Catalytic α-alkylation of esters with primary alcohols is a desirable process because it uses low-toxicity agents and generates water as the by-product. Reported herein is a NCP pincer/Ir catalyst which is highly efficient for α-alkylation of a broad scope of unactivated esters under mild reaction conditions. For the first time, alcohols alkylate unactivated α-substituted acyclic esters, lactones, and even methyl and ethyl acetates. This method can be applied to the synthesis of carboxylic acid derivatives with diverse structures and functional groups, some of which would be impossible to access by conventional enolate alkylations with alkyl halides. In a pinch: An NCP pincer/iridium catalyst is highly efficient for the α-alkylation of unactivated esters using alcohol under mild reaction conditions. The reaction is simple, clean, and scalable (1-10 mmol), and the scope with respect to the ester is wide.
Guo, Le,Ma, Xiaochen,Fang, Huaquan,Jia, Xiangqing,Huang, Zheng
supporting information
p. 4023 - 4027
(2015/03/30)

METHOD FOR PRODUCING CARBOXYLIC ACID AND ALCOHOL BY HYDROLYSIS OF ESTER
As shown by the following formula (1), after methyl laurate (2 mmol) and water (8 mL) are added to an ammonium pyrosulfate catalyst (5 mol%), a hydrolysis reaction of methyl laurate is carried out by heating for 24 hours at 60°C while stirring is performed, so that lauric acid can be obtained with a yield of 86%.
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Paragraph 0063; 0064; 0065

(2014/11/13)

Unexpected dehomologation of primary alcohols to one-carbon shorter carboxylic acids using o-iodoxybenzoic acid (IBX)
A novel and efficient transformation of primary alcohols to one-carbon shorter carboxylic acids using IBX is reported. Mechanistic studies revealed that the combination of IBX and molecular iodine produces a different active hypervalent iodine species.
Xu, Shu,Itto, Kaori,Satoh, Masahide,Arimoto, Hirokazu
supporting information
p. 2758 - 2761
(2014/03/21)

N,N-diarylammonium pyrosulfate as a highly effective reverse micelle-type catalyst for hydrolysis of esters
Reverse micelle-type N,N-diarylammonium pyrosulfate (3-5 mol %) efficiently catalyzes the hydrolysis of esters (up to 100 mmol scale) under organic solvent-free conditions. The present method is successfully applied to the hydrolysis of various esters without the decomposition of the base-sensitive moieties and without any loss of optical purity for α-heterosubstituted carboxylic acids.
Koshikari, Yoshiki,Sakakura, Akira,Ishihara, Kazuaki
supporting information; experimental part
p. 3194 - 3197
(2012/07/31)

Syntheses and evaluation of anticonvulsant activity of novel branched alkyl carbamates
A novel class of 19 carbamates was synthesized, and their anticonvulsant activity was comparatively evaluated in the rat maximal electroshock (MES) and subcutaneous metrazol (scMet) seizure tests and pilocarpine-induced status epilepticus (SE) model. In spite of the alkyl-carbamates' close structural features, only compounds 34, 38, and 40 were active at the MES test. The analogues 2-ethyl-3-methyl-butyl-carbamate (34) and 2-ethyl-3-methyl-pentyl- carbamate (38) also exhibited potent activity in the pilocarpine-SE model 30 min postseizure onset. Extending the aliphatic side chains of homologous carbamates from 7 to 8 (34 to 35) and from 8 to 9 carbons in the homologues 38 and 43 decreased the activity in the pilocarpine-SE model from ED50 = 81 mg/kg (34) to 94 mg/kg (35) and from 96 mg/kg (38) to 114 mg/kg (43), respectively. The most potent carbamate, phenyl-ethyl-carbamate (47) (MES ED50 = 16 mg/kg) contains an aromatic moiety in its structure. Compounds 34, 38, 40, and 47 offer the optimal efficacy-safety profile and, consequently, are promising candidates for development as new antiepileptics.
Hen, Naama,Bialer, Meir,Yagen, Boris
experimental part
p. 2835 - 2845
(2012/06/15)

Synthesis and evaluation of antiallodynic and anticonvulsant activity of novel amide and urea derivatives of valproic acid analogues
Valproic acid (VPA, 1) is a major broad spectrum antiepileptic and central nervous system drug widely used to treat epilepsy, bipolar disorder, and migraine. VPA's clinical use is limited by two severe and lifethreatening side effects, teratogenicity and hepatotoxicity. A number of VPA analogues and their amide, N-methylamide and urea derivatives, were synthesized and evaluated in animal models of neuropathic pain and epilepsy. Among these, two amide and two urea derivatives of 1 showed the highest potency as antineuropathic pain compounds, with ED50 values of 49 and 51 mg/kg for the amides (19 and 20) and 49 and 74 mg/kg for the urea derivatives (29 and 33), respectively. 19, 20, and 29 were equipotent to gabapentin, a leading drug for the treatment of neuropathic pain. These data indicate strong potential for the above-mentioned novel compounds as candidates for future drug development for the treatment of neuropathic pain. 2009 American Chemical Society.
Kaufmann, Dan,Bialer, Meir,Shimshoni, Jakob Avi,Devor, Marshall,Yagen, Boris
experimental part
p. 7236 - 7248
(2010/07/04)

A MILD METHOD FOR THE PRODUCTION OF DI-N-PROPYLACETIC ACID (VALPROIC ACID)
A novel process for the production of valproic acid of Formula (I): comprising, heating a reaction mixture comprising di-n-propylmalonic acid of Formula (II): metal catalyst in the form of its salt or oxide, and (3) a polar organic solvent, alone or in combination with one another, at 60° to 100 °C for 6 to 15 hours to decarboxylate the di-n- propylmalonic acid of Formula (II).
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Page/Page column 10

(2008/12/05)

Solid-phase synthesis of isotope-labeled 2-propyloctanoic acid, a therapeutic agent for stroke and Alzheimer's disease
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Ho, Jonathan Z.,Tang, Cheng,Braun, Matthew P.
p. 496 - 497
(2008/02/08)

Microwave assisted hydrolysis of Meldrum's acid derivatives and decarboxylation of derived malonic acids
Microwave induced hydrolysis of alkyl Medrum's acids and decarboxylation of derived malonic acids using poly-4-vinylpyridine as a catalyst gives high yields of carboxylic acids in a short time.
Helavi,Solabannavar,Desai,Mane
p. 174 - 175
(2007/10/03)

Rearrangement of epoxynitriles: A convenient homologation of acyclic and cyclic ketones to carboxylic acids
A convenient two-step homologation of both aliphatic and aromatic ketones to the corresponding carboxylic acid has been developed. First ketones were converted to epoxynitriles with the Darzens reaction. Second, a Lewis acid mediated rearrangement of these epoxynitriles with lithium bromide was achieved to give homologated secondary alkanoic acids (as well as aryl-alkanoic) in good yields. The mechanism and the scope of the rearrangement reaction were investigated. This strategy constitutes a two- step homologation of ketones to secondary carboxylic acids.
Badham, Neil F.,Mendelson, Wilford L.,Allen, Andrew,Diederich, Ann M.,Eggleston, Drake S.,Filan, John J.,Freyer, Alan J.,Killmer Jr., Lewis B.,Kowalski, Conrad J.,Liu, Li,Novack, Vance J.,Vogt, Frederick G.,Webb, Kevin S.,Yang, Jennifer
p. 5440 - 5443
(2007/10/03)

Pentanoic acid derivatives
Formula (I) compounds: wherein R1 is alkyl substituted by fluorine(s); R2 is hydroxy, alkoxy, alkoxy substituted by phenyl, NR3R4, in which R3, R4 is (i) hydrogen, (ii) alkyl, (iii) phenyl, (iv) phenyl substituted by alkoxy or carboxyl, (v) heterocyclic ring containing nitrogen atom, (vi) alkyl substituted by phenyl, phenyl subsituted by alkoxy or carboxyl, heterocyclic ring containing nitrogen atom, (vii) the nitrogen bonded to R3 and R4, taken together is a saturated heterocyclic ring or amino acid residue; and non-toxic salts and acid addition salts thereof. Also, Formula (X) compounds: wherein n is 0 or 1, R11 is hydrogen and chlorine, R5 is R7—CH2— or R8, or R5 and R11, taken together is alkylidene; R6 is hydroxy, alkoxy, alkoxy substituted by phenyl, NR9R10, in which R9, R10 is (i) hydrogen, (ii) alkyl, (iii) phenyl, (iv) phenyl substituted by alkoxy or carboxyl, (v) heterocyclic ring containing nitrogen atom, (vi) alkyl substituted by phenyl, phenyl-substituted by alkoxy or carboxyl, heterocyclic ring containing nitrogen atom, (vii) the nitrogen bonded to R9 and R10, taken together is a saturated heterocyclic ring or amino acid residue, R7 is (i) F—(CH2)m— or F3C—CH2—, (ii) alkyl subsstituted by chlorine, (iii) alkyl substituted by alkoxy, cycloalkyl, phenyl, phenoxy; R8 is alkyl, alkenyl, alkoxy, alkylthio, cycloalkyl, phenyl, phenoxy. Non-toxic and acid addition salts thereof are useful to prevent and/or treat neurodegenerative disease (e.g., Alzheimer's) and neuronal dysfunction by stroke or traumatic injury (e.g., Multiple sclerosis).
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(2008/06/13)

A mild and convenient 'dry' hydrolysis of amides to carboxylic acids
A one-pot preparation of carboxylic acids is described that proceeds from their corresponding amides by a 'dry' hydrolysis with phthalic anhydride in the absence of water and solvent. The method affords carboxylic acids in good yields and is applicable to a variety of substrates. (C) 2000 Elsevier Science Ltd.
Chemat, Farid
p. 3855 - 3857
(2007/10/03)

Cleavage of tertiary amidomethyl ester prodrugs of carboxylic acids by rat liver homogenates
The hydrolysis of tertiary amidomethyl ester prodrugs of carboxylic acids by rat liver homogenates is reported. Amidomethyl esters are rapidly and quantitatively converted to the corresponding acid and secondary amide. Reactivity is inversely dependent upon the molar refractivity and lipophilicity of the ester, as well as with steric bulk in the carboxylic acid moiety. In contrast to chemical and plasma hydrolyses, no dependence upon the pK(a) of the carboxylate leaving group was observed, nor was there any dependence upon the amide N-substituent. The rate of decomposition was inhibited by the carboxylesterase inhibitor eserine but not by the cytochrome P450 inhibitor SKF-525A, indicating the involvement of esterases in the hydrolysis reaction. These results indicate that amidomethyl esters may be expected to be readily cleaved in vivo. Copyright (C) 1999 Elsevier Science B.V.
Iley, Jim,Mendes, Eduarda,Moreira, Rui,Souza, Sofia
p. 201 - 205
(2007/10/03)

Process for producing valproic acid
A process for making valproic acid from an alkyl alkanoylacetate is disclosed. The alkyl alkanoylacetate is reacted with an n-propyl halide in a biphasic system in the presence of a base and a phase transfer catalyst. The product mixture is acidified to convert the resulting valproate salt into valproic acid.
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(2008/06/13)

Acyloxymethyl as a drug protecting group. Part 5. Kinetics and mechanism of the hydrolysis of tertiary N-acyloxymethylsulfonamides
Tertiary acyloxymethylsulfonamides undergo hydrolysis via pH-independent and acid- and base-catalysed processes. Reactions are also buffer catalysed for buffer species with pKa values > ca. 10.5. For the pH-independent pathway, hydrolysis takes place via formation of an N-sulfonyl iminium ion. There is no general-base or nucleophilic catalysis in this region. The mechanism of the acid-catalysed process involves pre-equilibrium protonation of the substrate followed by iminium ion formation. General-acid catalysis is not observed. The base-catalysed pathway involves the normal BAc2 mechanism of ester hydrolysis. The buffer-catalysed reaction gives rise to a curved Bronsted plot, with β values of 1.6 and 0.25 for nucleophiles with pKa values 13, respectively. This is indicative of nucleophilic catalysis associated with a change in rate-limiting step from formation of the tetrahedral intermediate for buffer species with pKa > 13 to decomposition of the tetrahedral intermediate for buffer species with pKa f, and atomic charges, q, for acyloxymethyl- and chloromethyl-sulfonamides and amides and their derived iminium ions were performed. These reveal that (1) iminium formation from the sulfonamide series is thermodynamically slightly favoured, and (2) the charge difference at the nitrogen atom, ΔqN, between the neutral molecule and the iminium ion is similar for both sulfonamides and amides.
Lopes, Francisca,Moreira, Rui,Iley, Jim
p. 431 - 439
(2007/10/03)

'Dry' hydrolysis of nitriles by sodium perborate and copper salts in heterogeneous media
Nitriles react with sodium perborate or copper salts to yield carboxylic acids under mild acidic conditions. The multiphase reaction can be carried out in the absence of solvent, water, added acid or base. The yields are good, and the nitrile group can be hydrolysed in the presence of other functional groups. A comparative study between microwave and conventional heating shows that there is no specific activation from the electromagnetic field. However, careful attention to temperature and pressure measurements in the experimental apparatus is clearly needed.
Chemat, Farid,Poux, Martine,Berlan, Jacques
p. 1781 - 1784
(2007/10/03)

Acyloxymethyl as a drug protecting group. Part 3. Tertiary O-amidomethyl esters of penicillin G: Chemical hydrolysis and anti-bacterial activity
Purpose. O-(N-alkylamido)methyl esters of penicillin G were studied as a new class of prodrugs. Methods. Their hydrolysis in aqueous buffers containing 20% (v/v) of acetonitrile was investigated by HPLC. Results. A U-shaped pH-rate profile was seen with a pH-independent process extending from pH ca. 2 to pH ca. 10. This pathway is characterised by kinetic data that are consistent with a unimolecular mechanism involving rate-limiting iminium ion formation and penicillinoate expulsion. Penicillin G and the corresponding amide are the ultimate products detected and isolated, indicating that p-lactam ring opening is much slower than ester hydrolysis. The O-(N-alkylamido)methyl esters of penicillin G displayed similar in vitro antibacterial activity to penicillin G itself. Conclusions. Compared to the penicillin G derivatives, the much higher stability of the O-(N-methylbenzamido)methyl benzoate, acetate and valproate esters (which gave rise to a Bronsted β(1g) value of ca. -1) suggests that tertiary N-acyloxymethylamides may be useful prodrugs for carboxylic acid drugs with pK(a) > 4.
Moreira, Rui,Calheiros, Teresa,Cabrita, Jose,Mendes, Eduarda,Pimentel, Madalena,Iley, Jim
p. 70 - 75
(2007/10/03)

'Dry' Hydrolysis of Nitriles Effected by Microwave Heating
The preparation of carboxylic acids from their corresponding nitriles by a 'dry hydrolysis' with dicarboxylic acids, in the absence of solvent, has been investigated.The reaction proceeds very slowly at atmospheric pressure, but high yields can be obtained in much shorter reaction times under pressure.The mechanism of the reeaction has been studied and its rate constant and activation energy determined in the case of a model reaction (preparation of phenylacetic acid from benzyl cyanide with phthalic acid) under both microwave and conventional heating.No 'microwave kinetic effect' has been detected, but at high temperatures microwave heating gives better yields and selectivities.
Chemat, Farid,Poux, Martine,Berlan, Jacques
p. 2597 - 2602
(2007/10/02)

Process for production of lower alkanoic acids
A process for production of lower alkanoic acids. A reaction mixture comprising a substituted malonic acid, an acid catalyst, and a limited amount of water is heated to a temperature sufficient to hydrolyze and decarboxylate the ester. The reaction mixture is maintained at the temperature by periodic addition of limited amounts of water, and the reaction is continued for a period of time sufficient to remove substantially all of the alcohol and carbon dioxide generated by the hydrolysis reaction, thereby converting substantially all of the ester to alkanoic acid. The process is particularly useful for the production of valproic acid.
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(2008/06/13)

HETEROCUMULENES IN ACYLATION REACTIONS II. REACTIVITY OF ALKYL-SUBSTITUTED KETENES IN SPONTANEOUS HYDROLYSIS REACTIONS
The structures and electronic states of six ketenes were investigated by the semiempirical MNDO, MINDO/3, and AM1 quantum-chemical methods.The kinetics of the spontaneous hydrolysis of mono- and dialkylsubstituted ketenes in water and water-acetonitrile mixtures at 20 deg C were studied.The induction and steric effects of the substituents on the process rate were evaluated quantitatively in terms of a ρ? analysis.An increase in the number, length, and branching of the hydrocarbon substituents at the terminal carbon atom of the ketenes leads to a large decrease in the hydrolysis rate.The results of the calculations were compared with experimental data.Possible alternatives for the mechanism of the process are discussed.
Lyashchuk, S. N.,Skrypnik, Yu. G.
p. 10 - 17
(2007/10/02)

Process for mono-, di-, trisubstituted acetic acids
An improved process for the preparation of mono-, di-, or trisubstituted acetic acids including 5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoic acid by a novel synthesis is described where a carboxylic acid is converted to a soluble metalated magnesium or zinc carboxylate containing a ligand and subsequent alkylation of this intermediate in the presence of an alkali amide to afford the desired product in two steps.
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(2008/06/13)

Prodrug derivatives of carboxylic acid drugs
Novel ester derivatives of carboxylic acid medicaments of formula (I), wherein R--COO--represents the acyloxy residue of a carboxylic acid drug or medicament, n is an integrer from 1 to 3, and R1 and R2 are the same or different and are selected from a group consisting of an alkyl, an alkenyl, an aryl, an aralkyl, a cycloalkyl and which group may be unsubstituted or substituted, or R1 and R2 together with the N forms a 4-, 5-, 6- or 7-membered heterocyclic ring, which in addition to the nitrogen atom may contain one or two further heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and which heterocyclic group may be substituted. These compounds are highly biolabile prodrug forms of the corresponding carboxylic acid compounds and are highly susceptible to undergoing enzymatic hydrolysis in vivo whereas they are highly stable in aqueous solution. The novel derivatives are less irritating to mucosa than the parent carboxylic acids and may provide an improved bio-availability of the drugs.
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(2008/06/13)

On the hydrolysis of valpromide to valproic acid
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Gedan,Kleemann,Pfeifer
p. 865 - 865
(2007/10/02)

Process for introducing alkyl radicals into carbon chains having a functional group and compounds prepared by said process
Process for introducing a substituent selected from branched- or straight-chain alkyl radicals having from 1 to 12 carbon atoms, aralkyl or cycloalkyl radicals in which the alkyl moiety has from 1 to 4 carbon atoms, into a carbon chain bearing a stable functional group the said carbon chain having at least one proton in α-position in relation to this functional group, process whereby, in a first step, this carbon chain is reacted with a complex base comprising a mixture of alkali metal amide and alkali metal alcoholate suspended in an anhydrous organic solvent to provide temporarily a carbanion, then in a second step this carbanion is reacted in an anhydrous organic solvent with an alkyl, aralkyl or cycloalkyl halide corresponding to the substituent to be introduced.
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(2008/06/13)

The Regiospecific Palladium Catalysed Hydrocarboxylation of Alkenes under Mild Conditions
Alkenes react with carbon monoxide, water, oxygen, hydrochloric acid, and palladium and copper chlorides, to give branched chain acids in good yields.
Alper, Howard,Woell, James B.,Despeyroux, Bertrand,Smith, David J. H.
p. 1270 - 1271
(2007/10/02)

Process for the preparation of acetic acid derivatives
Process for the preparation of di-n-propyl acetic acid of formula: STR1 and its non-toxic alkali and alkaline earth metal salts whereby in a single stage, sodium n-propylate in n-propanol medium is added to a reaction medium formed of a cyanacetic ester of general formula: STR2 in which R represents an alkyl radical having from 1 to 4 carbon atoms, and n-propyl bromide or iodide, the alkylation reaction taking place under reflux, the crude ester obtained is saponified with a 10 to 20% solution of sodium or potassium hydroxide, the salt thus obtained is acidified with a strong acid, to give the crude di-n-propyl cyanacetic acid, which is decarboxylated by heating at a temperature between 140° and 190° C, to provide the di-n-propyl acetonitrile, the di-n-propyl acetonitrile obtained is hydrolysed by means of an aqueous solution of 75 to 80% sulphuric acid at a temperature of 80°-140° C to give the crude di-n-propyl acetamide, which is hydrolyzed by means of an aqueous solution of 75-80% sulphuric acid at a temperature of 40°-80° C in the presence of sodium nitrite, to provide di-n-propyl acetic acid, which is caused to react, if so desired, with an alkali metal hydroxide or alkaline earth metal oxide in order to obtain the corresponding salt.
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(2008/06/13)

On azoniaspire-compounds. 2. Preparation of esterified azoniaspire-compounds of nortropan-3-alpha- or 3-beta-ol (1)
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Bertholdt,Pfleger,Schulz
p. 719 - 726
(2007/10/04)